CA2827301A1 - Compositions and methods for the therapy and diagnosis of influenza - Google Patents

Compositions and methods for the therapy and diagnosis of influenza Download PDF

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Publication number
CA2827301A1
CA2827301A1 CA 2827301 CA2827301A CA2827301A1 CA 2827301 A1 CA2827301 A1 CA 2827301A1 CA 2827301 CA2827301 CA 2827301 CA 2827301 A CA2827301 A CA 2827301A CA 2827301 A1 CA2827301 A1 CA 2827301A1
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seq
tcn
antibody
amino acid
acid sequence
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Andres G. Grandea
Gordon King
Thomas C. Cox
Ole Olsen
Jennifer Mitcham
Matthew Moyle
Phil Hammond
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Theraclone Sciences Inc
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Theraclone Sciences Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018Orthomyxoviridae, e.g. influenza virus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/16Antivirals for RNA viruses for influenza or rhinoviruses
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306Solid-phase reaction mechanisms
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983Viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507Comprising a combination of two or more separate antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51Complete heavy chain or Fd fragment, i.e. VH + CH1
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515Complete light chain, i.e. VL + CL
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08RNA viruses
    • G01N2333/11Orthomyxoviridae, e.g. influenza virus

Abstract

The present invention provides compositions, vaccines, and methods for diagnosing, treating, and preventing influenza infection using a combination of antibodies raised against the influenza hemagglutinin and the matrix 2 ectodomain polypeptides.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

COMPOSITIONS AND METHODS FOR THE THERAPY AND DIAGNOSIS OF
INFLUENZA
RELATED APPLICATIONS
[01] This application claims the benefit of provisional application USSN
61/442,733, filed February 14, 2011, the contents of which are herein incorporated by reference in their entirety.
INCORPORATION OF SEQUENCE LISTING
1021 The contents of the text file named "37418-518001W0 ST25.txt," which was created on January 6, 2012 and is 910 KB in size, are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
[03] The present invention relates generally to prevention, diagnosis, therapy and monitoring of influenza infection. The invention is more specifically related to compositions containing a combination of human antibodies raised against either the influenza hemagglutinin or matrix 2 protein. Such compositions are useful in pharmaceutical compositions for the prevention and treatment of influenza, and for the diagnosis and monitoring of influenza infection.
BACKGROUND OF THE INVENTION
[04] Influenza virus infects 5-20% of the population and results in 30,000-50,000 deaths each year in the U.S. Disease caused by influenza A viral infections is typified by its cyclical nature. Antigenic drift and shift allow for different A strains to emerge every year. Added to that, the threat of highly pathogenic strains entering into the general population has stressed the need for novel therapies for flu infections.
SUMMARY OF THE INVENTION
t [05] The invention provides diagnostic, prophylactic, and therapeutic compositions including a human antibody raised against the Influenza hemagglutinin protein and a human monoclonal antibody raised against the Influenza M2 protein. Moreover, the invention provides diagnostic, prophylactic, and therapeutic compositions including an isolated human antibody raised against an epitope of the Influenza hemagglutinin protein and an isolated human monoclonal antibody raised against an epitope of the Influenza M2 protein.

Furthermore, these compositions are pharmaceutical compositions that include a pharmaceutical carrier. These compositions address a long-felt need in the art for pharmaceutical compositions that both strongly neutralizes Influenza virus infection and recognizes constant regions within proteins common to all Influenza strains.
[06] Specifically, the invention provides a composition including: (a) an isolated human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) an isolated human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus. In certain embodiments of this composition, the isolated human monoclonal antibody that specifically binds an epitope of the M2e polypeptide is TCN-032 (8110), 21B15, TCN-031 (23K12), 3241_G23, 3244_110, 3243_107, 3259_121, 3245_019, 3244_H04, 3136_G05, 3252_C13, 3255_106, 3420_123, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B11, or 3242_P05. Moreover, the isolated human antibody that specifically binds an epitope of the HA glycoprotein is optionally TQN-522 (3212_112), TCN-(3280_D18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-(5086_C06), TCN-528 (5087_P17), TCN-529 TCN-530 (5248_H10), TCN-53I
(509 1_H13), TCN-532 (5262_H18), TCN-533' (5256' A17), TCN-534 (5249_B02), TCN-(5246_P19), TCN-536 (5095_NO1), TCN-537 (3194_D21), TCN-538 (3206_017), TCN-(5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-546 (5089_L08), TCN-547 (5092_F11), TCN-548 (5092_P01), TCN-549 (5092_PO4), TCN-550 (5096_F06), TCN-551 (5243_DO1), TCN-552 (5249_123), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), TCN-557 (5081_A04), TCN 558 (5248_Hl0b), TCN-559 (5097_G08), TCN-560 (5084_P10), TCN-504 (3251_K17), SC06-141, SC06-255, S206-257, SC06-260, SC06-261, SC06-262, SC06-268, SC06-272, 296, 5C06-301, 5C06-307, SC06-310, SC06-314, SC06-323, SC06-325, SC06-327, 328, SC06-329, SC06-331, 5C06-332, 5C06-334, SC06-336, SC06-339, SC06-342, 343, SC06-344, CR6141, CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6272, CR6296, CR6301, CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, , -CR6329, CR6331, CR6332, CR6334, CR6336, CR6339, (R6342, CR6343, CR6344, 2A, D7, D8, F10, G17, H40, A66, D80, E88, E90, or H÷.
[07] The epitope of the HA glycoprotein is optionally GVTNKVNSIIDK (SEQ ID NO:

198), GVTNKVNSIINK (SEQ ID NO: 283), GVTNKENSIIDK (SEQ ID NO: 202), GVTNKVNRIIDK (SEQ ID NO: 201), GITNKVNSVIEK (SEQ ID NO: 281), GITNKENSVIEK (SEQ ID NO: 257), GITNKVNSIIDK (SEQ ID NO: 225), and KITSKVNNIVDK (SEQ ID NO: 216). The influenza hemaglutinin (HA) glycoprotein includes an HAI and HA2 subunit. Exemplary epitopes of the HA glycoprotein include the HAI subunit, HA2 subunit, or both the HAI and HA2 subunits. Alternatively, or in addition, the epitope of the M2e polypeptide is a discontinuous epitope. For example, the epitope of the M2e polypeptide includes the amino acid at pdsitions 2, 5, and 6 of MSLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1) or the amino acid at positions 2, 5, and 6 of SLLTEV (SEQ ID NO: 42).
[08] The invention further provides a composition including: (a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, including a heavy chain variable region (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL
domain each contain three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR includes the following amino acid sequences: VH CDR1: SEQ ID
NOs:
247, 571, 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251, 242, or 222; VH CDR2: SEQ ID NOs: 248, 572, 587, 592, 598, 604, 610, 616, 628, 634, 638, 644, 650, 655, 659, 665, 671, 306, 249, 307, or 221; VH CDR3: SEQ ID NOs: 568, 573, 588, 593, = 599, 605, 611, 617, 629, 635, 639, 645, 651, 656, 660, 666, 672, 725, 246, 290, or 220; VL
CDR1: SEQ ID NOs: 569, 574, 577, 580, 583, 589,594, 612, 618, 621, 624, 640, 646, 652, 661, 667, 285, 289, 245, 224, or 219; VL CDR2: ÞQ ID NOs: 570, 575, 578, 581, 584, 590, , 595, 601, 607, 613, 619, 622, 625, 631, 653, 662, 668, 3b5;223, or 231;VL
CDR3: SEQ ID
.,1 NOs: 289, 576, 579, 582, 585, 591, 596, 602, 608, 6r4, 620, 623, 626, 632, 636, 642, 648, , 654, 657, 663, 669, 308, 250, 227, or 280; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, including a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each contain three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR includes the following amino acid sequences: VH CDR1: SEQ 1D NOs: 72, 103, 179, 187, 203, 211, 228, 252, 260, 268, 284, 293, or 301; VH CDR2: SEQ ID NOs: 74, 105, 180, 188, 204, 212, 229, 237, 253, 261, 269, 285, or 294; VH CDR3 SEQ ID NOs: 76, 107, 181, 189, 197, 205, 213, 230, 238, 254, 262, 270, 286, or 295; VL CDR1: SEQ ID NOs:
59, 92, 184, 192, 208, 192, 233, 241, 265, or 273; VL CDR2: SEQ ID NOs: 61, 94, 185, 193, 209, 217, 226, 234, 258, 274, or 282; and VL CDR3: SEQ ID NOs: 63, 96, 186, 194, 210, 218, 243, 259, 267, 275, 291, or 300.
0., 3 ;
t Alternatively, or in addition, the invention provides a composition including:
(a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, including a heavy chain variable region (VH) domain and a light chain variable (VL) domain, wherein the VH
domain and the VL domain each contain three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR includes the following amino acid sequences: VH
CDR1:
SEQ ID NOs: 247, 571, 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251, 242, or 222; VH CDR2: SEQ ID NOs: 248, 572, 587, 592, 598, 604, 610, 616, 628, 634, 638, 644, 650, 655, 659, 665, 671, 306, 249, 307, or 221; VH CDR3: SEQ ID NOs:
568, 573, 588, 593, 599, 605, 611, 617, 629, 635, 639, 645, 65-1, 656, 660, 666, 672, 725, 246, 290, or 220; VL CDR1: SEQ ID NOs: 569, 574, 577, 580:5.83,.589, 594, 612, 618, 621, 624, 640, 646, 652, 661, 667, 285, 289, 245, 224, or 219; VII, 'CDR2: SEQ ID NOs: 570, 575, 578, 581, 584, 590, 595, 601, 607, 613, 619, 622, 625, 631, 653, 662, 668, 305, 223, or 231; VL CDR3:
SEQ ID NOs: 289, 576, 579, 582, 585, 591, 596, 602, 608, 614, 620, 623, 626, 632, 636, 642, 648, 654, 657, 663, 669, 308, 250, 227, or 280; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, including a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each contain three complementarity determining regions 1 to 3 (CDRI-3), and wherein each CDR includes the following amino acid sequences: VH CDR1: SEQ ID NOs: 109, 112, 182, 190, 206, 214, 239, 255, 263, 271, 287, 296, or 304; VH CDR2: SEQ ID NOs: 110, 113, 183, 191, 207, 215, 232, 240, 256, 264, 272, 288, or 297; VH CDR3 SEQ ID NOs: 76, 107, 181, 189, 197, 205, 213, 230, 238, 254, 262, 270, 286, or 295; VL CDR1: SEQ ID NOs:
59, 92, 184, 192, 208, 192, 233, 241, 265, or 273; VL CDR2: SEQ ID NOs: 61, 94, 185, 193, 209, 217, 226, 234, 258, 274, or 282; and VL CDR3 SEQ ID NOs: 63, 96, 186, 194, 210, 218, 243, 259, 267, 275, 291, or 300.
=
[09] The invention provides a composition including:.(a) an isolated human anti-HA
antibody, or an antigen-binding fragment thereof, i'ncluding a heavy chain variable region (VH) domain, wherein the VH domain includes the following amino acid sequences: SEQ ID
NOs 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349, 353, 357, 361, 365, 369, 373, 377, 381, 385, 389, 393, 397, 401, 405, 409, 199, 417, 423, 429, 435, 441, 447, 453, 459, 465, 471, 477, 483, 489, 495, 501, 507, 513, 519, 525, 531, 537, 543, 550, 556, or 562, and a light chain variable (VL) domain, wherein the VL domain includes the following amino acid sequences: SEQ ID NOs 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 366, 370, 374, 378, 382, 386, 390, 394, 398, 402, 406, 410, 414, 420, 426, 432, 438, ,õ

=
444, 450, 456, 462, 468, 474, 480, 486, 492, 498, 504, 510, 516, 522, 528, 534, 540, 547, 553, 559, or 565; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, including a heavy chain variable (VH) domain, wherein the VH
domain includes the following amino acid sequences: SEQ ID NOs 44, 277, 276, 50, 236, 235, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, or 176, and a light chain variable (VL) domain, wherein the VL domain includes the following amino acid sequences: SEQ ID NOs 46, 292, 52, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, or 178.
[10] Furthermore, the invention provides a multivalent vaccine composition including any of the compositionsdescribed herein containing an isolated human anti-HA
antibody, or an antigen-binding fragment thereof and an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof. Alternatively, the multivalent vaccine includes antibodies that bind to the epitopes to which the antibodies of the invention bind. Exemplary antibodies of the invention include, but are not lirriite' d to,.TCN-032 (8I10), 21B15, TCN-031 (23K12), 3241_G23, 3244_110, 3243_107, 3259_121, 3245_019, 3244_H04, 3136_G05, 3252_C13, 3255_106, 3420_123, 3139323, 32483f 8, 3253310, 3260_D19, 3362_B11, 3242_P05, TCN-522 (3212_112), TCN-521 (3280_D18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-528 (5087_P17), TCN-(5297_H01), TCN-530 (5248_H10), TCN-531 (5091_H13), TCN-532 (5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-535 (5246_P19), TCN-536 (5095_N01), TCN-537 (3194_D21), TCN-538 (3206_017), TCN-539 (5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-546 (5089_L08), TCN-547 (5092_F11), TCN-(5092_P01), TCN-549 (5092_PO4), TCN-550 (5096_F06), TCN-551 (5243_D01), TCN-(5249_123), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-(5089_K12), TCN-557 (5081_A04), TCN 558 (5248_Hl0b), TCN-559 (5097_G08), TCN-560 (5084_P10), TCN-504 (3251_K17), SC06-141, SC06-255, SC06-257, SC06-260, 261, SC06-262, SC06-268, SC06-272, SC06-296, SC06-301, SC06-307, SC06-310, 314, SC06-323, 5C06-325, SC06-327, SC06-328,,SC06-329, SC06-331, SC06-332, 334, SC06-336, 5C06-339, SC06-342, SC06-343SC06-344, CR6141, CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6272, CR6296, CR6301, CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, CR6329, CR6331, CR6332, CR6334, CR6336, CR6339, CR6342, CR6343, CR6344, D7, D8, F10, G17, H40, A66, D80, E88, E90, and H98. For example, the multivalent vaccine may include one or more of the following epitopes: GVTNKVNSIIDK (SEQ ID NO: 198), GVTNKVNSIINK (SEQ ID NO: 283), GVTNKENSIIDK (SEQ ID NO: 202), GVTNKVNRIIDK.(SEQ ID NO: 201), GITNKVNSVIEK (SEQ ID NO: 281), GITNKENSyIE.K (SEQ ID NO: 257), ,,-GITNKVNSIIDK (SEQ ID NO: 225), KITSKYNNIVDK (SEQ ID NO: 216), MSLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1), and MSLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1) provided in its native conformation.
[11] The multivalent vaccine also includes a composition including: (a) a human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) a human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus.
[12] The invention provides a pharmaceutical composition including any one of the compositions described herein. Moreover, the pharmaceutical composition includes a pharmaceutical carrier.
[13] The invention provides a method for stimulating an immune response in a subject, including administering to the subject the pharmaceutical composition described herein. The pharmaceutical composition may administered prior to or after exposure of the subject to an Influenza virus.
[14] The invention also provides a method for the treatirient of an influenza virus infection in a subject in need thereof, including administering to the subject the pharmaceutical composition described herein. The subjection may have been exposed to an influenza virus.
Alternatively, or in addition, the subject has not been diagnosed with an influenza infection.
The pharmaceutical composition may administered prior to or after exposure of the subject to an Influenza virus. Preferably, the pharmaceutical composition is administered at a dose sufficient to promote viral clearance or eliminate influenza infected cells.
[15] The invention further provides a method for the prevention of an influenza virus infection in a subject in need thereof, including administering to the subject a vaccine composition described herein, prior to exposure of the subject to an influenza virus. In certain embodiments of this method, the subject is at risk of contracting an influenza infection. The pharmaceutical composition may administered prior to or after exposure of the subject to an Influenza virus. Preferably, the pharmaceutical composition is administered at a dose sufficient to promote viral clearance or eliminate influenza infected cells.
.1.
VI.
6 =' [16] The treatment and prevention methods provided by the invention further include administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.
Exemplary anti-viral drugs include, but are not limited to, a neuraminidase inhibitor, a HA
inhibitor, a sialic acid inhibitor, or an M2 ion channel inhibitor. In certain aspects of these methods, the M2 ion channel inhibitor is amantadine or rimantadine. In other aspects of these methods, the neuraminidase inhibitor is zanamivir or oseltamivir phosphate.
The antiviral drug may administered prior to or after exposure ofthe subject to an Influenza virus.
[17] The treatment and prevention methods provided by the invention further include administering a second anti-Influenza A antibody...The second antibody is optionally an antibody described herein. The second antibody may administered prior to or after exposure of the subject to an Influenza virus.
[18] The invention provides a method for determining the presence of an Influenza virus infection in a subject, including the steps of: (a) contacting a biological sample obtained from the subject with any one of the antibodies or pharmaceutical compositions described herein;
(b) detecting an amount of the antibody that binds to the biological sample;
and (c) comparing the amount of antibody that binds to the.biological sample to a control value, and therefrom determining the presence of the Influenza virus in the subject.
Optionally, the control value is determined by contacting a control sample obtained from the subject with any one of the antibodies or pharmaceutical compositions described herein and detecting an amount of the antibody that binds to the control sample.
[19] The invention also provides a diagnostic kit including any one of the antibodies, , compositions, or pharmaceutical compositions described .herein.
[20] The invention further provides a prophylactic kit including a vaccine composition described herein. Preferably, the vaccine is a multivalent vaccine. The term "multivalent =
vaccine" describes a single vaccine that elicits an immune response either to more than one infectious agent, e.g. the influenza HA glycoprotein and the influenza M2e polypeptide, or to several different epitopes of a molecule, e.g. HA epitopes shown in SEQ ID NOs 198, 283, 202, 201, 281, 257, 225, and 216. Alternatively, or in addition, the term multivalent vaccine is meant to describe the administration of a combination of human antibodies raised against more than one infectious agent, e.g. the influenza HA glycoprotein and the influenza M2e polypeptide.
[21] Other features and advantages of the invention will be apparent from and are encompassed by the following detailed description and claims.

, , ;
BRIEF DESCRIPTION OF THE DRAWINGS
[22] Figure 1 shows the binding of three antibodies of the present invention and control hul4C2 antibody to 293-HEK cells transfected with an M2 expression construct or control vector, in the presence or absence of free M2 peptide.
[23] Figures 2A and B are graphs showing human monoclonal antibody binding to influenza A/Puerto Rico/8/32.
[24] Figure 3A is a chart showing amino acid sequences of extracellular domains of M2 variants (SEQ ID NOS 1-3, 679 &5-40, respectively, in order of appearance).
[25] Figures 3B and C are bar charts showing binding of human monoclonal anti-influenza ' antibody binding to M2 variants shown in Figure 3A.
[26] Figures 4A and B are bar charts showing binding of human monoclonal anti-influenza antibody binding to M2 peptides subjected to alanine scanning mutagenesis.
[27] Figure 5 is a series of bar charts showing binding of MAbs 8i10 and 23K12 to M2 protein representing influenza strain A/HK/483/1997;.sequence that was stably expressed in the CHO cell line DG44.
[28] Figure 6A is a chart showing cross reactivity binding of anti-M2 antibodies to variant M2 peptides (SEQ ID NOS 680-704, respectively, in order of appearance).
[29] Figure 6B is a chart showing binding activity of M2 antibodies to truncated M2 peptides (SEQ ID NOS 680, 705-724 &19, respectively, in order of appearance).
[30] Figure 7 is a graph showing survival of influenza infected mice treated with human anti-influenza monoclonal antibodies.
[31] Figure 8 is an illustration showing the anti-M2 antibodies bind a highly conserved region in the N-Terminus of M2e (SEQ ID NO: 19).
[32] Figure 9 is a graph showing anti-M2 rHMAb clones from crude supernatant bound to influenza on ELISA, whereas the control anti-M2e mAb 14C2 did not readily bind virus.
=
[33] Figure 10 is a series of photographs showing anti-M2 rHMAbs bound to cells infected with influenza. MDCK cells were or were not infected wiil influencza A/PR/8/32 and Ab = binding from crude supernatant was tested 24 hours later. Data were gathered from the FMAT plate scanner.
[34] Figure 11 is a graph showing anti-M2 rHMAb clones from crude supernatant bound to cells transfected with the influenza subtypes H3N2, HK483, and VN1203 M2 proteins.
Plasmids encoding full length M2 cDNAs corresponding to influenza strains H3N2, HK483, and VN1203, as well as a mock plasmidcontrol, were transiently transfected into 293 cells.
The 14C2, 8i10, 23K12, and 21B15 mABs were tested fcir binding to the transfectants, and were detected with an AF647-conjugated anti-human IgG, secondary antibody.
Shown are the mean fluorescence intensities of the specific mAB 'bound after FACS analysis.
[35] Figures 12A-B are amino acid sequences of the variable regions of anti-M2e mAbs.
Framework regions 1-4 (FR 1-4) and complementarity determining regions 1-3 (CDR 1-3) for VH and Vk are shown. FR, CDR, and gene names are defined using the nomenclature in the [MGT database (IMGTO, the International ImMunoGeneTics Information system http://www.imgt.org). Grey boxes denote identity with the germline sequence which is shown in light blue boxes, hyphens denote gaps, and white boxes are amino acid replacement mutations from the germline.
[36] Figure 13 is a graph depicting the results of a competition binding analysis of a panel of anti-M2e mAbs with TCN-032 Fab. The indicated anti-M2e mAbs were used to bind to the stable CHO transfectant expressing M2 of A/Hong Kong/483/97 that had previously been treated with or without 10 p.g/mL TCN-032 Fab fragment. The anti-M2e mAb bound to the cell surface was detected with goattanti7huIgG FcAlexafluor488 FACS and =
analyzed by flow cytometry. The results are deed from one experiment.
, [37] Figure 14A is a graph depicting the ability 'of anii-M2e mAbs TCN-032 and TCN-.t 031 to bind virus particles and virus-infected cells but not M2e-derived synthetic peptide.
Purified influenza virus (A/Puerto Rico/8/34) was coated at 10 1.1.g/m1 on ELISA wells and binding of anti-M2e mAbs TCN-031, TCN-032, chl4C2, and the HCMV mAbs 2N9 was evaluated using HRP-labeled goat anti-human Fc. Results shown are representative of 3 experiments.
[38] Figure 14B is a graph depicting the ability of anti-M2e mAbs TCN-032 and TCN-031 to bind virus particles and virus-infected cells but not M2e-derived synthetic peptide.
23mer synthetic peptide of M2 derived from A/Fort Worth/1/50 was coated at 1 ptg/m1 on ELISA wells and binding of mAbs TCN-031, TCN-032, chl4C2, and 2N9 were evaluated as in panel a. Results shown are representative of 3 experiments.
[39] Figure 14C is .a graph depicting the ability of anti-M2e mAbs TCN-032 and TCN-031 to bind virus particles and virus-infecied cells but not M2e-derived synthetic peptide.
MDCK cells were infected with A/Puerto Rico/8/34 (PR8). and subsequently stained with mAbs TCN-031, TCN-032, chl4C2 and the HCMV mAb.5J12. Binding of antibodies was . .

=

detected using Alexafluor 647-conjugated goat anti-Human IgG H&L antibody and quantified by flow cytometry. Results shown are representative of 3 experiments.
[40] Figure 14D is a series of photographs depicting HEK 293 cells stably transfected with the M2 ectodomain of A/Fort Worth /1/50 (D20) were stained with transient transfection supernatant containing mAbs TCN-031, TCN-032, or the control chl4C2 and analyzed by FMAT for binding to M2 in the presence or absenci Of 5 ùg/ml M2e peptide. Mock transfected cells are 293 cells stably transfected witli'veCtor alone. Results shown are representative of one experiment.
[41] Figures 15A-D are graphs depicting the Therapeutic efficacy of anti-M2 mAbs TCN-031 and TCN-032 in mice. Mice (n=10) were infected by intranasal inoculation with 5 x LD50 A/Vietnam/1203/04 (H5N1) (panels A-B) or (n=5) with 5 x LD50 A/Puerto Rico 8/34 (H1N1) (panels C-D), followed by 3 intraperitoneal (ip) injections with mAbs at 24, 72, and 120 hours post-infection (a total of 3 mAb injections per mouse) and weighed daily for 14 days. Percentage survival is shown in a and c, whereas percent weight change of mice is shown in B and D. The results shown for the treatment study of mice infected with ANietnam/1203/04 (H5N1) are representative of 2 experiments.
[42] Figure 16 is,a series of graphs depicting the viral titers in lung, liver, and brain of mice treated with anti-M2e mAbs TCN-031 and TCN-032 after challenge with H5N1 ANietnam/1203/04. BALB/C mice (n=19) were treated i.p. injection of a 400m/2001AL
dose of TCN-031, TCN-032, control human mAb 2N9, control chimeric mAb chl4C2, PBS, or left untreated. Tissue viral titers were determined from 3 mice per group at 3 and 6 days i` = =
post-infection in the lungs (as an indicator of loca replication) and in liver and brain (as an indicator of the systemic spread which is characteristic of H5N1 infection).
[43] Figure 17 is a graph depicting the ability of TCN-031 and TCN-032 can potentiate cytolysis by NK cells. MDCK cells were infected with A/Solomon Island/3/2006 (H1N1) virus, and were treated with mAbs TCN-031, TCN-032, or the subclass-matched negative control mAb 2N9. The cells were then challenged with purified human NK cells, and the lactate dehydrogenase released as a result of cell lysis was measured through light absorbance.
The results are representative of two separate experiments with two different normal human donors.
[44] Figure 18 is a graph depicting complement-dependent cytolysis (CDC) of M2-expressing cells bound with anti-M2 mAb. The stable transfectant expressing M2 of A/Hong Kong/483/97 and a mock control were treated with the indicated mAbs and subsequently J.:

=

= PCT/US2012/024971 = challenged with human complement. Lysed cells were visualized by Propidium Iodide staining followed by FACS analysis. The data are representative of two experiments.
[45] Figures 19A-C are graphs depicting binding of anti-M2e mAbs TCN-031 and TCN-032 to M2 mutants indicates the epitope is located in the highly conserved N-terminal of M2e. Mutants with alanine substituted at each position of the M2 ectodomain of A/Fort Worth /1/50 (D20)(A) or forty wild-type M2 mutants including A/Vietnam/1203/04 (VN) and A/Hong Korig/483/97 (HK) (B) were transiently transfected into 293 cells. The identity of each wild-type M2 mutant is listed in Table 6.
Transfected cells were stained with mAbs TCN-031, TCN-032, or the control chl4C2 and analyzed by FACS for binding to M2 at 24 hours post-transfeCtion. mAbs TCN-031 and TCN-032 do not bind variants with amino acid substitutions at positions 1, 4, or 5 of M2e. (C) The deduced epitope for TCN-031 and TCN-032 occurs in a highly conserved region of M2e and is distinct from that found for chl4C2. Results shown for (A) and (B) are representative of 3 experiments.
[46] Figure 20 is a graph depicting mAbs TCN-031 and TCN-032 recognize the same region on M2e. The CHO transfectant stably expressing M2 for A/Hong Kong/483/97 as stained with 10 i.tg/mL TCN-031, TCN-032, or 2N9, followed by detection with Alexafluor647-labeled TCN-031 (TCN-031AF647) or TCN-032(TCN-032AF647) and analysis by flow cytometry. The results are representative of three experiments.
[47] Figure 21 is a graph depicting anti-M2e mAbs TCN-031 and TCN-032 bind cells that have been infected with H1N1 A/California/4/09. MDCK cells were infected with Influenza A strain H1N1 A/Memphis/14/96, H1N1 A/California/4/09, or mock infected.
Twenty four hours post-infection cells were stained with mAbs TCN-031, TCN-032, or the control chl4C2 and analyzed by FACS for binding to M2. Results shown are for one experiment.
I
DETAILED DESCRIPTION
[48] Influenza viruses consist of three types; A, B and 6. Influenza A viruses infect a wide variety of birds and mammals, including humans, horses, marine mammals, pigs, ferrets, and chickens. In animals most influenza A viruses cause mild localized infections of the respiratory and intestinal tract. However, highly pathogenic influenza A
strains such as H5N1 exist that cause systemic infections in poultry in which mortality may reach 100%. Animals infected with influenza A often act as a reservoir for the influenza viruses and certain subtypes have been shown to cross the species barrier to humans.

=
=
[49] Influenza A viruses can be classified into subtypes'based on allelic variations in antigenic regions of.two genes that encode surface glycoproteins, namely, hemagglutinin (HA) and neuraminidase (NA) which are required for viral attachment and cellular release.
Other major viral proteins include the nucleoprotein, the nucleocapsid structural protein, membrane proteins (M1 and M2), polymerases (PA, PB and PB2) and non-structural proteins (NS1 and NS2). Currently, sixteen subtypes of HA (H1-H16) and nine NA (N1-N9) antigenic variants are known in influenza A virus. Previously, only three subtypes have been known to circulate in humans (H IN] , H1N2, and H3N2).
[50] However, in recent years, the pathogenic H5N1 subtype of avian influenza A has been reported to cross the species barrier and infect humans as documented in Hong Kong in 1997 and 2003, leading to the death of several patients. In humans, the avian influenza virus infects cells of the respiratory tract as well as the intestinal tract, liver, spleen, kidneys and other organs. Symptoms of avian influenza infection include fever, respiratory difficulties including shortness of breath and cough, lymphopenia, diarrhea and difficulties regulating = blood sugar levels. In contrast to seasonal influenza, the,group most at risk is healthy adults, which make up the bulk of the population. Due to-ihe high pathogenicity of certain avian influenza A subtypes, particularly H5N1, and their demonstrated ability to cross over to infect humans, there is a significant economic and public health risk associated with these viral strains, including a real epidemic and pandemic threat. The scale of the threat is illustrated by the 1918 influenza pandemic which killed over 50 million people.
[51] Currently, no effective vaccines for H5N1 infection are available, so passive immunotherapy with immunoglobulins may be an alternative strategy. Use of passive immunization during the 1918 pandemic reportedly halved the death rate. In view of their therapeutic benefit in humans, there is thus a need for antibodies, preferably human antibodies, capable of neutralizing influenza infection, including H5N1.
[52] The invention provides compositions including human antibodies raised against two influenza proteins, hemagglutinin (HA) and matrix 2 ectodomain (M2e), and shows that these compositions can be used in medicine, in particular for diagnosis, prevention and treatment of I
influenza infections, including H5N1.
HuM2e Antibodies [53] The present invention provides fully human monoclonal antibodies specifically directed against M2e. Optionally, the antibody is isolated form a B-cell from a human donor.
Exemplary monoclonal antibodies include TCN-032 (8I10), 21B15, TCN-031 (23K12), 3241_023, 3244_110, 3243_107, 3259_121, 3245_019, 3244_H04, 3136_005, 3252_C13, . 3255_106, 3420_123, 3139_P23, 3248_P1'8, 3253_P10, 3260_D19, 3362_811, and 3242_P05.described herein. Alternatively, the monoclonal antibody is an antibody that binds to the same epitope as TCN-032 (8I10), 21815, TCN-031 (23K12), 3241_023, 3244_110, 3243_107, 3259_121, 3245_019, 3244_H04, 3136_005, 252_C13, 3255_106, 3420_123, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 362_1411, and 3242_P05. The antibodies respectively referred to herein are huM2e antibodies. The huM2e antibody has one or more of the following characteristics: a) binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus; b) binds to influenza A
infected cells; or c) binds to influenza A virus.
[54] The epitope that huM2e antibody binds to is a non-linear epitope of a M2 polypeptide.
Preferably, the epitope includes the amino terminal region of the M2e polypeptide. More preferably the epitope wholly or partially includes the amino acid sequence SLLTEV (SEQ
ID NO: 42). Most preferably, the epitope includes the amino acid at position 2, 5 and 6 of the M2e polypeptide when numbered in accordance with SEQ ID NO: 1. The amino acid at position 2 is a serine; at position 5 is a threonine; and at position 6 is a glutamic acid.
[55] A huM2e antibody contains a heavy chain variable having the amino acid sequence of SEQ ID NOs: 44, 277, 276, 50, 236, 235, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, or 176 and a light chain Vaiiable having the amino acid sequence of SEQ ID NOs: 46, 52, 118, 122, 126, 130, 134, 138, 142, 1146, 150, 154, 158, 162, 166, 170, 174, or 178. Preferably, the three heavy chainCdRiincli:ide an amino acid sequence at least 90%, 92%, 95%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID
NOs: 72,.74, 76, 103, 105, 107, 179, 180, 181, 187, 188, 189, 197, 203, 204, 205, 21, 212, =
213, 228, 229, 230, 237, 238, 252, 253, 254, 260, 261, 262, 268, 269, 270, 284, 285, 286, 293, 294, 295, and 301 (as determined by the Kabat method) or SEQ ID NOs: 109, 110, 76, 112, 113, 107, 182, 183, 181, 190, 191, 189õ 197, 206, 207, 205, 214, 215, 213, 232, 230, 239, 240, 238, 255, 256, 254, 263, 264, 262, 271, 272, 270, 287, 288, 286, 296, 297, 295, and 304 (as determined by the Chothia method) and a light chain with three CDRs that include an amino acid sequence at least 90%, 92%, 95%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NOs: 59, 60, 61, 92, 94, 96, 184, 185, 186, 192, 193, 194, 208, 209, 210õ 217, 218, 226, 223, 234, 241, 243, 258, 259, 265, 267, 273, 274, 275, 282, 291, and 300 (as determined by the Kabat method) or SEQ ID NOs: 52, 60, 61, 92, 94, 96, 184, 185, 186, 192, 193, 194, 208, 209, 210õ 217, 218, 226, .2,23, 234, 241, 243, 258, 259, 265, 267, ' t 4 13 ' 273, 274, 275, 282, 291, and 300 (as determined by the Chothia method). The antibody binds M2e.
[56] The heavy chain of a M2e antibody is derived from a germ line V
(variable) gene such as, for example, the IgHV4 or the IgHV3 germline gene.
[57] The M2e antibodies of the invention include a variable heavy chain (VH) region encoded by a human IgHV4 or the IgHV3 germline gene sequence. A IgHV4 germline gene sequence are shown, e.g., in Accession numbers L10088, M29812, M95114, X56360 and M95117. IgHV3 germline gene sequence are shown, e.gt, in Accession numbers X92218, X70208, Z27504, M99679 and AB019437. The M2e antibodies of the invention include a VH
, region that is encoded by a nucleic acid sequence that is at least 80%
homologous to the IgHV4 or the IgHV3 germline gene sequence. Preferably, the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgHV4 or the IgHV3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgHV4 or the IgHV3 germline gene sequence. The VH region of the M2e antibody is at least 80% homologous to the amino acid sequence of the VH region encoded by the IgHV4 or the IgHV3 VH germline gene sequence. Preferably, the amino acid sequence of VH region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgHV4 or the IgHV3 germline gene sequence, and more preferably, at least 98%, 99%
homologous to the sequence encoded by the IgHV4 or the IgHV3 germline gene sequence.
[58] The M2e antibodies of the invention also include a variable light chain (VL) region encoded by a human IgKV1 germline gene sequence. A human IgKV1 VL germline gene sequence is shown, e.g., Accession numbers X59315, X59312, X59318, J00248, and .
Y14865. Alternatively, the M2e antibodies include a VL region that is encoded by a nucleic . , acid sequence that is at least 80% homologous to the IgKV1 germline gene sequence.
Preferably, the nucleic acid sequence is at least 90%, 95%; 96%, 97%
homologous to the IgKV1 germline gene sequence, and more preferably, at least 98%, 99%
homologous to the IgKV1 germline gene sequence. The VL region of the M2e antibody is at least 80%
=
homologous to the amino acid sequence of the VL region encoded the IgKV1 germline gene sequence. Preferably, the amino acid sequence of VL region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgKV1 germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by e the IgKV1 germline gene sequence.

= i =
[59] In another aspect the invention provides a composition including an huM2e antibody according to the invention. In various aspects the composition further includes an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor. The anti-viral drug is for example a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 ion channel inhibitor. The M2 ion channel inhibitor is for example amantadine or rimantadine. The neuraminidase inhibitor for example zanamivir, or oseltamivir phosphate. In a further aspect the composition further includes a second anti-influenza A antibody.
[60] In a further aspect the huM2e antibodies according to the invention are operably-linked to a therapeutic agent or a detectable label.
[61] Additionally, the invention provides methods for stimulating an immune response, treating, preventing or alleviating a symptom of an influenza viral infection by administering an huM2e antibody to a subject [62] Optionally, the subject is further administered with a second agent such as, but not limited to, an influenza virus antibody, an anti-viral drug such as a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 itm charinel inhibitor, a viral entry inhibitor or a viral attachment inhibitor. The M2 ion channel inhibitor is, for example, amantadine or rimantadine. The neuraminidase inhibitor is, for example, zanamivir or oseltamivir phosphate. The subject is suffering from or is predisposed to developing an influenza virus infection, such as, for example, an autoimmune disease or an inflammatory disorder.
[63] In another aspect, the invention provides methods of administering the huM2e antibody of the invention to a subject prior to, and/or after exposure to an influenza virus.
For example, the huM2e antibody of the invention is used to treat or prevent rejection influenza infection. The huM2e antibody is administered at a dose sufficient to promote viral clearance or eliminate influenza A infected cells.
[64] Also included in the invention is a method for determining the presence of an influenza virus infection in a patient, by contacting a biological sample obtained from the patient with a humM2e antibody; detecting an amount of the antibody that binds to the biological sample; and comparing the amount of anfibody..that binds to the biological sample to a control value.
[65] The invention further provides a diagnostic Ickt comprising a huM2e antibody.
[66] Other features and advantages of the invention will be apparent from and are encompassed by the following detailed description and claims.

[67] The present invention provides fully human monoclonal antibodies specific against = the extracellular domain of the matrix 2 (M2) polypCptide. The antibodies are respectively referred to herein as huM2e antibodies.
[68] M2 is a 96 amino acid transmembrane protein:pre ent as a homotetramer on the surface of influenza virus and virally infected cells. M2 contains a 23 amino acid ectodomain (M2e) that is highly conserved across influenza A strains. Few amino acid changes have occurred since the 1918 pandemic strain thus M2e is an attractive target for influenza therapies. In prior studies, monoclonal antibodies specific to the M2 ectodomain (M2e) were derived upon immunizations with a peptide corresponding to the linear sequence of M2e. In contrast, the present invention provides a novel process whereby full-length M2 is expressed in cell lines, which allows for the identification of Human antibodies that bound this cell-expressed M2e. The huM2e antibodies have been shown to bind=conformational determinants on the M2-transfected cells, as well as native M2, either on influenza infected cells, or on the virus itself. The huM2e antibodies did not bind the linear M2e peptide, but they do bind several natural M2 variants, also expressed upon cDNA transfection into cell lines. Thus, this invention has allowed for the identification and production of human monoclonal antibodies .4) that exhibit novel specificity for a very broad range bf influenza A virus strains. These antibodies may be used diagnostically to identify influenza A infection and therapeutically to I ' treat influenza A infection.
[69] The huM2e antibodies of the invention have one or more of the following characteristics: the huM2e antibody binds a) to an epitope in the extracellular domain of the matrix 2 (M2) polypeptide of an influenza virus; b) binds to influenza A
infected cells;
and/or c) binds to influenza A virus (i.e., virons). The huM2e antibodies of the invention eliminate influenza infected cells through immune effector mechanisms, such as ADCC, and promote direct viral clearance by binding to influenza virons. The huM2e antibodies of the invention bind to the amino-terminal region of the M2e polypeptide.
Preferably, the huM2e antibodies of the invention bind to the amino-terminal region of the M2e polypeptide wherein the N-terminal methionine residue is absent. Exemplary M2e sequences include those sequences listed on Table 1 below .µ17;
- ;
=
fl=
, t =

[70] Table 1 Type Name Subtype M2E Sequence SEQ ID NO
A BREVIG MISSION.1.1918 H1N1 MSLLTEVETPTRNEWGCRCNDSSD SEQ ID NO: 1 A FORT MONMOUTH.1.1947 H1N1 MSLLTEVETPTKNEWECRCNDSSD SEQ ID NO: 2 A .SINGAPORE.02.2005 H3N2 MSLLTEVETPIRNEWECRCNDSSD SEQ ID NO: 3 A WISCONSIN.10.98 H1N1 MSLLTEVETPIRNGWECKCNDSSD SEQ ID NO: 4 A WISCONS1N.301.1976 H1N1 MSLLTEVETPIRSEWGCRCNDSSD SEQ ID NO:= 5 A PANAMA.1.66 H2N2 MSFLPEVETPIRNEWGCRCNDSSD SEQ ID NO: 6 A NEW YORK.321.1999 ' H3N2 MSLLTEVETPIRNEWGCRCNDSSN SEQ ID NO: 7 A CARACAS.1.71 H3N2 MSLLTEVETPIRKEWGCRCNDSSD SEQ ID NO: 8 A TAIWAN.3.71 H3N2 MSFLTEVETPIRNEWGCRCNDSSD SEQ ID NO: 9 A WUHAN.359.95 H3N2 MSLPTEVETPIRSEWGCRCNDSSD SEQ ID NO: 10 A HONG KONG.1144.99 H3N2 MSLLPEVETPIRNEWGCRCNDSSD SEQ ID NO: 11 A HONG KONG.1180.99 H3N2 MSLLPEVETPIRNGWGCRCNDSSD SEQ ID NO: 12 A HONG KONG.1774.99 H3N2 MSLLTEVETPTRNGWECRCSGSSD SEQ ID NO: 13 A NEW YORK.217.02 H1N2 MSLLTEVETPIRNEWEYRCNDSSD SEQ ID NO: 14 A NEW YORK.300.2003 H1N2 MSLLTEVETPIRNEWEYRCSDSSD SEQ ID NO: 15 A SWINE.SPAIN.54008.2004 H3N2 MSLLTEVETPTRNGWECRYSDSSD SEQ ID NO: 16 A GUANGZHOU.333.99 H9N2 MSFLTEVETLTRNGWECRCSDSSD SEQ ID NO: 17 A HONG KONG.1073.99 H9N2 MSLLTEVETLTRNGWECKCRDSSD SEQ ID NO: 18 A HONG KONG.1.68 H3N2 MSLLTEVETPIRNEWGCRCNDSSD SEQ ID NO: 19 A SW1NE.HONG H3N2 MSLLTEVETPIRSEWGCRCNDSGD SEQ ID NO: 20 KONG.126.1982 A NEW YORK.703.1995 H3N2 MSLLTEVETPIRNEWECRCNGSSD SEQ ID NO: 21 A SWINE.QUEBEC.192.81 H1N1 MSLPTEVETPIRNEWGCRCNDSSD SEQ ID NO: 22 A PUERTO RIC0.8.34 H1N1 MSLLTEVETPIRNEWGCRCNGSSD SEQ ID NO: 23 A =HONG KONG.485.97 H5N1 MSLLTEVDTLTRNGWGCRCSDSSD SEQ ID NO: 24 A HONG KONG.542.97 H5N1 MSLLTEVETLTKNGWGCRCSDSSD SEQ ID NO: 25 MSLLTEVETPTRNGWECKCSDSSD SEQ ID NO: 26 CHICKEN.SHANTOU.1826.2 A CHICKEN.TAIWAN.0305.04 H6N1 MSLLTEVETHTRNGWECKCSDSSD SEQ ID NO: 27 A QUAIL.ARKANSAS.16309- H7N3NSA
MSLLTEVKTPTRNGWECKCSDSSD SEQ ID NO: 28 7.94 A HONG KONG.486.97 H5N1 MSLLTEVETLTRNGWGCRCSDSSD SEQ ID NO: 29 A CHICKEN.PENNSYLVANIA.1 H7N2NSB MSLLTEVETPTRDGWECKCSDSSD SEQ ID NO: 30 ..
3552-1.98 .
A CHICKEN.HEILONGJIANG.4 H9N2 MSLLTEVETPTRNGWGCRCSDSSD SEQ ID NO: 31 8.01 v - .
A SWINE.KOREA.S5.2005 H1N2 MSLLTEVETPTRNGWECKCNDSSD SEQ ID NO: 32 A HONG KONG.1073.99 H9N2 MSLLTEVETLTRNGWECKCSDSSD SEQ ID NO: 33 c A WISCONSIN.3523.88 H1N1 MSLLTEVETPIRNEWGCKCNDSSD SEQ ID NO: 34 MSFLTEVETPIRNEWGCRCNGSSD SEQ ID NO: 35 =
A CHICKEN.ROSTOCK.8.1934 H7N1 MSLLTEVETPTRNGWECRCNDSSD SEQ ID NO: 36 A ENVIRONMENT.NEW H7N2 MSLLTEVETPIRKGWECNCSDSSD SEQ ID NO: 37 YORK.16326-1.2005 A INDONESIA.560H.2006 H5N1 MSLLTEVETPTRNEWECRCSDSSD SEQ ID NO: 38 A CHICKEN.HONG H9N2 MSLLTGVETHTRNGWGCKCSDSSD SEQ ID NO: 39 KONG.SF1.03 A CHICKEN.HONGKONG.YU427 H9N2 MSLLPEVETHTRNGWGCRCSDSSD SEQ ID NO: 40 .03 [71] In one embodiment, the huM2e antibodies of the invention bind to a M2e that wholly or partially includes the amino acid residues from position 2 to position 7 of M2e when .,..
.r.7 *:;=
i numbered in accordance with SEQ ID NO: 1. For example, the huM2e antibodies of the invention bind wholly or partially to the amino acid sequence SLLTEVET (SEQ ID
NO: 41) Most preferably, the huM2e antibodies of the invention bind wholly or partially to the amino acid sequence SLLTEV (SEQ ID NO: 42). Preferably, the huM2e antibodies of the invention bind to non-linear epitope of the M2e protein. For example, the huM2e antibodies bind to an epitope comprising position 2, 5, and 6 of the M2e polypeptide when numbered in accordance to SEQ ID NO: 1 where the amino acid at a) position 2 is a serine;b) position 5 is a threonine; and c) position 6 is a glutamic acid. Exemplary huM2e monoclonal antibodies that bind to this epitope are the TCN-032 (8110), 21B15, TCN-031 (23K12), 3241_G23, 3244_110, 3243J07, 3259_.121, 3245_019, 3244_1-104, 3136_G05, 3252_C13, 3255J06, 3420_123, 3139_P23, 3248_P18, 3253_P10, 3260_D.19, 3362_B11, and 3242_P05 antibodies described herein.
[72] The TCN-032 (8I10) antibody includes a heayy chain variable region (SEQ
ID NO:
44) encoded by the nucleic acid sequence shown below in SEQ ID NO: 43, a short heavy chain variable region (SEQ ID NO: 277) encoded by the nucleic acid sequence shown below in SEQ ID NO: 278, a long heavy chain variable region (SEQ ID NO: 276) encoded by the nucleic acid sequence shown below in SEQ ID NO: 196, and a light chain variable region (SEQ ID NO: 46) encoded by the nucleic acid sequence shown in SEQ ID NO: 45.
[73] The amino acids encompassing the. CDRs as defined by Chothia, C. et al.
(1989, Nature, 342: 877-883) are underlined and those defined by Kabat E.A. et al.(1991, Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 U.S.
Department of Heath and Human Services.) are highlighted in bold in the sequences below.
[74] The heavy chain CDRs of the TCN-032 (8110) antibody have the following sequences per Kabat definition: NYYWS (SEQ ID NO: 72), FIYYGGNTKYNPSLKS (SEQ ID NO:
74) and ASCSGGYCILD (SEQ ID NO: 76). The light chain CDRs of the TCN-032 (8110) 4) =
antibody have the following sequences per Kabat definition: RASQNIYKYLN (SEQ
ID NO:
59), AASGLQS (SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).
[75] The heavy chain CDRs of the TCN-032 (8110) antibody have the following sequences per Chothia definition: GSSISN (SEQ ID NO: 109), FIYYGGNTK (SEQ ID NO: 110) and ASCSGGYCILD (SEQ ID NO: 76). The light chain CDRs of the TCN-032 (8110) antibody have the following sequences per Chothia definition: RASQNIYKYLN (SEQ ID NO:
59), AASGLQS (SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).

, [76] TCN-032 (8I10) VH nucleotide sequencel(SEQ ID NO: 43) CAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAaCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCCCCAG
GGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCCTCC
CTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTCTCCCTGACGATGAG
CTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCTGTGCGAGAGCGTCTTGTAGTGGTGGTT
ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCG
[77] TCN-032 (8110) VH amino acid sequence: (SEQ ID NO: 44) Kabat Bold, Chothia underlined QVQLQE S GP GLVK P SE TL SL T
C T VS GS S I SNY YWSW IRQSP G
K GLEW I GF I YYGGNTK YNPSL
KSRV T I SQD TSK SQVSL TMS S
/ T A AE S A V YF C AR ASCSGGYC
ILDYWGQG T L V T V S
[78] TCN-032 (8110) VH short nucleotide sequence: (SEQ ID NO: 278) CAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCITCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTTCGTCCATCAGTAATTACtACTGGAGCTGGATCCGGCAGTCCCCAG
GGAAGGGACTGGAGTGGATTGGGTTTATCTATTAdGGTGGAAACACCAAGTACAATCCCTCC
CTCAAGAGCCGCGTCACCATATCACAAGACACTTC`CAAdAGICAGGTCTCCCTGACGATGAG
CICTGTGACCGCTGCGGAATCGGCCGICTATTICTGTGCGAGAGCGICTTGTAGTGGTGGTT
ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGT
[79] TCN-032 (8110) VH short amino acid sequence: (SEQ ID NO: 277) Kabat Bold, Chothia underlined QVQLQE S GP GL VK P SE T L SL T
C T VS GS S I SNYYWS W IRQSP G
K GLEW I GF I Y Y GGN TK YNPSL
KSRV T I SQDTSK SQVSL T MS S
/ T A AES AV YF C AR ASCSGGYC
ILDYWGQG T L V T
[80] TCN-032 (8110) VH long nucleotide sequence: (SEQ ID NO: 196) CAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCCCCAG
GGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCCTCC
CTCAAGAGCCGCGTCACCATATCACAAGACACTTCGAAGAGTCAGGTCTCCCTGACGATGAG
CTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCT:GTGCGAGAGCGTCTTGTAGTGGTGGTT
ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC

[81] TCN-032 (8110) VH long amino acid sequence: (SEQ ID NO: 276) Kabat Bold, Chothia underlined QVQLQE S GP GLVK P SE T LSL T
C T VS GS S I SNYYWS W IRQSP G
K GLEW I GF I Y YG-GNTK YNPSL
KSRV T I SQD T Si< S QV SL TMSS
/ T A A E S A V Y F C ARASCSGGYC
ILDYWGQG T L V T V.S S
=
[82] TCN-032 (8110) VL nucleotide sequence: (SEQ ID NO: 45) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCGAGTCAGAACATTTACAAGTATTTAAATTGGTATCAGCAGAGACCAGGGA
AAGCCCCTAAGGGCCTGATCTCTGCTGCATCCGGGTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGAGTTACAGTCCCCCTCTCACTTTCGGCGGAGGGACCAGGG
TGGAGATCAAAC
[83] TCN-032 (8110) VL amino acid sequence: (SEQ ID NO: 46) Kabat Bold, Chothia underlined DIQMTQSP S SL S A S VGDR V T I
T CR ASQNIYK YLNW YQQRP GK
AP K GL I S AASGLQSG V P SRF S
GSGSGTDF T L T I T S LQP EDF A
T Y YCQQSYSPPL,TF GGG TR VE
I K
[84] The 21B15 antibody includes a heavy chain variable region (SEQ ID NO: 44) encoded by the nucleic acid sequence shown below in SEQ ID NO: 47, a short heavy chain variable region (SEQ JD NO: 277) encoded by the nucleic acid sequence shown below in SEQ ID NO: 278, a long heavy chain variable region (SEQ ID NO: 276) encoded by the nucleic acid sequence shown below in SEQ ID NO: 196, and a light chain variable region (SEQ ID NO: 46) encoded by the nucleic acid sequence shown in SEQ ID NO: 48.
[85] The amino acids encompassing the CDRs as defined by Chothia et al. 1989, are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
,[861 The heavy chain CDRs of the 21B15 antibody have the following sequences per Kabat definition: NYYWS (SEQ ID NO: 72), FIYYGGNTKYNPSLKS (SEQ ID NO: 74) and ASCSGGYCILD ,(SEQ ID NO: 76). The light chain CDRs of the 21B15 antibody have 4 "

the following sequences per Kabat definition: RASQNIYKYLN (SEQ ID NO: 59), AASGLQS (SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).
[87] The heavy chain CDRs of the 21B15 antibody have the following sequences per Chothia definition: GSSISN (SEQ ID NO: 109), FIYYGGNTK (SEQ ID NO: 110) and ASCSGGYCILD (SEQ ID NO: 76). The light chain CDRs of the 21B15 antibody have the following sequences per Chothia definition: RASQNIYKYLN (SEQ ID NO: 59), AASGLQS
(SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).
[88] 21B15 VH nucleotide sequence: (SEQ ID NO: 47) CTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCCCCAG
GGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCCTCC
CTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTCTCCCTGACGATGAG

ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCG
[89] 21B15 VH amino acid sequence: (SEQ ID NO: 44) Kabat Bold, Chothia underlined QVQLQE S GP GLVK P SE TL SL T
C T V S GS S I SNYYWS W I RQSP G
K GLE WI GF I Y YGGN TK YNPSL
K SR V T I SQDT-SK S QV S L T MS S
/ T A A E S AV YF CAR ASCSGGYC
ILDY WGQG T L V T V S
[90] 21B15 VH short nucleotide sequence: (SEQ ID NO: 278) CAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGICTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCCCCAG
GGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCCTCC
CTCAAGAGCCGCGTCACCATATCACAAGACACT'faCAAGAGTCAGGTCTCCCTGACGATGAG

ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGT
[91] 21B15 VH short amino acid sequence: (SEQ ID NO: 277) Kabat Bold, Chothia underlined QVQLQES GP GLVK P SE T L SL T
C TVS GS S I SNYYWS W IRQSP G
K GLE W I GF I Y YGGNTK YNP SL
K SR V T I SQD T SK S QV S L T MS S
/ T A AES AV YF C AR ASCSGGYC
ILDYWGQG T L V

=

, .
, [92] 21B15 VH long nucleotide sequence: (SEQ ID NO: 196) CAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCCCCAG
GGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCCTCC
CTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTCTCCCTGACGATGAG
= CTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCTGTGCGAGAGCGTCTTGTAGTGGTGGTT
ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
[93] 21B15 VH long amino acid sequence: (SEQ ID NO: 276) Kabat Bold, Chothia underlined QVQLQE S GP GLVK P SE T L SL T
C TVS GS S I SNYYWS W IRQSP G
K GL EW I GF I YYGGN TK YNPSL
K SR V T I SQD TSK SQVS L TMSS
/ T A AES A V Y F CAR ASCSGGYC
ILDYWGQG T L V TV S S
[94] 21B15 VL nucleotide sequence: (SEQ ID NO: 48) GACATCCAGGTGACCCAGTCTCCATCCTCCCTGCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGCGCGAGTCAGAACATTTACAAGTATTTAAATTGGTATCAGCAGAGACCAGGGA
AAGCCCCTAAGGGCCTGATCTCTGCTGCATCCGGGTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGAGTTACAGTCCCCCTCTCACTTTCGGCGGAGGGACCAGGG
TGGATATCAAAC
[95] 21815 VL amino acid sequence: (SEQ ID NO: 292) Kabat Bold, Chothia underlined DIQV TQ SP S SL S AS VGDR V T I
TCRASQNI YK YLNW y QQR p GK
AP K GL I SAASGLQS GVP SRF S
GSGSGTDF T L T I T S LQP EDF A
T Y YCQQS YSPPLTF GGG T R V D
I K
=
[96] The TCN-031 (23K12) antibody includes k'heavy chain variable region (SEQ
ID NO:
50) encoded by the nucleic acid sequence shown below in SEQ ID NO: 49, a short heavy chain variable region (SEQ ID NO: 236) encoded by the nucleic acid sequence shown below in SEQ ID NO: 244, a long heavy chain variable region (SEQ ID NO: 195) encoded by the = 22 =
, nucleic acid sequence shown below in SEQ ID NO: 235, and a light chain variable region (SEQ ID NO: 52) encoded by the nucleic acid sequence shown in SEQ ID NO: 51.
[97] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[98] The heavy chain CDRs of the TCN-031 (23K12) antibody have the following sequences per Kabat definition: SNYMS (SEQ ID NO: 103), VIYSGGSTYYADSVK (SEQ
ID NO: 105) and CLSRMRGYGLDV (SEQ ID NO: 107). The light chain CDRs of the TCN-031 (23K12) antibody have the following sequences per Kabat definition:
RTSQSISSYLN (SEQ ID NO: 92), AASSLQSGVPSRF (SEQ ID NO: 94) and QQSYSMPA
(SEQ ID NO: 96).
[99] The heavy chain CDRs of the TCN-031 (23K12) antibody have the following sequences per Chothia definition: GFTVSSN (SEQ ID NO: 112), VIYSGGSTY (SEQ ID
NO: 113) and CLSRMRGYGLDV (SEQ ID NO: 107). The light chain CDRs of the TCN-031 (23K12) antibody have the following sequences per Chothia definition:
RTSQSISSYLN
(SEQ ID NO: 92), AASSLQSGVPSRF (SEQ ID NO: 94) and QQSYSMPA (SEQ ID NO:
96).
[100] TCN-031 (23K12) VH nucleotide sequence: (SEQ ID NO: 49) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAATCTC
CTGTGCAGCCTCTGGATTCACCGTCAGTAGCAACTACATGAGTTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGTGGTGGTAGCACATACTACGCAGACTCC
GTGAAGGGCAGATTCTCCTTCTCCAGAGACAACTCCAAGAACACAGIGTTTCTTCAAATGAA
CAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATGTCTGAGCAGGATGCGGG
GTTACGGTTTAGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCG
[101] TCN-031 (23K12) VH amino acid sequence: (SEQ ID NO: 50) Kabat Bold, Chothia underlined EVQLVESGGGLV'QP GGSLR IS
C A A S GF T V SSNYMS W V R Q A P G
K G LE W V S V I YSGGS T Y y ADS V
K GRF SF SR DNS K N T VF LQMNS
LR AED T A V Y YC A RCL SRMRG Y
GLDVWGQG T T V T V S

[102] TCN-031 (23K12) VH short nucleotide sequence: (SEQ ID NO: 244) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAATCTC
CTGTGCAGCCTCTGGATTCACCGTCAGTAGCAACTACATGAGTTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGTGGTGGTAGCACATACTACGCAGACTCC
GTGAAGGGCAGATTCTCCTTCTCCAGAGACAACTCCAAGAACACAGTGTTTCTTCAAATGAA
CAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATGTCTGAGCAGGATGCGGG
GTTACGGTTTAGACGTCTGGGGCCAAGGGACCACGGTCACCGT
[103] TCN-031 (23K12) VH short amino acid sequence: (SEQ ID NO: 236) Kabat Bold, Chothia underlined EVQL VESGGGLVQP GG S LR I S
C A A SGF T V SSNYMS WV R Q A,P G
K GLE WV S V I YS G.GS T Y Y ADS V
K GRF SF SR DNS K N T VF LQMNS
LR AED T A V Y Y C AR CL SRMRGY
GL.DVWGQG T T V T V S
[104] TCN-031 (23K12) VH long nucleotide sequence: (SEQ ID NO: 195) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAATCTC
CTGTGCAGCCTCTGGATTCACCGTCAGTAGCAACTACATGAGTTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGTGGTGGTAGCACATACTACGCAGACTCC
GTGAAGGGCAGATTCTCCTTCTCCAGAGACAACTCCAAGAACACAGTGTTTCTTCAAATGAA
CAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATGTCTGAGCAGGATGCGGG
GTTACGGTTTAGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[105] TCN-031 (23K12) VH long amino acid sequence: (SEQ ID NO: 235) Kabat Bold, Chothia underlined EVQLVESGGGLVQ'P GGSLR IS
C A A S GF T V S SNYMS W V R Q AP G
K G LE WV S V I YS G-G'S T YY ADS V
K GRF SF SR DNS,K N T VF LQMNS
L R AED T A V Y YC AR CL SRMRGY
GLDVWGQG T T V T V S S
[106] TCN-031 (23K12) VL nucleotide sequence: (SEQ ID NO: 51) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGACAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGA
AAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGGTCTGCAACCTGAAGATTT
TGCAACCTACTACTGTCAACAGAGTTACAGTATGCCTGCCTTTGGCCAGGGGACCAAGCTGG
AGATCAAA

, , CA 02827301 2013:08-13.

[107] TCN-031 (23K12) VL amino acid sequence: (SEQ ID NO: 52) Kabat Bold, Chothia underlined DIQMTQSP S SL S AS VGDR V T I
T CR TSQSISSYLNW YQQK P GK
AP K LL I Y AASSLQSGVP SRF S
GS GS G TDF TL T IS G.LQPEDF A
T Y YCQQSYSMPAF GQG TK LEI
[108] The 3241_G23 antibody (also referred to herein as G23) includes a heavy chain variable region (SEQ ID NO: 116) encoded by the nucleic acid sequence shown below in SEQ ID NO: 115, and a light chain variable region (SEQ ID NO: 118) encoded by the nucleic acid sequence shown in SEQ ID NO: 117.
[109] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991-are highlighted in bold in the sequences below.
[110] The heavy chain CDRs of the G23 antibody' have the following sequences per Kabat definition: GGGYSWN (SEQ ID NO: 179), FMFHSGSPRYNPTLKS (SEQ ID NO: 180) , and VGQMDKYYAMDV (SEQ ID NO: 181). The light chain CDRs of the G23 antibody have the following sequences per Kabat definition: RASQSIGAYVN (SEQ ID NO:
184), GASNLQS (SEQ ID NO: 185) and QQTYSTPIT (SEQ ID NO: 186). =
[111] The heavy chain CDRs of the G23 antibody have the following sequences per Chothia definition: GGPVSGGG (SEQ ID NO: 182), FMFHSGSPR (SEQ ID NO: 183) and VGQMDKYYAMDV (SEQ ID NO: 181). The light chain CDRs of the G23 antibody have the following sequences per Chothia definition: RASQSIGAYVN (SEQ ID NO: 184), GASNLQS (SEQ ID NO: 185) and QQTYSTPIT (SEQ ID NO: 186).
[112] 3241_G23 VH nucleotide sequence (SEQ ID NO: 115) CAGGTGCAGCTGCAGCAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCAC
TTGCACTGTCTCTGGTGGCCCCGTCAGCGGTGGTGGTTACTCCTGGAACTGGATCCGCCAAC
GCCCAGGACAGGGCCTGGAGTGGGTTGGGTTCATG'TTTCACAGTGGGAGTCCCCGCTACAAT
CCGACCCTCAAGAGTCGAATTACCATCTCAGTCGACACGTCTAAGAACCTGGTCTCCCTGAA
GCTGAGCTCTGTGACGGCCGCGGACACGGCCGTGTATITTTGTGCGCGAGTGGGGCAGATGG
ACAAGTACTATGCCATGGACGTCTGGGGCCAAGGGACCCGGTCACCGTCTCGAGC
[113] 3241_G23 VH amino acid sequence (SEQ ID NO: 116) Kabat Bold, Chothia underlined QVQLQQSGPGLVKPSQTLSLTCTVSGGPVSGGGYSWNWIRQRPGQGLEWVGFMFHSGSPRYN
PTLKSRITISVDTSKNLVSLKLSSVTAADTAVYFCARVGQMDKYYAMDVWGQGTTVTVSS

[114] 3241_G23 VL nucleotide sequence (SEQ ID NO: 117) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTTCCTCTGTCGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTGGCGCCTATGTAAATTGGTATCAACAGAAAGCAGGGA
AAGCCCCCCAGGTCCTGATCTTTGGTGCTTCCAATTTACAAAGCGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGACTT
TGCAACTTACTTCTGTCAACAGACTTACAGTACCCCGATCACCTTCGGCCAAGGGACACGAC
TGGAGATTAAACG
[115] 3241_G23 VL amino acid sequence (SEQ ID NO: 118) Kabat Bold, Chothia underlined DIQMTQSPSSLSSSVGDRVTITCRASQSIGAYVNWYQQKAGKAPQVLIFGASNLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYFCQQTYSTPITFGQGTRLEIK
[116] The 3244_110 antibody (also referred to herein as 110) includes a heavy chain variable region (SEQ ID NO: 120) encoded by the nucleic acid sequence shown below in SEQ ID
NO: 119, and a light chain variable region (SEQ ID NO: 122) encoded by the nucleic acid sequence shown in SEQ ID NO: 121.
[117] The amino acids encompassing the CDRs as 'defiiied by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[118] The heavy chain CDRs of the Il 0 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and HDAKFSGSYYVAS (SEQ ID NO: 189). The light chain CDRs of the 110 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS =
(SEQ ID NO: 193) and QQSYN'TPLI (SEQ ID NO: 194).
[119] The heavy chain CDRs of the 110 antibody have the following sequences per Chothia definition: GGSITS (SEQ ID NO: 190), FFYNGGSTK (SEQ ID NO: 191) and HDAKFSGSYYVAS (SEQ ID NO: 189). The light chain CDRs of the 110 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS
(SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).
[120] 3244_110 VH nucleotide sequence (SEQ ID NO: 119) CAGGTCCAGCTGCAGGAGTCGGGCCCAGGACTGCTGAACCTTCGGACACCCTGGCCCTCAC
TTGCACTGTCTCTGGTGGCTCCATCACCAGTGACTACTGGAGCTGGATCCGGCAACCCCCAG
GGAGGGGACTGGACTGGATCGGATTCTTCTATAACGGCGGAAGCACCAAGTACAATCCCTCC
CTCAAGAGTCGAGICACCATTTCAGCGGACACGTCCAAdAACCAGTTGTCCCTGAAATTGAC

CTCTGTGACCGCCGCAGACACGGGCGTGTATTATTGTQCGAGACATGATGCCAAATTTAGTG
GGAGCTACTACGTTGCCTCCTGGGGCCAGGGAACCCGAGTCACCGTCTCGAGC
[121] 3244_110 VH amino acid sequence (SEQ ID NO: 120) QVQLQESGPGLLKPSDTLALTCTVSGGSITSDYWSWIRQPPGRGLDWIGFFYNGGST
KYNPSLKSRVTISADTSKNQLSLKLTSVTAADTGVYYCARHDAKFSGSYYVASWG
QGTRVTVSS
[122] 3244_110 VL nucleotide sequence (SEQ ID NO: 121) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CTCTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTAAATTGGTATCAGCAGCAACCTGGGA
AAGCCCCTAAGGTCCTCATTTTTGGTGCAACCAACTTGCAAAGTGGGGTCCCATCTCGCTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGAGTTACAATACCCCCCTCATTTTTGGCCAGGGGACCAAGC
TGGAGATCAAACG
[123] 3244_110 VL amino acid sequence (SEQ ID NO: 122) DIQMTQSPSSLSASVGDRVTISCRASOSISTYLNWYQQQPGKAPKVLIFGATNLOSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCOOSYNTPLIFGQGTKLEIK
[124] The 3243_J07 antibody (also referred to herein as J07) includes a heavy chain variable region (SEQ ID NO: 124) encoded by the nucleic acid sequence shown below in SEQ ID NO: 123, and a light chain variable region (SEQ ID NO: 126) encoded by the nucleic acid sequence shown in SEQ ID NO: 125.
[125] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[126] The heavy chain CDRs of the J07 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and HDVKFSGSYYVAS (SEQ ID NO: 197). The light chain CDRs of the J07 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS
(SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).
[127] The heavy chain CDRs of the J07 antibody have the following sequences per Chothia definition: GGSITS (SEQ ID NO: 190), FFYNGG,STK (SEQ ID NO: 191) and HDVKFSGSYYVAS (SEQ ID NO:.197). The light-chdin CDRs of the J07 antibody have the t, following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS
(SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).

[128] 3243_J07 VH nucleotide sequence (SEQ ID NO: 123) CAGGTCCAGCTGCAGGAGTCGGGCCCAGGACTGCTGAAGCCTTCGGACACCCTGGCCCTCAC
TTGCACTGTCTCTGGTGGCTCCATCACCAGTGACTACTGGAGCTGGATCCGGCAACCCCCAG
GGAGGGGACTGGACTGGATCGGATTCTTCTATAACGGCGGGAGCACCAAGTACAATCCCTCC
= CTCAAGAGTCGAGTCACCATATCAGCGGACACGTCCAAGAACCAGTTGTCCCTGAAATTGAC
CTCTGTGACCGCCGCAGACACGGGCGTGTATTATTGTGCGAGACATGATGTCAAATTTAGTG
GGAGCTACTACGTTGCCTCCTGGGGCCAGGGAACCCGAGTCACCGTCTCGAGC
[129] 3243_J07 VH amino acid sequence (SEQ ID NO: 124) QVQLQESGPGLLKPSDTLALTCTVSGGSITSDYWSWIRQPPGRGLDWIGFFYNGGST
KYNPSLKSRVTISADTSKNQLSLICLTSVTAADTGVYYCARHDVKFSGSYYVASWG
QGTRVTVS S
[130] 3243_J07 VL nucleotide sequence (SEQ ID NO: 125) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CTCTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTAAATTGGTATCAGCAGCAACCTGGGA
AAGCCCCTAAGGTCCTGATCTCTGGTGCAACCAACTTGCAAAGTGGGGTCCCATCTCGCTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGAGTTACAATACCCCCCTCATTTTTGGCCAGGGGACCAAGC
TGGAGATCAAACG
= [131] 3243_J07 VL amino acid sequence (SEQ ID NO: 126) DIQMTQSPSSLSASVGDRVTISCRASOSISTYLNWYQQQPGICAPKVLISGATNLOSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCOOSYNTPLIFGQGTKLEIK
[132] The 3259_121 antibody (also referred to herein as J21) includes a heavy chain variable region (SEQ ID NO: 128) encoded by the nucleic acid sequence shown below in SEQ ID NO: 127, and a light chain variable region (SEQ ID NO: 130) encoded by the nucleic acid sequence shown in SEQ ID NO: 129.
[133] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[134] The heavy chain CDRs of the J21 antibody have the following sequences per Kabat definition: SYNWI (SEQ ID NO: 203), HIYDYGRTFYNSSLQS (SEQ ID NO: 204) and PLGILHYYAMDL (SEQ ID NO: 205). The lighrehain CDRs of the J21 antibody have the following sequences per Kabat definition: RASQSIDKFLN (SEQ ID NO: 208), GASNLHS
(SEQ ID NO: 209) and QQSFSVPA (SEQ ID NO: 210).
[135] The heavy chain CDRs of the J21 antibody have the following sequences per Chothia definition: GGSISS (SEQ ID NO: 206), HIYDYGRTF (SEQ ID NO: 207) and PLGILHYYAMDL (SEQ ID NO: 205). The light chain CDRs of the J21 antibody have the following sequences per Chothia definition: RASQSIDKFLN (SEQ ID NO: 208), GASNLHS (SEQ ID NO: 209) and QQSFSVPA (SEQ ID NO: 210).
[136] 3259_J21 VH nucleotide sequence (SEQ ID NO: 127) CAGGTGCAGCTGCAGGAGTCGGGCCCACGAGTGGTGAGGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCGGGGGGCTCCATCAGTTCTTACAACTGGATTTGGATCCGGCAGCCCCCTG
GGAAGGGACTGGAGTGGATTGGGCACATATATGACTATGGGAGGACCTTCTACAACTCCTCC
CTCCAGAGTCGACCTACCATATCTGTAGACGCGTCCAAGAATCAGCTCTCCCTGCGATTGAC
CTCTGTGACCGCCTCAGACACGGCCGTCTATTACTGTGCGAGACCTCTCGGTATACTCCACT
ACTACGCGATGGACCTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[137] 3259_J21 VH amino acid sequence (SEQ ID NO: 128) QVQLQESGPRVVRPSETLSLTCTVSGGSISSYNWIWIRQPPGKGLEWIGHIYDYGRTF
YNSSLQSRPTISVDASKNQLSLRLTSVTASDTAVYYCARPLGILHYYAMDLWGQGT
TVTVSS
[138] 3259_J21 VL nucleotide sequence (SEQ ID NO: 129) GACATCCAGATGACCCAGTCTCCATTATCCGTGTCTGTATCTGTCGGGGACAGGGTCACCAT
CGCTTGCCGGGCAAGTCAGAGTATTGACAAGTTTTTAAATTGGTATCAGCAGAAACCAGGGA
AAGCCCCTAAACTCCTGATCTATGGTGCCTCCAATTTGCACAGTGGGGCCCCATCAAGGTTC
AGTGCCAGTGGGTCTGGGACAGACTTCACTCTAACAATCACCAATATACAGACTGAAGATTT
CGCAACTTACCTCTGTCAACAGAGTTTCAGTGTCCCCGCTTTCGGCGGAGGGACCAAGGTTG
AGATCA'AACG
:
[139] 3259_J21 VL amino acid sequence (SEQ_ID NO: 130) DIQMTQSPLSVSVSVGDRVTIACRASOSIDKANWYQQKPGKAPKWYGASNLHSG
APSRFSASGSGTDFTLTITNIQTEDFATYLCOOSFSVPAFGGGTKVEIK
[140] The 3245_019 antibody (also referred to herein as 019) includes a heavy chain variable region (SEQ ID NO: 132) encoded by the nucleic acid sequence shown below in SEQ ID NO: 131, and a light chain variable region (SEQ ID NO: 134) encoded by the nucleic acid sequence shown in SEQ ID NO: 133.
[141] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[142] The heavy chain CDRs of the 019 antibody have the following sequences per Kabat definition: STYMN (SEQ ID NO: 211), VFYSETRTYYADSVKG (SEQ ID NO: 212) and VQRLSYGMDV (SEQ ID NO: 213). The light chain CDRs of the 019 antibody have the 29 (' r t following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GASTLQS
(SEQ ID NO: 217) and QQTYSIPL (SEQ ID NO: 218).
[143] The heavy chain CDRs of the 019 antibody have the following sequences per Chothia definition: GLSVSS (SEQ ID NO: 214), VFYSETRTY (SEQ ID NO: 215) and VQRLSYGMDV (SEQ ID NO: 213). The light chain CDRs of the 019 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GASTLQS
(SEQ ID NO: 217) and QQTYSIPL (SEQ ID NO: 218).
[144] 3245_019 VH nucleotide sequence (SEQ I!) NO:131) GAGGTGCAACTGGTGGAGTCTGGAGGGGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC
CTGTACGGCCTCTGGGTTAAGTGTCAGTTCCACCTACATGAACTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGAATGGGTCTCAGTTTTTTATAGTGAGACCAGGACGTACTACGCAGACTCC
GTGAAGGGCCGATTCACCGTCTCCAGACACAATTCCAACAACACGCTCTATCTTCAGATGAA
CAGCCTGAGAGTTGAAGACACGGCCGTGTATTATTGTGCGAGAGTCCAGAGATTGTCGTACG
GTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[145] 3245_019 VH amino acid sequence (SEQ ID NO: 132) EVQLVESGGGLVQPGGSLRLSCTASGLSVSSTYMNWVRQAPGKGLEWVSVFYSET
RTYVADSVKGRFTVSRHNSNNTLYLQMNSLRVEDTAVYYCARVORLSYGMDVW
GQGTTVTVSS
[146] 3245_019 VL nucleotide sequence (SEQ ID NO: 133) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTAAATTGGTATCAGAAGAGACCAGGGA
AAGCCCCTAAACTCCTGGTCTATGGTGCATCCACTTTGCAGAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCGCCAGTCTGCAACCTGAAGATTC
TGCAACTTACTACTGTCAACAGACTTACAGTATCCCCCTCTTCGGCCAGGGGACACGGCTGG
AGATTAAACG
[147] 3245_019 VL amino acid sequence (SEQ ID N6: 134) DIQMTQSPSSLSASVGDRVTITCRASOSISTYLNWYQKRPGKAPKLLVYGASTLOSG
VPSRFSGSGSGTDFTLTIASLQPEDSATYYCQQTYSIPLFGQGTRLEIK
[148] The 3244_H04 antibody (also referred to herein as H04) includes a heavy chain variable region (SEQ ID NO: 136) encoded by the nucleic acid sequence shown below in SEQ ID NO: 135, and a light chain variable region (SEQ ID NO: 138) encoded by the nucleic acid sequence shown in SEQ ID NO: 137.
[149] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
=
µV.
e =

st. t v, 4 [150] The heavy chain CDRs of the H04 antibody have the following sequences per Kabat definition: STYMN (SEQ ID NO: 211), VFYSETRTYYADSVKG (SEQ ID NO: 212) and VQRLSYGMDV (SEQ ID NO: 213). The light chain CDRs of the H04 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GASSLQS
(SEQ ID NO: 226) and QQTYSIPL (SEQ ID NO: 218).
[151] The heavy chain CDRs of the H04 antibody have the following sequences per Chothia definition: GLSVSS (SEQ ID NO: 214), VFYSETRTY (SEQ ID NO: 215) and, VQRLSYGMDV (SEQ ID NO: 213). The light chain CDRs of the H04 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GASSLQS
(SEQ ID NO: 226) and QQTYSIPL (SEQ ID NO: 218).
[152] 3244_H04 VH nucleotide sequence (SEQ ID NO: 135) GAGGTGCAGCTGGTGGAATCTGGAGGGGGCTTGGICCAGCCTGGGGGGTCCCTGAGACTCTC
, CTGTACAGCCICTGGGTTAAGCGTCAGTTCCAC6TACATGAACTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGAATGGGICTCAGTITTTTATAGTGAAACCAGGACGTATTACGCAGACTCC
GTGAAGGGCCGATTCACCGTCTCCAGACACAATTCC:AACAACACGCTGTATCTTCAAATGAA
CAGCCTGAGAGCTGAAGACACGGCCGTGTATTATTGTGCGAGAGTCCAGAGACTGTCATACG
GTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[1531 3244_H04 VH amino acid sequence (SEQ ID NO: 136) EVQLVESGGGLVQPGGSLRLSCTASGLSVSSTYMNWVRQAPGKGLEWVSVFYSET
RTYYADSVKGRFTVSRHNSNNTLYLQMNSLRAEDTAVYYCARVORLSYGMDVW
GQGTTVTVSS
[154] 3244_H04 VL nucleotide sequence (SEQ ID NO: 137) GACATCCAGATGACCCAGTCTCCATCGTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTAAATTGGTATCAGAAGAGACCAGGGA
AAGCCCCTAAACTCCTGGTCTATGGTGCATCCAGTTTGCAGAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCGCCAGTCTGCAACCTGAAGATTC
TGCAGTTTATTACTGTCAACAGACTTACAGTATCCCCCTCTTCGGCCAGGGGACACGACTGG
AGATTAAACG
[155] 3244_H 4 VL amino acid sequence (SEQ-11D NO: 138) DIQMTQSPSSLSASVGDRVTITCRASOSISTYLNWYQKRPGKAPKLLVYGASSLQSG
VPSRFSGSGSGTDFTLTIASLQPEDSAVYYCOOTYSIPLFGQGTRLEIK
[156] The 3136_G05 antibody (also referred to hefein as G05) includes a heavy chain variable region (SEQ ID NO: 140) encoded by the nucleic acid sequence shown below in SEQ ID NO: 139, and a light chain variable region (SEQ ID NO: 142) encoded by the nucleic acid sequence shown in SEQ ID NO: 141.

[157] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991.are highlighted in bold in the sequences below. ;
[158] The heavy chain CDRs of the G05 antibodS, have the following sequences per Kabat definition: SDFWS (SEQ ID NO: 228), YVYNRGSt KYSPSLKS (SEQ ID NO: 229) and NGRSSTSWGIDV (SEQ ID NO: 230). The light chain CDRs of the 3136_G05 antibody have the following sequences per Kabat definition: RASQSISTYLH (SEQ ID NO:
233), AASSLQS (SEQ ID NO: 234) and QQSYSPPLT (SEQ ID NO: 63).
[1591 The heavy chain CDRs of the 3136_005 antibody have the following sequences per Chothia definition: GGSISS (SEQ ID NO: 206), YVYNRGSTK (SEQ ID NO: 232) and NGRSSTSWGIDV (SEQ ID NO: 230). The light chain CDRs of the 3136_G05 antibody have the following sequences per Chothia definition: RASQSISTYLH (SEQ ID NO:
233), AASSLQS (SEQ ID NO: 234) and QQSYSPPLT (SEQ ID NO: 63).
[160] 3136_005 VH nucleotide sequence (SEQ ID NO: 139) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCCTCGGAGACCCTGTCCCTCAC
CTGCAGTGTCTCTGGTGGCTCCATTAGTAGTGAT,tTCTGGAGTTGGATCCGACAGCCCCCAG
GGAAGGGACTGGAGTGGATTGGGTATGTCTATAACAGAGGGAGCACTAAGTACAGTCCCTCC
CTCAAGAGTCGAGTCACCATATCAGCAGACATGatCAAGAACCAGTTTTCCCTGAATATGAG
TTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAAAATGGTCGAAGTAGCACCA
GTTGGGGCATCGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCGAGC
[161] 3136_015 VH amino acid sequence (SEQ ID NO: 140) QVQLQESGPGLVKPSETLSLTCSVSGGSISSDFWSWIRQPPGKGLEWIGYVYNRGST
KYSPSLKSRVTISADMSKNQFSLNMSSVTAADTAVYYCAKNGRSSTSWGIDVWGK
GTTVTVSS
[162] 3136_GO5 VL nucleotide sequence (SEQ ID NO: 141) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGACTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTACATTGGTATCAGCAGAAACCAGGGA
AAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTAGATCAGGAACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGATGACTT
TGCAACTTACTACTGTCAACAGAGTTACAGTCCCCCCCTCACTTTCGGCCCTGGGACCAAAG
TGGATATGAAACG
[163] 3136_G05 VL amino acid sequence (SEQ ID NO: 142) DIQMTQSPSSLSASVGDRLTITCRASOSISTYLHWYQQKPGKAPI(LLIYAASSLQSGV
PSRFSGSRSGTDFTLTISSLQPDDFATYYCOOSVSPPLTFGPGTKVDMK
=

[164] The 3252_C13 antibody (also referred to herein as C13) includes a heavy chain variable region (SEQ ID NO: 144) encoded by the nucleic acid sequence shown below in SEQ ID NO: 143, and a light chain variable region (SEQ ID NO: 146) encoded by the nucleic acid sequence shown in SEQ ID NO: 145.
[165] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991.are highlighted in bold in the sequences below.
[166] The heavy chain CDRs of the C13 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), YIYNRGSTKYTPSLKS (SEQ ID NO: 237) and HVGGHTYGIDY (SEQ ID NO: 238). The light chain CDRs of the C13 antibody have the following sequences per Kabat definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
(SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
[167] The heavy chain CDRs of the C13 antibody have the following sequences per Chothia definition: GASISS (SEQ ID NO: 239), YIYNRGSTK (SEQ ID NO: 240) and HVGGHTYGIDY (SEQ ID NO: 238). The light chain CDRs of the C13 antibody have the following sequences per Chothia definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
(SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
[168] 3252_C13 VH nucleotide sequence (SEQ ID NO: 143) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACtGGTGAAGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTGCCTCCATCAGTAGTGACTACTGGAGCTGGATCCGGCTGCCCCCAG
GGAAGGGACTGGAGTGGATTGGGTATATCTATAA;TAGAGGGAGTACCAAGTACACCCCCTCC
CTGAAGAGTCGAGTCACCATATCACTAGACACGGCCGAGAACCAGTTCTCCCTGAGGCTGAG
GTCGGTGACCGCCGCAGACACGGCCATCTATTAcTGTGCGAGACATGTAGGTGGCCACACCT
ATGGAATTGATTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
[169] 3252_C13 VH amino acid sequence (SEQ ID NO: 144) QVQLQESGPGLVKPSETLSLTCTVSGASISSDYWSWIRLPPGKGLEWIGYIYNRGSTK
YTPSLKSRVTISLDTAENQFSLRLRSVTAADTAIYYCARHVGGHTYGIDYWGQGTL
VTVSS
[170] 3252_C13 VL nucleotide sequence (SEQ ID NO: 145) GACATCCAGATGACCCAGTCTCCATCGTCCCTGTCTGCCTCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCAACTAT TAAATTGGTATCAACACAAACCTGGGG
AAGCCCCCAAGCTCCTGAACTATGCTGCGTCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGCCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTTCAACCTGAAGATTT
TGCCACTTACTACTGTCAACAGAGTTACAATACTCCGATCACCTTCGGCCAAGGGACACGAC
TGGAAATTAAACG

,;%;

- =

[171] 3252_C13 VL amino acid sequence (SEQ ID NO: 146) DIQMTQSPSSLSASVGDRVTITCRASOSISNYLNWYQHKPGEAPKLLNYAASSLOSG
VPSRFSASGSGTDFTLTISSLQPEDFATYYCOOSYNTPITFGQGTRLEIK
[172] The 3259_J06 antibody (also referred to herein as J06) includes a heavy chain variable region (SEQ ID NO: 148) encoded by the nucleic acid sequence shown below in SEQ ID NO: 147, and a light chain variable region (SEQ ID NO: 150) encoded by the nucleic acid sequence shown in SEQ ID NO: 149.
[173] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below., [174] The heavy chain CDRs of the J06 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), YIYNRGSTKYT,PSLKS (SEQ ID NO: 237) and HVGGHTYGIDY (SEQ ID NO: 238). The light chain CDRs of the J06 antibody have the following sequences per Kabat definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
(SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
[175] The heavy chain CDRs of the J06 antibody have the following sequences per Chothia definition: GASISS (SEQ ID NO: 239), YIYNRGSTK (SEQ ID NO: 240) and HVGGHTYGIDY (SEQ ID NO: 238). The light chain CDRs of the J06 antibody have the following sequences per Chothia definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
(SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
[176] 3255_106 VH nucleotide sequence (SEQ ID NO: 147) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTGCCTCCATCAGTAGTGACTACTGGAGCTGGATCCGGCTGCCCCCAG
GGAAGGGACTGGAGTGGATTGGGTATATCTATAATAGAGGGAGTACCAAGTACACCCCCTCC
CTGAAGAGTCGAGTCACCATATCACTAGACACGGCCGAGAACCAGTTCTCCCTGAGGCTGAG
GICGGTGACCGCCGCAGACACGGCCGICTATTACiGTGCGAGACATGTGGGTGGCCACACCT
ATGGAATTGATTACTGGGGCCAGGGAACCCTGGT,CACCGTCTCGAGC
[177] 3255_106 VH amino acid sequence (SEQ ID NO: 148) QVQLQESGPGLVKPSETLSLTCTVSGASISSDYWSWIRLPPGKGLEWIGYIYNRGSTK
YTPSLKSRVTISLDTAENQFSLRLRSVTAADTAVYYCARHVGGHTYGIDYWGQGT
LVTVSS

=
[178] 3255_J06 VL nucleotide sequence (SEQ ID NO: 149) GACATCCAGATGACCCAGTCTCCATCGTCCCTGTCTGCCTCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCAACTATriAAATTGGTATCAACACAAACCTGGGG
AAGCCCCCAAGCTCCTGAACTATGCTGCGTCCAGTT.TGCAAAGTGGGGTCCCATCAAGGTTC
AGTGCCAGTGGATCTGGGACAGATTTCACTCTCAGCATCAGCGGTCTTCAACCTGAAGATTT
TGCCACTTACTACTGTCAACAGAGCTACAATACTCCGATCACCTTCGGCCCAGGGACACGAC
TGGAAATTAAACG
=
[179] 3255_J06 VL amino acid sequence (SEQ ID NO: 150) DIQMTQSPSSLSASVGDRVTITCRASOSISNYLNWYQHKPGEAPI(LLNYAASSLOSG
VPSRFSASGSGTDFTLSISGLQPEDFATYYCOOSYNTPITFGPGTRLEIK
[180] The 3410_123 antibody (also referred to herein as 123) includes a heavy chain variable region (SEQ ID NO: 152) encoded by the nucleic acid sequence shown below in SEQ ID
NO: 151, and a light chain variable region (SEQ ID NO: 154) encoded by the nucleic acid sequence shown in SEQ ID NO: 153.
[181] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991. are highlighted in bold in the sequences below., =
, [182] The heavy chain CDRs of the 3410_123 antibody have the following sequences per Kabat definition: SYSWS (SEQ ID NO: 252), YLYYSGSTKYNPSLKS (SEQ ID NO: 253) and TGSESTTGYGMDV (SEQ ID NO: 254). The light chain CDRs of the 3410_123 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ
ID NO:
192), AASSLHS (SEQ ID NO: 258) and QQSYSPPIT (SEQ ID NO: 259).
[183] The heavy chain CDRs of the 3410_123 antibody have the following sequences per Chothia definition: GDSISS (SEQ ID NO: 255), YLYYSGSTK (SEQ ID NO: 256) and TGSESTTGYGMDV (SEQ ID NO: 254). The light chain CDRs of the 3410_123 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO:
192), AASSLHS (SEQ ID NO: 258) and QQSYSPPIT (SEQ ID NO: 259).
[184] 3420_123 VH nucleotide sequence (SEQ ID NO: 151) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCGTCAC
CTGCAAAGTCTCTGGTGACTCCATCAGTAGTTATTCCTcGAGCTGGATCCGGCAGCCCCCAG
GGAAGGGACTGGAGTGGGTTGGCTATTTGTATTA'fAGTGGGAGCACCAAGTACAACCCCTCC
CTCAAGAGTCGAACCACCATATCAGTAGACACGTCCACGAACCAGTTGTCCCTGAAGTTGAG
TTTTGTGACCGCCGCGGACACGGCCGTGTATTTCTGTGCGAGAACCGGCTCGGAATCTACTA
CCGGCTACGGTATGGACGTCTGGGGCCAAGGGA'alCACGdTCACCGTCTCGAGC

[185] 3420_123 VH amino acid sequence (SEQ ID NO: 152) QVQLQESGPGLVKPSETLSVTCKVSGDSISSYSWSWIRQPPGKGLEWVGYLYYSGST
KYNPSLKSRTTISVDTSTNQLSLKLSFVTAADTAVYFCARTGSESTTGYGMDVWGQ
GTI'VTVSS
' [186] 3420_123 VL nucleotide sequence (SEQ ID NO: 153) =
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCACeTATTTAAXTTGGTATCAGCAGAAACCAGGGA
AAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGT TGCACAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCGCTCTCACCATCAGCAGTCTGCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGAGTTACAGTCCCCCGATCACCTTCGGCCAAGGGACACGAC
TGGAGATTAAACG
[187] 3420_123 VL amino acid sequence (SEQ ID NO: 154) DIQMTQSPSSLSASVGDRVTITCRASOSISTYLNVVYQQKPGKAPKLLIYAASSLHSG
VPSRFSGSGSGTDFALTISSLQPEDFATYYCOOSYSPPITFGQGTRLEIK
[188] The 3139_P23 antibody (also referred to herein as P23) includes a heavy chain variable region (SEQ ID NO: 156) encoded by the nucleic acid sequence shown below in SEQ ID NO: 155, and a light chain variable region (SEQ ID NO:158) encoded by the nucleic acid sequence shown in SEQ ID NO:157.
[189] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences ' below.
[190] The heavy chain CDRs of the P23 antibody have the following sequences per Kabat -definition: NSFWG (SEQ ID NO: 260), YVYNSGNTKYNPSLKS (SEQ ID NO: 261) and HDDASHGYSIS (SEQ ID NO: 262). The light chain CDRs of the 3139_P23 antibody have the following sequences per Kabat definition: RASQTISTYLN (SEQ ID NO: 265), AASGLQS (SEQ ID NO: 61) and QQSYNTPLT (SEQ ID NO: 267).
[191] The heavy chain CDRs of the 3139_P23 antibody have the following sequences per Chothia definition: GGSISN (SEQ ID NO: 263), YVYNSGNTK (SEQ ID NO: 264) and HDDASHGYSIS (SEQ ID NO: 262). The light chain CDRs of the 3139_P23 antibody have the following sequences per Chothia definition: RASQTISTYLN (SEQ ID NO: 265), AASGLQS (SEQ ID NO: 61) and QQSYNTPLT (SEQ ID NO: 267).
36 f, [192] 3139_P23 VH nucleotide sequence (SEQ ID NO: 155) CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGAAGCCTTCGGAGAGCCTGTCCCTCAC
CTGCACTGTCTCTGGTGGCTCCATTAGTAATTCCTTCTGGGGCTGGATCCGGCAGCCCCCAG
GGGAGGGACTGGAGTGGATTGGTTATGTCTATAACAGTGGCAACACCAAGTACAATCCCTCC
CTCAAGAGTCGAGTCACCATTTCGCGCGACACGTCCAAGAGTCAACTCTACATGAAGCTGAG
GTCTGTGACCGCCGCTGACACGGCCGTGTACTACTGTGCGAGGCATGACGACGCAAGTCATG
GCTACAGCATCTCCTGGGGCCACGGAACCCTGGTCACCGTCTCGAGC
[193] 3139_P23 VH amino acid sequence (SEQ ID NO: 156) QVQLQESGPRLVICPSESLSLTCTVSGGSISNSFWGWIRQPPGEGLEWIGYVYNSGNT
KYNPSLKSRVTISRDTSKSQLYMKLRSVTAADTAV,YYCARHDDASHGYSISWGHG
TLVTVSS
[194] 3139_P23 VL nucleotide sequence (SEQ:ID NO: 157) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGGGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGACCATTAGTACTTATTTAAATTGGTATCAACAGAAATCAGGGA
AAGCCCCTAAGCTCCTGATCTATGCTGCATCCGGTTTGCAAAGTGGAGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTTCAACCTGAAGATTT
TGCAACTTACTTCTGTCAACAGAGTTACAATACTCCCCTGACGTTCGGCCAAGGGACCAAGG
TGGAAATCAAA
[195] 3139_P23 VL amino acid sequence (SEQ ID NO: 158) DIQMTQSPSSLSASVGDRVTITCRASOTISTYLNWYQQKSGKAPKLLIYAASGLOSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCOOSYNTPLTFGQGTKVEIK
[196] The 3248_P18 antibody (also referred to herein as P18) includes a heavy chain variable region (SEQ ID NO: 160) encoded by the nucleic acid sequence shown below in SEQ ID NO: 159, and a light chain variable region (SEQ ID NO: 162) encoded by the nucleic acid sequence shown in SEQ ID NO: 161.
[197] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991-are highlighted in bold in the sequences below.
[1981 The heavy chain CDRs of the 3248_P1 8 antibOdy have the following sequences per Kabat definition: AYHWS (SEQ ID NO: 268), HIFDSGSTYYNPSLKS (SEQ ID NO: 269) and PLGSRYYYGMDV (SEQ ID NO: 270). The light chain CDRs of the 3248_P18 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ
ID NO:
273), GASTLQN (SEQ ID NO: 274) and QQSYSVPA (SEQ ID NO: 275).
[199] The heavy chain CDRs of the 3248_P18 antibody have the following sequences per Chothia definition: GGSISA (SEQ ID NO: 271), HIFDSGSTY (SEQ ID NO: 272) and PLGSRYYYGMDV (SEQ ID NO: 270). The light chain CDRs of the 3248_P18 antibody =

=

=
have the following sequences per Chothia definition::RASQSISRYLN (SEQ ID NO:
273), GASTLQN (SEQ ID NO: 274) and QQSYSVPA (SEQ ID NO: 275).
[200] 3248_P18 VH nucleotide sequence (SEQ ID NO: 159) CAGGTGCAACTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCAC
CTGCACTGTCTCGGGTGGCTCCATCAGTGCTTACCACTGGAGCTGGATCCGCCAGCCCCCAG
GGAAGGGACTGGAGTGGATTGGGCACATCTTTGACAGTGGGAGCACTTACTACAACCCCTCC
CTTAAGAGTCGAGTCACCATATCACTAGACGCGTCCAAGAACCAGCTCTCCCTGAGATTGAC
CTCTGTGACCGCCTCAGACACGGCCATATATTACTGTGCGAGACCTCTCGGGAGTCGGTACT
ATTACGGAATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[201] 3248_P18 VH amino acid sequence (SEQ ID NO: 160) QVQLQESGPGLVKPSETLSLICTVSGGSISAYHWSWIRQPPGKGLEWIGHIFDSGST
YYNPSLKSRVTISLDASKNQLSLRLTSVTASDTAIYYCARPLGSRYYYGMDVWGQG
TTVTVSS
[202] 3248_P18 VL nucleotide sequence (SEQ ID NO: 161) GACATCCAGATGACCCAGTCTCCGTCCTCCCTGTCTGCATCTGTCGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGTATTAGCAGGTATTTAAATTGGTATCAGCAGAAACCAGGGA
AAGCCCCTAAGCTCCTGATCTATGGTGCCTCCACTTTGCAAAATGGGGCCCCATCAAGGTTC
AGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTACAACCTGAAGATTC
CGCAACTTACCTCTGTCAACAGAGTTACAGTGTCCCTGCTTTCGGCGGAGGAACCAAGGTGG
AGGTCAAA
[203] 3248_P18 VL amino acid sequence (SEQ ID NO: 162) DIQMTQSPSSLSASVGDRVTITCRASOSISRYLNWYQQKPGKAPKWYGASTLONG
APSRFSGSGSGTDFTLTISSLQPEDSATYLCOOSYSVPAFGGGTKVEVK
[204] The 3253_P10 antibody (also referred to herein as P10) includes a heavy chain variable region (SEQ ID NO: 164) encoded by the nucleic acid sequence shown below in SEQ ID NO: 163, and a light chain variable region (SEQ ID NO: 166) encoded by the nucleic acid sequence shown in SEQ ID NO: 165.
[205] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below. L, [206] The heavy chain CDRs of the 3253_P10 antibody`have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187),,FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and HDAKFSGSYYVAS (SEQ ID NO: 189). The light chain CDRs of the 3253_P10 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ
ID NO:
192), GATDLQS (SEQ ID NO: 282) and QQSYNTPLI (SEQ ID NO: 194).

=

[207] The heavy chain CDRs of the 3253_P10 antibody have the following sequences per Chothia definition: GGSITS (SEQ ID NO: 190), FFYNGGSTK (SEQ ID NO: 191) and HDAKFSGSYYVAS (SEQ ID NO: 189). The light chain CDRs of the 3253_P10 antibody have the following sequences per Chothia definition:.RASQSISTYLN (SEQ ID NO:
192), GATDLQS (SEQ ID NO: 282) and QQSYNTPLI (SEQ ID NO: 194).
[208] 3253_P10 VH nucleotide sequence (SEQ-ID NO: 163) CAGGTCCAGCTGCAGGAGTCGGGCCCAGGACTGCTGAAGCCTTCGGACACCCTGGCCCTCAC
TTGCACTGTCTCTGGTGGCTCCATCACCAGTGACTACTGGAGCTGGATCCGGCAACCCCCAG
GGAGGGGACTGGACTGGATCGGATTCTTCTATAACGGCGGGAGCACCAAGTACAATCCCTCC
CTCAAGAGTCGAGTCACCATATCAGCGGACACGTCCAAGAACCAGTTGTCCCTGAAATTGAC
CTCTGTGACCGCCGCAGACACGGGCGTGTATTATTGTGCGAGACATGATGCCAAATTTAGTG
GGAGCTACTACGTTGCCTCCTGGGGCCAGGGAACCCGAGTCACCGTCTCGAGC
[209] 3253_P10 VH amino acid sequence (SEQ ID NO: 164) QVQLQESGPGLIKPSDTLALTCTVSGGSITSDYWSWIRQPPGRGLDWIGFFYNGGST
KYNPSLKSRVTISADTSKNQLSLKLTSVTAADTGVYYCARHDAKFSGSYYVASWG
QGTRVTVSS
[210] 3253_P10 VL nucleotide sequence (SEQ ID NO: 165) GACATCCAGATGACCCAGTCTCCCTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CTCTTGCCGGGCAAGTCAGAGCATTAGCACCTATTTAAATTGGTATCAGCAGCAACCTGGGA
AAGCCCCTAAGGTCCTGATCTCTGGTGCAACCGACTTGCAAAGTGGGGTCCCATCTCGCTTC
AGTGGCAGIGGATCTGGGACAGATTTCACTCTCAC,CATCAGCAGTCTGCAACCTGAAGATTT
TGCAACTTACTACTGICAACAGAGTTACAATAC6dCCCT.CATTTTTGGCCAGGGGACCAAGC
TGGAGATCAAA
[211] 3253_P10 VL amino acid sequence (SEQ ID NO: 166) DIQMTQSPSSLSASVGDRVTISCRASOSISTYLNVVYQQQPGKAPKVLISGATDLOSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCOOSYNTPLIFGQGTKLEIK
[212] The 3260_D19 antibody (also referred to herein as D19) includes a heavy chain variable region (SEQ ID NO: 168) encoded by the nucleic acid sequence shown below in SEQ ID NO: 167, and a light chain variable region (SEQ ID NO: 170) encoded by the nucleic acid sequence shown in SEQ ID NO: 169.
[213] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
f 39 1.

[214] The heavy chain CDRs of the 3260_D19 antibody have the following sequences per Kabat definition: DNYIN (SEQ ID NO: 284), VFYSADRTSYADSVKG (SEQ ID NO: 285) and VQKSYYGMDV (SEQ ID NO: 286). The light chain CDRs of the 3260_D19 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO:
273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ ID NO: 291).
[215] The heavy chain CDRs of the 3260_D19 antibody have the following sequences per Chothia definition: GFSVSD (SEQ ID NO: 287), VFYSADRTS (SEQ ID NO: 288) and VQKSYYGMDV (SEQ ID NO: 286). The light chain CDRs of the 3260_D19 antibody have the following sequences per Chothia definition: RASQSISRYLN (SEQ ID NO: 273), .
GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ'ID NO: 291).
[216] 3260_D19 VH nucleotide sequence (SEQ ID NO: 167) GACATGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCCGCCGGGGGGGTCCCTGAGACTCTC
CTGCGCAGCCTCTGGGTTTTCCGTCAGTGACAACTACATAAACTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGACTGGGTCTCAGTCTTTTATAGTGCTGATAGAACATCCTACGCAGACTCC
GTGAAGGGCCGATTCACCGTCTCCAGCCACGATTCCAAGAACACAGTGTACCTTCAAATGAA
CAGTCTGAGAGCTGAGGACACGGCCGTTTATTACTGTGCGAGAGTTCAGAAGTCCTATTACG
GTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[217] 3260_D19 VH amino acid sequence (SEQ ID NO: 168) DMQLVESGGGLVPPGGSLRLSCAASGFSVSDNYINWVRQAPGKGLDWVSVFYSADRTSYADS
VKGRFTVSSHDSKNTVYLQMNSLRAEDTAVYYCARVQKSYYGMDVWGQGTTVTVSS
[218] 3260_D19 VL nucleotide sequence (SEQ ID NO: 169) =
GGCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCAGATATTTAAATTGGTATCTGCAGAAACCAGGGA
AAGCCCCTAAGCTCCTGATCTCTGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCACTGGGTCTGGGACAGAATTCACTCTCACCATCAGCAGTTTGCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGACTTTCAGTATCCCTCTTTTTGGCCAGGGGACCAAGGTGG
AGATCAAA
[219] 3260_D19 VL amino acid sequence (SEQ ID NO: 170) GIQMTQSPSSLSASVGDRVTITCRASOSISRYLNWYLQI(PGKAPKLLISGASSLOSGV
PSRFSGTGSGTEFTLTISSLQPEDFATYYCOOTFSIPLFGQGTKVEIK
[220] The 3362_B11 antibody (also referred to herein as B11) includes a heavy chain variable region (SEQ ID NO: 172) encoded by the nucleic acid sequence shown below in SEQ ID NO: 171, and a light chain variable region (SEQ ID NO: 174) encoded by the nucleic acid sequence shown in SEQ ID NO: 173.
= , =
, =PCT/US2012/024971 [221] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[222] The heavy chain CDRs of the B11 antibody have the following sequences per Kabat definition: SGAYYWT (SEQ ID NO: 293), YIYYSGNTYYNPSLKS (SEQ ID NO: 294) and AASTSVLGYGMDV (SEQ ID NO: 295). The light chain CDRs of the B I I antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO: 273), AASSLQS (SEQ ID NO: 234) and QQSYSTPLT (SEQ ID NO: 300).
[223] The heavy chain CDRs of the B11 antibody have the following sequences per Chothia definition: GDSITSGA (SEQ ID NO: 296), YIYYSGNTY (SEQ ID NO: 297) and AASTSVLGYGMDV (SEQ ID NO: 295). The light chain CDRs of the B11 antibody have the following sequences per Chothia definition: RASQSISRYLN (SEQ ID NO.: 273), AASSLQS (SEQ ID NO: 234) and QQSYSTPLT (SEQ ID NO: 300).
[224] 3362_B11 VH nucleotide sequence (SEQ ID NO: 171) CAGGTGCAGCTGCAGGCGTCGGGCCCAGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCAC
CTGCACTGTCTCTGGTGACTCCATCACCAGTGGTGCTTACTACTGGACCTGGATCCGCCAGC
ACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAACACCTACTACAAC
CCGTCCCTCAAGAGTCGAGTTACCATATCACTAGACACGTCTAAGAACCAGTTCTCCCTGAA
GGTGAACTCTGTGACTGCCGCGGACACGGCCGTATATTACTGTGCGCGAGCTGCTTCGACTT
CAGTGCTAGGATACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[225] 3362_B11 VH amino acid sequence (SEQ ID NO: 172) QVQLQASGPGLVKPSETLSLTCTVSGDSITSGAYYWTWIRQHPGKGLEWIGYIYYSG
NTYYNPSLKSRVTISLDTSKNQFSLKVNSVTAADTAVYYCARAASTSVLGYGMDV
WGQGTTVTVSS
[226] 3362_B11 VL nucleotide sequence (SEQ ID NO: 173) =
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
CACTTGCCGGGCAAGTCAGAGCATTAGCAGATATTTAAATTGGTATCAGCAGGAACCAGGGA
AGGCCCCTAAGCTCCTGGTCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACdATAAGCAGTCTTCAACCTGAAGATTT
TGCAACTTACTACTGTCAACAGAGTTATAGTACCCCCCTCACCTTCGGCCAAGGGACACGAC
TGGAGATTAAA
[227] 3362_B11 VH amino acid sequence (SEQ ID NO: 174) DIQMTQSPSSLSASVGDRVTITCRASOSISRYLNWYQQEPGKAPKLLVYAASSLOSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCOOSYSTPLTFGQGTRLEIK

õ .
[228] The 3242_P05 antibody (also referred to herein as P05) includes a heavy chain variable region (SEQ ID NO: 176) encoded by the nucleic acid sequence shown below in SEQ ID NO: 175, and a light chain variable region (SEQ ID NO: 178) encoded by the nucleic acid sequence shown in SEQ ID NO: 177.
= [229] The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
[230] The heavy chain CDRs of the 3242_P05 antibody have the following sequences per Kabat definition: VSDNYIN (SEQ ID NO: 301), VFYSADRTSYADSVKG (SEQ ID NO:
285) and VQKSYYGMDV (SEQ ID NO: 286). The light chain CDRs of the 3242_P05 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ
ID NO:
273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ ID NO: 291).
[231] The heavy chain CDRs of the 3242_P05 antibody have the following sequences per Chothia definition: SGFSV (SEQ ID NO: 304), VFYSADRTS (SEQ ID NO: 288) and VQKSYYGMDV (SEQ ID NO: 286). The light chain CDRs of the 3242_P05 antibody have the following sequences per Chothia definition: Tlie light chain CDRs of the 3242_P05 antibody have the following sequences per Kabatidehriiiio'n: RASQSISRYLN (SEQ
ID NO:
273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL-(SEQ ID NO: 291).
= [232] 3242_P05 VH nucleotide sequence (SEQ ID NO: 175) GACATGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCCGCCGGGGGGGTCCCTGAGACTCTC
CTGCGCAGCCTCTGGGTTTTCCGTCAGTGACAACTACATAAACTGGGTCCGCCAGGCTCCAG
GGAAGGGGCTGGACTGGGTCTCAGTCTTTTATAGTGCTGATAGAACATCCTACGCAGACTCC
GTGAAGGGCCGATTCACCGTCTCCAGCCACGATTCCAAGAACACAGTGTACCTTCAAATGAA
CAGTCTGAGAGCTGAGGACACGGCCGTTTATTACTGTGCGAGAGTTCAdAAGTCCTATTACG
GTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
[233] 3242_P05 VH amino acid sequence (SEQ ID NO: 176) DMQLVESGGGLVPPGGSLRLSCAASGFSVSDNYINWVRQAPGKGLDWVSVFYSAD
RTSYADSVKGRFTVSSHDSKNTVYLQMNSLRAEDTAVYYCARVOKSYYGMDVW
GQGTTVTVSS
[234] 3242_P05 VL nucleotide sequence (SEQ ID NO: 177) GGCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT
= CACTTGCCGGGCAAGTCAGAGCATTAGCAGATATTIAMTTGGTATCTGCAGAAACCAGGGA
AAGCCCCTAAGCTCCTGATCTCTGGTGCATCCAUTTGCAAAGTGGGGTCCCATCAAGGTTC
AGTGGCACTGGGTCTGGGACAGAATTCACTCTCACCATCAGCAGTTTGCAACCTGAAGATTT

TGCAACTTACTACTGTCAACAGACTTTCAGTATCCCTCTTTTTGGCCAGGGGACCAAGGTGG
AGATCAAA
[235] 3242_P95 VL amino acid sequence (SEQ ID NO: 178) GIQMTQSPSSLSASVGDRVTITCRASOSISRYLNWYLQKPGIKAPKLLISGASSLOSGV
PSRFSGTGSGTEFTLTISSLQPEDFATYYCOOTFSIPLFGQGTKVEIK
, [236] HuM2e antibodies of the invention also include antibodies that include a heavy chain variable amino acid sequence that is at least 90%, -92%, 95%, 97% 98%, 99% or more identical the amino acid sequence of SEQ ID NO: 44, 277, 276, 50, 236, 235, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, or 176. and/or a light chain variable amino acid that is at least 90%, 92%, 95%, 97% 98%, 99% or more identical the amino acid sequence of SEQ ID NO: 46, 52, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178.
[237] Alternatively, the monoclonal antibody is an antibody that binds to the same epitope as TCN-032 (8110), 21B15, TCN-031 (23K12), 3241_G23, 3244_110, 3243_107, 3259_121, 3245_019, 3244_H04, 3136_G05, 3252_C13, 3255J06, 3420_123, 3139323, 3248318, 3253_P10, 3260_D19, 3362_B11, or 3242_P05.
[238] The heavy chain of a M2e antibody is derived from a germ line V
(variable) gene such as, for example, the 1gHV4 or the IgHV3 germline gene.
[239] The M2e antibodies of the invention include.,a variable heavy chain (VH) region encoded by a human IgHV4 or the IgHV3 germline gene sequence. An IgHV4 germline gene sequence is shown, e.g., in Accession numbersi1e0188, M29812, M95114, X56360 and M95117. An IgHV3 germline gene sequence is shoWn, e.g., in Accession numbers X92218, X70208, Z27504, M99679 and AB019437. The M2e antibodies of the invention include a VH
region that is encoded by a nucleic acid sequence that is at least 80%
homologous to the IgHV4 or the IgHV3 germline gene sequence. Preferably, the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgHV4 or the IgHV3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgHV4 or the IgHV3 germline gene sequence. The VH region of the M2e antibody is at least 80% homologous to the amino acid sequence of the VH region encoded by the IgHV4 or the IgHV3 VH germline gene sequence. Preferably, the amino acid sequence of VH region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgHV4 or the 43 .

IgHV3 germline gene sequence, and more preferably, at least 98%, 99%
homologous to the sequence encoded by the IgHV4 or the IgHV3 germline gene sequence.
The M2e antibodies of the invention also include a variable light chain (VL) region encoded by a human IgKV1 germline gene sequence. A human IgKV1 VL germline gene sequence is shown, e.g., Accession numbers X59315, X59312, X59318, J00248, and Y14865.
Alternatively, the M2e antibodies include a VL region that is encoded by a nucleic acid sequence that is at least 80% homologous to the IgKV I germline gene sequence.
Preferably, the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgKV1 germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgKV1 germline gene sequence. The VL region of the M2e antibody is at least 80%
homologous to the amino acid sequence of the VL region encoded_the IgKV1 germline gene sequence.
Preferably, the amino acid sequence of VL region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgKV1 germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by e the IgKV1 germline gene sequence.
HA Antibodies I
[240] The HA antibodies of the invention may also be capable of specifically binding to one or more fragments of influenza virus H5N1, such as the surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which are required for viral attachment and cellular release, or membrane proteins (M1 and M2). In a specific embodiment, the HA antibodies of the invention are capable of specifically binding to the HA molecule of H5N1 strains. They may be capable of specifically binding to the HAI and/or HA2 subunit of the HA
molecule. They may be capable of specifically binding to linear or siru. aural and/or conformational epitopes on the HAI and/or HA2 subunit of the HA molecule. The HA molecule may be purified from viruses or recombinantly produced and optionally isolated before use.
Alternatively, HA may be expressed on the surface of cells.
[241] For diagnostic purposes, the HA antibodies may also be capable of specifically binding to proteins not present on the surface of H5N1 including the nucleoprotein, the nucleocapsid structural protein, polymerases (PA, PB and PB2), and non-structural proteins (NS1 and NS2). The nucleotide and/or amino acid sequence of proteins of various H5N1 strains can be found in the GenBank-database, NCBI Influenza Virus Sequence Database, =
,t; t Influenza Sequence Database (ISD), EMBL-database and/or other databases. It is well within the reach of the skilled person to find such sequences in the respective databases.
In another embodiment the HA antibodies of the invention are capable of specifically binding to a fragment of the above-mentioned proteins and/or polypeptides, wherein the fragment at least includes an antigenic determinant recognized by the HA antibodies of the invention. An "antigenic determinant" as used herein is a moiety that is capable of binding to an HA
antibody of the invention with sufficiently high affinity to form a detectable antigen-antibody complex. As used herein, the terms "antigenic determinant" and "epitope" are equivalents.
The HA antibodies of the invention may or may not be capable of specifically binding to the extracellular part of HA (also called herein soluble HA (sHA)).
[242] The HA antibodies of the invention can be intact immunoglobulin molecules such as polyclonal or monoclonal antibodies or the HA antibodies can be antigen-binding fragments including, but not limited to, Fab, F(ab'), F(ab')2, Fv, dAb, Fd, complementarity determining region (CDR) fragments, single-chain antibodies (saFv), bivalent single-chain antibodies, single-chain phage antibodies, diabodies, triabodies, tetrabodies, and (poly)peptides that contain at least a fragment of an immunoglobulin that is sufficient to confer specific antigen binding to influenza virus H5N1 strains or a fragment thereof. In a preferred embodiment the HA antibodies are human monoclonal antibodies.
[243] HA antibodies can be used in non-isolated or isolated form. Furthermore, the HA
antibodies can be used alone or in a mixture including at least one HA
antibody (or variant or fragment thereof). Thus, HA antibodies can be used in-combination, e.g., as a pharmaceutical composition comprising two or more antibodies of the invention, variants or fragments thereof. For example, antibodies having different, but complementary activities can be combined in a single therapy to achieve a desired prophylactic, therapeutic or diagnostic effect, but alternatively, antibodies having identical activities can also be combined in a single therapy to achieve a desired prophylactic, therapeutic or diagnostic effect. Optionally, the mixture further includes at least one other therapeutic agent.
Preferably, the therapeutic agent such as, e.g., M2 inhibitors (e.g., amantidine, rimantadine) -and/or neuraminidase inhibitors (e.g., zanamivir, oseltamivir) is useful in the prophylaxis and/or treatment of an influenza virus H5N1 infection. = ' Ai.;
=
[244] Typically, HA antibodies can bind to their binding-partners, i.e.
influenza virus H5N1 or fragments thereof, with an affinity constant (Kd-vlue) that is lower than 0.2x10-4 M, 1.0x10-5 M, 1 .0X 10-6 M, 1 .0X 1 0-7 M, preferably lower than 1.0x10-8 M, more preferably lower than 1.0x1(19 M, more preferably lower than 1.0x10 10 M, even more preferably lower than 1.0x10-I I M, and in particular lower than 1.0x10-12 M. The affinity constants can vary for antibody isotypes. For example, affinity binding foi an IgM isotype refers to a binding affinity of at least about 1.0x10-7M. Affinity constants can for instance be measured using surface plasmon resonance, for example usinOhe BIACORE system (Pharmacia Biosensor AB, Uppsala, Sweden).
[245] HA antibodies may bind to influenza virus H5N1 or a fragment thereof in soluble form such as for instance in a sample or in suspension or may bind to influenza virus H5N1 or a fragment thereof bound or attached to a carrier or substrate, e.g., microtiter plates, membranes and beads, etc. Carriers or substrates may be made of glass, plastic (e.g., polystyrene), polysaccharides, nylon, nitrocellulose, or Teflon, etc. The surface of such supports may be solid or porous and of any convenient shape. Furthermore, the HA
antibodies may bind to influenza virus H5N1 in purified/isolated or non purified/non-isolated form.
[2461 HA antibodies exhibit neutralizing activity. Neutralizing activity can for instance be measured as described in International Patent Application PCT/EP2007/059356 (Publication No. WO 2008/028946, the contents of which are incorporated herein in their entirety).
Alternative assays measuring neutralizing activity are described in for instance WHO Manual on Animal Influenza Diagnosis and Surveillance, Oeneva: World Health Organization, 2005, version 2002.5.
[247] The invention relates to an isolated human HA antibody that recognizes and binds to an epitope in the HA2 subunit of the influenza haemagglutinin protein (HA), characterized in that said HA antibody has neutralizing activity against an influenza virus, for instance, including HA of the H5 subtype. Examples of influenza strains that contain such a HA of the H5 subtype and that are important strains in view of pandemic threats are H5N1, H5N2, H5N8, and H5N9. Particularly preferred are HA antibodies that at least neutralize the H5N1 influenza strain. Preferably, HA antibodies do not depend on an epitope in the HAI subunit of the HA protein for binding to said HA protein.
Definitions [248] The term "human HA antibody" describes an intact immunoglobulin including monoclonal antibodies, such as chimeric, humanized or human monoclonal antibodies, or to an antigen-binding and/or variable domain compri ing fragment of an immunoglobulin that WO 2012/112489 =

competes with the intact immunoglobulin for specific binding to the binding partner of the immunoglobulin, e.g. H5N1. Regardless of structure, the antigen binding fragment binds with the same antigen that is recognized by the intact immunoglobulin. An antigen-binding fragment can comprise a peptide or polypeptide comprising an amino acid sequence of at least 2, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or 250 contiguous amino acid residues of the amino acid sequence of the HA antibody.
[249] The term "HA antibody", includes all immunoglobulin classes and subclasses known in the art. Depending on the amino acid sequence of the constant domain of their heavy chains, HA antibodies can be divided into the five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
= [250] Antigen-binding fragments include, inter alia, Fab, F(ab'), F(ab')2, Fv, dAb, Fd, complementarity determining region (CDR) fragments, single-chain antibodies (scFv), bivalent single-chain antibodies, single-chain phage antibodies, diabodies, triabodies, tetrabodies, (poly)peptides that contain at least a fragment of an immunoglobulin that is sufficient to confer specific antigen binding to the (poly)peptide, etc. The above fragments may be produced synthetically or by enzymatic or chemical cleavage of intact immunoglobulins or they may be genetically engineered by recombinant DNA
techniques.
The methods of production are well known in the art and are described, for example, in Antibodies: A Laboratory Manual, Edited by: E. Harlow and D, Lane (1988), Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, which is incorporated herein by reference. An HA antibody or antigen-binding fragment thereof may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one it another or they may be different. t.
[251] With respect to HA antibodies, the term "complementarity determining regions"
(CDR) as used herein means sequences within the variable regions of HA
antibodies, such as immunoglobulins, that usually contribute to a large extent to the antigen binding site which is =
complementary in shape and charge distribution to the epitope recognized on the antigen. The CDR regions of HA antibodies can be specific for linear epitopes, discontinuous epitopes, or conformational epitopes of proteins or protein fragments, either as present on the protein in its native conformation or, in some cases, as present on the proteins as denatured, e.g., by solubilization in SDS. Epitopes of HA antibodies may also consist of posttranslational modifications of proteins.

.11 .
;18 CA 02827301 2013-.08-13 .=
=
[252] The term "functional variant", as used herein, refers to an HA antibody that includes a nucleotide and/or amino acid sequence that is altered by one or more nucleotides and/or amino acids compared to the nucleotide and/or amino acid sequences of the parental HA
antibody and that is still capable of competing for binding to the binding partner, e.g. H5N1, with the parental HA antibody. In other words, the modifications in the amino acid and/or nucleotide sequence of the parental HA antibody do not significantly affect or alter the binding characteristics of the HA antibody encoded by the nucleotide sequence or containing the amino acid sequence, i.e. the antibody is still able to recognize and bind its target. The functional variant may have conservative sequence modifications including nucleotide and amino acid substitutions, additions and deletions. These modifications can be introduced by standard techniques known in the art, such as site-directed mutagenesis and random PCR-mediated mutagenesis, and may include natural as well as.non-natural nucleotides and amino acids. =
[253] Conservative amino acid substitutions include the ones in which the amino acid residue is replaced with an amino acid residue having similar structural or chemical properties. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lYsine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). It will be clear to the skilled artisan that other classifications of amino acid residue families than the one used above can also be employed.
Furthermore, a HA antibody functional variant may have non-conservative amino acid substitutions, e.g., replacement of an amino acid with an amino acid residue having different f structural or chemical properties. Similar minor vanations may also include amino acid deletions or insertions, or both. Guidance in determining Which amino acid residues may be substituted, inserted, or deleted without abolishing 'immunological activity may be found using computer programs well known in the art.
[254] A mutation in a nucleotide sequence can be a single alteration made at a locus (a point mutation), such as transition or transversion mutations, or alternatively, multiple nucleotides may be inserted, deleted or changed at a single locus. In addition, one or more alterations may be made at any number of loci within a nucleotide sequence. The mutations may be performed by any suitable method known in the att.
[255] The term "human", when applied to HA antibodies, refers to molecules that are either directly derived from a human or based upon a human sequence. When an HA
antibody is derived from or based on a human sequence and subsequently modified, it is still to be considered human as used throughout the specification. In other words, the term human, when applied to HA antibodies is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences or based on variable or constant regions occurring in a human or human lymphocyte and modified in some form. Thus, the human HA antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences, contain substitutions and/or deletions (e.g., mutations introduced by for instance random or site-specific mutagenesis in vitro or by somatic mutation in vivo). "Based on" as used herein refers to the situation that a nucleic acid sequence may be exactly copied from a template, or with minor mutations, such as by error-prone PCR methods, or synthetically made matching the template exactly or with minor modifications. Semi-synthetic molecules based on human sequences are also considered to be human as used herein.
;t.
Single Chain HA Antibodies [256] The heavy chain of an HA antibody is derived from a germ line V
(variable) gene such as, for example, the VH1 or VH3 germline gene (see, Tomlinson IM, Williams SC, Ignatovitch 0, Corbett SJ, Winter G. V-BASE Sequence Directory. Cambridge, United Kingdom: MRC Centre for Protein Engineering (1997)). The HA antibodies of the invention include a VH region that is encoded by a nucleic acid sequence that is at least 80%
homologous to the VH1 or VH3 germline gene sequence. Preferably, the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the VH1 or VH3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the VH1 or VH3 germline gene sequence. The VH region of the HA antibody is at least 80% homologous to the amino acid sequence of the VH region encoded by the VH1 or VH3 VH germline gene sequence.
Preferably, the amino acid sequence of VH region of the HA antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the VH1 or VH3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by the VH1 or VH3 germline gene sequence. =

[257] In certain aspects of the invention the VH1 germline gene is VH1 (1-2), VH1 (1-18), VH1 (3-23), or VH1 (1-69). In other aspects of the invention the VH3 germline gene is VH3 (3-21) [258] The HA antibodies of the invention also include a variable light chain (VL) region encoded by a human germline gene sequence selected from the group consisting of VKI, VKII, VKIII, VKIV, VL1, VL2, and VL3 (see, Torfflinson IM, Williams SC, Ignatovitch 0, Corbett SJ, Winter G. V-BASE Sequence Directory.- Cambridge, United Kingdom:
MRC
Centre for Protein Engineering (1997)). Alternatively, the HA antibodies include a VL region that is encoded by a nucleic acid sequence that is at least 80% homologous to the germline gene sequence of VKI, VKII, VKIII, VKIV, VL1, VL2, or VL3. Preferably, the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the germline gene sequence of VKI, VKII, VKIII, VKIV, VL1, VL2, or VL3, and more preferably, at least 98%, 99%
homologous to the germline gene sequence of VKI, VKII, VKIII, VKIV, VL1, VL2, or VL3.
The VL region of the HA antibody is at least 80% homologous to the amino acid sequence of the VL region encoded the germline gene sequence of VKI, VKII, VKIII, VKIV, VL1, VL2, or VL3. Preferably, the amino acid sequence of VL region of the HA antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the germline gene sequence of VKI, VKII, VKIII, VKIV, VL1, VL2, or VL3, and more preferably, at least 98%, 99% homologous to the sequence encoded by the germline gene sequence of VKI, VKII, VKIII, VKIV, VL1, VL2, or VL3. =
[259] In certain aspects of the invention the VKI germline gene is VKI (A20), the VKII
germline gene is VKII (A3), the VKIII germline gene is VKIII (A27), and the VKIV
germline gene is VKIV (B3). In other aspects Of the invention, the VL1 germline gene is VL1 (V1-13), VL1 (V1-16), VL1 (V1-17), or. VL1 (V1-19). Alternatively, the VL2 germline gene is VL2 (V1-3) or VL2 (V.1-4). Furthermore, the VL3 germline gene is VL3 (V2-14).
[260] Specific combinations of a VH- and HL-locus are provided for each HA
antibody described below.
[261] The CDR regions of the HA antibodies of the invention were determined according to Kabat et al. (1991) as described in Sequences of Proteins of Immunological Interest. In =
certain embodiments of the invention, HA antibodies contain two, three, four, five or all six CDR regions as disclosed herein. Preferably, HA antibodies contain at least two of the CDRs disclosed herein.

=

[262] The SC06-141 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 309) and a light chain variable region (SEQ ID NO: 310) encoded by the nucleic acid sequence shown in SEQ ID NO: 311 and the amino acid sequence shown in SEQ ID NO: 312. The VH-locus is VH1 (1-18) and the VL locus is HKIV (B3).
[263] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the 5C06-141 antibody have the following CDR
sequences:
GYYVY (HCDR1, SEQ ID NO: 247), WISAYNGNTNYAQKFQG (HCDR2, SEQ ID NO:
248) and SRSLDV (HCDR3, SEQ ID NO: 568). The light chain CDRs of the SC06-141 antibody have the following CDR sequences: KSSQSVLYSSNNICNYLA (LCDR1, SEQ ID
NO: 569), WASTRES (LCDR2, SEQ ID NO: 570)'and QQYYSTPLT (LCDR3, SEQ ID
NO: 289).
[264] SC06-141 nucleotide sequence (SEQ ID NO: 311) gaggtccagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctgggta caccttcacc ggctactatg tgtactgggt gcgacaggcc 120 = cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagaagtaga 300 tccctggacg tctggggcca agggaccacg gtcaccgtct cgagcggtac gggcggttca 360 ggcggaaccg gcagcggcac tggcgggtcg acggatgttg tgatgactca gtctccagac 420 tccctggctg tgtctctggg cgagagggcc accatcaact gcaagtccag ccagagtgtt 480 ttatacagct ccaacaataa gaactactta gcttggtacc agcagaaacc aggacagcct 540 cctaagctgc.tcatttactg ggcatctacc cgggaatccg gggtccctga ccgattcagt 600 ggcagcgggt ctgggacaga tttcactctc accatcagca gcctgcaggc tgaagatgtg 660 gcagtttatt actgtcagca atattatagt actcctctca ctttcggcgg agggaccaaa 720 gtggatatca aacgt 735 [265] SC06-141 amino acid sequence (SEQ ID NO: 312) EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYVYWVRQAPGQGLEWMGWISAYNGNTN
YAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSRSLDVWGQGTTVTVSSGTGGS
GGTGSGTGGSTDVVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP
KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPLTFGGGTKVDIK
[266] SC06-141 VH amino acid sequence (SEQ ID NO: 309) EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYVYWVRQAPGQGLEWMGWISAYNGNTN
YAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSRSLDVWGQGTTVTVSS
[267] SC06-141 VL amino acid sequence (SEQ ID NO: 310) DVVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPICLLIYWAST
RESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPLTFGGGTKVDIKR
[268] The SC06-255 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 313) and a light chain variable region (SEQ ID NO: 314) encoded by the nucleic acid sequence shown in SEQ ID NO: 315 and the amino acid sequence shown in SEQ ID NO: 316. The VH-locus is VH1 (1-69) aqd the VL locus is VL1 (V1-16).
[269] The amino acids encompassing the CDRs are,highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-255 antibody have the following CDR
sequences:
SYAIS (HCDR I, SEQ ID NO: 571), GIIPIFGTTKYAPICFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573). The light chain CDRs of the SC06-255 antibody.have the following CDR sequences: SGSTFNIGSNAVD (LCDR 1 , SEQ ID
NO: 574), SNNQRPS (LCDR2, SEQ ID NO: 575) and AAWDDILNVPV (LCDR3, SEQ ID
NO: 576).
[270] SC06-255 nucleotide sequence (SEQ ID NO: 315) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60 tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180 gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 290 atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300 gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420 ctgactcagc caccctcagc gtctgggacc cccgggcaga gg4tcaccat ctcttgttct 980 ggaagcacgt tcaacatcgg aagtaatgct gtagactggt acCggcagct cccaggaacg 540 gcccccaaac tcctcatcta tagtaataat cagcggccct caggggtccc tgaccgattc 600 tctggctcca ggtctggcac ctcagcctcc ctggccaica. gt4ggctcca gtctgaggat 660 gaggctgatt attactgtgc agcatgggat gacatcctga atgttccggt attcggcgga 720 gggaccaagc tgaccgtcct aggt = 794 [271] SC06-255 amino acid sequence (SEQ ID NO: 316) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTSYVLTQPPSASGTPGQRVTISCSGSTFNIGSNAVDWYRQLPGTAPKLLI
YSNNQRPSGVPDRFSGSRSGTSASLAISGLQSEDEADYYCAAWDDILNVPVFGGGTKLTVLG
[272] SC06-255 VH amino acid sequence (SEQ ID NO: 313) EVQLVESGAEVKICPGSSVKVSCICASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYA
PKFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHIMEGYQVRETMDVWGKG
TTVTVSS
[273] SC06-255 VL amino acid sequence (SEQ ID NO: 314) SYVLTQPPSASGTPGQRVTISCSGSTFNIGSNAVDWYRQLPGTAPKWYSNNQRPSGVPDRF
SGSRSGTSASLAISGLQSEDEADYYCAAWDDILNVPVFGGGTKLTVLG
[274] The SC06-257 HA-specific single-chain Fv antibo4 includes a heavy chain variable region (SEQ ID NO: 317) and a light chain variable region (SEQ ID NO: 318) encoded by the nucleic acid sequence shown in SEQ ID NO: 319.and he amino acid sequence shown in SEQ ID NO: 320. The VH-locus is VH1 (1-69) and the VL locus is VL2 (V1-4).

[2751 The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-257 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIIPIEGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573). The light chain CDRs of the SC06-257 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDR1, SEQ ID
NO: 577), EVSNRPS (LCDR2, SEQ ID NO: 578) and SSYTSSSTY (LCDR3, SEQ ID NO:
579).
[276] SC06-257 nucleotide sequence (SEQ ID NO: 319) caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60 tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180 gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240 atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300 gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcagtctgcc 420 ctgactcagc ctgccgccgt gtctgggtct cctggacagt cgatcaccat ctcctgcact 480 ggaaccagca gtgacgttgg tggttataac tatgtctcct ggtaccaaca gcacccaggc 540 aaagccccca aactcatgat ttatgaggtc agtaatcggc cctcaggggt ttctaatcgc 600 ttctctggct ccaagtctgg caacacggcc tccctgacca tctctgggct ccaggctgag 660 gacgaggctg attattactg cagctcatat acaagcagca gcacttatgt cttcggaact 720 . gggaccaagg tcaccgtcct aggt 744 [277] SC06-257 amino acid sequence (SEQ ID NO: 320) QVQLVQSGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTQSALTQPAAVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPK
LMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTYVFGTGTKVTVL
[278] SC06-257 VH amino acid sequence (SEQ ID NO: 317) QVQLVQSGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYA
PKFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVS
[279] SC06-257 VL amino acid sequence (SEQ ID NO: 318) QSALTQPAAVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSN
RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTYVFGTGTKVTVLG
[280] The SC06-260 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 321) and a light chain variable region (SEQ ID NO: 322) encoded by the nucleic acid sequence shown in SEQ ID NO: 323 and the amino acid sequence shown in SEQ ID NO: 324. The VH-locus is VH1 (1-69) and the VL locus is VL1 (V1-17).
' -it 53 ' [281] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-260 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIIPIFGTTKYAPICFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573). The light chain CDRs of the SC06-260antibody have the following CDR sequences: SGSRSNVGDNSVY (LCDR1, SEQ ID
NO: 580), KNTQRPS (LCDR2, SEQ ID NO: 581) and VAWDDSVDGYV (LCDR3, SEQ
ID NO: 582).
[282] SC06-260 nucleotide sequence (SEQ ID No: 323) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60 tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180 gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240 atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300 gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420 ctgactcagc caccctcagt ctctgggacc cccgggcaga gggtcaccat ctcttgctct 480 ggaagccgct ccaacgtcgg agataattct gtatattggt atcaacacgt cccagaaatg 540 gcccccaaac tcctcgtcta taagaatact caacggccct caggagtccc tgcccggttt 600 tccggctcca agtctggcac ttcagcctcc ctggccatca ttggcctcca gtccggcgat 660 gaggctgatt attattgtgt ggcatgggat gacagcgtag atggctatgt cttcggatct 720 gggaccaagg tcaccgtcct aggt 744 [283] SC06-260 amino acid sequence (SEQ ID NO: 324) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWIvIGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTSYVLTQPPSVSGTPGQRVTISCSGSRSNVGDNSVYWYQHVPEMAPKL
LVYKNTQRPSGVPARFSGSKSGTSASLAIIGLQSGDEADYYCVAWDDSVDGYVFGSGTKVTV
LG
[284] SC06-260 VH amino acid sequence (SEQ ID NO: 321) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISIVVRQAPGQGPEWMGGIIPIFGTTKYA

.;
[285] SC06-260 VL amino acid sequence (SEQ ID NO: 322) SYVLTQPPSVSGTPGQRVTISCSGSRSNVGDNSVYWYQHVPEMAPKLLVYKNTQRPSGVPA
RFSGSKSGTSASLAIIGLQSGDEADYYCVAWDDSVDGYVFGSGTKVTVLG
[286] The SC06-261 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 325) and a light chain variable region (SEQ ID NO: 326) encoded by the nucleic acid sequence shown in SEQ ID NO: 327 and the amino acid sequence shown in SEQ ID NO: 328. The VH-locus is VH1 (1-69) and the VL locus is VL1 (V1-19).

, A.! s =
[287] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-261 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573). The light chain CDRs of the SC06-261 antibody have the following CDR sequences: SGSSSNIGNDYVS (LCDR1, SEQ ID
NO: 583), DNNKRPS (LCDR2, SEQ ID NO: 584) and ATWDRRPTAYVV (LCDR3, SEQ
ID NO: 585).
[288] SC06-261 nucleotide sequence (SEQ ID NO: 327) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60 tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180 gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240 atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300 gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcagtctgtg 420 ttgacgcagc cgccctcagt gtctgcggcc ccaggacaga aggtcaccat ctcctgctct 480 ggaagcagct ccaacattgg gaatgattat gtatcctggt accagcagct cccaggaaca 540 gcccccaaac tcctcattta tgacaataat aagcgaccct cagggattcc tgaccgattc 600 tctggctcca agtctggcac gtcagccacc ctgggcatcai ccggactcca gactggggac 660 gaggccaact attactgcgc aacatgggat cgccgcccga ctgcttatgt tgtcttcggc 720 ggagggacca agctgaccgt cctaggt 747 [289] SC06-261 amino acid sequence (SEQ ID NO: 328) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGHPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGYINTVSSG
TGGSGGTGSGTGGSTQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNDYVSWYQQLPGTAPKLL
IYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEANYYCATWDRRPTAYVVFGGGTKLTV
LG
[290] SC06-261 VH amino acid sequence (SEQ ID NO: 325) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYA

[291] SC06-261 VL amino acid sequence (SEQ ID NO: 326) SVLTQPPSVSAAPGQKVTISCSGSSSNIGNDYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFS
GSKSGTSATLGITGLQTGDEANYYCATWDRRPTAYVVFGGGTKLTVLG
[292] The SC06-262 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 329) and a light chain variable region (SEQ ID NO: 330) encoded by the nucleic acid sequence shown in SEQ ID NO: 33,1 and the amino acid sequence shown in SEQ ID NO: 332. The VH-locus is VH1 (1-69) and the VL locus is VKI (A20).

[293] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-262 antibody'have the following CDR
sequences:
GSAIS (HCDR1, SEQ ID NO: 586), GISPLFGTTNYAQKFQG (HCDR2, SEQ ID NO: 587) and GPKYYSEYMDV (HCDR3, SEQ ID NO: 588). =Thelight chain CDRs of the SC06-262 antibody have the following CDR sequences: RASQGISSYLA (LCDR1, SEQ ID NO:
589), DASTLRS (LCDR2, SEQ ID NO: 590) and QRYNSAPPI (LCDR3, SEQ ID NO: 591).
[294] SC06-262 nucleotide sequence (SEQ ID NO: 331) caggtacagc tgcagcagtc aggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg tttccggagt cattttcagc ggcagtgcga tcagctgggt gcgacaggcc 120 cctggacaag gccttgagtg gatgggaggg atcagccctc tctttggcac aacaaattac 180 gcacaaaagt tccagggcag agtcacgatt accgcggacc aatccacgaa cacaacctac 240 atggaggtga acagcctgag atatgaggac acggccgtgt atttctgtgc gcgaggtcca 300 aaatattaca gtgagtacat ggacgtctgg ggcaaaggga ccacggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga catccagatg 420 acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 480 gcgagtcagg gcattagcag ttatttagcc tggtatcagc agaagccagg gaaagttcct 540 acactcctga tctatgatgc atccactttg cgatcagggg tcccatctcg cttcagtggc 600 agtggatctg cgacagattt cactctcacc atcagcagcc tgcagcctga agatgttgca 660 acttattact gtcaaaggta taacagtgcc cccccgatca ccttcggcca agggacacga 720 ctggagatta aacgt 735 [295] SC06-262 amino acid sequence (SEQ 332) QVQLQQSGAEVKKPGSSVKVSCKVSGVIFSGSAISWVRQAPGQGLEWMGGISPLFGTTNYAQ
KFQGRVTITADQSTNTTYMEVNSLRYEDTAVYFCARGPKYYSEYMDVWGKGTTVTVSSGT

DASTLRSGVPSRFSGSGSATDFTLTISSLQPEDVATYYCQRYNSAPPITFGQGTRLEIKR
[296] SC06-262 VH amino acid sequence (SEQ ID NO: 329) QVQLQQSGAEVKKPGSSVKVSCKVSGVIFSGSAISWVRQAPGQGLEWMGGISPLFGTTNYA
QKFQGRVTITADQSTNTTYMEVNSLRYEDTAVYFCARGPKYYSEYMDVWGKGTTVTVSS
[297] SC06-262 VL amino. acid sequence (SEQ ID NO: 330) DIQMTQSPSSLSASVGDRVTITCRASQGISSYLAWYQQKPGKVPTLLIYDASTLRSGVPSRFS
GSGSATDFTLTISSLQPEDVATYYCQRYNSAPPITFGQGTRLEIKR
[298] The SC06-268 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 333) and a light chain variable region (SEQ ID NO: 334) encoded by the nucleic acid sequence shown in SEQ ID NO: 335 and the amino acid sequence shown in SEQ ID NO: 336. The VH-locus is VH1 (1-69) and the VL locus is VL3 (V2-14).
[299] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-268 antiody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIMGMFGTT:NYNpKFQG (HCDR2, SEQ ID NO:
592) and SSGYYPEYFQD (HCDR3, SEQ ID NQ t 593). The light chain CDRs of the .;
268 antibody have the following CDR sequences: SGHKLGDKYVS (LCDR1, SEQ ID NO:
594), QDNRRPS (LCDR2, SEQ ID NO: 595) and QAWDSSTA (LCDR3, SEQ ID NO:
596).
[300] SC06-268 nucleotide sequence (SEQ ID NO: 335) caggtccagc tggtacagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagt agttatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggagga atcatgggta tgtttggcac aactaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aattcacgag cgcagcctac 240 atggagctga ggagcctgag atctgaggac acggccgtct actactgtgc gaggtctagt 300 ggttattacc ccgaatactt ccaggactgg ggccagggca ccctggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgtgctg 420 actcagccac cctcagagtc cgtgtcccca ggacagacag ccagcgtcac ctgctctgga 480 cataaattgg gggataaata tgtttcgtgg tatcagcaga agccaggcca gtcccctgta 540 ttactcatct atcaagataa caggcggccc tcagggatcc ctgagcgatt cataggctcc 600 aactctggga acacagccac tctgaccatc agcgggaccc aggctctgga tgaggctgac 660 tattactgtc aggcgtggga cagcagcact gcggttttcg gcggagggac caagctgacc 720 gtcctaggt 729 [301] SC06-268 amino acid sequence (SEQ ID NO: 33,6) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYPOWVRQAPGQGLEWMGGIMGMFGTTNY
AQKFQGRVTITADEFTSAAYMELRSLRSEDTAV YYCARSSGYYPEYFQDWGQGTLVTVSSG
TGGSGGTGSGTGGSTQS VLTQPPSES V SPGQTASVTCSGHKLGDKYVS WYQQKPGQSPVLLI
YQDNRRPSGIPERFIGSNSGNTATLTISGTQALDEADYYCQAWDSSTAVFGGGTKLTVLG
[302] SC06-268 VH amino acid sequence (SEQ ID NO: 333) QVQLVQSGAEVKKPGSS VKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIMGMFGTTN
YAQKFQGRVTITADEFTSAAYMELRSLRSEDTAVYYCARSSGYYPEYFQDWGQGTLVTVS
[303] SC06-268 VL amino acid sequence (SEQ ID NO: 334) QS VLTQPPSES V SPGQTAS VTCSGHKLGDKYVSWYQQKPGQSPVLLIYQDNRRPSGIPERFI
GSN SGNTATLTIS GTQALDEADYYCQA WDSSTA VFGGGTKLTVLG
[304] The SC06-272 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 337) and a light chain variable region (SEQ ID NO: 338) encoded by the nucleic acid sequence shown in SEQ ID NO: 339 and the amino acid sequence shown in SEQ ID NO: 340. The VH-locus is VH1 (1-69) and the VL locus is VL2 (V1-3).
[305] The amino acids encompassing the CDRs are highlighted in bold in the sequences <
below. The heavy chain CDRs of the SC06-272 antibody have the following CDR
sequences:
,1 SYAIT (HCDR1, SEQ ID NO: 597), GIIGMFGSTNYAQNFQG (HCDR2, SEQ ID NO:
598) and STGYYPAYLHH (HCDR3, SEQ ID NO:`599). The light chain CDRs of the SC06-272 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDR1, =
SEQ ID NO: 577), DVSKRPS (LCDR2, SEQ ID Nob. 601) and SSYTSSSTHV (LCDR3, SEQ ID NO: 602).
[306] SC06-272 nucleotide sequence (SEQ ID NO: 339) cagatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttctcc agttatgcta tcacctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcggta tgtttggttc aacaaactac 160 gcacagaact tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctcag atctgaggac acggccgtgt attactgtgc gagaagtact 300 ggttattacc ctgcatacct ccaccactgg ggccagggca ccctggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgccctg 420 actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480 accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540 gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600 tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660 gaggctgatt attactgcag ctcatataca agcagcagca ctcatgtctt cggaactggg 720 accaaggtca ccgtcctagg t 741 [307] SC06-272 amino acid sequence (SEQ ID NO: 340) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWMGGIIGMFGSTYAQ
NFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSTGYYPAYLHHWGQGTLVTVS
SGTGGSGGTGSGTGGSTQSALTQPRSVSGSPGQSV.TISCTGTSSDVGGYNYVSWYQQHPG
KAPKLMIYDVSKRPSGVPDRFSGSKSGNTASLTI8.QLQAEDEADYYCSSYTSSSTHVFGTG
TKVTVLG
, [308] SC06-272 VH amino acid sequence (SEQ ID NO: 337) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWMGGIIGMFGSTNY
AQNFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSTGYYPAYLHHWGQGTLVTVSS
[309] SC06-272 VL amino acid sequence (SEQ ID NO: 338) QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVP
DRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTHVFGTGTKVTVLG
[310] The SC06-296 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 341) and a light chain variable region (SEQ ID NO: 342) encoded by the nucleic acid sequence shown in SEQ ID NO: 343 and the amino acid sequence shown in SEQ ID NO: 344. The VH-locus is VH1 (1-2) and the VL locus is VKIII (A27).
[311] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-296 antibody have the following CDR
sequences:
SYYMH (HCDR1, SEQ ID NO: 603), WINPNSGGTNYAQKFQG (HCDR2, SEQ ID NO:
604) and EGKWGPQAAFDI (HCDR3, SEQ ID NOi 605). The light chain CDRs of the SC06-296 antibody have the following CDR sequences: RASQSVSSSYLA (LCDR1, SEQ
ID NO: 646), DASSRAT (LCDR2, SEQ ID NO: 6'079 and QQYGSSLW (LCDR3, SEQ ID
NO: 608).

[312] SC06-296 nucleotide sequence (SEQ ID NO: 343) gaggtgcagc tggtggagac cggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60 tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180 gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240 atggagctga gcaggctgag atctgacgac acggccgpgt attactgtgc gagagagggg 300 aaatggggac ctcaagcggc ttttgatatc tggggccaag ggacaatggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac ggaaattgtg 420 atgacgcagt ctccaggcac cctgtctttg tctccagggg aaagagccac cctctcctgc 480 agggccagtc agagtgttag cagcagctac ttag'cctgge accagcagaa acctggccag 540 gctcccaggc tcctcatcta tgatgcatcc agcagggcca ctgacatccc agacaggttc 600 agtggcagtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 660 tttgcagtgt attactgtca gcagtatggt agctcacttt ggacgttcgg ccaagggacc 720 aaggtggaga tcaaacgt 738 [313] SC06-296 amino acid sequence (SEQ ID NO: 344) EVQLVETGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGWINPNSGGTN
YAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCAREGKWGPQAAFDIWGQGTMVTV
SSGTGGSGGTGSGTGGSTEIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAP
= RLLIYDASSRATDIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLWTFGQGTKVEIKR
[314] SC06-296VH amino acid sequence (SEQ ID NO: 341) EVQLVETGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGWINPNSGGTN
YAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCAREGKWGPQAAFDIWGQGTMVT
VSS
[315] SC06-296 VL amino acid sequence (SEQ ID NO: 342) EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAy. YQQKPGQAPRLLIYDASSRATDIPDRF
SGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLWTFGQGTKVEIKR
1, [316] The SC06-301 HA-specific single-chain F;v, antibody includes a heavy chain variable region (SEQ ID NO: 345) and a light chain variable region (SEQ ID NO: 346) encoded by the nucleic acid sequence shown in SEQ ID NO: 347 and the amino acid sequence shown in SEQ ID NO: 348. The VH-locus is VH1 (3-23) and the VL locus is VKII (A3).
[317] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-301 antibody have the following CDR
sequences:
IYAMS (HCDR1, SEQ ID NO: 609), AISSSGDSTYYADSVKG (HCDR2, SEQ ID NO:
610) and AYGYTFDP (HCDR3, SEQ ID NO: 611). The light chain CDRs of the SC06-antibody have the following CDR sequences: RSSQSLLHSNGYNYLD (LCDR I, SEQ ID
NO: 612), LGSNRAS (LCDR2, SEQ ID NO: 613) and MQALQTPL (LCDR3, SEQ ID NO:
614).
<

[318] SC06-301 nucleotide sequence (SEQ ID NO: 347) gaggtgcagc tggtagagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc atctatgcca tgagctgggt ccgccaggca 120 ccagggaagg ggctggagtg ggtctcagct attagtagta gtggtgatag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca acgccaggaa cacgctgtat 240 ctgcaaatga acagtctgag agccgaggac acggctgtgt attactgtgc gagagcgtat 300 ggctacacgt tcgacccctg gggccaggga accctggtca ccgtctcgag cggtacgggc 360 ggttcaggcg gaaccggcag cggcactggc gggtcgacgg aaattgtgct gactcagtct 420 ccactctccc tgcccgtcac ccctggagag ccggccttea tctcctgcag gtctagtcag 480 agcctcctgc atagtaatgg atacaactat ttggattggt acctgcagaa gccagggcag 540 tctccacagc tcctgatcta tttgggttct aatcggg-cct ccggggtccc tgacaggttc 600 agtggcagtg gatcaggcac agattttaca ctgaaaa.hca gcagagtgga ggctgaggat 660 gttggggttt attactgcat gcaagctcta caaactcccc tcactttcgg cggagggacc 720 aaggtggaga tcaaacgt 738 [319] SC06-301 amino acid sequence (SEQ ID NO: 348) EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSAISSSGDSTYYAD
SVKGRFTISRDNARNTLYLQMNSLRAEDTAVYYCARAYGYTFDPWGQGTLVTVSSGTGGSG
GTGSGTGGSTEIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIY
LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIKR
[320] SC06-301 VH amino acid sequence (SEQ ID NO: 345) EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSAISSSGDSTYYA
DSVKGRFTISRDNARNTLYLQMNSLRAEDTAVYYCARAYGYTFDPWGQGTLVTVSS
[321] SC06-301 VL amino acid sequence (SEQ ID NO: 346) EIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGV
PDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIKR
[322] The SC06-307 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 349) and a light chain variable:regi,on.(SEQ ID NO: 350) encoded by the nucleic acid sequence shown in SEQ ID NO: 3.51 and the amino acid sequence shown in SEQ ID NO: 352. The VH-locus is VH3 (3-21) and the VL locus is VKIII (A27).
[323] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-307 antibody have the following CDR
sequences:
SYSMN (HCDR1, SEQ ID NO: 615), SISSSSSYIYYVDSVKG (HCDR2, SEQ ID NO: 616) and GGGSYGAYEGFDY (HCDR3, SEQ ID NO: 617). The light chain CDRs of the SC06-307 antibody have the following CDR sequences: RASQRVSSYLA (LCDR1, SEQ ID NO:
618), GASTRAA (LCDR2, SEQ ID NO: 619) and QQYGRTPLT (LCDR3, SEQ ID NO:
620).
=
=
=

[324] SC06-307 nucleotide sequence (SEQ ID NO: 351) caggtccagc tggtgcagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcatcc attagtagta gtagtagtta catatactac 180 gtagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggtggt 300 gggagctacg gggcctacga aggctttgac tactggggcc agggcaccct ggtcaccgtc 360 tcgagcggta cgggcggttc aggcggaacc ggcagcggca ctggcgggtc gacggaaatt 420 gtgctgactc agtctccagg caccctgtct ttgtctccag gggaaagagc caccctctcc 480 tgcagggcca gtcagcgtgt tagcagctac ttagcctggt accaacagaa acctggccag 540 gctcccaggc tcctcatcta tggtgcatcc accagggccg ctggcatccc agacaggttc 600 agtggcagtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 660 tctgcagtgt attactgtca gcagtatggt aggacaccgc tcactttcgg cggagggacc 720 aaggtggaga tcaaacgt = 738 [325] SC06-307 amino acid sequence (SEQ ID NO: 352) QVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYVD
SVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGGGSYGAYEGFDYWGQGTLVTVSS
GTGGSGGTGSGTGGSTEIVLTQSPGTLSLSPGERATLSCRASQRVSSYLAWYQQKPGQAPRLL
IYGASTRAAGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYGRTPLTFUGGTKVEIKR
[326] SC06-307 VH amino acid sequence (SEQ ID NO: 349) QVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYVD
SVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCiARGGGSYGAYEGFDYWGQGTLVTVSS
[327] SC06-307 VL amino acid sequence (SEQ ID NO: 350) v.
EIVLTQSPGTLSLSPGERATLSCRASQRVSSYLAWYQQKPGQAPRLLIYGASTRAAGIPDRFS
GSGSGTDFTLTISRLEPEDSAVYYCQQYGRTPLTFGGGTKVEIKR
[328] The SC06-310 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 353) and a light chain variable region (SEQ ID NO: 354) encoded by the nucleic acid sequence shown in SEQ ID NO: 355 and the amino acid sequence shown in SEQ ID NO: 356. The VH-locus is VH1 (1-69) and the VL locus is VL3 (V2-14).
[329] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-310 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573). The light chain CDRs of the SC06-310 antibody have the following CDR sequences: GGNNIGSKSVH (LCDR I , SEQ ID
NO:
621), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVWDSSSDHAV (LCDR3, SEQ ID NO:
623).
, t 61 , [330] SC06-310 nucleotide sequence (SEQ ID NO: 355) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac atggagctga gcagcctgcg atctgaggac acggccat,gt actactgtgc gaaacatatg gggtaccagg tgcgcgaaac tatggacgtc tggggcaa'ag ggaccacggt caccgtctcg agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg ctgactcagc caccctcggt gtcagtggcc ccaggadaga cggccaggat tacctgtggg ggaaacaaca ttggaagtaa aagtgtgcac tggtacCagc agaagccagg ccaggcccct gtgctggtcg tctatgatga tagcgaccgg ccctcaggga tccctgagcg attctctggc tccaactctg ggaacacggc caccctgacc atcagcaggg tcgaagccgg ggatgaggcc gactattact gtcaggtgtg ggatagtagt agtgatcatg ctgtgttcgg aggaggcacc cagctgaccg tcctcggt [331] SC06-310 amino acid sequence (SEQ ID NO: 356) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTSYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVV
YDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHAVFGGGTQLTVLG
[332] SC06-310 VH amino acid sequence (SEQ ID NO: 353) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIEGTTKYA
PKFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVS
[333] SC06-310 VL amino acid sequence (SEQ ID NO: 354) SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFS
GSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHAVFOGGTQLTVLG
[334] The SC06-314 HA-specific single-chain Fy, antibody includes a heavy chain variable . , region (SEQ ID NO: 357) and a light chain variable region (SEQ ID NO: 358) encoded by the nucleic acid sequence shown in SEQ ID NO: 359 and the amino acid sequence shown in SEQ ID NO: 360. The VH-locus is VH1 (1-69) and the VL locus is VL1 (V1-17).
[335] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-314 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573). The light chain CDRs of the SC06-=
3.14 antibody have the following CDR sequences: SGSSSNIGSNYVY (LCDR1, SEQ ID
NO: 624), RDGQRPS (LCDR2, SEQ ID NO: 625) and ATWDDNLSGPV (LCDR3, SEQ ID
NO: 626).
62 , 41(., [336] SC06-314 nucleotide sequence (SEQ ID NO: 359) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaagtc 60 tcttgcaagg cttctggagg ccccttccgc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcctgagtg gatgggaggg atcatcccta tttttggtac aacaaaatac 180 gcaccgaagt tccagggcag agtcacgatt accgcggacg atttcgcggg cacagtttac 240 atggagctga gcagcctgcg atctgaggac acggccatgt actactgtgc gaaacatatg 300 gggtaccagg tgcgcgaaac tatggacgtc tggggcaaag ggaccacggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420 ctgactcagc caccctcagc gtctgggacc cccgggcaga gggtcaccat ctcttgttct 480 ggaagcagct ccaacatcgg aagtaattat gtatactggt accagcagct cccaggcacg 540 gcccccaaac tcctcatcta tagggatggt cagcggccct caggggtccc tgaccgattc 600 tctggctcca agtctggcac ctcagcctcc ctggccatca gtggactccg gtccgatgat 660 gaggctgatt attactgtgc aacatgggat gacaacctga gtggtccagt attcggcgga 720 gggaccaagc tgaccgtcct aggt 744 [337] SC06-314 amino acid sequence (SEQ ID NO: 360) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTSYVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLI
YRDGQRPSGVPDRFSGSKSGTSASLAISGLRSDDEADYYCATWDDNLSGPVFGGGTKLTVLG
[338] SC06-314 VH amino acid sequence (SEQ ID NO: 357) EVQLVESGAEVKKPGSSVKVSCICASGGPFRSYAISWVRQAPGQGPEWIVIGGIIPIFGTTKYA
PKFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKIIMGYQVRETMDVWGKGTTVTVS
[339] SC06-314 VL amino acid sequence (SEQ ID NO: 358) SYVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKWYRDGQRPSGVPDRF
SGSKSGTSASLAISGLRSDDEADYYCATWDDNLSGPVFGGGTKLTVLG
[340] The SC06-323 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 361) and a light chain variable region (SEQ ID NO: 362) encoded by the nucleic acid sequence shown in SEQ ID NO: 363 and the amino acid sequence shown in SEQ ID NO: 364. The VH-locus is VH1 (1-69) arid the VL locus is VKIII (A27).
[341] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SCO6-32'3 antibody have the following CDR
sequences:
SYGIS (HCDR1, SEQ ID NO: 627), DIIGMFGSTNYAQNFQG (HCDR2, SEQ ID NO:
628) and SSGYYPAYLPH (HCDR3, SEQ ID NO: 629). The light chain CDRs of the SC06-323 antibody have the following CDR sequences: RASQSVSSSYLA (LCDR1, SEQ ID NO:

646), GASSRAf(LCDR2, SEQ ID NO: 631) and QQYGSSPRT (LCDR3, SEQ ID NO:
632).

.==
)L1"

[342] SC06-323 nucleotide sequence (SEQ ID NO: 363) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc cagggtcctc ggtgaaggtc 60 tcctgtaagg cctctggagg caccttctcc agctatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggagac atcatcggta tgtttggttc aacaaactac 180 gcacagaact tccagggcag actcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaagtagt 300 ggttattacc ctgcatacct cccccactgg ggccagggt'a ccttggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga aattgtgttg 420 acccagtctc caggcaccct gtctttgtct ccagggga'aa gagccaccct ctcctgcagg 480 gccagtcaga gtgttagcag cagctactta gcctggtacc.agcagaaacc tggccaggct 540 cccaggctcc tcatctatgg tgcatccagc agggccactg gcatcccaga caggttcagt 600 ggcagtgggt ctgggacaga cttcactctc accatcagca gactggagcc tgaagatttt 660 gcagtgtatt actgtcagca gtatggtagc tcacccagaa ctttcggcgg agggaccaag 720 gtggagatca aacgt 735 [343] SC06-323 amino acid sequence (SEQ ID NO: 364) EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYGISWVRQAPGQGLEWIVIGDIIGMFGSTNYA
QNFQGRLTITADESTSTAYMELSSLRSEDTAVYYCARSSGYYPAYLPHWGQGTLVTVSSGTG
GSGGTGSGTGGSTEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIY
GASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPRTFGGGTKVEIKR
[344] SC06-323 VH amino acid sequence (SEQ ID NO: 361) EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYGISWVRQAPGQGLEWMGDIIGMFGSTNYA
QNFQGRLTITADESTSTAYMELSSLRSEDTAVYYCARSSGYYPAYLPHWGQGTLVTVSS
[345] 5C06-323 VL amino acid sequence (SEQ ID NO: 362) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS
GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPRTFGGGTKVEIKR
[346] The SC06-325 HA-specific single-chain Fv antibody includes a heavy chain variable i4 region (SEQ ID NO: 365) and a light chain variable region (SEQ ID NO: 366) encoded by the nucleic acid sequence shown in SEQ ID NO: 367 and the amino acid sequence shown in SEQ ID NO: 368. The VH-locus is VH1 (1-69) and the VL locus is VL2 (V1-4).
[347] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-325 antibody have the following CDR
sequences:
FYSMS (HCDR I, SEQ ID NO: 633), GIIPMFGTTNYAQKFQG (HCDR2, SEQ ID NO:
634) and GDKGIYYYYMDV (HCDR3, SEQ ID NO: 635). The light chain CDRs of the 5C06-325 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDR I, SEQ ID NO: 577), EVSNRPS (LCDR2, SEQ ID NO: 578) and SSYTSSSTLV (LCDR3, SEQ ID NO: 636).

=
.-{==
;=?
,t, [348] SC06-325 nucleotide sequence (SEQ ID NO: 367) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc cggggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc ttctattcta tgagctgggt gcgacaggcc 120 cctggacaag gacttgagtg gatgggaggg atcatcccta tgtttggtac aacaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggtcg aatccacgag cacagcctac 240 atggaggtga gcagcctgag atctgaggac acggccgttt attactgtgc gagaggtgat 300 aagggtatct actactacta catggacgtc tggggcaaag ggaccacggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gcagtctgcc 420 ctgactcagc ctgcctccgt gtctgggtct cctggacagt cgatcaccat ctcctgcact 480 ggaaccagca gtgacgttgg tggttataac tatgtctcct ggtaccaaca gcacccaggc 540 aaagccccca aactcatgat ttatgaggtc agtaatcggc cctcaggggt ttctaatcgc 600 ttctctggct ccaagtctgg caacacggcc tccctgacca tctctgggct ccaggctgag 660 gacgaggctg attattactg cagctcatat acaagcagca gcactcttgt cttcggaact 720 gggaccaagg tcaccgtcct aggt 744 [349] SC06-325 amino acid sequence (SEQ ID NO: 368) EVQLVESGAEVKKPGSSVKVSCKASGGTFSFYSMSWVRQAPGQGLEWMGGIIPMFGTTNYA
QKFQGRVTITAVESTSTAYMEVSSLRSEDTAVYYCARGDKGIYYYYMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPK
LMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGTGTKVTVL
[350] SC06-325 VH amino acid sequence (SEQ ID NO: 365) EVQLVESGAEVKKPGSSVKVSCKASGGTFSFYSMSWVRQAPGQGLEWMGGIIPMFGTTNY
AQKFQGRVTITAVESTSTAYMEVSSLRSEDTAVYYCARGDKGIYYYYMDVWGKGTTVTVS
[351] SC06-325 VL amino acid sequence (SEQ ID NO: 366) QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSN
RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGTGTKVTVLG
[352] The SC06-327 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 369) and a light chain variable region (SEQ ID NO: 370) encoded by the nucleic acid sequence shown in SEQ ID NO: 371 and the amino acid sequence shown in SEQ ID NO: 372. The VH-locus is VH1 (1-69) and the.V-L locus is VL3 (V2-14).
[353] The amino acids encompassing the CDRs areµhighlighted in bold in the sequences below. The heavy chain CDRs of the SC06-327 antibody have the following CDR
sequences:
THAIS (SEQ ID NO: 637), GIIAIFGTANYAQKFQG (SEQ ID NO: 638) and GSGYHISTPFDN (SEQ ID NO: 639). The light chain CDRs of the SC06-327 antibody have the following CDR sequences: GGNNIGSKGVH (SEQ ID NO: 640), DDSDRPS (SEQ ID
NO: 622) and QVWDSSSDHVV (SEQ ID NO: 642).
=

$, =
=
[354] SC06-327 nucleotide sequence (SEQ ID NO: 371) gaggtgcagc tggtggagac cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cctctggagg caccttcagg acccatgcta tcagttgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcgcta tcttcggaac agcaaactac 180 gcacagaagt tccagggcag aatcacgatt accgcggacg aatccacgag tacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagaggcagt 300 ggttatcata tatcgacacc ctttgacaac tggggccagg gaaccctggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac gtcctatgtg 420 ctgactcagc caccctcggt gtcagtggcc ccaggacaga cggccaggat tacctgtggg 480 ggaaacaaca ttggaagtaa aggtgtgcac tggtaccagc agaagcctgg ccaggcccct 540 gtgctggtcg tctatgatga tagcgaccgg ccctcaggga tccctgagcg attctctggc 600 tccaactctg ggaacacggc caccctgacc atcagcaggg tcgaagccgg ggatgaggcc 660 gactattact gtcaggtgtg ggatagtagt agtgatcatg tggtattcgg cggagggacc 720 aagctgaccg tcctaggt 738 [355] SC06-327 amino acid sequence (SEQ ID NO: 372) =
EVQLVETGAEVKKPGSSVKVSCKASGGTFRTHAISWVRQAPGQGLENVIVIGGIIAIFGTANYA
QKFQGRITITADESTSTAYMELSSLRSEDTAVYFCARGSGYHISTPFDNWGQGTLVTVSSG
TGGSGGTGSGTGGSTSYVLTQPPSVSVAPGQTARITCGGNNIGSKGVHWYQQKPGQAPVLV
VYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTKLTVL
[356] SC06-327 VH amino acid sequence (SEQ ID NO: 369) EVQLVETGAEVKKPGSSVKVSCKASGGTFRTHAISWVRQAPGQGLEWMGGIIAIFGTANYA
QKFQGRITIfADESTSTAYMELSSLRSEDTAVYFCARGSGYHISTPFDNWGQGTLVTVSS
[357] SC06-327 VL amino acid sequence (SEQ ID NO: 370) SYVLTQPPSVSVAPGQTARITCGGNNIGSKGVHWYQQKPGQAPVLVV YDDSDRPSGIPERFS
GSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTKLTVLG
[358] The SC06-328 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 373) and a light chain variable region (SEQ ID NO: 374) encoded by the nucleic acid sequence shown in SEQ ID NO: 375 and the amino acid sequence shown in SEQ ID NO: 376. The VH-locus is VH1 (1-69) and the VL locus is VKIII (A27).
[359] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-328 antibody have the following CDR
sequences:
GYAIS (HCDR1, SEQ ID NO: 643), GIIPIFGTTNYAQKFQG (HCDR2, SEQ ID NO: 644) and VKDGYCTLTSCPVGWYFDL (HCDR3, SEQID NO: 645). The light chain CDRs of the SC06-328 antibody have the following CDR sequence's: RASQSVSSSYLA (LCDR1, SEQ ID NO: 646), GASSRAT (LCDR2, SEQ`1111ST. 0: 63) and QQYGSSLT (LCDR3, SEQ
ID NO: 648). =

[360] SC06-328 nucleotide sequence (SEQ ID NO: 375) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggaca catcttcagc ggctatgcaa tcagttgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac aacaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacc aatccacgag cacagcctac 240 atggacctga gcaacttgag atctgaggac acggccgtct attactgtgc gagagtgaaa 300 gatggatatt gtactcttac cagctgccct gtcggctggt acttcgatct ctggggccgt 360 ggcaccctgg tcactgtctc gagcggtacg ggcggttcag gcggaaccgg cagcggcact 420 ggcgggtcga cggaaattgt gatgacgcag tctccaggca ccctgtcttt gtctccaggg 480 gaaagagcca ccctctcgtg cagggccagt cagagtgtta gcagcagcta cttagcctgg 540 taccagcaga aacctggcca ggctcccagg ctcctcatct ttggtgcctc cagcagggcc 600 actggcatcc cagacaggtt cagtggcagt gggtctggga cagacttcac tctcaccatc 660 agcagactgg agcctgaaga ttttgcagtg tattactgtc agcagtatgg tagctcactc 720 actttcggcg gagggaccaa gctggagatc aaacgt , . 756 =
[361] SC06-328 amino acid sequence (SEQ ID-NO: 376) EVALVESGAEVKKPGSSVKVSCKASGHIFSGYAISWVRQAPGQGLEWMGGIIPIFGTTNYAQ
KFQGRVTITADQSTSTAYMDLSNLRSEDTAVYYCARVKDGYCTLTSCPVGWYFDLWGRGTL
VTVSSGTGGSGGTGSGTGGSTEIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQ
QKPGQAPRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLT
FGGGTKLEIKR
[362] SC06-328 VH amino acid sequence (SEQ ID NO: 373) EVALVESGAEVKKPGSSVKVSCKASGHIFSGYAISWVRQAPGQGLEWMGGIIPIFGTTNYA
QKFQGRVTITADQSTSTAYMDLSNLRSEDTAVYYCARVKDGYCTLTSCPVGVVYFDLWGR
GTLVTVSS
[363] SC06-328 VL amino acid sequence (SEQ ID NO: 374) EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATG
IPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLTFGGGTKLEIKR
[364] The SC06-329 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 377) and a light chain variable region (SEQ ID NO: 378) encoded by the nucleic acid sequence shown in SEQ ID NO: 3,79, and the amino acid sequence shown in SEQ ID NO: 380. The VH-locus is VH1 (1-69) apd-the VL locus is VKIII (A27).
[365] The amino acids encompassing the CDRs dre,highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-329 antibiody have the following CDR
sequences:
SNSIS (HCDR1, SEQ ID NO: 649), GIFALFGTTDYAQKFQG (HCDR2, SEQ ID NO: 650) and GSGYTTRNYFDY (HCDR3, SEQ ID NO: 651). The light chain CDRs of the SC06-329 antibody have the following CDR sequences: RASQSVSSNYLG (LCDR1, SEQ ID NO:

652), GASSRAS (LCDR2, SEQ ID NO: 653) and QQYGSSPLT (LCDR3, SEQ ID NO:
654).

[366] SC06-329 nucleotide sequence (SEQ ID NO: 379) gaggtccagc tggtacagtc tggggctgag gttaagaagc ctgggtcctc ggtgaaggtc tcctgcaagg cttctggagg catcttcaga agcaattcta tcagttgggt gcgacaggcc cctgggcaag ggcttgagtg gatgggaggg atcttcgctc ttttcggaac aacagactac gcgcagaagt tccagggcag agtcacgatt accgcggacg aatcttcgac cacagtctac ctggagctga gtagcctgac atctgaggac acggccgttt attactgtgc gagaggcagt ggctacacca cacgcaacta ctttgactac tggggccagg gcaccctggt caccgtctcg agcggtacgg gcggttcagg cggaaccggc agcggcactg gcgggtcgac ggaaattgtg ctgactcagt ctccaggcac cctgtctttg tctccagggg aaagagccac actctcctgc agggccagtc agagtgttag cagcaactac ttaggctggt accagcagaa acctggccag gctcccaggc tcctgatcta tggtgcatcc agcagggcca gtggcatccc agacaggttc =
agtggcggtg ggtctgggac agacttcact ctcaccatca gcagactgga gcctgaagat 660 tttgcagtgt attactgtca gcagtatggt agctcacccc tcactttcgg cggagggacc aaggtggaga tcaaacgt [367] SC06-329 amino acid sequence (SEQ ID NO: 380) EVQLVQSGAEVKKPGSSVKVSCKASGGIFRSNSISWVRQAPGQGLEWMGGIFALFGTTDYAQ
KFQGRVTITADESSTTVYLELSSLTSEDTAVYYCARGSGYTTRNYFDYWGQGTLVTVSSGTG
GSGGTGSGTGGSTEIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLGWTQQKPGQAPRLLIY
GASSRASGIPDRFSGGGSGTDFTLTISRLEPEDFAVyYCQQYGSSPLTFGGGTKVEIKR
[368] SC06-329 VH amino acid sequence (SEQ ID NO: 377) EVQLVQSGAEVKKPGSSVKVSCKASGGIFRSNSISWVRQAPGQGLEWMGGIFALFGTTDYA
QKFQGRVTITADESSTTVYLELSSLTSEDTAVYYCARGSGYTTRNYFDYWGQGTLVTVSS
[369] SC06-329 VL amino acid sequence (SEQ ID NO: 378) EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLGWTQQKPGQAPRLLIYGASSRASGIPDRFS
GGGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKR
[370] The SC06-331 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 381) and a light chain variable region (SEQ ID NO: 382) encoded by the nucleic acid sequence shown in SEQ ID NO: 383 and the amino acid sequence shown in SEQ ID NO: 384. The VH-locus is VH1 (1-69) and the VL locus is VL3 (V2-14).
[371] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-331antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 571), GIIGMFGTANYAQKFQG (HCDR2, SEQ ID NO:
655) and GNYYYESSLDY (HCDR3, SEQ ID NO::!656)., The light chain CDRs of the SC06-331 antibody have the following CDR sequences: GGNNIGSKSVH (LCDR1, SEQ ID
NO: 621), DDSDRPS (LCDR2, SEQ ID NO: 622)`and QVWDSSSDH (LCDR3, SEQ ID
=
NO: 657).

[372] SC06-331 nucleotide sequence (SEQ ID NO: 383) gaggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatg-Cta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatccigta tgttcggtac agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatttacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggaaat 300 tatiactatg agagtagtct cgactactgg ggccagggaa ccctggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgtcgtg 420 acgcagccgc cctcggtgtc agtggcccca ggacagacgg ccaggattac ctgtggggga 480 aacaacattg gaagtaaaag tgtgcactgg taccagcaga agccaggcca ggcccctgtg 540 =
ctggtcgtct atgatgatag cgaccggccc tcagggatcc ctgagcgatt ctctggctcc 600 aactctggga acacggccac cctgaccatc agcagggtcg aagccgggga tgaggccgac 660 tattactgtc aggtgtggga tagtagtagt gatcattatg tcttcggaac tgggaccaag 720 gtcaccgtcc taggt 735 [373] SC06-331 amino acid sequence (SEQ ID NO: 384) EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIGMFGTANYA
QKFQGRVTITADEFTSTAYMELSSLRSEDTAVYYCARGNYYYESSLDYWGQGTLVTVSSGT
GGSGGTGSGTGGSTQSVVTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVV
YDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVLG
[374] SC06-331 VH amino acid sequence (SEQ ID NO: 381) EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIGMFGTANY
AQKFQGRVTITADEFTSTAYMELSSLRSEDTAVyõYCARGNYYYESSLDYWGQGTLVTVSS
[375] SCO6-331 VL amino acid sequence (SEQ ID NO: 382) QSVVTQPPSVSVAPGQTARITCGGNNIGSKSVHNNYQQKPGQAPVLVVYDDSDRPSGIPERFS
GSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVLG
[376] The SC06-332 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 385) and a light chain variable region (SEQ ID NO: 386) encoded by the nucleic acid sequence shown in SEQ ID NO: 387 and the amino acid sequence shown in SEQ ID NO: 388. The VH-locus is VH1 (1-69) and the VL locus is VKI (A20).
[377] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-332 antibody have the following CDR
sequences:
NFAIN (HCDR1, SEQ ID NO: 658), GIIAVFGTTKYAHKFQG (HCDR2, SEQ ID NO:
659) and GPHYYSSYMDV (HCDR3, SEQ ID NO: 660). The light chain CDRs of the SC06-332 antibody have the following CDR sequences: RASQGISTYLA (LCDR1, SEQ ID

NO: 661), AASTLQS (LCDR2, SEQ ID NO: 662) and QKYNSAPS (LCDR3, SEQ ID NO:
663).
, [378] SC06-332 nucleotide sequence (SEQ ID NO: 387) caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggta'aaggtc 60 tcctgcaagg cttctggagg ccccttccgc aattttgcta tcaactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcgctg tctttgggac gacaaagtac 180 gcacataagt tccagggcag agtcaccatc accg'cggacg actccacaaa tacagcttac 240 atggagctgg gcagcctgaa atctgaggac acggccgtgt attactgtgc gagaggtccc 300 cactactact cctcctacat ggacgtctgg ggcgaaggga ccacggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga catccagttg 420 acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 480 gcgagtcagg gcattagcac ttatttagcc tggtatcagc agaaacccgg gaaagttcct 540 aaactcctga tctatgctgc atccactttg caatcagggg tcccatctcg gttcagtggc 600 agtggatctg ggacagattt cactctcacc atcagcagcc tgcagcctga agatgttgca 660 acttattact gtcaaaagta taacagtgcc ccttctttcg gccctgggac caaagtggat 720 atcaaacgt 729 =
[379] SC06-332 amino acid sequence (SEQ ID NO: 388) QVQLVQSGAEVKKPGSSVKVSCKASGGPFRNFAINWVRQAPGQGLEWMGGHAVFGTTKYA
HKFQGRVTITADDSTNTAYMELGSLKSEDTAVYYCARGPHYYSSYMDVWGEGTTVTVSSGT
GGDGGTGSGTGGSTDIQLTQSPSSLSASVGDRVTITCRASQGISTYLAWYQQKPGKVPICLLIY
AASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPSFGPGTKVDIKR
[380] SC06-332 VH amino acid sequence (SEQ ID NO: 385) QVQLVQSGAEVKKPGSS VKVSCKASGGPFRNFAINWVRQAPGQGLEWMGGIIAVFGTTKY
AHKFQGRVTITADDSTNTAYMELGSLKSEDTAVY,YCA,RGPHYYSSYMDVWGEGTTVTVSS
[381] SC06-332 VL amino acid sequence (SEQ ID NO: 386) a DIQLTQSPSSLSASVGDRVTITCRASQGISTYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFS

[382] The SC06-334 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 389) and a light chain variable region (SEQ ID NO: 390) encoded by the nucleic acid sequence shown in SEQ ID NO: 391 and the amino acid sequence shown in SEQ ID NO: 392. The VH-locus is VH1 (1-69) and the VL locus is VL3 (V2-14).
[383] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-334 antibody have the following CDR
sequences:
SNAVS (HCDR1, SEQ ID NO: 664), GILGVFGSPSYAQKFQG (HCDR2, SEQ ID NO:
665) and GPTYYYSYMDV (HCDR3, SEQ ID NO: 666). The light chain CDRs of the SC06-334 antibody have the following CDR sequences: GGNNIGRNSVH (LCDR1, SEQ ID

NO: 667), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVWHSSSDHYV (LCDR3, SEQ ID
NO: 669).
a .

CA 02827301 =2013-08-13 [384] SC06-334 nucleotide sequence (SEQ ID NO: 391) gaggtgcagc tggtggagac tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 ccctgcaaat cttctggaag ccccttcagg agtaatgctg tcagctgggt gcgacaggcc 120 cccggacaag ggcttgagtg ggtgggagga atcctcggtg tctttggttc accaagctac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccaccaa cacagtccac 240 atggagctga gaggtttgag atctgaggac acggccgtgt attattgtgc gagaggtcct 300 acctactact actcctacat ggacgtctgg ggcaaaggga ccacggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgtc ctatgtgctg 420 actcagccac cctcggagtc agtggcccca ggacagacgg ccaggattac ctgtggggga 480 aataacattg gaagaaatag tgtgcactgg tatcagcaga agccaggcca ggcccctgtg 540 ctggtcgtgt atgatgatag cgaccggccc tcagggatcc ctgagcgatt ttctggctcc 600 aagtctggga acacggccac cctgattatc agcagggtcg aagtcgggga tgaggccgac 660 tactactgtc aggtgtggca tagtagtagt gatcattatg tcttcggaac tgggaccaag 720 gtcaccgtcc taggt 735 [385] SC06-334 amino acid sequence (SEQ ID NO: 392) EVALVETGAEVKKPGSSVKVPCKSSGSPFRSNAVSWVRQAPGQGLEWVGGILGVFGSPSYA
QKFQGRVTITADESTNTVHMELRGLRSEDTAVYYCARGPTYYYSYMDVWGKGTTVTVSSG
TGGSGGTGSGTGGSTSYVLTQPPSESVAPGQTARITCGGNNIGRNSVHWYQQKPGQAPVLVV
YDDSDRPSGIPERFSGSKSGNTATLIISRVEVGDEADYYCQVWHSSSDHYVFGTGTKVTVLG
[386] SC06-334 VH amino acid sequence (SEQ ID NO: 389) EVALVETGAEVKKPGSSVKVPCKSSGSPFRSNAVSWVRQAPGQGLEWVGGILGVFGSPSYA
QKFQGRVTITADESTNTVHMELRGLRSEDTAVYYCARGPTYYYSYMDVWGKGTTVTVSS
[387] SC06-334 VL amino acid sequence (SEQ ID NO: 390) SYVLTQPPSESVAPGQTARITCGGNNIGRNSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFS
GSKSGNTATLIISRVEVGDEADYYCQVWHSSSDHYVFGTGTKVTVLG
[388] The SC06-336 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 393) and a light chain variable, region (SEQ ID NO: 394) encoded by the nucleic acid sequence shown in SEQ ID NO: 395 and the amino acid sequence shown in SEQ ID NO: 396. The VH-locus is VH1 (1-69) and the VL locus is VKIII (A27).
[389] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-336 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 670), GIFGMFGTANYAQKFQG (HCDR2, SEQ ID NO:
671) and SSGYYPQYFQD (HCDR3, SEQ ID NO672)., The light chain CDRs of the SC06-336 antibody have the following CDR sequences: RASQSVSSSYLA (LCDR1, SEQ ID NO:

646), GASSRAT (LCDR2, SEQ ID NO: 631) andQQYGSSSLT (LCDR3, SEQ ID NO:
308).

=

[390] SC06-336 nucleotide sequence (SEQ ID NO: 395) cagatgcagc tggtacaatc tggagctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgs'cta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcttcggtatgtttgggac agcaaactac 180 gcgcagaagt tccagggcag agtcacgatt accgcggacg aattcacgag cgcggcctac 240 atggagctga gcagcctggg atctgaggac acggccatgt attactgtgc gaggtctagt 300 ggttattacc cccaatactt ccaggactgg ggccagggca ccctggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgga aattgtgatg 420 acacagtctc caggcaccct gtctttgtct ccagggcaaa gagccaccct ctcctgcagg 480 gccagtcaga gtgttagcag cagctactta gcctggtacc agcagaaacc tggccaggct 540 cccagactcc tcatgtatgg tgcatccagc agggccactg gcatcccaga caggttcagt 600 ggcagtgggt ctgggacaga cttcactctc accatcagca gactggagcc tgaagatttt 660 gcagtgtatt actgtcagca gtatggtagc tcatcgctca ctttcggcgg agggaccaag 720 ctggagatca aacgt = 735 [391] SC06-336 amino acid sequence (SEQ ID NO: 396) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIFGMFGTANY
AQKFQGRVTITADEFTSAAYMELSSLGSEDTAMYYCARSSGYYPQYFQDWGQGTLVTVSSG
TGGSGGTGSGTGGSTEIVMTQSPGTLSLSPGQRATLSCRASQSVSSSYLAWYQQKPGQAPRL
LMYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSSLTFGGGTKLEIKR
[392] SC06-336 VH amino acid sequence (SEQ ID NO: 393) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIFGMFGTAN
YAQKFQGRVTITADEFTSAAYMELSSLGSEDTAWYCARSSGYYPQYFQDWGQGTLVTVS
=r, [3931 SC06-336 VL amino acid sequence (SEQ ID NO: 394) EIVMTQSPGTLSLSPGQRATLSCRASQSVSSSYLAWYQQKPGQAPRLLMYGASSRATGIPDR
FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSSLTFGGGTKLEIKR
[394] The SC06-339 HA-specific single-chain Fv antibody includes a heavy chain variable =
region (SEQ ID NO: 397) and a light chain variable region (SEQ ID NO: 398) encoded by the nucleic acid sequence shown in SEQ ID NO: 399 and the amino acid sequence shown in SEQ ID NO: 400. The VH-locus is VH1 (1-69) and the VL locus is VL3 (V2-14).
[395] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-339 antibody have the following CDR
sequences:.
SYAIS (HCDR I , SEQ ID NO: 303), GIIAIFHTPKYAQKFQG (HCDR2, SEQ ID NO: 306) and GSTYDFSSGLDY (HCDR3, SEQ ID NO: 725). The light chain CDRs of the SC06-339 antibody have the following CDR sequences: GGNNIGSKSVH (LCDR1, SEQ ID NO:
621), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVVVDSSSDHVV (LCDR3, SEQ ID NO: 642).
s.

=

[396] SC06-339 nucleotide sequence (SEQ ID NO: 399) gaggtgcagc tggtggagtc cggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg catcttcaac agttatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggc atcatcgcta tctttcatac accaaagtac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgaa cacagcctac 240 atggaactga gaagcctgaa atctgaggac acggc'cctgt attactgtgc gagagggtcc 300 acttacgatt tttcgagtgg ccttgactac tggggccagg gaaccctggt caccgtctcg 360 agcggtacgg gcggttcagg cggaaccggc agcggcabt'g gcgggtcgac gcaggcaggg 420 ctgactcagc caccctcggt gtcagtggcc ccaggacaga cggccaggat tacctgtggg 480 ggaaacaaca ttggaagtaa aagtgtgcac tggtaccagc agaagccagg ccaggcccct 540 gtcctagtcg tctatgatga tagcgaccgg ccctpaggga tccctgagcg attctctggc 600 tccaactctg ggaacacggc caccctgacc atcagcagg4 tcgaagccgg ggatgaggcc 660 gactattact gtcaggtgtg ggatagtagt agtgatcatg tggtattcgg cggagggacc 720 aagctgaccg tcctaggt 738 [397] SC06-339 amino acid sequence (SEQ ID NO: 400) EVQLVESGAEVKKPGSSVKVSCKASGGIFNS YAISWVRQAPGQGLEWMGGRAIFHTPKYAQ
KFQGRVTITADESTNTAYMELRSLKSEDTALYYCARGSTYDFSSGLDYWGQGTLVTVSSGTG
GSGGTGSGTGGSTQAGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVY
DDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTKLTVLG
[398] SC06-339 VH amino acid sequence (SEQ ID NO: 397) EVQLVESGAEVKKPGSSVKVSCKASGGIFNSYAISWVRQAPGQGLEWMGGIIAIFHTPKYA
QKFQGRVTITADESTNTAYMELRSLKSEDTALYYCARGSTYDFSSGLDYWGQGTLVTVSS
[399] SC06-339 VL amino acid sequence (SEQ ID NO: 398) GSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTKLTVLG
[400] The SC06-342 HA-specific single-chain Frantibody includes a heavy chain variable region (SEQ ID NO: 401) and a light chain variable'region (SEQ ID NO: 402) encoded by the nucleic acid sequence shown in SEQ ID NO: 4'03.:and the amino acid sequence shown in SEQ ID NO: 404. The VH-locus is VH1 (1-69) and the VL locus is VKIV (B3).
[401] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-342 antibody have the following CDR
sequences:
SYAIS (HCDR1, SEQ ID NO: 251), GVIPIFRTANYAQNFQG (HCDR2, SEQ ID NO: 249) and LNYHDSGTYYNAPRGWFDP (HCDR3, SEQ ID NO: 246). The light chain CDRs of the SC06-342 antibody have the following CDR sequences: KSSQSILNSSNNKNYLA
(LCDR1, SEQ ID NO: 245), WASTRES (LCDR2, SEQ ID NO: 570) and QQYYSSPPT
(LCDR3, SEQ ID NO: 250).
' ( =
[402] SC06-342 nucleotide sequence (SEQ ID NO: 403) caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg cttcttcagc agctatgcta tcagctgggt gcgccaggcc cctggacaag gacttgagtg gatggggggg gtcatcccta tctttcgtac agcaaactac gcacagaact tccagggcag agtcaccatt accgcggacg aattcacatc gtatatggag ctgagcagcc= tgagatctga cgacacggcc gtgtattact gtgcgaggtt gaattaccat gattcgggga cttattataa cgccccccgg ggctggttcg acccctgggg ccagggaacc ctggtcaccg tctcgagcgg tacgggcggt tcaggcggaa ccggcagcgg cactggcggg tcgacggaca tccagatgac ccagtctcca gactccctgg ctgtgtctct gggcgagaag gccaccatca actgcaagtc cagccagagt attttaaaca gctccaacaa taagaactac ttagcttggt accagcagaa accaggacag cctcctaagc tgctcattta ctgggcatct acccgggaat ccggggtccc tgaccgattc agtggcagcg ggtctgggac agatttcact .

ctcaccatca gcagcctgca ggctgaagat gtggcagttt attactgtca gcaatattat agtagtccgc cgacgttcgg ccaagggacc aaggtggaaa tcaaacgt [403] SC06-342 amino acid sequence (SEQ ID=NO: 404) QVQLVQSGAEVKKPGSSVKVSCKASGGFFSSYAISWVRQAPGQGLEWMGGVIPIFRTANYA
QNFQGRVTITADEFTSYMELSSLRSDDTAVYYCARLNYHDSGTYYNAPRGWFDPWGQGTLV
TVSSGTGGSGGTGSGTGGSTDIQMTQSPDSLAVSLGEKATINCKSSQSILNSSNNKNYLAWYQ
QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPPTFGQ
GTKVEIKR
[404] SC06-342 VH amino acid sequence (SEQ ID NO: 401) QVQLVQSGAEVKKPGSSVKVSCKASGGFFSSYAISWVRQAPGQGLEWMGGVIPIFRTANYA
QNFQGRVTITADEFTSYMELSSLRSDDTAVYYCARLNYHDSGTYYNAPRGWFDPWGQGT
LVTVSS
[405] SC06-342 VL amino acid sequence (SEQ ID NO: 402) DIQMTQSPDSLAVSLGEKATINCKSSQSILNSSNNKNYLAWYQQKPGQPPKWYWASTRES
GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPPTFGQGTKVEIKR =
= [406] The SC06-343 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 405) and a light chain variable region (SEQ ID NO: 406) encoded by the nucleic acid sequence shown in SEQ ID NQ: 407 and the amino acid sequence shown in SEQ ID NO: 408. The VH-locus is VH1 (1-69) and the VL locus is VL3 (V2-14).
t [407] The amino acids encompassing the CDRs are highlighted in bold in the sequences = =
below. The heavy chain CDRs of the SC06-343 antibody have the following CDR
sequences:
YYAMS (HCDR1, SEQ ID NO: 242), GISPMFGTTTYAQKFQG (HCDR2, SEQ ID NO:
307) and SSNYYDSVYDY (HCDR3, SEQ ID NO: 290). The light chain CDRs of the 5C06-343 antibody have the following CDR sequences: GGHNIGSNSVH (LCDR1, SEQ ID

NO: 224), DNSDRPS (LCDR2, SEQ ID NO: 223) and QVVVGSSSDH (LCDR3, SEQ ID
NO: 227).
=

-t:.' [408] SC06-343 nucleotide sequence (SEQ ID NO: 407) caggtccagc tggtgcagtc tggagctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagt caccttcagt tactatgcta tgagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggagga atcagcccta tgtttgggac aacaacctac 180 gcacagaagt tccagggcag agtcacgatt actgcggacg actccacgag tacagcctac 240 atggaggtga ggagcctgag atctgaggac acggCcgtgt attactgtgc gagatcttcg 300 aattactatg atagtgtata tgactactgg ggccagggaa ccptggtcac cgtctcgagc 360 ggtacgggcg gttcaggcgg aaccggcagc ggcactggcg ggtcgacgca gtctgtcgtg 420 acgcagccgc cctcggagtc agtggccpca ggacagacgg ccaggattac ctgtggggga 480 cataacattg gaagtaatag tgtgcactgg taccagcaga agccaggcca ggcccctgtg 540 ctggtcgtgt atgataatag cgaccggccc tcagggatcc ctgagcgatt ctctggctcc 600 aactctggga acacggccac cctgaccatc agcagggtcg aagccgggga tgaggccgac 660 tattactgtc aggtgtgggg tagtagtagt gaccattatg tcttcggaac tgggaccaag 720 gtcaccgtcc taggt 735 [409] SC06-343 amino acid sequence (SEQ ID NO: 408) QVQLVQSGAEVKKPGSSVKVSCKASGVTFSYYAMSWVRQAPGQGLEWMGGISPMFGTITY
=
AQKFQGRVTITADDSTSTAYMEVRSLRSEDTAVYYCARSSNYYDSVYDYWGQGTLVTVSSG
TGGSGGTGSGTGGSTQSVVTQPPSESVAPGQTARITCGGHNIGSNSVHWYQQKPGQAPVLVV
YDNSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWGSSSDHYVFGTGTKVTVLG
[410] SC06-343 VH amino acid sequence (SEQ ID NO: 405) QVQLVQSGAEVKKPGSSVKVSCKASGVTPSYYAMSWVRQAPGQGLEWMGGISPMFGTTT
YAQKFQGRVTITADDSTSTAYMEVRSLRSEDTAVYYCARSSNYYDSVYDYWGQGTLVTVS
[411] SC06-343 VL amino acid sequence (SEQ ID NO: 406) QSVVTQPPSESVAPGQTARITCGGHNIGSNSVHWYQQKPGQAPVLVVYDNSDRPSGIPERFS
GSNSGNTATLTISRVEAGDEADYYCQVWGSSSDHYVFGTGTKVTVLG
, [412] The SC06-344 HA-specific single-chain Fvantibody includes a heavy chain variable region (SEQ ID NO: 409) and a light chain varialire region (SEQ ID NO: 410) encoded by the nucleic acid sequence shown in SEQ ID NO: 411.and the amino acid sequence shown in SEQ Ill NO: 412. The VI-I-locus is VH1 (1-69) and the VL locus is VL1 (V1-13).
[413] The amino acids encompassing the CDRs are highlighted in bold in the sequences below. The heavy chain CDRs of the SC06-344 antibody have the following CDR
sequences:
NYAIVIS (HCDR1, SEQ ID NO: 222), GIIAIFGTPKYAQKFQG (HCDR2, SEQ ID NO:
221) and IPHYNFGSGSYFDY (HCDR3, SEQ ID NO: 220). The light chain CDRs of the SC06-344 antibody have the following CDR sequences: TGSSSNIGAGYDVH (LCDR1, SEQ ID NO: 219), GNSNRPS (LCDR2, SEQ ID NO: 231) and GTWDSSLSAYV (LCDR3, SEQ ID NO: 280).

=
[414] SC06-344 nucleotide sequence (SEQ ID NO: 411) caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgagagtc 60 tcctgcaagg cttctggaag catcttcaga aactatgcta tgagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcgcta tttttgggac accaaagtac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatcgacgag cactgtctac 240 atggaactga gcggactgag atctgaggac acggccatgt attactgtgc gaggattccc 300 cactataatt ttggttcggg gagttatttc gactactggg gccagggaac cctggtcacc 360 gtctcgagcg gtacgggcgg ttcaggcgga accggcagcg gcactggcgg gtcgacgact 420 gtgttgacac agccgccctc agtgtctggg gccccagggc agagggtcac catctcctgc 480 actgggagca gctccaacat cggggcaggt tatgatgtac actggtacca gcagcttcca 540 ggaacagccc ccaaactcct catctatggt aacagcaatc ggccctcagg ggtccctgac 600 cgattctctg gctccaagtc tg9cacgtca gccaccct4 gcatcaccgg actccagact 660 ggggacgagg ccgattatta ctgcggaaca tgggatagca gcctgagtgc ttatgtcttc 720 ggaactggga ccaaggtcac cgtcctaggt 750 [415] SC06-344 amino acid sequence (SEQ ID NO: 412) QVQLVQSGAEVKKPGSSVRVSCKASGSIFRNYAMSWVRQAPGQGLEWMGGIIAIFGTPKYA
QKFQGRVTITADESTSTVYMELSGLRSEDTAMYYCARIPHYNFGSGSYFDYWGQGTLVTVSS

LLIYGNSNRPSGVPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAYVFGTGTKVT
VLG
[416] SC06-344 VH amino acid sequence (SEQ ID NO: 409) QVQLVQSGAEVKI(PGSSVRVSCICASGSIFRNYAMSWVRQAPGQGLEWMGGHALFGTPKY
AQKFQGRVTITADESTSTVYMELSGLRSEDTAMYYCARIPHYNFGSGSYFDYWGQGTLVT
VSS
[417] SC06-344 VL amino acid sequence (SEQ ID NO: 410) TVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKWYGNSNRPSGVPDR
FSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAYVFGTGTKVTVLG
IgG HA Antibodies [418] The CR6141 HA-specific IgG antibody inCludes a heavy chain variable region (SEQ
= t ID NO: 199) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
279 and the heavy chain amino acid sequence shown in SEQ ID NO: 413. The CR6141 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 414) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 415 and the light chain amino acid sequence shown in SEQ ID NQ: 416.

;..
1,=1 =
g - LL
SdcldIA A SdVVV2INICIANIDODArldISA A OODA A AV ACITVOISSIETIA CUD S SDRINCId AD
SMLLSVM AITDIdd090100A M VIANDINNIS SA1A SS31 DNIIVIlg D1SA SCId SOIIAI A ACI
(9It7 :ON m Oas) aauanbas ppe (mum umtD 1b19113 [aid LS9 q6.45pb3 688633eeol qobvbppoop 6.4633305vo bv6q33666e 33-epoovb15 009 5v50543063 y46'466ee3P obev6v53e.4 3v63065-epo hp6.4333v34 333vofreobp ObS 61336epplo 3e3313ebbe Pobeopbbvo beboop8.463 6y6e5by336 poevo6506e 08b 5e35q33383 pv3Pbb-456P p6645y3645 5v-e3o5bp.55 533333E134 goeyop-OZb 84335q6q66 '4636Poo633 vo663bpbpp fy4o6v3Eyebo v63o4oppoo 33.4-434eoql 09E 61635y3poe 3533563515 opppolp126 616pppoop5 .55p.5535831 Tqopaloloo 00 .1.3E-45y-1E-11 plve36v31.5 qoPT4p-4148 -2365'451p5p e6q368y36-1 pobv35polp ObZ oppoqoqopo q4-4ebeop55 6q3485535v 386-46yoqqy 633v5.4303.4 558633gyp5 081 65poppgogy 3656-43E-4.44 vo.4381.36-ep lopwobeoe bbpoopppbp p6poop45.61 OZI qp5p3p.43 PPBERT2POP yoolo6popq p.4.4.4'45.46p6 poo6pool5p e3bloppoqu 09 oop33668-26 p5358.6.43.43 qb-451065-ao poqop5p33.4 3-46yoqoy6q v645-4464p5 (Sit :coN Oas) aauanbas amwaianu tnnto 11-12111 IVI9113 Ezzrl SS AIALLOODMAUISNSIIIIDAA A VICIaSSISS131A1AVISISMGVILLANDOAMOVA
NIN9NAVSIM9IAIMF1009dVOIIMAAAAAD1AIADSVNDSANASV9d)INARVOSOKIOA1 (661 :coN.m bas) aauanbas Nan oupue HA ItI9113 [UV]
, 2=
N9dSISISMOLAHNITIV1HIAIASDS4 ANDOOMNSNU AEDISKIAASOUSCriAddilNANNgdOONSaMg A VICISd AA ON AIDEI SA
ONN,LIAI3MISddliLA AOdg21d0 N S AN DN
A RN ON-MC[0M A S A
AllAISNAOgglIcININVNHAgAOCIAAMNI4NAgdG2HSACIAAADIAgdINSIIAIIICINcDiddA
Id A SdD DTI3dVdDddaL1-11,31COSNdRA UNUANIN SdN H NANDIA.LOID1S S SdAl AAS AIDSSOIA
VddlHADSEIVOSNIM SA1AdAdd ACIN AIDDIVVIDOSISN S SdtrIdA A S
dONISVSSAIALLOODMACIISIISIIVDAAAVICOSIIISSIMAIAVISISNCIVILLANDOAMOVA
NINDNAV SIMOIAIMTIDODd AMA A A AD141A DSVNDSAN AS V9dN31 AMIDSOAIOA
(fib :ON m Oas) 33uanbasppeoummumoSneallivi9u3 [lynd SECT beeob .633335v613 OZEI 35p5-4335p8 PP6POOOPDP qOPOOPPOPO bqopo58253 po5.4pb.4538 pobqp6p3qq 09ZI 6-483-ep3656 p36y355465 338P6peop5 bqb33-23438 py3bppy.451 334q3-4.435E.
00ZI 3563vbobvp Et6436.4643 000000PODE bev3p4pypo yv6e63336e pobboey36e ObII 5-2565-46-ebb 4533504pou 636popoov4 3143868p-e6 q56.4315130 poq3331615 0801 be33vp52E3 pefqybP66p 655335epop 3308.4opoe3 E-46.45.6e333 obe5563333 OZOI 6pop665-evo 385-2-e35-epq yoop5PP5P6. olvoo=o64 336403356y poep38p645 096 6vvo616pp3 p-46P65Pyob 6ovv513864 3v6bpoppo6 .436.4633y3.4 38-4506v648 006 6485533v43 ovo6vor,voy 46Po6p5by5 6633336peo 3vbeyo353E. voyob.456p8 068 6463563-258 483.24554ov v3.446pPb4.6 5v53333p66 Ebovoo6pb4 53v56.456.45 08L 54836qoop6 .486e633033 p65036po3,p 842o4oppv3 v56vpoo36v 203=3=4-4 OZL 84334.45.45o 3q3Doe5635 66135.438eb =33354333 5.433333336 gpoupuoo3v 099 6ppop635.43 6-26-e-epoofre 65-4836ovep op65-455ppo opoevobe33 obvvoppope 009 615opv3643 4v3P4o3p5v po3v3666-43 36=236235p3 336q5povbq 6.6.4638v36v ObS 54336rov36 430,653636 v6P.36'436.45 3353333110 op3p354838 535-e=y51.4 08b 33836836Po Py66435-28.4 533'eblb000 5p63333-413 yloebbey54 OZb 610=6335y ovo5635635 poovo5y6pp obp3.5v000p 366.4p000aq 16q5p5poop 095 36b5ppopyo 5y-436.45p63 q3.4533P3.46 5opoop5,65-2 uo36665q3-4 63y55-00E p5v.45-ep5P6 36-461op.4.4p q6q5qob5oP 3p6Py64olp 5p5q338E38 p5q3bu.68.4v ObZ 3E-4335voyo bebopoolye por,6635ope glybovoqbe 5p3656e33.4 45pebv3e35 081 . qp.4opyeoPo PP.465gypop 1.43635.231p 554v565qp6 546ebT4358 6-e-epp55-OZT 3386poe836 165613p-46-4 61plop1366 33e3-41opeo p1666431-43 65y-23.5.433q 09 = 346.8e-e648p 3.4336566.43 36p-25-ev6-1,6 5p51355654 345v06.156-4 p6vool.56v5 (6LZ :0N ca Oas) a3uanbas 3pp0apnu umto Simi' jump [6117]
IL6tZ0/ZI0ZS91I3cl 68tZII/ZIOZ OM

I.DdS'ISISMOIAHNHIVRHIAIASOSAANOOOM
NSNCIAEDISAIAASOGSCIIAdd.LLNANNgdOONSgMgAVICESdAADNAIDEISAON)111Alg gliSdcIlLAAOdglidODNYMSIINHIdVdIV,INSANDNAMIDNIMCIOHIAIIASAANAISN
AORgIldNINVNHA3A9OAAMNANA3dCl1HSAUAAA3IAgdI1SIJAIIIC13101daTIAASd9 D113dVdDddaLHINCIDSNdgMDIGANINSOIHNANDIAIOIDISSSdAJLAASSISKIDS
SOIAVddIHADSEIVDSNIASAIAdgdAAGNAIDDIVVIDOSISNSSdIVIdgASdONIS
VSSAIALL9MDMACHAIIMIAOADIAIHNVDAAVIVICOSNISSIMATAAIDVdCKIVILLAN90.4.31 dVANIIDAIdIIDOIAIMgd[DOWVONAMSIVASNMODMIDSANASSOd3DIA3VDSgAIOA2 (6117 :ON GI O3S) aauanbas man oupue uinto Annall ssz9H3 [at]
ESET 52E, obboopofreb qopbpbqopb 26PE6POOOP
OZET ovqopoopvp vobgpoobbv bovobgeb.45 ofyeobwovo 4.451.6ogyo6 56vo5yo5bq 09ZI bboobpbppo PHY4booppq obpyobvovq bqopqqoglo bv3b5op6ob po-e6b4o545 0OZT qoopopoovo py6PyoPqop PoPybyboop bupobbopyo bp5pb55-45v 55.4bopboqu Obit 3vba5yopo3 Pq3qq365.5P e54b6log5q ooPoqopoge, q65poor-ebv poop5qp5p.5 0801 bp6560o6p3 oppopeqopo uop-45-45beo 0006p56600 335-poo.665p 2o365-ev35v OZOT oqyoaebvv6 p6o4P00000 6.43o513335 5o P355 .45bppo545-e. yopq6p6fiep 096 paboppbqob 5.4oy6bepov obwbgboop 3136.48o6vb 4561b5boov loopobpoyv 006 ovqbvo5v65 ybbb0000bp opPEveyoo6 oepaeofqbb e56-4bob5op 56-4bovqbbq Ob8 ovpD-4.46pe5 qffyebooDop 55opoobu 6qbaebb.455 -466-46obqoo u5.456p600p 08L oppbboDbeo lvfyqpolopo eoa5peopo bepopooppo qqfyloolqb; bool000ebb OZL = 3655qp6gob uboo33p5qo pobloop000 obqopeopoo ov5pyop6o6 qobebee000 5p5E.q5obop vpopE6q5bp ep?vovpofre 3oo5Epop33 vp&T63pp35 qoqpovloov 009 6vpoovo556 qop5p06-eob vpooblboop bqayqbobeo bp5wobeop .16.4036505v ObS
obpEoppErqob gboob0000l 16ovoyobqb obbobyDopb qqpobobbob vovpbblobp 08b 6-45=26.46o pobp5oopoq -43E-4D-E,66ey 5.455-4=5-40 655 x5 6epeo6bob5 OZb 36po3p3Ere5 ppobeof)Poo 000bbloopo oqqbqbDbpo pop65bpupo vo5eqp5gbp 4Eopyo qbbovooP56 bpPpobbbbq oq6opbbqpq 3v-ev53bobq bbypoyqbbb Ervelpoppe5 3b5 P3 161Poo6bov oebbPoloTe Eofyloo5vp5 v6gobebblp ObZ opqq15-eopo 56805D-1.4qp bov5636pop lgyboupq&e. 5po565-epoq q6p-e5ooya6 081 ovqvppyoyv opqaqq.4.4-4 pq000qvoqp bbb-25.66.4p6 bqbp6.40355 fiepoebbqop OZT po66voy6o5 lbbfyw6.23.1 PlooTewbp obooqlooDo bby.56q3113 86ppo6qqpq 09 olbpppbqbb 3.4=165510 o5vybp-26q6 erebqobbbbq ogfre55q6bq obvpbqbbvb ND :0N ai Ogs) aauanbas appoapnu umo SAnall sszwn [9zp]
.ZZI7 :ON GI Os ui umogs aouonbos mor ou!wr Lump lt12!1 oto pur Zt :ON GI OHS u! umoys ootionbas oppoolonu u!rgo 1142!!
papooug (ozt, :0N cii Ogs) uo!2o.! alcryun lump 1112!! sopniou! sir Xpoquuu DUP3ds-VH SSZ9):I3 NI '6117 :ON GI bas unnogs aouonbas por otuum upio icAraq Pug 8 It :ON GI ORS ui umogs oouonbas appogionu turtio Xnuog oip q papopuo (Lit :ON GI
Ogs) uo!o.! alquygn. Lump Xnuottu sapnpu! Xpoq!lur I ou!oads-vH cgz9N3 oqj [szt]
NNICIANI9DOArIdISAA003AAAVACITVOISSIEILAI1DS9SDSANUdA9 SaI1SVMAYIDIddODd,100AMVIANNNNSSAIASOSSN3NIIIVI9ISAVISGdS011A1AACI
(pip :oN m 03s) aauanbas man ougun IA IVI9II3 [Kt]
32MINASNIAdSSIDORLARDVAANHMgAUV
NSIIIISSISAISCINSCIOgIAMSNDSO1VNCIAMMOANVglIdAANNITIDAASVIDSNIOM
IL61'a/ZIOZS9lID.:1 68tZII/ZIOZ OM

[428] CR6255 VH amino acid sequence (SEQID NO: 417) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKY
APKFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVS
[429] CR6255 Light Chain nucleotide sequence (SEQ ID NO: 421) tcctatgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60 tcttgttctg gaagcacgtt caacatcgga agtaatgctg tagactggta ccggcagctc 120 ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccctc aggggtccct 180 gaccgattct ctggctccag gtctggcacc tcagcctccc tggccatcag tgggctccag 240 tctgaggatg aggctgatta ttactgtgca gcatgggatg acatcctgaa tgttccggta 300 ttcggcggag ggaccaagct gaccgtccta ggtgcggccg caggccagcc caaggccgct 360 cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420 gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480 agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540 gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600 tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660 [430] CR6255 Light Chain amino acid sequence (SEQ ID NO: 422) SYVLTQPPSASGTPGQRVTISCSGSTFNIGSNAVDWYRQLPGTAPKLLIYSNNQRPSGVPDRFS
GSRSGTSASLAISGLQSEDEADYYCAAWDDILNVPVFGGGTKLTVLGAAAGQPKAAPSVTLF
PPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSL
TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
[4311 CR6255 VL amino acid sequence (SEQ IDNO: 420) SYVLTQPPSASGTPGQRVTISCSGSTFNIGSNAVDWYRQLPGTAPKLLIYSNNQRPSGVPDRFS
GSRSGTSASLAISGLQSEDEADYYCAAWDDILNVPVFGGGTKLTVLG
[432] The CR6257 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 423) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
424 and the heavy chain amino acid sequence shown in SEQ ID NO: 425. The CR6257 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 426) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 427 and the light chain amino acid sequence shown in SEQ ID NO: 428.

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ogobbbloqo gpooybqoop loo5bopopv 3bbqpq6epo olobbgolog 4obaluvqp1 llbbbbpoqo pobbolpelb eogbbper4pq. qqpbqpoqop vv000pobvp eobbpopoeo OZT
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SAIALLONDMAGIALLMIAOADIAIHNVDAAVIVICOSHISSITAIAAIDVACIGVILLANOOANdV
ANLLOdIdIIDDIAIMgc1000cIVOWASIVASII4dODSVMDSANASSOd3INATIOSONIOAO
= (czp :own Oas) aauanbas rope oupun HA LSZ9213 [Sa]
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(szp :0N ui Oas) 33uanbas p[au oup.un mega Anna"' isz9H3 [pcp]
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pubobuopoo egoggobb5u e61.55.401b1 popog000qb qbbppoee5u epoebqp6e5 bp5553o6eo oppoobwoo po.elbqbbpo opobp6o600 Do6poobbbp poo66epobp OZOT
Dqvpoybueb vboqpop000 bloobloop5 bypoepo5p6 qbbvpob.45-e yoyqbebbep obboyybqob 6qopb6pooP ofy4oblbooe ow6.4.56pb 1551556=e loppobeo2p ougbpo6p65 p6.66poop5P pooebypoo6 oppopp6q65 pbbq5obbop 56-46peq6bq 068 3yea416-e-e6 -46.5u6opooe bbyboPpo5p fy4boy.65.46.6 qbbq635-4po e6q6b-eboop poubboobuo qubquol000 vot,b8wepop bPp00000po qqbqDolqbq booq000p55 OZL
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oby5yobgob qboob0000q wovoyo5q5 35636-eooy5 qgpobobBob yoyy5bqobp 08b bqb0ae5353 oofrebopooq govqpv6frev 5-455.4=64o 5bbqopoboo 5vopobbo6b OZb oovooyobv5 vrobeoboo oopbbq000p ogq6.4bo6po 000bberevoo pobvqobqby boqoqopovo 165oeooP55 bvvvo656.6q oq6ov5.6qeq ovvv6o636q .65vopeqe65 bqpqpoyypb obqbqoPiov A61vDobbot, oP66vbqoqp bobqoobpob e6lobe661p ObZ
opqqq6povo 565363-my boebboboov .qq-ebopolbu fy2o665-eooq qbpvboopDb OPTePPEOPP oPqbblqq.1.4 Ploopqvaqp 68bpbbbqe6 blbp6loobb Ereeoeftrloo OZT
oobbuov6o6 q56bqobvol uqp5qPqobP obooqqoppo 65p661D1qo bbupobqloq ogbppv51.66 alop1655qo obpebppb16 6pblobb66-4 pqbpob-46b1 obypo-lb5pD
(pzp :coNUI Ogs) aauanbas aimoalanu u[gto JAeH Lsz9113 [ccp]
IL61'a/ZIOZS9II3.:1 681'ZII/ZIOZ OM

IASAANAISNAOgglIdNINVNHA2A9c1A1MNANAgdsagHSACIAAADIAgd111811AIIICINd31 ddrIAASdOOTIgdVdDddDIRDICIDS31dgA2DICIANINSOIHNIANDIAIOIDISSSdAIAASSI
SAIDSSOIAVd.41HADSIIVDSKAASAIAd.gd,4ACINAIDDIVVIDOSISNSSAgd,dASdONIS
VSSAIAJLIONDMACIIALMAOADMINVDAAINVIC13SWISS-121AIAAIDVKICIVIIIA1100.431 dVAN.LIDAIdllODIAIM3dOODdVOIIAMSIVASIldc1D9SVNDSANASSO(DINA3VDSgAIOAR
(La :0N ai Oas) 3' uanbas man ounun tquip Siteall 09z9H3 Mt]
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69[s) uo!S'al ziqrprik Lnrqo 4Aroq r sopnian Xpoqpur 951 wads-1m 09z913 oqi [6cid DIA.LANIDIOJAAISSSIASSDAACIdgMVOIDSIEISVINDSNSOSJII
NSADScIIINSA3AIIAIINdV)IDdHOOAMSAANADDACISSIDIDSIIISODdSOSAVVdOrIVS0 (9zt :43N ai Ogs) aauanbas ppe ounue LSZ9113 SDgidVAINgAISDHHIAOD SASSHSNMOgcli ISIASSVVANNNSONSdillgADVNAdSSCIV3IMVAIAVDdkAISMATMINVOlggSSddd TLASdIfsr>lcIOOVVVD1A,LANIDIDdAAISSSIASSDAACIVgCOVOIDSILISVINDSNSOS.411 NSADScIIINSAgAIIAIINdYNDdHOOAMSAANAD9ACISS19.0SIIISO9dSOSAVVdOrIVS0 (8Zt :0N al ()as) aauanbas man ounun uluto 10!-I LSZ911D La]
IL6tZ0/ZIOZS9/IDcl 68tZII/ZIOZ OM

TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL
VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH
EALHNHYTQKSLSLSPGK
[442] CR6260 VH amino acid sequence (SEQ ID NO: 429) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWMGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSS
[443] CR6260 Light Chain nucleotide sequence (SEQ ID NO: 433) tcctatgtgc tgactcagcc accctcagtc tctgggaccc ccgggcagag ggtcaccatc 60 tcttgctctg gaagccgctc caacgtcgga gataattctg tatattggta tcaacacgtc 120 ccagaaatgg cccccaaact cctcgtctat aagaatactc aacggccctc aggagtccct 180 gcccggtttt ccggctccaa gtctggcact tcagcctccc tggccatcat tggcctccag 240 tccggcgatg aggctgatta ttattgtgtg gcatgggatg acagcgtaga tggctatgtc 300 ttcggatctg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360 cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420 gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480 agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540 gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600 tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660 [444] CR6260 Light Chain amino acid sequence (SEQ ID NO: 434) SYVLTQPPSVSGTPGQRVTISCSGSRSNVGDNSVYWYQHVPEMAPKLLVYKNTQRPSGVP
ARFSGSKSGTSASLAIIGLQSGDEADYYCVAWDDSVDGYVFGSGTKVTVLGAAAGQPKAAP
SVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKY
AASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
[445] CR6260 VL amino acid sequence (SEQ L NO; 432) SYVLTQPPSVSGTPGQRVTISCSGSRSNVGDNSVYWYQklyPEMAPKLLVYKNTQRPSGVP
ARFSGSKSGTSASLAIIGLQSGIDEADYYCVAWDEPSVDbiNFGSGTKVTVLG
[446] The CR6261 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 435) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
436 and the heavy chain amino acid sequence shown in SEQ ID NO: 437. The CR6261 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 438) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 439 and the light chain amino acid sequence shown in SEQ ID NO: 440.

=

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OZET
OVqOPOOPPO Pobqpoobbp boPobqp5.46 obeobqpbpo qq6.46Dppob 5bpo6pD6.6-4 6boofyebpvo pb6q5oovol o6pPobpopq 6.400qqa4.40 5pobbov6o6 pova>go6q6 qopoppopeo OP6PPOPqOP pbpybuboo bvpobboupp bybv6b5q5u 561booboqp OPIT
py6o6poppo pqpqq3656p pb4b6-4D-461 oppoq000qb 165-epoupfm yopp61p6p6 bebbboo6vo 0000pf,qoop .23.245166pp 3oobv6bb3o 3obeopb6bp poo66veobp OZOT
oqvoop5pu5 p5oqPooppo 6-4=643 36 6ppopeoft.6 .466-epo6-46v yovq6e66pv obbovpbqo6 bloyELPoov obqobqboov ow6q5obpb q56166boop wovobpope ovgbpobv65 pbE6poop5P PDDp6vvoob oppopobqbe. P66.16o66op 66-4bopq66q oepoqq5ppb qbe.P5p000P 6bP6opDp6p 6q6DE.55q65 165qopfiqop p6-455y6poo oopbboo6vo qe6.4Poqpoo v3e.66pPoop 5vv0000poo qq5looq151 boowoopb6 OZL 365.6.435-4o6 v6oppoper4o poblopopoo 361Doppypo op5upopbob go6vbeeopo 6p55.46o6pe pvoPE6-466P POOPOPV05P 0006PPOE00 pp5-4bovvo6 loqppegoov Eyeopopo666 goobvp6Pob yopo61600p 5q6.6.45o5po Bp5wobpoy -45qop66o6y ObS obpbpo5w5 .463oboopoq gooppv35.45 ob5o5yooe5 qqopbob6ob vopebb.436-e, 08b 5.45pp-2516o po5e6p000q qoPqoe66pe 5-466qoper4o bboloopboo 5poe366366 OZb obpoovo5p6 ePo6r.oboo poobbqoppo oqq6q8obvp opob6bpeoo po5elo6gbp boqolboopo 155oPoovbE, bpPvo65551 oqbovaylvl ovvp6obobq 55v3op166.6 blygpoppp5 obqbqopqoP lblpoo66op opbbefyloqv bD6loo5moe. p6qo5pbbqy ObZ
ovqqqbpopo 655o5pqqqp bopbboboop qqpbopoTheye buo66bpopq -46.225oppob ovqpvppoyy ovlbblqqqq eg000qpoqp bbbp655qpb 6g6rebloobb Empopb6goo OZT
opbfreop5o6 q6b6-4obpog egobqpqobP obooqqopoo bbeaqoqqo bbypobT4Dq 09 olEyepv5-456 pqopq56Erlo obpp6ev6-45 6v6qo6566q p;6p66.4661 ofyeD5q66p6 (917 :ON CH 03S) aauanbas appoalanu uma Aga"' 19z9m3 [Lpid =
IL 6tZ0/ZI OZSIVIDcl 68tZII/ZIOZ OM

re: "
= ,;
=
t8 NAIDEISAONNLIAIgglISddlIAAOdglidOONYNSIINgIdVdIV3INSANDNATSIONIMGOIll AZIASAANAISNAO3g&ININVNHAgAOCIAAMN3NAMIgHSACIAAADIAgdINSITAIIIGN
cnicIdTUASd0011ThdVdDddaLHINCIDSNdgA2DICIANINSdNHNANDIAIOIDISSSdAIAAS
SISAIDSSZYIAVddIHAOSEIVOSNMSAIAdgdgACINAI3DIVVID9SISNSSdVid4ASdON
ISVSSAIALLONDMAGINAgSAANdONVDAAAVICOAWISNAMAIALIALLSOCIVILLANDOAN
OVANLIDAIdSIDDIAIMTIDODdVONAMSIVSDSdIADSANDSANASSDOINATVOSOOIOAO
(cm, :ON ai Ogs) aauanbas plan (mum tunto Xitnall z9z9H2) [sstd OSET
freppb6po3p Ecebqop6v64 oo6bpp6vo ()ZEE povopqopoo vPovo6qopo 66y6opobqe 5q6obvp513 fypoqq515op po666vo6vo 09ZI 68q553ofye8 uPopboqEop pogo6Ppobv Dv16.4poqqo qlobpobboe bo6pop5.6.10 0OZT bqbq000ppo ovooPfwvov qopeove6vb poobpoobbo ppobv&ebbb qbebbqboob 0611 ogyoybobPo poovqoqqob bbyybqb6go qbqopeoqop oqb.46bpooy yby-eopvb.42 080T 6e5bpbbboo bppooppobq poovo8q6.18 bpoppobp6.6 bopoobeoob E6ppoobbeP
OZOT obpoleDov6 evEreboqi6o poo'bqoo5qo oobbvpaepo 6v6qbbppob lbppaelbe6 096 6v-ep6BovvE. gobbqoyby ooPo6.43516 oovoloblbo be5q561.6.6b 00Pq00P06P
006 oveopqbpob pb5p5bbDoo p4P.epov6pe ooboveovob lawbbqbob 63.255-45peq 068 bbqoevoqqb e'Per4b6P5oo opP5byb 54boebb qbbqbbqbp6 qooeb-46bEb 08L poopovbboo bPoqPbqvol od3Pov55pp poobpp000p 000llblooq q6q6Doqopo OZL v6.53555.4ob lo6P600000 bqpoobl000 p000bqoovo POOOPbPPOP boe.go6Pbvv 099 oDobp65153 5oPPPoP56q 56puppeove ofm000bppo pooppfqbop ypbqaq-eopq 009 ooy5yoopPo 666-4o36.205 .eofyeopo5-46 ooy61.66-463 beo6p8goo5 poy16-06S 36-eo6pEceob goblEopEop ooqqoovopo 6.46p5535-eo opfyfloobob bob 086 o6ybgboop6 qboop6Pboo poqlovlopb bpp6-466loo 6.4obbbqopo boofreopo56 OZ6 obbobvpoyo br.ByPobP35 v000D355qo p000llbgeo 6eopoo655p ypoyobr.gob 09C q6p5oqol6o peo156oeoo p666pr-epE6 55.13q5op66 leovq6p6q5 eopqleqpee 00C pooq6by6o6 obl5logq1P .1.616o365ov opbbv5qpqe fwErwobpop pbqbbvbblp 06Z pygpoyeovo PPBOPOOT2E 00E650bDOU qqp6opoq6p 6pD65Erepoq q5ppuuppo6 081 aelqPPPOPU oppepermag oloopbpole bbe.pbbblp6 5q5p5glope) bppDpbbwo OZT oobbpopbob q6b5qobypq pbobg6PD55 p6poqq1qpo lbp5booglq 5bevo6looq 09 pq5pp5q6E. ogooqbbbqo p6Ppbp-efylb bp6.435656p albpobvpbq obvpv-465po (zi't' :coN m 03s) a3uanbas ap90apnu mega Sneall z9z9ND [pgt7]
.9tt :ON GI OgS u! umogs aouanbas mpg oup.up u!eqo 10!! oq pue Stt :ON cu Os ui umogs amoebas oppoolonu u!eqo AO!!
ocp /Cc! popoouo (11717 :ON CII Os) uo!2o.! Nguyen uno 142!1 g sapniou! osig Xpocplueci DII!oods-VH Z9Z9020 oqj.17-17 :ON CU Os u! umoys aouanbos p!ou ou!we uno Xneogotp Puu Zt7t7 :ON CEI OgS u! umogs aouonbos op9oolonu u!eqo Xnuaqoq og popoouo (1117 :ON GI
Os) uo!23.1 alqupen uno /CAMq p sopniou! Apocipue 92j oultoads-vll z9z9ND oqi [csf]
DIAI'DLIDDOAAAAVIcilINUMINTDAANV3UaLOIDIIMIVSIOS)1S9 SdllUdIDScRI>INNCIAITDIdVIDchOOAMSAACINDINSSSOSDSIIANO9dVVSASddOLLIASO
(go, :oN ai Ogs) aauanbas rope our= 1A19Z9113 [ZSt]
S3aLdVAINgAISOgHIAO3SAS2IHSNMO1dr1 SIASSVVANNNSONSd ___ gADV>IAdSSCIVMMVALLAVOdAlCESMAIIV)INVOIggSSddll IAScIVV,IdOOVVVMAETNIDODAAAAVIc:12121WAIVDAANYgClaL01911911VSIDSNSD
SDICIdIDSdIDINNUAITINdViDdlOOAMSAACINDINSSSOSDSIIANO9dVVSASddOrIASO
(orp :ON ai Oas) aauanbas pp e ounue u!uto 10!-If I9Z9113 [1St]
IL6tZ0/ZI0ZS91IDcl 68tZII/ZIOZ OM

=
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK
[456] CR6262 VH amino acid sequence (SEQ ID NO: 441) QVQLQQSGAEVKKPGSSVKVSCKVSGVIFSGSAISWVRQAPGQGLEWMGGISPLFGTTNYAQ
KFQGRVTITADQSTNTTYMEVNSLRYEDTAVYFCARGPKYYSEYMDVWGKGTTVTVSS
[457] CR6262 Light Chain nucleotide sequence (SEQ ID NO: 445) gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcgagtca gggcattagc agttatttag cctggtatca gcagaagcca 120 gggaaagttc ctacactcct gatctatgat gcatccactt tgcgatcagg ggtcccatct 180 cgcttcagtg gcagtggatc tgcgacagat ttcactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcaaagg tataacagtg cccccccgat caccttcggc 300 caagggacac gactggagat taaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360 tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgcc6 tgcagagcgg caacagccag 480 gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagt gt. 642 [458] CR6262 Light Chain amino acid sequence (SEQ ID NO: 446) DIQMTQSPSSLSASVGDRVTITCRASQGISSYLAWYQQKPGKVPTLLIYDASTLRSGVPSRFSG
SGSATDFTLTISSLQPEDVATYYCQRYNSAPPITFGQGTRLEIKRAAAPSVFIFPPSDEQLKSGT
ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK
VYACEVTHQGLSSPVTKSFNRGEC
[459] CR6262 VL amino acid sequence (SEQ ID NO: 444) DIQMTQSPSSLSASVGDRVTITCRASQGISSYLAWYQQKPGKVPTLLIYDASTLRSGVPSRFSG
SGSATDFTLTISSLQPEDVATYYCQRYNSAPPITFGQGTRLEIKR
[460] The CR6268 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 447) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
448 and the heavy chain amino acid sequence shown in SEQ ID NO: 449. The CR6268 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 450) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 451 and the light chain amino acid sequence shown in SEQ ID NO: 452.

=

=
sõ.
869 obvp6g6y Booppoopob 515popfyeR5 p.6.6.4600yob vobb6p5o23 oppbqbbeop blotreovqob vE6oppoo6P buub5qbpo6 P5DDOODE0q pobpblooeq ObS
obpoovoo5o obaeqbype ',"oppobv6vo 5ye3bpoopo peoppoopfm 5518365=f) 08b 6yp6q6opoo 5eo5poP6op 5Ere.26513o5 516pop51.63 obobbloopy goqwv5o6p OZb ogyoloo5q6 q551opoyoo 56-evoppoob 62o5w5p55 pbooqoplop poopoqq..613' ooybgEobeo oogoBoobbp voop6poo65 yoboo5bo6; 6brgool5oo yblobpeopp 555v553563 q11165o5qo eof)pobovb 66.46o56eol 6.4peqqpqpv .6-4356y6lyb ObZ
5qoqo.66voo 326bbobepq poopfyipqop op5popopp5 bbqoqoppoo 1366uipoqq u5p6p5400p TebbbPogoo obbobbpopp qpbyvoqvqo qyogoyllyq bqoopoqbpo OZT
D66poobppb pobpoqp166 qboqqqbqeq ppplu.66665 qqpppqvaeb bqoqobqopp ogEobepobp oybyoy55ED 00 550o 5v5poqopoe po6voqopbq obgbloqbvp (ISV :ON UI OHS).a3unbs aP1loalanu uluto 1114-1 89Z910 Er9b1 SS AINILDOOM030.4A3dikADSSIIVDAA AVICIHSWISIMIAIA VVS,L4RCEVILLANDOJNO V
AN,LIDAIAIDIAIIDDIADATIDODd VONMASIVA, S SAJDOSVNDSAMA S S9d)INAUVOSONIOA
(Lpt, :coN UI Ogs) aauanbas mae untie HA 89Z911.3 l917.1 MOdSISISMOIAHNHIV3 MAI AS DSAA NDOOMN SNUAITN S AldASOCI SCUI AddIDIA NNgdOON SHM3AVICI SdAdON A
I3E1S AONN,LIAlgg2ISddliAAOdaNdOONVN SIINgIdVd1VMNSANDNAMIDNIAVIOHI
SAMIAISNAO3allaNINVNHAgAWAAMNLIMA3c1CM-1 SACIAAA DIAgdiN SINTLCD101 ddS1AA SdOOTIgdVdDddaLEDICD SMCISAIDICIANIN SOIHNANDIA.LOIDIS S Sd AIA A S
S AID S S VcIAIH AO SETVD SNMS AIAcIgdAAGN AIDDIVVID9 USN S SdVIcIdA SdONIS
V S S AINILOODMUCHARdA AO S SIIVDAA AVICOSNISIMIAIAVVS,L4TIVILLANDOJNOV
ANLIDAIAIDIAIIDDIVATIDOOdVONAMSIVASSAIDOSYNDSANASSDODIA2VOSOAIOAO
(at :0N UI OaS) 3,3uanbas man ounue mega 89z913 [z9p]
OSET
bpvo6.6opoo Ece6wobpbq pobvErev6po OZET DOPDPWPOD
pvopoblopo 5.6y5ovo6qe Eqbobpoblo 6yoqq64boe pobb5pobeo 55165oobv5 ppop58q5po vogobpeobv ovq5qooqqo qqobpobbop 5o5eou6643 0OZT blbwoopoo opoopfyeepe qopvoesbeb opobvp356o eeobvbv6b6 .16ebbqboob Obit alpopbobvp opopqoqqpb 552Pbqb5lo qbloopoqoo olbgbbpoop uereE.00vbge 6p55pb65oo 6Poppopo5l pooeopqb.45 5PoopobP66 5oopp6poo6 56pvoo65mp OZOT
o5poqeopp5 p-ebeboleoo opo5qop5.43 oo&yevovvo bp5.455-evo5 q5-evopqb-26 096 bepo5532-26 qobblop5b2 ooeofyloblb oovoqoblbo 6e6.4551.656 ooPqoopp6.2 ovvoyq6vo6 P55e565000 ObPPODE5PP oobovpopob -458v55-45a6 bopbbgboPq Ob8 bblovvollb vv.6465e5oo opebeyeboeo obefylbopbb -456455q6o6 qopp5q55-26 08L opoope65=
beoqeeraeog oopeoP65pv opo5peopoo 000qqblool 16q6Dowoo OZL
ve.bobbblob w6P5opoop 5woo5woo oppobwoPo POOD25PPOP 6D51D5P5PP

opo5v55y4bo 5ouPyov55q bbppooPoPP obpopobevp poopp515op pobqoqpopq poybp000vo 666goo5mo5 yo5eopo6.45 00P6-46616o Beo5p5loob voyqbgoo5.6 ObS
obvpbpbpob loblboaboo oplqooppE,D blEobbo6Po opb-qopboe. bobeop?bbl o5refq.5ooP5 qboopereboo oolgovlovb 5PP5q5bwo bqobbbwoo 5oo5povo5b OZb obbobeoovo 5v5Pvofmo5 voppoobbqo 0000qqfq.bo bp0000bbby yoovo6pw5 16y.bowq5o oPoq.55.1.poo Po56Bepo65 6.6w-e6.6poo qqovweboo opyggy1465 00E 16p-43-465y5 p645-43-eqot, qoq5oo56op op5bp5goly bv5goo5p55 e6gobpb5qy ObZ
opqpD5po5o 6P5opoTwe 5oP6605pop qqpboeolfie 52o.666pDpq q5ue5popp.6 ovqoppqovv oPob51.416q .pq.E.6.6gpolv -255v66.6.4eb bqbeerqlobb byvoy65qoo OZT
opbemopbob -45b5w6epq elo5legq6e lbpoglopPo 66Pberqoqqo 66veo5qopq 09 0q55v-25.455 plopq655qo o5v.ebvP6.45 5p5-406566.4 ogbypp.456q o5eopq66po (9117 :ON GI Oas) aauanbas apnoalanu upetn 89z9H3 [LW
IL 617ZO/ZI OZSIVIDcl 681'ZI
I/ZIOZ OM

=
N NNIIAIggli SddliA ANglidOONVN SaNgIdVdIVNN S AN ON AUNDNIIMCIOHI
AIIA SA ANAISNIAORg2IdNINVNIAD.CIAAMNd NAgdGgH SAGA AADIAgdINSHAIIIGN
dNdddIdASd9011gdVdDddaLHINCDSNdgMDICIANINScINHNANDIAIOIDISSSdAIAAS
SISAIDSSOI/WcHIHAOSIIVOSNLAkSAJAdgdAMINAIDDIVVIDDSISNSSdVIdIASdON
ISVSSAIAIIDOOMHHIAWAADISNVDAAAVICOSHISSIMAIAVISISTIVILLANDOANO
VA NISOA 1A1911091A1Mg1DO9dVONAAUIVASSAIDOSVNDS AN AS SOdNN AgV9 SONIC:MO
(sst :ON ai Ogs) aauanbas man ouRueuwq Situall za9N3 [69t]
SET
bee0660000 5e5-333be5q opbebeebep OZEI
opepeqoepo vuoupb-4030 56e50e0bqe 6-4636eo5qp 620.1.4B-45pp Po566eo5po 5blbb0pbeb Q2026616= e0q0beepbe pelbqop-410 1-40beobboe b3beoe6bg0 Eq6-4000000 0-eopybee0e loveopebeb 000by=b50 peobebebbb lbeb5q6=6 ObTI
pgepebobe0 000eq01q05 bbeebqbbqp qbqp0e0100 pqbqbbeppe ebeeppubge 080i bebbebbb= 6v===51 000epeq5q5 beop=bebb 500006e=b bbee=bbee OZOI
obepqppoeb ee6e6a4e00 00pbqp0bq0 0066PEOPPO bebqbbee05 qbeepelbeb beyobboppb qobbl0Pbby 00e0bl36q5 Poe0106-160 bebqbbqbbb 00e3=e06e 0e-e0eqbp05 ebbebbbo= obee00ebey 0pEope0y0b qbbebbgbob 6oe65q60eq Ob8 66-402e0qq6 pebqbbeb= 00-ebbebovo obebgboebb .4E61661605 -400e5q66e6 000poebb= beolebleol oppeoebbey 000bee0000 000-4.15100-4 q5qb=q000 OZL
y560E86.406 qpbeboopop 5qopo54030 00005.4=y0 vo00-ebeepe bobqpbebee 00p6ebbq60 bovevoebbq 65EPODEDEP pbeopobep0 eopeybgboe e06qoqe0eq poebpoope0 558100beob Pobe=oblb 00ebq55qb0 beobebloob voeqbq=bb ObS
obeobebypb qpbqb00600 poll=e0e0 bgbobbobe0 0ebT400b0b bpbepeebbq 08b obebqb=vb qb000beboo 004qpegpeb 6ey6q55.400 5-43555qooD boobeopobb OZb obbpby00y0 bebe-e0by0b y0000065q0 0000.4qbgbp bep000555e yopeobeq0b qbeb0.40gbp peoqbbl.000 'obbbe0055 bbl0e00e0o qopeqe0bqo pollellbb gpeqbeebeb 064510e-41e gbib=bboe pebbebqpqe bypq=be0b ebqobebbge ObZ
peqopbepeo bebovoolee boebbo6ope qqebpepqbe 6eo556popq qpeebe0epb OPqOPPPOPP 0-4.4b6qqbq eqbboqe0ge bbbebbbgeb bqbebglobb beepe56.400 OZT
0065-epebob .466.5.4=e0-q ebqeqqbe 00q0qqopeo bbebbqpqqp 55peobqopq pqbbeebqbb 0q00.4bb5g0 0-b'eebeebqb 5e6q05555.4 0q6-eo8q66q 06e0ble6eo (rst :ON m Ogs) aauanbas amoalanu umtla Situall ZLZ9113 [89171 =gct :ON GI Ogs u! umoys omanbas wog ou!wg u!utio NS! an nue Lt' :ON cu Ogs ui umoys aouonbos apnoopnu u!rtio NS!!
oq Xci papoouo Oct :ON GI 03S) uo!53.1 apcipprn u!utp 1q2!I e sapniou! osp poqnuu 021 0!Poods-VH ZLZ913 *ggi7 :ON GI OgS ui umogs omonbos ppu oup.uu u!up Anual all Puu tgt :ON GI Os ui umogs aouanbos opnoolonu u!ego Xikroy ap iq popopuo (c17.
:ON GI
Ogg) uo!2oi oiquyrit u!uqo Anual sopnpu! Xpocinur D51 oupals-VH ZLZ9ND 0LL
[L91'i MAIMILOODAAVISSGAWODAAGVgGIVOIDSIIIIVINDSNS
DIPMIOScIIIIINGOAITIAdSODd3100AMSAANUDINHOS3IASVIODdSASgSddOLIASO
(ost, :ON (H Ogs) aauanbas PPR Mule 89Z911) [9917]
SDaLdVAINgAIS9gHIAODSASIIHSNMO
gdEISIASSVVANNNSONSd.LLISADVNAdSSCRiNMVAIAVOdAdUSIIDATINNNIVOIggS
SdcITILASdVV3IdODVVVDIA,LIN.LOODAAVISSWAVODAAGVgGIVOIDSIETIVINDSNS
01.421gdIOScIIRINGOAITIAdSOOdNOOAMSAANGOINHOSDIASVIOOdSASRSddOEIASO
(ZSV :ON (II Oas) aauanbas man oupue ltOrI 89Z9113 [591']

IL6ta/ZIOZSIILL34:1 68tZII/ZIOZ OM

CA 02827301 2013708-13, ,i=
=
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK
[470] CR6272 VH amino acid sequence (SEQ ID NO: 453) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWMGMIGMFGSTNYA
QNFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSTGYYPAYLHHWGQGTLVTVSS
[471] CR6272 Light Chain nucleotide sequence (SEQ ID NO: 457) cagtctgccc tgactcagcc tcgctcagtg tccgggtctc ctggacagtc agtcaccatc 60 tcctgcactg gaaccagcag tgatgttggt ggttataact atgtctcctg gtaccaacag cacccaggca aagcccccaa actcatgatt tatgatgtca gtaagcggcc ctcaggggtc cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc caggctgagg atgaggctga ttattactgc agctcatata caagcagcag cactcatgtc ttcggaactg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc [472] CR6272 Light Chain amino acid sequenee'(SEQ ID NO: 458) QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPD
RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTHVFGTGTKVTVLGAAAGQPKAAPSVTL
FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSL
TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
[473] CR6272 VL amino acid sequence (SEQ ID NO: 456) RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTHVFGTGTKVTVLG
[474] The CR696 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 459) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
460 and the heavy chain amino acid sequence shown in SEQ ID NO: 461. The CR6296 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 462) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 463 and the light chain amino acid sequence shown in SEQ ID NO: 464.
h 1 =
= 88 Zb9 qb qbubobb6bo ovvolqobvb ypooyblboo 335-2052510 3656pope3o 3pb-455-e535 .43053-Q1545 6yporp6pv6 pboyqoyboo 66ypo6pblo ObS
popoq000vo 5eo6y5.1036 poeqoaeopq op6bppoEyeo pft.pobeboo p61536e6e6 08b 6v3obpo2po 56o6vbpo5q pooboy?ov6 5yab6ep56.16 pobqbbppop b5e6.6boopo OZb opqoqqopuo pefylobqopb 1.6156q6o6p opboopobbo 6p6pp6qp6p obveopbool opooppoqqo qeol.-45.46o6 poopeoboob bobqboeevo qvbp56qb6p yooe565eeo 35Boqq5op6 Ermovo-435 vq66.4p-46po 5poqbqopqq. vq6q5pobT4 -4.4p62v6-4DD
ObZ
6p6bqoPfreo Ecepq.eopyol ogovoqqopb poy6b5qp-45 66gbyo6b-46 voqqb6poyb poopqvop51 opoobbfieo5 pooqpo5Teb qpqoqpoqop qobbpopolo bovoobbwo OZI
pppbPobyoo p.1.56.4336E-4 qovqobvp&e, obvqqbqbpb vogfieoo666 poboo 33P3D5P5PP p665bPpoqo qbqqqoqblo oppo66vooq ol6po5opec4 vbgblqp.epb (c917 :ON Ern Ogs) aauanbas apnoalanu umq3142Y1 96Z9113 [8Ltd SS
AIAIALLOODMICITIVOdOMN DglIVDAA A VICKISNINSIMAIAVISISICIILLIALLAIIDOANO VA
NIODSNIdNIMOIAIMTIDODdVONAMHINA A SIILADS VNDSANA SVDODI ATV aLgA1OAg (6St CIR OHS) aauanbas man mute HA 96Z9113 [aid -=
)19dSISISNOIAIMIHIV1HIAI
A SD SAA NOOOMNSMCIA,LIN S iV1AA SOCi SGIAdd.LLNANNIgdO9 SgA1gAVIU SdAADNATIL
IS AO Sddl,LA A
OdgIld0931V)1 SIINgldVdIVN NS ANDNA3)10 NIMUOWIAEIA S
AANAISNAOgglicININVNHAgADUAAMNANAgalalSACMAADIAgd.LIISIIAITLUNdNddd IAA SaDDIladVdDddaLHINCIDSNdRAIDICIANINSdNHNANDIAIOIDI S S SdAJAA S SISA1 S SOIAVcaLHA SETVD SNIM S AIAdgcL4ACDI DOIVVIDO USN S Sdb"IdgA SdONIS V S S
/VIA INILDOOMICI4VVOdOMN OglIVDA A A VICKI SHINSIgIAIKVI SI SICIIIIINIAN90.4}{
OVA
NIDOSINIdNIPADIAIMWIDOOdVONAMHINIAASIILADSVNDSANASVDd3DIA2VaLgAIOAg (or :ON m Oas) aauanbas mar ounue mein Anna"' 96z913 [oLtd obb00005pb qoo62.64Dob pbev5E.330p OZEI
OPIOPOOPPO pofyloopbEre bopoblpb15 p6po6lobro qqbqboppob bEreobpobbq 65poEmbeep 256q6poPol obeeobeopq 6103-floqqo 5po6E.D25D6 poebbloblb qoopopoovo opbeeppqoe povebeboop bpoobboppo 6p6e65b15p bblbooboqe ObTI
opbobpoppo vgoqqobbEce Pbqbbqoqbq op-eoloopqb qbbpopE,Eby P3oebp6eb 080'1 bebbboobpo poopoEcloop epegblbEyeo 000bpbbboo pobpoobbbv e3366yp062 OZOI
oleopebyvb ebogeoppoo blop6g0005 beeppyobvb .46bpeobqbe yopq6ebbpv 3bb3pp6l36 6qopb5pooP o6y4o6q63ot, ogo6l5pbe6 465q66600p qopyobpope opq5eo6p66 p.666p0006e pooP6vpoo5 oPpopp5.466 p55q5o6bop aq.bopqbbq 0b8 opeo-416pp6 166v6p000p 56p6oyoobv 5-450p56qE6 -465.45o5.4Do p6q56p5000 ooebboobeo 1P6y4Pal000 poPbbPP000 bvv0000000 qq5.43oT461 booqopoPbb OZL
obbbqobqpf, Pb00000bqo bofyloop000 obloopovoo ovErepopbob qobv&evoop fyebbgbobop PPoPbbqbby booPoP'eoby DOO6PPOPOO vvbgeoppob goqvovqooE

freoopyobbb loDbpobyob y000bqboop 6.45.4o6mo 5p5-4305voy q5qoo55o5p ObS
ofiebpobqpb qboo5poopq q33eoep.5.46 ofthobvpoy6 qqopbobbob vopybbqobp 08b 516opper4o oo6e6006pq gpvqoP65v2 bq66yloo5qo 555loop600 bvoyobbobb OZb ' obE.00vo6Pb Pvo5pobeop oopbbq0000 314-4bo5vo oop555PPoo Po6Plobqbp 09E 6p-401630Po qb6qppop6B 6vvoo6656q oqvq-e5qqqg ob5o5vvoqo oe6565qype bbbbp6e5e5 o5g6qopqqy 16-46o6532 Deboebqoge be6qobbpob e6.435e6ble ObZ
opgpoopoPo 6epqvoo.453 voyE66PooP 6lvooraq55 byo6b6poll 16up6voupb lygoepyopo 66q56-4beop 2q333PP0gy 661pb56qeb 5-45-25-4-4obb bypopbbqop OZT
pobbeov5pb .455-43po5q 2Tego-eqo6p poyolgoopo pq.266g3gyo 56pvp5gool qq66epbq5v owo655bqo 3bp-e6P26q5 6e5.4o5bbbo op5v56.4bbq p6p06.456v5 (091, :ON GI 03[s) aauanbas annoatanu uleto Atteall 96z9HD [sLid IL 6tZ0/ZI OZSIVIDcl =
68tZII/ZIOZ OM

=
, .
, [479] CR6296 Light Chain amino acid sequence (SEQ ID NO: 464) EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYDASSRATDIPDRFS
GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLWTFGQGTKVEIKRAAAPSVFIFPPSDEQLKSG
TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
[480] CR6296 VL amino acid sequence (SEQ ID NO: 462) EIVMTQSPGILSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYDASSRATDIPDRFS
GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLWTFGQGTKVEIKR
[481] The CR6301 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 465) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
466 and the heavy chain amino acid sequence shown in SEQ ID NO: 467. The CR6301 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 468) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 469 and the light chain amino acid sequence shown in SEQ ID NO: 470.
[482] CR6301 Heavy Chain nucleotide sequence (SEQ ID NO: 466) gaggtgcagc tggtagagtc tgggggaggc ttggt'acagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc atctatgcca tgagctgggt ccgccaggca 120 ccagggaagg ggctggagtg ggtctcagct attagtagta gt.4gtgatag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca acgccaggaa cacgctgtat 240 ctgcaaatga acagtctgag agccgaggac acggctgtgt attactgtgc gagagcgtat 300 ggctacacgt tcgacccctg gggccaggga accctggtca ccgtctcgag tgctagcacc 360 aagggcccca gcgtgttccc cctggccccc agcagcaaga gcaccagcgg cggcacagcc 420 gccctgggct gcctggtgaa ggactacttc cccgagcccg tgaccgtgag ctggaacagc 480 ggcgccttga ccagcggcgt gcacaccttc cccgccgtgc tgcagagcag cggcctgtac 540 agcctgagca gcgtggtgac cgtgcccagc agcagcctgg gcacccagac ctacatctgc 600 aacgtgaacc acaagcccag caacaccaag gtggacaaac gcgtggagcc caagagctgc 660 gacaagaccc acacctgccc cccctgccct gcccccgagc tgctgggcgg accctccgtg 720 ttcctgttcc cccccaagcc caaggacacc ctcatgatca gccggacccc cgaggtgacc 780 tgcgtggtgg tggacgtgag ccacgaggac cccgaggtga agttcaactg gtacgtggac 840 ggcgtggagg tgcacaacgc caagaccaag ccccgggagg agcagtacaa cagcacctac 900 cgggtggtga gcgtgctcac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtga gcaacaaggc cctgcctgcc cccatcgaga agaccatcag caaggccaag 1020 ggccagcccc gggagcccca ggtgtacacc ctgcccccca gccgggagga gatgaccaag 1080 aaccaggtgt ccctcacctg tctggtgaag ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggcagct tcttcctgta cagcaagctc accgtggaca agagccggtg gcagcagggc 1260 aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagagc 1320 ctgagcctga gccccggcaa g 1341 [483] CR6301 Heavy Chain amino acid sequence (SEQ ID NO: 467) EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSAISSSGDSTYYAD
S V KGR FTISRDNARNTLYLQMNSLRAEDTAVYYCARA YGYTFDPWGQGTLVTVSSASTKGP
SVFPLAPSS KSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTePPCPAPELLGGPSVFLFPPKPKDT

=

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVESCSVMHEALHN
HYTQKSLSLSPGK
[484] CR6301 VH amino acid sequence (SEQ ID, NO: 465) EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSAISSSGDSTYYAD
SVKGRFTISRDNARNTLYLQMNSLRAEDTAVYY:CARA YGYTFDPWGQGTLVTVSS
[485] CR6301 Light Chain nucleotide sequence (SEQ ID NO: 469) gaaattgtgc tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120 tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180 tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240 agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactccc 300 ctcactttcg gcggagggac caaggtggag atcaaacgtg cggccgcacc cagcgtgttc 360 atcttccccc cctccgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420 aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480 ggcaacagcc aggagagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 540 agcaccctca ccctgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaggtg 600 acccaccagg gcctgagcag ccccgtgacc aagagcttca accggggcga gtgt 654 =
41486] CR6301 Light Chain amino acid sequence (SEQ ID NO: 470) EIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP
DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIKRAAAPSVFIFPPSDE
QLKSGTASVVCLLNNFYPREAKVQWKVDNALOSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[487] CR6301 VL amino acid sequence (SEQ ID-NO:468) =
EIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP
DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALOPLTFGGGTKVEIKR
[488] The CR6307 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 471) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
472 and the heavy chain amino acid sequence shown in SEQ ID NO: 473. The CR6307 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 474) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 475 and the light chain amino acid sequence shown in SEQ ID NO: 476.
91 , If =

qbqbv.bobb bbooppoqqo bybypoovErl. b0000bvaby bgpobbbpoo yoopy5-455t, bobqooboPq 8.465-evopo5 pebgboyqov boo66pyobp 06g blopopoqoo oyobyobv6.4 pobeoegooe oowebbeep beoybbeobe booeb4bobe bpbbpoobyo yyobbobebp o6g000b3vP ov66.4b5yeb bqbeD5.4b6E, pooffrebbbo 0000ygoggo vvoyybqp6.4 =546.466.46 obpoobooyo 66o6v5py51 ofwo6y6op6 polop0000p qqaqvpqq6.4 6o6p000.eo5 op6635gboy pvoqp5p66.q. 65-eppoe666 00E p.6635631-41 peogo600vo v65p.465Teg Emo5poq6lo plq-eqbqfyeo 6qoqqpbpp6 goobubbqop 6pobpoggoo voloqpeoqq op6vo-e6b64 oqb55-46y36 blbpoqqbbe ovbvpoogyo 56.406=668 popyooqvo6 qbblvlogyo looqoftmoo olobeyeop65 OZI
qopvevE,voy yoaeqbbqoo bvqqopqobe obvqqbqbob Poq6ppob6b poboo opyoo6p6ev u6555eoplo q611-40q6-43 povobbpopq pq5eolop62. oblbglype6 (sLy :oN m Ogs) aauanbas appoatanu u!nto 1112r1 LO9113 [Z617]
SSAIA11000MACIADgAVDAS99011YDAAAVICI2VIIISNIAIOIAISINDIVNCRISIIRIONAS
CIAAAIASSSSSISSAMTIONDcWOHAAV=11AI5ASSA,L49SVV3SIYISD9cDINI99DSOAIOAO
(llt, 30N GI Ogg) aauanbas man ou!tun HA LO911) [1617]
NOdSISIS3101AHNI-I1segH
INASDSAANDOOMNS)ICIAEDISKIAAS6CISCIIAddi.DIANNgdODNSgAl2AVICISdAdMIA1 DIISAONDILIAMNSddlIAAOdglIdOONVNSIINgIdVdIV,INSANDNAg)101\11AVIOHIAE1 A SAANAISNAOgglidN,DIVNHAgADCIAAMNANA3dClgHSACIAAADIAdINSIMIGNOld cITHAScIODTladVd3ddaL14,DIUDSNdgA2DIGANINSdNHNANDIAIOIDISSSdAIAASSIS
AIDSSOIANTMLHADSEIVOSNMSAIAdaddACINAIDOIVVIDDSISNSScPrIcL4ASdMILSV
SSAINIIDOOMACL4DgAVOASOOMPIDAAAVICIEVIIISNIAIMAISNNVNGIISIL4119MAS
GAAAIASSSSSISSAM310319dVONAMNIAISASSAIA9SVV3SIIIISOOdNAI99DSOKIOAO
(Ca :ON cu Oas) aauanbas man ouRun uma SitnaH LO9113 [06b]
9SET 6vp066 popobpbqop fiebqopbpbp P6PODOPO2q OZET
OPOOPPOP06 qpoobbv5op o6 66o6 obqobpoqq6 l6oveo666e obpo66q66o obv5vpop56 lboovoqobv vo6vov.46-43 olqoqqobvp 66ovbobpoe 664obq6qoo poopopoopb PPOPqOPPOP P6p60005po o56oppoEre6 2666.46-256q 5336aTeov5 ofieoopopqo qlobbbyybq 56qoqbqoop oqoop16.1.56 voopv&epoo e6gpembbv.6 0801 66=5popoo 000g000yov qbqbbpoopo 5e5563Doo5 poo6.65epoo bbvpobeoqv OZOT
pop6vp6p6o qv00000blo o6woo55PP ovvo5e6q66 vvo5-45epov -46v65evo6b opyblobblo ebbepoeobq obgbooPow 6q536e6156 lbbbooeqoo eobeoeppq 6p0be6bp66 b000p6pyoo v6y-eop6ovP oyoble5e56 16o5boyb61 6ovq56qopv ollEcepbqbb p6opooP66e 5oPoo56.16 oe66q56166 l6obloop6-4 66y5poopae 6boo5eolp5 leol000voy 56.e-epoo6yv 0000ppolq6 loolq6q6o3 g000y66065 OZL
6406,405E1)o =03610=6 ?opopoop61 opeov000p6 epop6oblob e5ep0005p5 6q6DE)Dvppo p66-466pvpo poppobp000 6vvovooppb qbovvofylol popqoopbpo 00e0.666.400 beobyobeop 36i600p6.16 63b0beo6e6 3oo5p0v4b4 opb6o6vobp 06g 6po63o616 oboopoqqop e0po636.056 36yooP6qw p5366ofmov e65106y536 povbgb000b uboopoqqoP 3o66p.e6y36,64=6-4o556 3000boo5yo pobbobbobp popobebeep beobeoopoo bbqopopolq 6.4bo6e0000 bbe,pepoet, eqpbqbeboq p3eoppo366 3000Pobb5y oo6b663oP1 ovbqqqobbv pbovqoa656 boyqobvbbb 2.6p6 36161oElle qbqblobbae ovaieboo6p fiebloobpop pfiqypeoblo 3e454opo3o v-ebeEopboy eoPbP5Poo3 olypopoqle 5Dobbbppb3 6po3oP6iel5 opqoplyqeo P446-e3by35 P36e45-2.4.4r. po3po4o.456 6.45e664o66 bbyp566poo OZT
3ob5poo5po 36663ovv6I Robuqpqoft. 46Po3400po 43.e663p300 6e061.6300.4 o3op6v5400 3.48656553 o6evo.1.65.43 p66p665553 035po64563 o6moo455Po (za :ors'01 Oas) aauanbas IITID Loolla [681']
=
IL6tZWZIOZS9IIDcl 6817ZII/ZIOZ OM

l3LISAONNIINggliSddlIAAOdgIWO9 VMSIDE1dVd1V)INSANDNA231D1=11/AGOH1A1 IASAANAISNAOggIldNINVMHAADCIAAMNIANAgdUgHSACIAAADIA2dISSIIAIIICINcIN
dd,TIAASc190111gclVdDdd31HINCIDSNOAIDICIANINSdNHNANDIAIOI9I5SSdAIAASSI
SAIDSSOIAWAIHADSEIVOSNMSAIAdgcldAGNAIDOIVVIDOSISNSSdVIcL4ASdONIS
VSSAIALIDNOMAGIALLMIAOADVIHNVDAMAIVICOSIFISSIgVNIAAIDValCIVILLANDOSN
dVAN.LL9dIdIIDDIAIMgdOODdVONAA1SIVASNAdDDMIDSAMASSDOINAgVOSgAIOAg (6Lt, :ON al Ogs) aauanbas man otnum meto SAnall oic9u3 [L60 CSEI bpv obbD000beb qopfiyebqoob ebppbpoopv OZEI
OPqOPOOPPO poe.goop56e 5D-236qp615 ofreD5igo6po -4-46.46Dpuo6 65poerep66.3 55po5ybppo pely4boovol obPeofyepeq ogoogloqqo 5vobbae5o5 popbec4o6-45 loopopoovD ovbvPopqpv vovp62b000 52oobbDppo 5p52556q6p 56-46op5ogp DP5D5POODD pqaqqpbbbr, Pbqbbqoqbq popDqopogb qb5yoppveye upopbqvbpb 5e5bboa5eo op000bgpoo poP16.4b6p3 opobebbboo 336poo5bby eoobbvpoby OZOI
aqvoopbypb ybogy0000p bgoobl000b bepovvoEveb .455vpo6-45E, povq5p55vt, obbopp5135 fywebbPooy oblo5qboor oqoblbo6pe. 166.4566=p loovobvoPv opl5pobp56 p5b5oopobe eooebppoob oevopo5-155 v6616o6boe 66263ea66a ovvolqbep5 .45525opoop 652.632=6p 5160v56.456 165q5a6wo p6.466e5poo oaebboabyo qvfyapolopo popbbepopo 6PPOOODODO qqbloolq61 booqopopbb OZL
obbfy4ofylob Pbooppobqo op6g0000po ofqoppopoo op5ppou5p5 qp5p6Pp000 6p66.48o6op PPOPE61.66P POOEOPPObV 0005PEOE00 ey6-45Dppab qoqeoploop Beopoup865 goabuo6P35 vpoo6-45pou. 6yl.E.E.q5o5po 5p6-4po5yv -454=5535p o6p6pobqob qboob000pq loovopobqb o55o5ypoy6 qloobobbob epey55qo5v 086 5535o oo5Pbopooq qoplopbbpv 6.4551pobqo 5561=353o bpopobbobb ofyeoovofy2.6 ppobvDbvpo boRbEyw000 o.4.45-4bo6po 000fthEcepoo vo5p.4o6.45e 09 bowlboopo qbboPooP66 ere.8TO5555q oqbp-ebbqvq opvpbobobq 55vpoPq655 blvleopppb oblbqoe.4 '-e. q5ivoobbae opa5pbqoqv bobqoot.vob vblobpbEr4E

opqqq&eopo E.fthoboqu Eop55o5D3p qqpeopoTbp bpobbeceopq q5ep5oovo6 OPIPPPEOPP oP-465-44-4-4.4 4opp-iPo1y 5555555 bq5ptc40055 5ppoy56qop OZT
pa56popeo6 4.65.6qa6upq v-435-4p.435-2 obooggoopo Myebbqoqqo 55-epo5qqaq oq5pppb.456 oqooqbbblo obppErepbqb 6pbqp55551 og5p5e.-466-1 obvp5q56p5 (9a:ONctiOas)aauanbasaml0alanuulutoiCtuallo1c910 [960 7817 :ON CII OEIS ut umous aouonbos p!ou ou!tuu tquip N2!j alp put tat :ON cu Ogs u! umous aouonbos appogionu Lump upt popooua (08t :ON GI OgS) uo!2al olquyun Lump 1142!1 t sapnpu! osiu Xpoquuu 921 oU!Dods-VH 0 I 921D .6L17.
:ON GI 638 ut umous aouonbos p!ou OUIWE Lump Xnuati oqì
put 8Lt :ON CII OgS umous omonbos oppoopnu u!uqo Anuag alp popooua (Lit :ON GI

Ogs) uo!2o.! oulu!Jun turtio XAV01.1 sapniou! Xpoquur D21 0upa's-yr-1 01E9N3 ota [sa]
11)1IgANIODadrIdilIDAOODAAAVSGgdg-IIISIELLAGIOSOSD
SAIICWIDVVILLSVOAITI2IdVOOdNOOAMVIASSMIOSVNDSTINNg9dSISII9dSOKIAIg (ttp :ON m Oas) aauanbas man ouuun IA LO9113 [V6V]
= 0201IN.4S311AdSSIDORIAgDVAA
311-1}1gAGVNSIKUSSISAISCDISGOMLAS2OSNOSZTIVNCIAMMOANV211dAANNTIDAASV
IOS31-102GSddL4HASdVVVIDIMANID90.4Eld1110AOODAAAVSGgdgINSIITIAGIOSOS
DS.42ICIcIIOVVILLSVDAMNdVO9d3100AMVIASSAMOSVIIDSTINIIHDdSISII9dSOrIAIg (9L,17 :0N ui Oas) aauanbas man minim mega LOC911D
[617]
IL6tZ0/ZIOZS9lIDcl 681'ZII/ZIOZ OM

WO 2012/112489 =

=
VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDQSFFLYSKLTVDKSRWQQGNVFSCSVMH
EALHNHYTQKSLSLSPGK
[498] CR6310 VH amino acid sequence (SEQ ID NO: 477) EVQLVESGAEVKKPGSSVKVSCKASGGPFRSYAISWVRQAPGQGPEWIVIGGIIPIFGTTKYAP
KFQGRVTITADDFAGTVYMELSSLRSEDTAMYYCAKHMGYQVRETMDVWGKGTTVTVSS
[499] CR6310 Light Chain nucleotide sequence (SEQ ID NO: 481) tcctatgtgc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60 acctgtgggg gaaacaacat tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120 caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180 ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240 gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatgc tgtgttcgga 300 ggaggcaccc agctgaccgt cctcggtgcg gccgcaggcc agcccaaggc cgctcccagc 360 gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420 ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480 gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540 agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600 gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654 [500] CR6310 Light Chain amino acid sequence (SEQ ID NO: 482) SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSG
SNSGNTATLTISRVEAGDEADYYCQVWDSSSDHAVFGG.QTQLTVLGAAAGQPKAAPSVTLF
PPSSEELQANKATLVCLISDFYPGAVTVAWKADS,SPVKAGVETTTPSKQSNNKYAASSYLSL
TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
[501] CR6310 VL amino acid sequence (SEQ ID NO: 480) SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSG
SNSGNTATLTISRVEAGDEADYYCQVWDSSSDHAVFGGGTQLTVLG
[502] The CR6314 HA-specific IgG antibody includes a heavy chain variable region (SEQ
=
ID NO: 483) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
484 and the heavy chain amino acid sequence shown in SEQ ID NO: 485. The CR6314 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 486) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 487 and the light chain amino acid sequence shown in SEQ ID NO: 488.
=

Ç6 099 obeobqbebo pep0000651 6ppe5epbeE. 5-45oopo6eo 555eboeopo p5155poobq 009 o6eopl3be5 600poobe5e e55q5eD5e5 00000voqoo 5ebqooe-405 e3bypo5Dob ObS opq5epopeo peobeopp5e eoboo op oovooe5e65 15355=55y e6q5oppobe 08b p5popeop55 pp65qp355.1 5Dop5q5=5 055l000pqo qqop5o6poq poqoo5156 OZb 54poppoobb PEOPPDD65E 351o5p5bub poqoogpoop opoqqbq000 e5gbofreDop 09C qp5oobbeep oo5poob5po 53055o5.456 eqpoqbooef) qp5peopp55 5p55DE.50-00E eq5eo3-455-4 bebloo'Pe6p 6.4e65bquae e3515qop-44 egleblobbp 61p5lebool ObZ bboogapb51 beogeop551 oo-pgoo5eol 3opo55.4oq5 ppooqp5510 qDqleboopb 081 qopo45665e Dqppo6535e 3155-4e5b5e lp;o1poqoo qoppepopoo 55oe365eop OZI olo5yobpoo el5610-eqe1 bleggevq5e p55oTepeeo 3gobeo5pe5 6.43T46-09 ogeoppolb5 5e5eo566op 000vE,65q31 505yogoope oo5eoloe5q ofyqblegool (L817 :ON m Ogs) a3uanbas appoapnu uleto ;On v1c910 [90s]
SSAIALLONDMAGIALLUNAOADIAIHNVDAMAIVICOSIIISSIHIAIAAIDVACKIVILLANDODI
dVANI,LOgIdIIDDIAIM3dOODdVONAMSIVAS2HdDOSVMDSANASSDOINATIDSgAIOAA
(cm, :ON al Ogs) aauanbas pilau oup.uu HA t'1911) [505]
31DdSISISMOIAHNHINIg FITAIASDSgANDOOMNSNCIA.LINSAIAASOCISGIAddLDIANNIadODNS3M3AVICISdAJDNA
I3EISAONN1IAMMISddl,LAAOdaNdOONVNSI.LN3IdVdIVNNSA)13)1ARM9NlAWOHIA.I.
IASAAHAISNAORMIcININVNHAgAOCIAAMNIANAgdUgHSACIAAADIAgdINSIIAIIICDIcD1 ddAIAASd0011gdVd3dd3IRDICI3SNdgAIDICIANINScINHNIAN3IA,LOI9ISSSdA.LAASSI
SAIDSSOIAVc1ILHAOS,LIVDSNMSAIAd3d3AGNAIDDIVVIDOSISMSSdVIcIdASdIDNIS
VSSAIA,LIONDMAGIALDITAOADIAIHNVDAMAIVICOSNISSIUIAIAAIDVAICIVILLANDO.431 dVAN,LIDdIdIIDDIAIMgdOODdVOIIAMSIVAPIAdDOSVNDSANASSOd)DIARVOSHAIOAR
(sgt :oN m Oas) aauanbas ppu oupug uptia Snuall t1C9113 [tos]
ESEI 5ep obboopobeb qoo5e5qop5 ebeebeopop OUT aelovooppo pobwoobfre boeoblefyqb obeobqobeo gler45opeob bbeobeobbq 09ZT bboobpbeep p55g5opeoq obevo5voeg boo 5eobbop5o5 poebbqobgb 00ZI gooppoopeo ovbeepegoe eopebpb000 5poobbopeo bpbebbbqbe bbqbooboge ObTI op5o5poopo pqoqqp5b5e ef,q5bgalbq povoq000qb q55epopebe epopbqp5pb 0801 6e55boo5po p000pbg000 poele.155eo oop6e55530 oo5poo55by poo5bepobe OZOT ogpoopbee5 p5ogyoopoo 5130543336 5ppoppo5e5 5b o55 popqbebbee 096 obbopp61ob bqoebbeope Dbqoblboop olobgbobeb 165q555Dop q00E0bPDPE
006 pelbeobeb5 e555oopo5e eope5evoo5 opeopp5166 E.58q5o55op 55153e.455q 068 oppoqqbepb 165e5333pe 56e53p3o5e 515op5515,5 155153.6qop p5165p633p 08L poebboo5po gebleol000 eoe55ev333 beep000000 115loolq5-1 5o3l33oe5.5' OZL p855.136qob pb00000bqo oo5qoop000 obwopopoo oebeeopbo5 wbebev000 099 5p66.4535op eepebbqbbe PODPOPEO6P opobepoppo pe5q5ope3b qoqeoplope 009 5pooppobbb wobeo5yo5 e3oo5q63op 5q65q5obpo 5p5.4336p3p qbwobbobe ObS 3bpbe3535 q53363pool goopopobqb 356o5poop5 qloobob535 popebbqpbe 086 bqbooe5gbp opbeboopoq loewebbee 6q55133543 5584=05= 6eopobbob5 OZb o5poopobe5 eyofreobeop poo55loopo ol.46-4bobpo 000atheepo eofrego516y 09E boq3.4.5opeo 1.653PooPbb Beeeobbe.5:i alboebbqpq peep5peabq bbpoopT5bb 00C bgeleoppe6 per45weg3e gbleopbbop op65e5q3qe 5o5loofmob e5q0.5p55qp ObZ oelqq5eopo 85505oqqqe 5oe55a5ooe 1-4pEopolbe 5eo656pooq .45pp5opeob 081 oelyeeppep 3vq56qq-41.4 el000qyoqe 55bp656geb 8q5e5goo85 5ppoeftwo OZT pobbeopbo5 .4.65.5qo5Poq egobTelobe obooql000p bbp554oggo 5bppo6.4.4oq 09 oq5eve5.455 ogooq6b5.43 o5eveme5q5 befylo5556.4 oq5e55155.4 p5pofy466p5 (i78t :0N m 03[S) 33uanbas apwaianu u!eq3 Angall p1c9H3 [Cos]
IL6tZ0/ZI0ZS91IDcl 68tZII/ZIOZ OM

=
a ArIASAAHAIS NAOggNcININ VNH AgAOCIAAMNINAgcRigH SAGA AA DIA3dIN SIIATIIGN
cDicIdAld A Sd DOTIgdVdDddaLHINGDS)Id2 A IDIGANINSOI HNIANDIAIOIDI S S SdAIAA
S
SISAIDSSOIA.VcIALHAOSEIVOSNAkSAIAd2cUMINAIDDIVVIDOSISNSSdVIcL4ASdON
ISVSSAIATLOOOMHdlA VdAAOSSNVDAA A VICIg SN1S SIMAIAVISIS3CIVIII11190.4NO
VANIS9,41A1OHCOIAIAOIDODdVONAMSIDASSAIODSVNDSANASSOODIAgVDSgAIOAg (1617 :ON ai Ogs) aauanbas rope oupuu umto Situall czoND [Hs]
OSEI
bpeobboopo Bv5loofyebq opbebeebeo OZET
ODPOPqDPOO Pyoeobl000 fthpbovobge bgbobpobqo bpoqqbgboe pob6bpo6po 5b.45boofyeb vvopb5gboo eowbeyobp oplbqooqqo llobvobboe bobpovbbqo 6161op0000 OPOOPE,PPOP qopeoppbp6 opobpoobbo ypo6p6p566 qbpbbqboob oqvop6o6yo poovlo.4136 bbvP61.6613 qboo oqblareoov pfmpoove.Te bp56p66boo Ecep0000p54 opopoploqb bp000pbeE6 6000pbeopb bbvepobbep OZOT
ofreoqvoop6 PP5Pbolvoo 0305100610 opEZPPovPo 6v6q&ErePab lbvpopqfm6 freyobbopyb .4066-43vb5v opobloe.;5 oppoloblbo Eveblb.6-4665 oovqooppbe opyaeqbpoe. ebbpb.55opo 3bvpopp5pp oo5opyopo5 q6Erebb.4505 Eopbbqbopq bblopeolqb eP61552b33 Dobbpbopo 3bp6163P66 qbeyqbbqbob looptrqbbvb op000ebboo 5poqpbqfoq p3peop65-ep opobep0000 oopqqbqopq qb-45ooq000 OZL
v563656.436 352 333 .6qpoo6q333 opoobloovo t.000p6rvor, 6o6-435pErev 3pobv5.6qb3 bopePoybbq 55peooyppp obp000bypo poopp5g5oy poblogpopq op?Ecepoppo 55E35 po5yopo5q6 3pe5q651bo 5eo5p6goD5 poeqbwobb p5po6p6po6 lobqeopboo polgoopopo 5qEobe35po op6lloo5o5 606poyv5bl obv6.16opv6 lb000bpboo oDlloplpe5 5pe5lbbloo 5w56.61poo bopbeopobb ob5o5p33e3 bp6238236 p000036613 oppoqq5q53 6v3p336562 2oppob2-136 qbvboqoqbo oo-156113o E,o666op66 561op00000 lnopli;,3610 oopi-aP1-1,55 qfreqbppbpb obqbqoplqp q5q53pe6ot. op5bp5qoqp 6pbqopEreo6 p6135266qv oplopopopo bpbopoolpp bopbboboov 11p5peoqop bp3555poog goupEreppob pegovvvove aqq6bqqqbq eq55ple3l2 oefyebayqpb 516p6.4.4o65 52p3e66.4po OZT ooMpoveob .4555qof)P3l vlayqpqobP oolallopeo 55pbbloloo 65pyq5lool D.4652E1)166 ogoolbbecep o5eebee5g6 5p5w5866-4 olereb5-466-4 p62obl6bpb (061' :ON m Ogs) a3uanbas ap9oapnu umo Siteall czolD [Ns]
17617 :ON CR Oas ui ummis aouanbas p!ou ou!tuu u!utio iq2!1 alp puu 617 :ON GI Ogs ui umoqs apuonbos appogionu u!uqo 1142!1 oqì Xci papooua (z6t cll Os) uo!2oi alqupun u!utio JOH g sopnpu! osiu Xpocipuu 921 DU!ogds-VH Z910 311,L 1617 :ON 01 Ogs ui umoqs aotionbos p!ou ou!tuu Limo Xnuoy oqì
Puu 0617 :ON GI 03S ui umoys aouonbas appoolonu u!uqo Xnuay popoouo (6817 :ofq sm Os) uo!2aloiciuturn u!utio Xnuog g sapniou! Xpocpluu D21 ouloods-vil amp ota [Ns]
A.UT)11060.4 Ad DSINCI GALINDAACIVgC1CISIIIDSIVISVSIDS)1 59 S.RICIdA0ScillOOCINAITINdVIDcrIZZAAA A AN &DINS S SOSDSLLA HOOd.LOSVSddOEIAAS
On :ON III Ogs) a3uanbas ppu ou!tuniA 1'IE9113 [80S]
S DaLcIVAINgAIS 9g HIAODSA SNH SNMOOd 1'jSIASSVVA}INNSOMSdILLgADVNAdSSGV3IMVAIAVDdAAGSMAIIV)INVOI2gSSd dd'ILAScIVV3IdOVVVOIAI'DII009AAdOSINCIGAUNDAAGVgGGSWIOSIVISVS,LOSNSD
S.PKIdADScIllOOMIAITINdV,IndlOOAMAAANSOINSSSOSDSIIAIIODdIDSVSddOrIAAS
(881, :om m Cogs) aauanbas may oupue mega 1112FI 1'IC9113 [LOSi IL6tZ0/ZIOZS9lIDcl 681'ZII/ZIOZ OM

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK. =
[512] CR6323 VH amino acid sequence (SEQ ID NO: 489) EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYGISWVRQAPGQGLEWMGDIIGMFGSTNYA
QNFQGRLTITADESTSTAYMELSSLRSEDTAVYYCARSSGYYPAYLPHWGQGTLVTVSS
[513] CR6323 Light Chain nucleotide sequence (SEQ ID NO: 493) gaaattgtgt tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacccag aactttcggc 300 ggagggacca aggtggagat caaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360 tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 [514] CR6323 Light Chain amino acid sequence (SEQ ID NO: 494) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS
GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPRTFGGGTKVEIKRAAAPSVFIFPPSDEQLKSG
TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
=
[515] CR6323 VL amino acid sequence (SEQ ID NO:: 492) EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS
= GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPRTFGGGTKVEIKR
[516] The CR6325 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 495) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
496 and the heavy chain amino acid sequence shown in SEQ ID NO: 497. The CR6325 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 498) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 499 and the light chain amino acid sequence shown in SEQ ID NO: 500.

=
=
=

. 0.: 86 obeobqbebo peoppoobbq booebeebeb bgbopeobeo bbbeboy000 eblbbepobq obeoelDbeb bopepobebe ebbqbeobeb opoopeogoo bebqopegob eobepoboob ObS
pelbeepevo eppbebuobe eobeoppope poeopebebb qbDbboobbe ebqb000pbe 08b obeoeboobb eybbqopbbq booebgboob obbgoopeqo qqoebobeo4 eogoobqbqb OZb b;opoepobb peoeepobbe o6go6eb6e6 polooloppo opallbloop efilbobeopo qoboobbeeo oobeopbbeo boo6bDbqbb eqoDqbooeo 186eepoebb 5-4Deeb5oll 46q4pqovo beDbeobeeo elegeoqobe obqDeqleTq ebqobbeboe bbebqobbeo ObZ
Dqobbbqoqo qeoorbqpoo qopbboeope D65qoq6eeo oqobbqoqoq. loboqeeqpq qqbbbbeaqo pobbogeelb yolbbebqvg lgebqeogoe ee00000bee eobbe000eo OZI
beoepooeqb bgoogoqbqe weegeqqbb gbbqgboebl beobeooveb blopobqopq oqeopeole5 olbeoebbqo oqoqb6bloq bqboogoobq pobeowebq poobwqbeo (66b :0N m Oas) aauanbas amoalanu ututD SZ9113 Eozsl sSAIALIDN9MAGIAIAAAAIDMCIONVDAAAVICPSIIISSARINAVISISRAVILLANDOJNO
VANLLOAMIIIDDIAIM7100001021AMSIAISAASJ,LOOSVMDSANASSDOINAgIVOSgAIOA2 (S6t Ogs) a3uanbas rope oup.uu HA 5Z9113 [61s1 c N9dSISISNOIAHNITIV3 HINASDSAANDOOMNSNUA,LINSAIdAOCESCrIAddlIMANNgdOONS2A1RAVIOSdAADMA
laLISAONDILIAT3allSddlIAANIRMOTIVNSII)131dVdIVNNISAN3NAUN9NIMUOHIA1 IASAANAISNA0331101INVNHA3ADCIAAMNANARKOHSACIAAADIA3dINSIVIIICD101 (IcITIAAS(19011gdVdDddDIHINGDSNdHA2DIGANINScINHNANDIAIOIDISSSdAIAASSI
SAIOSSOIAN/dAIHADSIIVOSNIMSAIAdRalACDIAIDDIVVIDDSISNSSdVIMASdOMIS
VSSAIALLONOMACIINAAAAIONCONVDAAAVICI3SWISSAMAIAVISISgAVILLANDOANO
VANLIDAMIIDDIVATIOODdVONAMSY\ISAdSdIDDSVNDSAMASSDODIARVOSRAIOAR
(L617 :ON m Ogs) aauanbas ppu mum mega Anuall 5zE913 [gts]
ESET bee obboopobeb qopbebloob ebeP6PODOP
OUT
pegoepoevo eobwoobbe boeoblebqb obeoblobeo 4.46.453-epob bbeobeobbq bboobebeeo ebbqbopeoq obepobeoeq bqopqq3qqo 6upbbDebob eoebblDbqb looppoDovo oebueoelpe PDPPE.PE.D3D bP03653UPD bebebbbqbe bblboDbpqe ObII
oebobepopo eloglobbby ebgbfq.ogbq popoqopoqb q66eooue6e pooebgebeb bebbboobeo opooDbq000 voeqbqbbeo 000bebbboo oobeoobbbe poobbeeobe OZOT
ogypoebeyb ebogepoopo 5goo6l0005 beeoeyobeb qbbeyobqbe eoelbebbey obboevbqob bqoebbeope obqobqbooe alobqbobeb qbbqbbbope qoopobeope oeqbeobebb ebbb0000be eooebeeoob opeopoblbb ebbqbobboe 6.6;53eq6bq 068.
oveolqbeyb qbbeboopoe bbeboepobe bqboebbqbb lbbgbobloo ebqb6eboop opubboobeo qebleogoop epebbeepoo beeop000po qqbqopqqbq booqoopebb OZL obbbw6w6 P8333305.43 Dobwooppo oblooppeop pebeepubob lobebeeDop bebbqboboe veDebbqbbe popeoueobe oopbeepepo vebqboueob qoqypeqooe buoopeobbb loobeobeob e000bgbooe bqbbqbobvp bubqopbeoe gbqoobbobe ObS
obebeobqob qboob000pq lo,pepeo6.45 obbobepoeb 4-43obobbob eopebblobe blbooe6lbo oobeb0000q qoeloebbee bqbbloobqo bbbl000boo bepeobbobb OZb obeooeo6vb eeobeobeop poobbl000p oqq6lbo5eo poobbbeepo eobeqobqbe boqoq.boaeo qbboepoebb beeeobbbfq. 3-46oeb6qeo egoeloegoe qoqeq656ee gebqbbebeb oblbgoeggy qi45oo55oe pebbebqoqe bebwobeob ebqbbebbge ObZ
ovqoobeopo bubpeoplee boqbbobooe 4Tebaeoqbe beobbbeDoq qbeebeovob oegoveyove ovq,55.411bq el000qvoqe bbbeb6bleb bqbebqweb beyoebbloo OZI
opbbeopbob qbbbqobebq egoglelogg obeolgoopo bbebblollo bbeyobgool oqbbeebqbb oqooqbbbbo obeebeebqb bebqobbbbq oqbe65.45b1 obeobqbbeb (96t, :0N 01 Oas) aauanbas appoapnu umq3 Situall sump [LIS]
IL6tZ0/ZIOZS9iIDcl 681'ZII/ZIOZ OM

AllASAANAISNACMIHNINVNHAgADCIAAMNANAgdGgHSACIAAADIAMINSIIAIIICIN
cDicIdTHASdOOTIgdVdDddDIHINCIDSNdRA2DICIANINScINHNANDIAIOIDISSSdAIAAS
SISAIOSSOIAVcL4IHADSEIVOSNIMSAI,Adgd4ACINAIDDIVVIDDSISNSSdVIcIdASdON
ISVSSAIATLOOOMNCIddISIHADS911Yd4AAVICOSNISSIMAIAVISISTIIIIINDOANO
VANIVIDAIVIIDDIAIMR1009dVONAM'SWHI11.4199SVNDSANASSDIDINA3VaLgAIOAH
(cos :oN ui O3S) 33uanbas Rau (mum wit SA8311 Lump [szs]
esu 6up 35.630306p6 loo6p6qD36 u6pubuopop octoploppouvo po6lopobbe bouo6qp6q6 o5reo6.306po 116q6pueo6 65po6p06.61 66po6p6upo p66q6Dopol obupo6poul 6goolloggo 6po66op6o6 pou66go6-46 g00000poup opfreyougov uouv6v6poo 6poo66op23 6p6p66616p 6616006oly op6obe0000 uqoqqo666v Q616610161 oopoqpool6 q65poopp6u voop61p6pb 6u666336po 000006loop vou.16166vo opo6p6663o op5poo665p poo66upobv OZOI
alpoopopu6 u6olu000po 6qop6.433o6 bupoupp6p6 166upo616p popl6p66up 096 366opp6-436 6-43p66poop o6q36163Dp olo6-1636p6 -4661666pop qoopo6popp opl6po6u66 u666o3p36p Poop6ueoo6 3ppopo6166 u66.16366op 6616op1651 oupolq6up6 166p6000pu 66u6opoo6p 6q6op66166 16616o6qop p6166p6poo o3y66336po quElquog000 voubbppoop 6puo33poo3 4-46loolq6q 6pogoopp65 OZL
0666.4o6q36 u600poo6lo po6g000000 o6qoppoupo ou6upopbo6 go6y6uppoo 6p661606op ppop65q66p poopoppo6p 0005PPOPOD up6q6oppo5 loquouqoop buopopobb6 goo6po6po6 upoobgboop 6166.3bo6po 6p6loo6upu 16.43366pbu o5p6p36q36 -46op6oppoq goopopo616 36606poop6 llop6ob6D6 popp66136p 51600ublbo pobeb000pq qopqop66pp 6-466qop6qo 66543306pp buoyo56o55 obpoppo6u6 ppo6po6poo 3Do66qopoo olq6q6o6po oop666ppop pofreqp6qbp 6oqoq6oppo q65-qo3ovu6 66poo6666.4 oppopbmo poppubolul plpoqp11.65 16po66p6u6 p6-46131q1u 16163366ov 3u66p6lolp 6.26qop6up6 p6qp6p6bqp opqoo6uouq 6P6oupplup 5op660600t, lqp6opolpu 6u3666popq 16pp6pop35 ouqopupp6p opp663.4qpq .Q-436olvoqp 666-2655Te6 6q6p6.4.1.366 6ppopbbqop OZI
po66poe6o6 .1666116pol pqoblepoop 66-polqopuo 66e66logoo 66ppo6gooq oq66pp6166 3.433166610 o6bp6pp616 6y61065663 op6u661663 o5vp6.466y6 (ZOS :ON ui Oas) oounbs 0p90alanu umo SAnaH Lump [tzs]
'90g :ON GI OgS ui umogs omonbos Nor ou!wu u!utio itO!!OLj puu cog :ON GI CAS ui umoys ootionbas appoolonu uno ILO!!
otp Xpq papoouo (tog :ON GI CAS) uo!2o.i alqupun u!utio 1q2!!g sapniou! osiu Xpocipuu 01.Poods-V1-1 LZ9113 0L1J..0g :0N c[i Ogs ut umotis opuonbas p!ou ou!wu u!utio Anuoti oq!
=
Pug WC :ON GI Os ui umogs aouanbos oppoolonu !quip Anuoti opXiq papooua (Tog :ON GI
Os) uo!o.! olgu!_ren uno rCAUZILI sapniou! Xpoqpuu 92I o!j!Docis-vH Lump aqi [as]
01A,LANIDIDANIISSSIASSDAACW3COVOIDSIEISVINDSNSOSJ
NNSADScRINSAgAIIAFINcIVNDdHOOAMSAANADDACISSIDIDSIIISODdS9SASVdOEIVSO
(8617 :ON ai Oas) aauanbas man oup.uF 5Z9113 [ZZS]
SDR.IAVAINgAISOHRIAODSASNHSNMOgai, ISIASSVVANNNSONSd.LLIgADVNAdSSCIVNMVAIAVOdAACISFIDATLVNNVOlggSSdd STLASdVV}IdOOVVVDIA.LANIDIDANIISSSIASSDAAGVgCOVOIDSIIISVINDS}ISDSA
2INSADSOINSAAAHAFINdVN9dHOOAANSAANADOMISSIDIDSIIISOOdSOSASVdOEIVSO
(00S :coN al ()as) aauanbas ppu ounnu Limo 5Z9113 [IZS]
=
IL6tZ0/ZIOZS9lID.:1 68tZII/ZIOZ OM

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAIWQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK
[526] CR6327 VH amino acid sequence (SEQ4D NO: 501) EVQLVETGAEVKKPGS SVKVSCKASGGTFRTHAISWVRQAPGQGLEWMGGIIAIFGTANYA
QKFQGRITITADESTSTAYMELSSLRSEDTAVYFCARGSGYHISTPFDNWGQGTLVTVSS
[527] CR6327 Light Chain nucleotide sequence (SEQ ID NO: 505) tcctatgtgc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60 acctgtgggg gaaacaacat tggaagtaaa ggtgtgcact ggtaccagca gaagcctggc 120 caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180 ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240 gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcatgt ggtattcggc 300 ggagggacca agctgaccgt cctaggtgcg gccgcaggcc agcccaaggc cgctcccagc 360 gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420 ctcatcagcg acttctaccc tggcgccgtg accgtggcct ggaaggccga cagcagcccc 480 gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540 agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600 gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654 [528] CR6327 Light Chain amino acid sequence (SEQ ID NO: 506) SYVLTQPPSVSVAPGQTARITCGGNNIGSKGVHWYQQKPGQAPVLVVYDDSDRPSGIPERFS
GSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTKLTVLGAAAGQPKAAPSVTL
FPPSSEELQANKATLVCLISDFYPGAVTVAWKAQS,SPVIAGVE __ ITI PSKQSNNKYAASSYLSL
TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
[529] CR6327 VL amino acid sequence (SEQ1D NO: 504) SYVLTQPPSVSVAPGQTARITCGGNNIGSKGVHWYQQKPGQAPVLVVYDDSDRPSGIPERFS
GSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTKLTVLG
[530] The CR6328 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 507) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
508 and the heavy chain amino acid sequence shown= in SEQ ID NO: 509. The CR6328 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 510) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 511 and the light chain amino acid sequence shown in SEQ ID NO: 512.

= N

IOI

.45.46E5355 bbooveoqqo bebypooebq b0000beobe 5loobb6voo eopoebqbbe bobgooboyq bqbbeeopob pebebopqoe boobbeeobe ObS
bq000poqoo orobeobebq oobeoeqooe ooloe65yeo buoebbeobe 5ooebq6o5e 08b bebbeoobeo yeobbobebe obl000boee oebbqbbeeb 616eo6q5be poobbebbbo OZb 0000eloqqo evoyebqobq ooblblbbqb obeoobooeo bbobebeybq obeobebovb oog0000poo qqogyoqqbq bobeoopeob pobbobgboy yeogebebbq obeepoebbb ebElobboqqg ovoloeo-lob eqbbqeqbeo beogbloygq elblbeoblq qlebeybgoo ObZ
bebbloybeo beogeopeol olopoggoeb yoebbbqoqb b64bpobbqb poqqbbeoeb p000qeobbq ovoob6beob eoqoo6qb6 qqqoqeoqoo qobbp000lo bbeoobbqop OZI
yeebeobeoo eqbbgoobeg qopqobeoby obeqqbqbeb poqbepobbb yobgbogoqo ,09 opeoobebee ebbbbeoOgo qbqqqoqbqo oopobbeooq oqbeoboybq ebqbqqeee6 (HS :ON m 03s)-5auanbas appoalanu um.0 itiOn 8Z9113 [Ks]
SS AIA
1,1011DMICHAM DAdDSIIIDA ANVDAA A
VICOSIIINSICHAIA VISISOCWILLA2190.4)1 OVA MI10,41d1I DOW MTIDO9dVONAM SIVA D SAIH 9S V)I3 SAN A S SOd)1 N AgVO
SgA1OA3 (LOS :ON (II Oas) aauanbas man num= HA 8Z9113 [Us]
NOd SIS1 SNOIAHN HIV3HIAIA SD
SAANDOOMSSNCIAETNSKIAASOCISGIAdd.LLNANNIgclOONS2A0AVICISdAdON AI3I1S A
ONDIIIAIgglISddlIAAOcIMIdOONVN aldVd1VM NS ANDNAJNONIMCIOHIAIIA SA A
AISNAOggliciNINVNH AgAOCI AAMND1 Agd(131-1S AGA AADIAgcall SIIAIIIGNOIddS14 A
SdDOTIgdVdDddDIHINGDSNc13 AIDICIANIN Sc131HN ANDIAIOIDIS S Sd AIA A S SAIDS S
OIAVcIAIHA 0 SI1VO SNM SAIAdgc1.4 ACDIAIDDIVVIDO SISN S SdViddA SdONISV S S
AIA
IIONDMIGAAMDAdDSIIIDADCDIAIIIIDAAAVICIRSHINSIUJAIAVISISOCRTILLA1100.4)1 OVANILDAIdIIDDIAIMTIDODdVONAM SIVA DSAIHOSVMD SANA S SO(DIN AMID S3A1OAg (60S :ON m Ckas) aauanbas Nag (mum LIMO SAR314 sump [zcs]
bLCI beep bb0000bebq oobeblooby beebeopoeo eloyooppoe obqopo6be6 OZET
peobgebqbo beobqobeol lbgboveobb beobeo6b.46 boobefmeoe 55gboopoqo beeobeoeqb googgoqqo6 eobboybobe oebbqobqbq 0000030E= ebeeoegove ouebeb000b poobbopeob eb.ebbbqbeb biboo6oqeo ebobeopooe goqqobbbee ObIT
6qb6qoq6qo opol000qbq bbeoopebee opeblebebb ebbboobeoo opoobq000e oelbqbbeoo oobebbb000 obeoobbbee oobbeeobeo geopebeebe bogeop0006 OZOI loobwoobb eeoeeobebq bbeeoblbep oeqbebbeeo bboeeb-lobb lopbbeopeo bqoblboopo 108.1606Pb-4 651666opel 00P06POPPO elbeo6p6be b55opoobee opebeepobo Peopoblbbe bbqbobboeb blboelbbqo ueolqbeebq bbeb0000eb bebovoobeb qboy65.4663 bblbobgooe bqb6e6opoo oebboobeoq ebqeoqopoy oebbey000b eepoop000q lblooqqbqb ooqopoubbo 6bbqobqo6e boopoobloo 4000300o bloovoepoo eberoebobq obebev000b ebblboboev voebblbbee oopoppobeo oobeeoepoy eblboveobq ogyoeqoaeb epooyobbbq oobeobeobe poobqbooeb qbbqbobeo6 ebqoobeoeq bqoobbobeo bebeoblobq boob0000qg ObS
oopopoblbo bbobeopebl wobobbobe opebblobeb lbooeblboo obeb0000ql 08b oeloebbeeb qbbwoblob bbq000boob eovobbobbo beoovobebe eobeobepoo OZb oobbl00000 Tabqbobeoo oobbbeyooy obegobl6e5 ologbqopoq bbl000yobb 16006556qo gogeboqloe -466.1066o-16 g000bqobeo oeglowelb llelebbgeb eeebqbebeb obqbqoeqqe goqboobboe oebbebqoqp bebqqoeyob ebgooebbge "
ObZ
oeloobeoeo beboeooqee ooebbobooe lleboeolbe beobbbeopq qbeebeopob oeqoepeoee oeq561.1qoq pqopogyoqe bb6ebbbme6 bqbebqqobb beeoebbgoo OZI
oobbeoebob qbabqqbeoq evobquqobb obeoqqoqeo voebbqoqqo bbeeobqooq oqbbeebqbb ogoolbbbqo obeebeebqb bebqobbbbq oqbebbqbbl obeoblbbeb (8O5 :ON m Ogs) aauanbas apnoaianu meto Xneall sump [Ks]
=
IL 6tZ0/ZI OZSIVIDcl 681'ZII/ZIOZ OM

ZOI
cnIdc1.41.4ASdOgrIgdVdDddaLHINCIDSNdgAIDICIANINSOIHNANDIAICUOISSSdAIAAS
SISAIDSSOIAVcL4IHADSIIVOSNMSAIAdgdgACDIAIDDIVVIDOSISNSScIVIcHASdON

OVACILL941VdIDDVNIMTIDOOdVONAMSISNISIL4IDDSV313SANASSOcINNAWDSOAIOAg -,t (Sts :0N (11 ) ounbas ppe ounue umto Snuall 6z9llo [6cs]
CSET 5pp o56opoo6p5 loo5p5-4005 p5p26p000p OZEI oploppopeo ep5g000LZE. 5oPo5qp615 obvp5qobeo lqblboppo5 5bpo5Pobbq 09ZI 56035e5ppo P55.45opPol p5ppo5popq 5-403110-44o bpo66o2.536 pop.55-435.45 00ZI gooppooppo oP5PPoPlop poppbpb000 5poobboppo 5pbpbb5qbp bbqboo5a4p Obit op5ofreoppo Pgolqp555p pbT5513q6q oppoq000lf) q6mpopp5p pDop5qp6p6 Ere6.583p5po oppoo5l000 pop-45-466pp opobebbboo op5poo556p poo56pPo5e OZOI ogypop5pp5 Pboqvpoopo 5goobwoob 5ppoppo5p5 qbbppobqbp popq5pbopy 096 o6boppEr4o5 6qoP56Poov o5.405q6opp 0405-4605-25 -458.48653ov goopobpopp 006 opq5po5p65 P56600po5P poop5ppoo5 oppopo51.68 p55q6o65op 66-45opqbbq 068 oppoqq5pp5 .465p5pop52 55p6Dpoo5p 8q5op55q55 .45518o5qoo p.5-4662.5pop 08L oop55ope.pD
Tebqvog000 popb5pp000 bppopoppoo -4.45.4oDllbq 5ooqopop55 OZL obbbqp5q06 yb0000p5qo pobw00000 obwopopoo ap5ppop5o6 qp5p6ppopo 099 E.p5b45p6op PPoP65.455P poopoppo6p opobppopoo pp515oppo5 qoqpopqoop 009 5p000po555 lopemobPob P000blboov blay4bobpo 5v5loo6pop qbqoobboece ObS o5ebpo5q05 q5oo5000pq wovovo5.45 obbo5voot.5 lwo5o55o6 popp55135-2 08b e.q5oopbgbp pobPbooppg qopqoebbpp 6155loo5qo 555l000boo 5popob5Db5 OZb o5poopp5p5 pPobv35Poo oop56l000p 31151635pp opp555ppoo pb5plo515p 09C 5owq6oppo qbbqoppyo5 bbeop5555q oplopErmo PqOPP050P0 poopopw55 00C q5po55p5v5 oblbqoPqqp qqqfpoobbop op56p6qale op5qoo5pq5 pblobebbqo ObZ opqoqbpopo op5oqqoqpp boebboboop .41-e5opoq5e 5eo555pooq q5pp6po5o5 oPPEthogq1.4 31363110-4p 5E55 6-46p5qqa66 5ppo6651op OZT op56pop5o6 -4565-116pp-4 pqpq1PPD6P pbpolloqpo 55P651pTqo 56-epp61=1 09 D.456pp6155 pq331565qo p5v5Pq15 5p61056551 ol5eopq551 o5eopq55p5 (VIS :ON sal Oas).
aSuanbas appoaianu tung3 Annall 6zolip [Ks]
=
'8 I ç :ON cil OHS ui umoys aotionbos ppu ouuuu uno142!! oqi puu Lig :0N al Ogs uï ummis opuonbas appoalonu u!ugoly2!!
alp Xq popoouo (91g :ON cii OgS) uo!2ai alquyun u!uqo NS!j sapniou! osiu Xpoquuu D21 DWoods-VH 6Z92I3 oq'gig :ON GI OgS u! umogs oDuanbas p!ou ouuuu up.13 Xnuoti oqi Pug 'HS :ON UI OgS ui umogs opuonbas appoopnu Lump XnuoLl oqì q popooua (E! g :ON cii Cogs) uo!2a.i alqu9un umo /CAM.' SOMOLI! Xpoqpuu D21 oupods-yll 6zE9N3 oq [Lcs]
2INITDILDODAEISSDA003AAAVJCI3dTRISIITIAGIDS9S9 S,PICHIDIVIISSVOJITTIldVO9d)106AMVIASSSASOSVNDS-IIVIIgOdSISIIDdSOIINAIg (OIS :oN m 03s) aauanbas man (mum 'IA 8Z9113 [95]
3gD1INAS311,AdSSIDOH,LAH3VAA
)1F1)13AUV3ISIK1.LSSISAISCDISCIOaLAS3OSNDSOIVNCIANMOANVHIldiUNNTIDAASV
IDSNIOgGSdcHIAASdVVV2D1I3DLIDD9drISSDAOODAAAVAGgdglIISIELLACILDSOS9 S.411GclIaLV2ISSVDAITRIdVODeDIOOAPAVIASSSASOSVIDSIIVIlgOdSISI.LOdSO.LIAIAIg (ZIS :ON ai Oas) aa,uanbas ppg oup.un u!nto ;On 8Z9113 [SES]
=
-68tZII/ZIOZ OM

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL
HNHYTQKSLSLSPGK
[540] CR6329 VH amino acid sequence (SEQ ID NO: 513) EVQLVQSGAEVKKPGSSVKVSCKASGGIFRSNSISWVRQAPGQGLEWMGGIFALFGTTDYAQ
KFQGRVTITADESSTTVYLELSSLTSEDTAVYYCARGSGYTTRNYFDYWGQGTLVTVSS
[541] CR6329 Light Chain nucleotide sequence (SEQ ID NO: 517) gaaattgtgc tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccaca 60 ctctcctgca gggccagtca gagtgttagc agcaactact taggctggta ccagcagaaa 120 cctggccagg ctcccaggct cctgatctat ggtgcatcca gcagggccag tggcatccca 180 gacaggttca gtggcggtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacccct cactttcggc 300 ggagggacca aggtggagat caaacgtgcg gccgcaggcc agaccaaggc cgctcccagc 360 gtgaccctgt tccccccctc ctccgaggag ctgcaggcca acaaggccac cctggtgtgc 420 ctcatcagcg acttctaccc tggcgccgtg accgtggCct ggaaggccga cagcagcccc 480 gtgaaggccg gcgtggagac caccaccccc agcaagcaga gcaacaacaa gtacgccgcc 540 agcagctacc tgagcctcac ccccgagcag tggaagagcc accggagcta cagctgccag 600 gtgacccacg agggcagcac cgtggagaag accgtggccc ccaccgagtg cagc 654 [542] CR6329 Light Chain amino acid sequence (SEQ ID NO: 518) EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLGWYQQKPGQAPRLLIYGASSRASGIPDRFS
GGGSGTDFILTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRAAAGQPKAAPSVTLFPPSS
EELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQ
WKSHRSYSCQVTHEGSTVEKTVAPTECS
[543] CR6329 VL amino acid sequence (SEQ ID NO: 516) EIVLIQSPGTLSLSPGERATLSCRASQSVSSNYLGWYQQKPGQAPRLLIYGASSRASGIPDRFS
GGGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKR
[544] The CR6331 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 519) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
520 and the heavy chain amino acid sequence shown in SEQ ID NO: 521. The CR6331 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 522) encoded by the = =
light chain nucleotide sequence shown in SEQ IDNO: 52;3 and the light chain amino acid sequence shown in SEQ ID NO: 524.

tOI
, r 6S9 3520 6b 33o 333654b33p Ecepfyebec4b3 3po6p36652 b3p3o326q6 bvpo5.1.3623 eqobebbooe D-56e6E-e66-4 6po6e6popo peoqoobelyq opeqobeo52 06S poboobDp-45 PPOPPOPPOb pobppob-e, DOODDE3DPD opbp55.16ob boobbppbqb 086 poopbpobpo pboobbPebb qop66153pp 6q6=60664 poovqoqqoe bobpolpoqo OZ6 35q616bq33 ovoo65epop poobbpofylo beb5p5ooqo oqoop0000q qbqopop515 09 obrooplobo obfrevoopfye 3p66-eo6o36 636466=21.33 qboovolbbv voov66513v 00 pf&olqoqbq eqq.eoqP6q6 plbeqb-elvb 6546q6byol Bqoyqqpqoe boof&pbqvb 06Z 566pobvp63 qbe&yo5P3.4 voaebq000v oobbouovvb bbloqop.epo qoe.e.qoqoqq pbofreblopo gy565Poloo obbooyboEre qe6TebTeqo qboqbbqo5-4 blo3p355yo OZT
obbpoDbpyt, PobypoPlab qoppb16.4bp pppqbppbbq TeOPPOEPP5 bbbbqblpoe 09 qlebbvoobb ov5eovb5vo opobb-16poq bqbboqopob 33b bb 5015'4o-45v (czs :ON m Oas) a3uanbas appoapnu u!gto jqr icc9HD [gps]
SSAIAIIDOOMAGISSHAAANONVDAAAVIUgSWISSIMAIAVISIADCWILLANOWNO
VANVIDAIADHODIAIMTIDO9dVOIIAMSIVASSAIDDSVNDSANASSOMIAgVDS3AIOAg (615 :ON m Ogs) aauanbas man otqwe HA 19113 [LbS]
NOcISISISNOIAHNH
TigHINASDSAANOOOMNSMCIAIMISKI4ASOCISCIIAdd,LDIANNgdOONSgMUAVICISdA.49 NAIDEISAONNIIAIRMISddlIAAOd311c100)1V}ISIINgIdVdIV)INSANDNAMIDNIMCIOW1 ArIASAANAISNAOggIMMINVNHAgADCIAAMNANAgdUgHSAGAAADIA2dINSIIAIIICDI
cDidc14-14ASdOOTIgdVd3cIdDIHINCIDS)Idg411)103AMINSOIHNANDIAIOIDISSSdAIAAS
SISKIOSSOIAWLILHAOSEIVOSNMSAIAdgcHACINAIDOIVVIDDSISNSSdVIcHASd0)1 ISVSSA,LAIIDOOMACIISSgAAANouypAAAVICMSIIISSIMAIAVIS.L4RUVILLANOODIO
VANVIDAIAIDIIDDIADATIDO9dVONA,MSIVASSAIODSVNDSANASSOOINAgVOSgAIOA3 (izs :ON in Oas) 33uanbas man mute mega Simi.' 1cc9113 [9ts]
SET 5vvDE6opoo 6.25q336-251 pobElyebeo OZET ooyoploppo pPoPobl000 er5E,bopo6lp 6.4bobvp6lo 5-po4-45gboy p3bbece36p3 becIbboo5pb epopbbqboo P3106PP35P 3u.16q33ql3 qq35p3563? bobvppbbqo 46l000000 OPOOPbPPOP qoppoppEceb oo36-233553 ppo6y5y666 qbp56.46306 Obit ogeoebobvp 3332g33,g35 E)6 65b gblooyogoo pqb.45byope ebyvoo2blp 0801 bv55v555po bPp00000bq pooeopqbqb Ere00005v55 bopoobvoo6 .65vvo365.2.2 OZOT obypTepopb uP5P6aTeoo poo5gooblo oobbyppppo bpfylbeyevo5 .16-evou"16p6 096 bpp3663vvb qof&lovbbv oaeoblobqb oovoqoblbo bp6gbfq65.6 33pq33.236.2 006 ovpovq5eob vbfiebbb000 obveopebve oobop-eopob qb5pb6q6o6 eopbbgboyq 068 bbqovv3qq5 Py615.6Pboo ooe56v63po 35uer463p6.6 bb 55j5 goop6.455e5 08L 00000vbboo E.v3lvb.423q 000vovbbvt, 000frev0000 pooqqfqool q6lb33q3o3 OZL vb53655-436 -435v633333 bg000bl000 33335l33p3 v000vbeov 6oblo6p6pv 099 opobebblbo boPvvaebbq bbvvoovopp obp000fmvo poopvbgboy yobqogpoyl poyErepoppo 568-4005Poe. P3em3335q5 39p5156-463 BypEcebloob yoy-45g3366 06S obvp6y5rob qob.4600boo ooqqooPoyo 611,35bobyo pybqq=636 5o6vorv5.6.4 086 p5e6q6o3p6 qboopfmeop pogloPq3e6 byy5-456-400 61o655goop 6oa6ypeo66 OZ6 ob6ofmooPo beerePoE,Pob voop936bq3 oopoqqbqbo 5poopobaye yopeofyegob 09c , .4525ololbo 3v3l661333 yPbbbPoo65 86-43eqov5o q3q5pq5e6e 5-4v;oeqqe1 00E qyypbbybpb oer4513egge -451boo65op ovbeceblogp fiebloo5pob y5gobp55ly ObZ opqopbpopo EYeboPqqqve boPbboboop qqp6oupq5p bp3555popq q5pp5ppeo6 081 opqaeyyp6P
3vq5b3glbq Pg6polvoqp bbbpb55-4-eb 6.46p5.4gobb bypoyay4po OZT
ooftheopbob qb6bq3531 Plppqpqobp obpolgoovo 65v66 ,40-410 66Ppobqool 09 oq5bvvbqab oqopqbbbq'o 36P'e5yy5-45 5y5q05.65bq 3.45?6thq66.4 36p3bqb5p5 (OZS :ON cu Oas) aauanbas app0al311U UM1.0 SAB3}{ jump [gps]
IL61'Z0/ZI0ZSII/I3c1 68tZII/ZIOZ OM

=
=
S I
IIASAANAISNAOgg&DIDIVNIHAgADCIAAPANdNA3dagHSACIAAADIA3dINSITAIIICDId NdcITUASd00113dVdDddaLHINCDSNdRAIDICIANINSdNHNIANDIALOIDISSSdAIAASS
ISKIDSSOIAVd.ILHADSIIVOSNANSAIAdgdAACNAIDDIVVIDDSISMSSdVIdAASdDNI
SVSSALALLOBDMAGIAIASSAAHdDNVDAAAVICIgSMISDIMAIAVINISCKIVILLANDODIH
VA.NLIDAAVIIDDINMg1DODdVOIIAMNIV4N21.4d99SYNDSANASSOd-NMAgVOSOAIOAO
(LZS :ON cll 03s) aauanbas man ouRun tneto SAC311 zcou3 [csg]
OSET
bpyobb0000 beerloo5pec4 opbebvubpo OZET
opyovlovoo vvopobloop 5.6-26oyobTe 516obvo5lo 6v311615op pobbbpo6po bbqbboobpb pyoybbgbo3,y9qp&eyobp oulbqopqqo qgobpobboy bob23vbbqo 6q5gooppoo OPOOP5EPOP qOPPOVebEe. poobeopbbo ppobp5p666 qbp55453ob Obit olvoybobyo 000yqoglob LbP-ebqbblo qbqoovoloo ol.61.6byooy ybypooyblv bybErebbboo bep0000bbq 000vovq5q5 5v3000bebb boo335v33b bbypobbev OZOT
obyogyooy5 vr..6veoq'epo d'..pobqoo5qo opbbyypyyp by6.4.65pyo.6 1.5ppopq5p6 bpeofthopp5 gobbloubbp por.peqobqb oop3lo6q6o bp6.4551665 opeqoppobp oveovq5yob Pb5pb5boop obvybov&ev oobovvopo5 qbbvbbqbob boybec4.6opq 55qopyoqqb pvbqbemboo povbbp5aeo obpb.45oPbb .455.455460.6 goop6q55E,E.

oopoor.55oo 5poly5Teog pooPopbbev poo6ppoopo 000ggolool. 15150o-woo OZL y6536.66-4o6 gobpboopop 5goop6lopo 00036lop2o V00025PROP 6oblobp6pp 099 3pp6R55-1.63 bopypop.bbq 55 33P o5ppo36pp3 epovpbqfpoP vobqoqvaeq oppereopopo 5681.335P35 pobyopo6lb op-e5q66.45o 5vo6v61=6 vop16.4po.65 ObS
35po5p5pob -40645305= ooqq.povopo 5qb36636po opeqqop6o6 5o5v3E-255-4 08b ofrefyl5o225 l5oop6p5op oplqpvloyb 6-2y6155loo 6136561 pp boobvor,o6E, OZb obbobpooyo OPE,PPobpob p000po5613 opool-abl5o bv0000bbbe poopobpqob 15p80.q.o.16o ovol6Bovoo p655pp5o6b 66-43.460p55 qpoplooloo loplovlo'eo opoq56p6v5 3.6.46-43v1qp q6q6poboop opb6p5lolp p.e6qpo5vob bblobybbly ObZ ovq-4o6popq PPEOP0010P 53p653.633v plE,00polEre 6vo655vool 3.6ppleopob oplEreppop6 opb56.111pq 6.4o6pleoqv 665v6551p5 bqbpbllobb bppoybbloo OZI
oobbypvbob 165.61ovvol vlo6qqqqyp oboogg0000 68p65golgo 55ppo6gool ole6evpq65 owo-4655qo obppbpvbq.E. 5v5lo.5566.4 ol5po5y1551 o6po5166po (9z5 :0N m Ogs) aauanbas appoalanu mega SitnaH zcoND [zss]
'Kg :ON GI Ws u! umoqs opuonbos mac ou!wu Lquqo it1511 L11 puu 6zg ONUI Os umoqs oouonbos oppoolonu tquqo otp Xq popoouo (gzg :ON GI Os) uo!5o.! olquygn Lquqo 1145!j u sopniou! osie Xpoqquu 951 Woods-NTH ZE92IDOU. *LZS :ON GI= Zias ut umoqs aouanbos p!ou oup.uu ultuqo Xnuoti otp Pug 9ZS :ON GI OS umoqs aouonbas oppooionu uiijo Anuoq otp Xq popoouo (gzg :0T=I Cll Ogg) uo!5ai oiqu!Jun tquqo Xnuaq u sopnpu! Xpoqpuu 95I ou!oods-vH zEoND oqi [iss]

SS213dI9SdlICISCRIAAAIAdVODOIOOAMHASMSDINND9DIRIVIO9dVASASddOIAASO
(ZZS :0NUI Ogs) aauanbas plan untie 1A IC911D [OSS]
SDRIdVAINgAISDHFILAODSASNHSNMORdi ISIASSVVANNINSONSd1113A9V)1AdSSCIVNMVALLAVDdAACISMATLV)INIVOlggSSddd TLASJVV)IdODVVVDIAIANIDI9AAA1-1(ISSSCIMAO3AACIVTIOVgANSIIIIVINDSNSO
SAIMIDScINGSCICIAAAIAdVODd)100AMHASNSOININDODIRIVIODdVASASddOIAASO
(7zs :ON al Ogs) aauanbas man oup.un upto 101 1C911D [617S]
IL61'Z0/ZIOZS9/IDcl 681'ZII/ZIOZ OM

VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV
KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
ALHNHYTQKSLSLSPGK
[554] CR6332 VH amino acid sequence (SEQ ID NO: 525) =
QVQLVQSGAEVKKPGSSVKVSCKASGGPFRNFAINWVRQAPGQGLEWMGGIIAVFGTTKYA
HKFQGRVTITADDSTNTAYMELGSLKSEDTAVYYCARGPHYYSSYMDVWGEGTTVTVSS
[555] CR6332 Light Chain nucleotide sequence (SEQ ID NO: 529) gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcgagtca gggcattagc acttatttag cctggtatca gcagaaaccc 120 gggaaagttc ctaaactcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180 cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcaaaag tataacagtg ccccttcttt cggccctggg 300 accaaagtgg atatcaaacg tgcggccgca cccagcgtgt tcatcttccc cccctccgac 360 gagcagctga agagcggcac cgccagcgtg gtgtgcctgc tgaacaactt ctacccccgg 420 gaggccaagg tgcagtggaa ggtggacaac gccctgcaga gcggcaacag ccaggagagc 480 gtgaccgagc aggacagcaa ggactccacc tacagcctga gcagcaccct caccctgagc 540 aaggccgact acgagaagca caaggtgtac gcctgcgagg tgacccacca gggcctgagc 600 agccccgtga ccaagagctt caaccggggc gagtgt636 ; .
[556] CR6332 Light Chain amino acid sequence (SEQ ID NO: 530) DIQLTQSPSSLSASVGDRVTITCRASQGISTYLAWyQQKPGKVPKLLIYAASTLQSGVPSRFSG

SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV
YACEVTHQGLSSPVTKSFNRGEC
[557] CR6332 VL amino acid sequence (SEQ ID NO: 528) DIQLTQSPSSLSASVGDRVTITCRASQGISTYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSG

[558] The CR6334 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 531) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
532 and the heavy chain amino acid sequence shown in SEQ ID NO: 533. The CR6334 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 534) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 535 and the light chain amino acid sequence shown in SEQ ID NO: 536.

bG9 obeo bqbpbopepo opobbgboop bPvbebbgbo peobpobbbe boepooeblb 5poobqo5pD pqp5P65Dop Dobebvvbbq 62obv6p000 oupqopbely4 opvqobPobP
ObG
oobopEop.45 PPOP2OPPO6 v6ea5peo5e 00000'200E0 opbpbbqbob 600bbPP6.16 08b popobpobeo pboo55P-ebb qpobbgboop blboobobbq oopvloqqov bobpoqvoqo OZb 35.4.6q56-4o3 ovoobbP'eov voo6beoblo bybbyboolo oloopoopoq -46.4pooPbqb obpopolo53 055vvoop52 R256vobo36 636.466pqoo .46paeo-465-2 pope658-43E, poboqlolfyq ullvoTeel5 pqopqbpqpo 661&465pol bqopqopqop boo65P6qp5 ObZ
56boqb2pbo qbabppempq p...lpfyqopop pobboPpeeb bbgole.ppoo lotbgalq11 p6ofrely4poo 4-2565Poqoo 365popbo6p gebqpbqpqb qb34651ofq. bqoppabbeo OZT
36bpo36pe5 pobepTe-455 qopp61515p qpppbvpe.bq qPOPPqPPE6 .6656.46qopy 11p5bpoobb opemov5fmo opobbqbvoq bvbbol000v ooSpowybq o6161ywoq (scs :( . ui ()as) aauanbas appaatanu u!miDltI2FI tE910 Ez9s1 = SSAIALLONOMACHAIASAAAMMWDAAAVIG3S1110111gIAIHAINISgoaVILLAIIDOSMO
VASdSDJAMIDDAMTIDOOdVONAMSAVNSIIAdSOSSMDdANASSOd)INAgVaLRAIOAg (Hs :01s1ii Ogs) aauanbas ppe oupue HA. t9113 [I95]
NOdSISISNO,LAHNHIVg HINASDSAANDOOMIISNCIAJUINSA-144SOCISMAddIDIANN3dOONIS3MUAVICISdAdDNA
= IDEISAONNIINgaNSddliAAOdglIdODNVMSIINaldVdIVNNSANDNAMIDNIIMUOHIAL
IASAAIIAISNAOgglIdNINVNHAgADCIAAMNANAgdMHSACIAAADIA3MISHAIIICD101 ddS1dASdOOTigdVd3dd3LHINU3SNd3AIDICIANINSdNHNAN3IA.LOIDISSSdAIAASSI
SAIDSSZYIANMAIHADSEIVOSN.MSAJLAd2dAAGNAIDDIVVIDOSISNSSdVidAASd9MIS
VSSAIA.1.19MDMAGINASAAAIdONVDAAAVICOSNIMMIAIHAINISgCIVIIIA21004310 VASdSDAAMIDOAMTIOODaVOITAPASAVNSII4dSOSSNOdANASSOd)DIAgVaLgAIOAg (ffs:010:11U3S)aauanbas ppeounuemetoSiteallpcoND [09s]
HET
bvvo6b000p bpfyloo&ebq poopEyerebpo OZI
00E3E3PD3 PPOPD8q0DO MpEoppfilp 6-45o5p36qo fmo-4-48.4bop pobb6pobpo b6155op5ub propbE:gboo vp-lobvpofm 3.2.16133.4.43 qq36p3553p 636p3pebl3 8.46.400p000 OPOOP6PPOP loppopv6p5 opoErepob6o vva6p5e556 .46p65.46oD6 olpopbobpo poovqoqw5 55PP6456-4o qbwopoqop oqb.465p3op pbppoopbqp bpbbpbbboo fieooppoobq pooPoPqbqb bpoopobe55 boDDobepob bbp?pobbE,e OZOT
obeolpooe5 evEyebolpoo poo5goo5qo op66epoeep be51562upb -45epoe-4626 bvyobbovvb qobbqaebbv oo.eobwfrab ooyogoblbo bvb-465q565 oaelooE,obr, opp3v4bp36 vb5pbbb000 p6P230.25ev oobovpovo5 1.6bpbbqbob baebblbovq 66.4pePo.415 PP5-45Ere5oo oovambopo 3bElya5oP55 qb.6qE.E.qbo5 qoovb.465p5 oppoov6503 byolPbTepq 00pp0pe6pp opobvpoopo Doollblopq gblboowoo OZL
ybbobbEy4ob lobvboopoo Erapo35qopo oppobgoovo p000y5v-eov 535-405pbey 0005y5bgeo Eov=e.eopbbq 65vPoovopp ofyeopobPvo roop5-4E.ov pobqogyoyq ooybpoopPo 6551pobvpb eobpoopfyq8 povb156.163 617o6v5qoob poplbloo56 Obg obpoSpbpo6 go615op5op poqqopyppo 5q5366o6eo oyfyqqoobob Bo5yopp684 a6v6.45oop5 q5000beboo oogloyqoPb Emvb-455wo 51o556.4000 boofieopobb OZb obbobeoopo EcebPPobpo6 voopoo5510 opooqqb.450 6popoo665e popeo6p135 qbpbolo150 ovolbbovoo ebbberyobb bbwq50-ebb qvovlDogoe loeloelooe gooq5bebeb oblbglellp 161boobboy op65vbqole bebqq-465-e6 -261o5e65.1e OPOD'16P3P0 PPOOP00qPP bopbboboop 1-4R53pogbp bpo6552oog qbpp6poppb oelabevoov oqq561.1-401 6q6bolooly vbbebayq5.6 5-46e6.4.4obe. Byvopb6opo OZT
op66popbob qbbbqp8voq bqobqpvqbE bbpoqqoppo 6-epbboqqo Tevpobqopo o165pp6q55 plooqb65qo obeenep616 6pErlobbe.5-4 opbe65.1661 obeonlEby6 (zEs :ON al Oas) 33uanbas appoatanu umq3 1A11311 pcoND [655]
=
=
=
IL6tZ0/ZIOZS9lIDcl 681'ZII/ZIOZ OM

= =
:1 ) IASAANAISNAOgaNd31131VNHA2AOGAAMNDIAgdGgHSAGAAADJAHdIASIIAIIIMId)1 dc1414ASd9DTIgcIVdDdcIDIRDIGDS)IdgAIDIGANINSdNHNANDIAIOIDISSSdAIAASSI
SAIDSSZYIAVaILHAOSEIVOSNMSAIAd3ddAGNAIDOIVVID9SISNSSdVIcHASdOXLS
VSSAIAILDOOMUO4A0dAAOSSIIVDAAINIVIGgSDISSIgINAVVS.L4gGVILLANDODIOV
ANVI9dIAIDAIODIAIA131909dVONAPASIVASSAIDDSVMDSAMASSOd3INA3VOSOA101A10 (6E5 :ON m 03s) aauanbas man ounue umq3 SAnall 9E0113 [L951 OSEI
beeo5boo33 bebloobebq oobebeebeo OZEI
00P0Eq3P3O PPOP05q000 66e53e3ble 6-4636e3613 breolqbgboe eobbbeobeo 09ZI 664b6=6eb peoe66.45= ealobeepbe De-151=143 llobeobboe bobeoebblo 00ZI 516.4===
OPOOP6PPOP qOPPOPP6Pb 000be=563 evo6e5e556 q5e56,4boo6 ObTI
oleoebobeo 000eloqlo5 55ee6155-lo q5lopeoloo 3q5.156pooe ebee=e6le bebbebbboo beopp0005-q loppeoe.4516 beopoobebb 533=5e336 bbeepobbee OZOI obeole=e6 evbeboqe= 3=51=6= oobbeeove3 5e5qbbee36 qbee3eqbeb beeobboveb qobbloebbe poob.436-4b opeolobqbo beb1561656 ooelooyobe opeoel5e3b ebbebbb000 06PPOOP5PP 3353epoe35 qbbebbqbob boebbqboeq Ob8 55loye=45 evE.155eboo ooebbeboeo obv5lboy65 466.1551536 qopy5-465-e5 08L opo=ebboo 6voleb4e= =beoebbee boobeep000 33=45-4=4 4615===
OZL v650565=6 lobeboo=o 54=o6== o=o6=oeo PODOP6PPOP boblobebee 099 =ob.-ebb-46o bovveoebbq bbeeoeove obeopobeeo epoeeblboe eoblolepeq =e5eo=yo 665q=beo5 P362=36-46) =e515615o byobe51=5 yoe161=66 ObS
36e3bebeob 43646=6= ooTlopepeo 64bo5b36e3 oebqq=bob bobepeebbq 08b obebgbooeb -45=35eboo o==eloeb bee5.455q= 6438561=o boobepeobb OZb obbobeoopo bebeeobe35 ep0000bb-= opoolq515o be==b5be popeobelob 09E 16e63=-46o ov=56q000 eo666e=65 55q3e65e= lqopleypoo poelleT155 qbe4315.5y5 obqbwegle 4,61voob5oe oboe 6661=5-eob e5=6e5b-le ObZ
oploobbobo 5e5opoT4ee boebbobooe qlebovoqbe 6-2o666vooq l5eebeobo5 oegoeueoby oebbbqq.464 elbboqqoqu 565e5b5geb 5-45e5q=66 eveyoebbgoo OZI
oobbeoebob qbbblobeol eq35.4ego5e obeogloovo bbebbloglo 65eeo5=3.4 ol55ee5.456 olo565= o5ep5ee5q5 5e6=6e66q 34-evoe1561 352361e5yo (8ES :omulOas) aauanbasamwatanu wimp Snuall9coup [995]
7t7C :ON GI OaS ui umoqs apuanbas Nor ou!Luu uno 1q24 all puu Itg :ON CH OHS ui umoqs oDuonbas appoopnu ump )1424 oto X4 popoDuo (otg :0N1 cll Ogs) uo!2a) olquyun u!uqou.12!) u sacinpu!
OSjuXpoculuu 021 Dupods-VH 9921D 3111 .6g :ON GI OHS u! umoqs 33u3nbas mou ou!we un3 XAU01.1 34) Puu 8C :ON GI OgS u! umoqs opumbas oppoolonu u!uqo Xnuoq ay X4 popoou3 (LE g :ON GI
Ogs) uo!2ai oicinpunuiuqo IAuoqu S3prIpll! Xpocmur 021 oupads-vii 9EE9ND ota 159sj DIA,LANIDIDdAAHGSSSHMAODAAGVMOngANSIITLVINDSNS
OS.411RdIDScRIGSGGAAAIAdV090100AMHASNIIDINNODDIIIIVIODdVASgSddOrIAAS
(t'E5 :oN uI Ogs) aauanbas pp e ounun 1Ec9113 [t795]
SDa.LdVAINgAISO3H,LAODSASIIHSNMO3d rISIASSVVANNNSONSdIJ-I2A9VMAdSSGV3IMVAIAV9dAAGSTIDATIN3INVOlg2SSd cITUASdVV)IdOOVVVDIAIAMIDIDJAAIRISSSHMAODAAGVaIDAgANSIIIIVINDS)IS
OSAllgdIOScRIUSGGAAKIAdVOOd3100AMHASNIIDINN9DDIRIVIO9dVASgSddOKIAAS
(9E5 :ON m Ogs) aauanbas man (mule mega 1q2n pEE9H3 [05]
IL6tZ0/ZIOZSIIII,Dcl 68tZII/ZIOZ OM

CA 02827301 20137,08-13', WO 2012/112489 ==

TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL
VKGFYPSDIAVEWESNGQPENNYKTIPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH
EALHNHYTQKSLSLSPGK
[568] CR6336 VH amino acid sequence (SEQ ID NO: 537) QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIFGMFGTANY
AQKFQGRVTITADEFTS AAYMELSSLGSEDTAM YYCARSSGYYPQYFQDWGQGTLVTVSS
[569] CR6336 Light Chain nucleotide sequence (SEQ ID NO: 541) gaaattgtga tgacacagtc tccaggcacc ctgtctttgt ctccagggca aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120 cctggccagg ctcccagact cctcatgtat ggtgcatcca gcagggccac tggcatccca 180 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcatcgct cactttcggc 300 ggagggacca agctggagat caaacgtgcg gccgcaccca gcgtgttcat cttccccccc 360 tccgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctcacc 540 ctgagcaagg ccgactacga gaagcacaag gtgtacggct gcgaggtgac ccaccagggc 600 ctgagcagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 [570] CR6336 Light Chain amino acid sequence (SEQ ID NO: 542) ElVMTQSPGTLSLSPGQRATLSCRASQSVSSSYLAWYQQKPGQAPRLLMYGASSRATGIPDRF
SGSGSGTDFTLTISRLEPEDFA VYYCQQYGSSSLTFGGGTKLEIKRAAAPSVFIFPPSDEQLKSG
TAS V VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
[571] CR6336 VL amino acid sequence (SEQ ID NO: 540) EIVMTQSPGTLSLSPGQRATLSCRAS QSVSSSYLAWYQQKF'GQAPRLLM YGASSRATGIPDRF
SGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSSLTFGGGTKLEIKR
[572] The CR6339 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 543) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
545 and the heavy chain amino acid sequence shown in SEQ ID NO: 546. The CR6339 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 547) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 548 and the light chain amino acid sequence shown in SEQ ID NO: 549. z =

' 011 bS9 obeo blbebooepo poobbqbooe beebebbqbo opobeobbbe boeopoybqb beoobqpbeo egobebbooe pobebeebbq beobeb000p peoqoobebq opeqpbeobe ObS
oobooboeqb eeoevoeyob ebeobeeoby DOOOPOOPO oebebbqbob boobbeebqb 08b 000pbeobeo eboo6beeb6 qopbbqboop bqboobobbq opoploqqoe bobeageoqo OZb DEcIfyi.bbqoo oepobbeepe epobbeobqo bebbebDoo oqoppoopoq qbqpocebb obepooqobo obbeepoobe oobbeoboob bo6.4.66eqoo q6ope6qp5e epoe686e6b obboggegbb qbquoqebqb eqbeqbeqvb bbqbqbbeol bloylgeloy boobbebleb ObZ
55boobeebo qbbbeobeoq eopeblopoe pobboepeeb bbqolopeoo lobbqalolq ebobybloop lebbbeogoo obbooyboby lebTebqelo qboqbewoq blopoobbeo OZI
obbepobeeb eobeopeqbb loyobqbgby eeeqbeebbq geoevoyeeb bbbbqbwoe ggebbypobb oebeoebbeo poobbqbeol bqbbowooy oobeoloe61 obbbeobbeo (gps :0N1 ai 03[s) aauanbas ap9oalanu upto NOVI 69113 [9L5]
SSAINILDODMACIIDSSAGAIS911VDAAIVICIgSNISIMIATAVINISUCWILLA2100.431 OVANdil-HIVIIDDIAIMTIDODdVONAMSIVASNIJI9DSVNDSAMASSOdNNARVDSgAIOAg (17s :ON altos) aauanbas man mum HA 69113 [SLS]
= .
N9dSISISNO.LAHNHIVRHINASDSAANDOOM
IISMGAETNSAIAASOCISCIIAddLLNANINHdOONSaM3AVICISdAdO
NAIDEISAON)111AlgHlISddlIAAOdallcIODNNOISIINgldVd1V3INSANDNAMIDNIMCIOH1 AJCIASAANAISNACM21(1)1,DIVNHA3ADCIAAMNANAcKlgHSACIAAADIA3dISSIIAITLCIN
OlddSIAASdODTIHdVd3ddaLFIDICIDSNdHAIDIGANINSdNHNANDIA.LOIDISSSdA.LAAS
S'ISAIDSSOIAVdd.LHADSEIVOSNANSAIAdgdAACINA1DOIVVIDDSISMSSd`rlddASdON
ISVSSAINIIDODMACIIDSSAUAISMWDAKIVICIgSNISIMINAVINISBUVIIIANDODI
OVANd1HAIVIIDDIAIMTIDODcWOMMASIVASNAIDDSYSIDSAMASS9d)INA3V9SgAIOAR
(9ts :ON ai Oas) aauanbas man ounue mega Xiteall 6cc9Ha [17Ls]
ESEI bee obboopobeb qopbebqoob ebeebeoppe OUT
oeqpeoopeo eobqopobbe bovobqebqb obeobqobeo qqbqboevob bEreobeobbq bboobebeep ebblbooepq obeeobeoyq blooqqa4qo beobboebob epebbqoblb qopp0000vo oebeeoeqoe voevbeb000 beoobbopeo beerebbbqbe bbgbooboTe Obit oebobe000p eqoqlobbbe ebqbbgolbq opeolopogb qbbypoeyby epoebqebeb bebbboobeo 00000bg000 yoegblbbeo poobebbboo oobepobbbe eoobbeeobe OZOI
oqeopebeeb eboqeop000 bqoobqopob beepeepbeb qbbeeobqbe eoeqbebbee obbovebqob bqoebbeooy obqobgbopy plobgbobeb lbbqbbbooe gpoeobepee peqbeobebb ebbb0000be eopebeeoob oveoeobqbb ebbqbobboe bbqboeqbbq opeoqqbeeb qbbebooppe bbeboyooby blboebblbb qbbqbobqoo eblbbeb000 ooebboobeo lebqvalopo voebbeepoo beep000000 qqbloolqbq bool000ebb OZL
obbbqobqob ebooppoblo opbq00000p obwoepeoo Debevoebob wbebevoop bebbqboboe veoebEqbbe epovoevobe 000beepeoo evbqboevob qoqppeqpoe be000eobbb goobeobeob y000blbooe bqbbgbobeo bebqoobeoe qbqopbbobe ObS
obebe36.4ob .45Do5oppoq qoovoeobqb obbobeopeb lqoobobbob epeebblobe 08b 61booeblbo opbeboopoq qoeloebbee bqbbqoobqo bbbqopoboo bepeobbob5 OZb obeooeobeb evobeobeoo opobbl0000 oqqbgbobeo 000bbbeyoo yobegobqbe bogogbopeo qbbloopeeb bbepobbbbq pegoebqqoo bbqbebarn lleboeq4pe ooqbbbebeb oblbweqle qbqopobboe oebbebqogy eybloobeeb ebloyebbly ObZ
oeloobeovo eeboeooqve boebbobooe qqeboepqbe byobbbeool lbeebeovob pelbeevooe oeqeollloq egoboleogy obbebbbleb blbebqlobb beyoebbloo OZT
opbbeoebob lbbblobeo; eqobqellbe Devoglogeo bbebbqoqqo bbeeDblopq oqbbeebqbb 3qopqbbblo obeebee6qb bealobbbbo oqbeb6.46.51 obeob.46526 (sps :oN ui Oas) aauanbas am0at31111 LIMO Linall 6c9up [us]
=
IL6I'ZO/ZIOZSII/I3c1 1, =
ITI
SdOOTIgdVdDddDIRDICDS)IdgAIDICIANINSd)IHNANDIAIOIDISSSdAIAASSISAIDS
SOIMMAIHADSIIVOSNPASAIAdgdAACINA7DDIVVIDDSISNSSdVIdJASdONISVSSAI
A11000Mda4M011dVNAAIDSCIHANINVDAAAVIGGSWISSIglAIASI4gGVIIIANDOANO
VA.NVIII4IdIADDIAIMWIDOOdVONAMSIVASSAADOSV)IDSANASSOOINAgVDSONIOAO
(zsg :0N m Oas) 33uanbas man ouuun mega Situall zpolo [Igs]

bevobboo opbpbqoobp 6loobebpp6 vooppovloe ooe?ovoblo OZCI
poBbyboyob qPbqbobPob go5Polgblb oevobbbvo5 pobblbboob pbvpov.66-45 popolofrepo 6PoP16qopq qolgobeo65 op6obeov66 go615qopoo 000VOOPE,PP

3vqpypoep6 PboopbPoob boyeo5vbeb bbgbpb616o obolpoebob popooy-40-41 o.666ve5-455 gogblooPol 000.4.6.4b6ea OPP5PPOOP5 qeopE.62856 op5poopoop 51.opovovq5 .165eopoo6P beth0000bvo o566ppoo.55 P.eofyeolvoo vfmpbvboqv OZOI
p00005-4336 qopp652eop po6p8.465up ofq.bepopq6 payepo66op -26q358qope.

bpoopofylob lbooPoqobq boEcebqber4b bbooeqopeo byoppoeqbp obpbbEbbbo opobpypop6 EPOO6OPPOP D.6q6.6p5545 3653yf5q53 pq651oppoq q6vp6.186ye.

opoopE6p5o poo5v5.4bop bplbbqb5q5 o6qopvb155 eboDooppa) op6polpblp 3q3oop3p66 PP0005PPOO oppooqqblo oqq616Doqo opv55o6B51 05.4o6pb000 OZL
op6g0006lo 0000pobqoo eop000pfyee oeboBlobe5 vpoop.626bq bobopppop5 bqbbuppopo vpobr.opobP popoppbqb oPPobgpleo pqoppbpopo pobbbgoobp obpo6ppoo6 16pov6i56A bp6pobpfylo o5voe-46133 66obpobpbe o6qp.6-q6=6 06g opooqqopvD voblbobbob yooPbgloob obboempeP6 blob-eblboo rblb000bp5 opoolloego ebb2ebq55; a":36..43b55-1.3 poboobepeo bbo6Bobyop yobebpvobe obvooDo.b5 l000poqq5; 5Dbeopoobb bevooebeq oblbeboqoq bopeolbblo ooev66-bepo 6666qopoop 5olq5B1365 5b000popEo velellelgo p55653-4126 lpooplq-P6 1156v63516 loyqly15.15 oobboPovEo v6lolvbv6q pobpobpblo ot'Zbpbblpqr-111 oleopollPe baebboboop qlepoPolbe Eyeabbbpopq qovebeoeob = opqDpvvo.by or-16oqq-lol plopagpoqb 6565555.1p6 bqbpbT4D-e5 fiepop6b.loo OZT
oobboobob qbbblobepq elobielobe obeoqqoqqo bbebbloggp bbeeobqooq pqbbvpb.456 ogopq55.6.43 obpPbuvbqb frebqDb655q plbpDbqbbq obpoDqbbpD
(us :ON ui Oas) aauanbas amloatanu uletip Situall zpc9ND [08s]
'Sgg :ON GI OgS ui umoqs oDuanbos =
p!ou ou!tur tquqo ILA oqi pur tgg :ON GI OS ui umoqs aouanbos oppoopnu !Aqui 10q all 'cog popooua (Egg :0N 01 Ogs) ucqa! oiquyun Lquqo u42!! sopniou! osp Xpoqpur D21 = 0UP0ds-VH Z1792ID oq*Zgg :ON GI OgS 4i umoqs aougnbas mor ou!um Lquqo Xnuotioqi Pug I SS :ON GI Ws ui umoqs oouonbos appoolonu tquqo Xneoq oqi/(q popoouo (ogg :ON GI
Ogs) uoio alquyen Louqo Xnuoq sopniou! Xpoqpuuoi DUP0ds-VH Zt911D 041 [6L51 SANgdIOScilICISGCIAAAIAdVO9DIOOAMHASNS9INND9DIIIIVIO9dVASASdd0119VO
(Lys :ON al Oas) aauanbas man ou!tue IA 6011D [8L5]
SDgIdVAINgAISDRHIAODSASIIHSNMOgd.I., ISIA.SSVVANNNSONSdillgADVNAdSSCIVNMVAIAVOdAKISMAI.MINVOIR3SSddA
I.LASdVV)IdODVVVDIA,L1)11000dAAHUSSSUMAODAACEVTIOVgASSIIIIVINDSNSD
SA2MdIDScIIICISCICIAANIAdV00(1)100AMHASNSDINNODDIIIIVIODdVASASddOEIDVO
= (6ts :ON al Oas) aauanbas man oup.un meto it121r1 6C91) [US]
IL61'a/ZIOZS9/ID.:1 68tZII/ZIOZ OM

=
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ
VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS
CSVMHEALHNHYTQKSLSLSPGK
[582] CR6342 VH amino acid sequence (SEQ ID NO: 550) QVQLVQSGAEVKKPGSSVKVSCKASGGFFSSYAISWVRQAPGQGLEWMGGVIPIFRTANYA
QNFQGRVTITADEFTSYMELSSLRSDDTAVYYCARLNYHDSGTYYNAPRGWFDPWGQGTLV
TVSS
[583] CR6342 Light Chain nucleotide sequence (SEQ ID NO: 554) gacatccaga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gaaggccacc 60 atcaactgca agtccagcca gagtatttta aacagctcca acaataagaa ctacttagct 120 tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180 gaatccgggg tccctgaccg attcagtggc agcgggtc63 ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtagt 300 ccgccgacgt tcggccaagg gaccaaggtg gaaatcaaac gtgcggccgc acccagcgtg 360 ttcatcttcc ccccctccga cgagcagctg aagagcggca ccgccagcgt ggtgtgcctg 420 ctgaacaact tctacccccg ggaggccaag gtgcagtgga aggtggacaa cgccctgcag 480 agcggcaaca gccaggagag cgtgaccgag caggacagca aggactccac ctacagcctg 540 agcagcaccc tcaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgcgag 600 gtgacccacc agggcctgag cagccccgtg accaagagct tcaaccgggg cgagtgt 657 [584] CR6342 Light Chain amino acid sequence (SEQ ID NO: 555) DIQMTQSPDSLAVSLGEKATINCKSSQSILNSSNNKNYLAWYQQKPGQPPKWYWASTRESG
VPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPPTFGQGTKVEIKRAAAPSVFIFPPSD
EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[585] CR6342 VL amino acid sequence (SEQ ID NO: 553) DIQMTQSPDSLAVSLGEKATINCKSSQSILNSSNNKNYLAWYQQKPGQPPKWYWASTRESG
VPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPPTFGQGTKVEIKR
[586] The CR6343 HA-specific IgG antibody includes a heavy chain variable region (SEQ
ID NO: 556) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO:
557 and the heavy chain amino acid sequence shown in SEQõID NO: 558. The CR6343 HA-specific . . =
IgG antibody also includes a light chain variable region (SEQ ID NO: 559) encoded by the light chain nucleotide sequence shown in SEQ 560 and the light chain amino acid sequence shown in SEQ ID NO: 561.
=

i;::.

=
36po 5q6p6opeop D3D66-;bpDP 5epbp5bbo opp6po666e 6opoo3v65 bypoblobpo Plobvbboop oD6pbppbbl frep6p5oppo opoqopbp6.1 opplobuobp Obq ooboo6oelb PPOPPOPPO5 ebpobyvoop 0000DPOOPO op6p6bqbo5 boobbepoqb opoobyobyo pboobbev65 qooffylbooe bqboobo661 oopy-loqqop bobpoqeolo OZb 35q51654D3 OPDD.55PPDP poobbpo6qo 5p56p5opqo Dqpoop000l .16-loope616 obp000gobo obbyepoobe pob623boob bobqffielop g5oovoq6be poopE6bqop vb5plqoger4 pqqpoovble, p*qbpq56 65q5165poq bqoyqquqop booamblvb ObZ
566opfyee6o .4.66bpobPol yooe6l000p opbbopopeb 561oloepoo 1366looll pbobpbqopo qyabbvoqoo apppoubobP qp-eqpbqpqb qba4.5bqp5-4 Er400pobbpo OZT
offrepoovre. pobPooPqb6 loppeqbqbp qppqberlthq qP0PWIPDP5 6666461=e 09 qq-ebbppobb ov5vo-eb5po oop55.48voq hpbbog000b oobvpbov5.4 6a46w1beo (09s :ON ai Oas) aauanbas amoapirm umto ii a9113 [06s]
SSAIATIDOOMMIAASUAANSSIIVDAAAVICMSWISHAMAIAVISISCICIVILLANDOSNOV
ALLIDAIAMSIODIAIMTIOC:10dVONAMSIAIVAASJIAOSVNOSANASSOcINNARVDSOAIOAO
(955 :ON GI OHS) aauanbas ppe outtue HA a9213 [685]
)19dSISISNOIAHNHIVg HIAIASDSAANDOOMIISNCIA,IINSAIAASDUSGIAddLINANN3dOONSHMHAVICESdAdDNA
111:1SAONN,LIAGHNSddliAAOdUlIdODMVNSIINgIdVd-ROINSANDNAMIDNIMUOFFIAI, IASAANAISNAOgaNcININVNHAgADCIAAMNANASKIRHSAOAAADIA3dINSIIAllICINcIN
daTIAASdOOTIgdVdDddaLEDIODSNdHAIINCIANINSOIHNANDIAIOIDISSSdAIAASSI
SAIDSSOIAVddlHADSEIVOSNIMSAIAd3dJACINAIDDIVVIODSISMSScIVIMASdONIS
VSSAIAIIDOOMACIAASCIAANSSNVDAAAVEIgSWISHABIAIAVISISOCIVIILLANOODIOV
1-1.I DJIAMSIDDIAIMTIDODdVONAMSIAIVAASAIADSVMDSANASSDOINAHVDSOAlOAO
(ggs :ON m Oas) aauanbas ppe ougue mega Situall ctomp [sgs]
SET 5ppo65=33 Bp51335p6q op6popp5po OZET
popapqovoo ppopoblDoo f;b.eboyobqv bgbobpoblo byoglblbov vobb6pobvo 46boobvb vpovE.646po yogo6ppobe opl6qoollo llobvobbop 635pop66.40 6.45g000ppo ovoov6-evpy qOPPOPP5P5 opo5voo653 ppobpbpbbb .16p6515oob Obit oqpop5o5yo oppeloqqob 852P6156-40 gblooyogoo al5q86poop pbppooefyly 6pe6p65600 beoDopoDbq poopopqbqb 5popoo6.265 63=352=6 bopppobbpv OZOT
o5yogypop6 Pyfrebolepo oopfyloobqo pobbyyouvo bpbqbbppob qbeppyqbeb Empobbovvb -4055govbfm oppobqpb-45 opeoqp5gbo by5q56q6E6 oppgoovo6v ovpovq5pob yethEbbb000 D5Ppooy5vv, opeovpopob q55pbblbob bopbeyleovq.

bbloveoqqb yvbgaYeboo oppbbyboyo obebq5op6b 1651661606 qoae.616bp6 00000v65po fieoqvbqvoq 000vo-255-ep 000bvv0000 poo-416gool qbgbool000 OZL
ybbobb5qob gobyboopoo bqopo6q000 0000bqoo?o popoyfreepv bo5lobv5vy opobEbbqbp boPP-eoPE6-4 be.vvoovotT obypoobepo pooppeqboy pobqolvovq oovfie000vo bbbloofmob yobPoo35-45 oop5155q5o brobveqopf) yoeqbwobb ofrs=
ofmoby5yob go5gboo5po ooqloovovo 5-45obbo6po ov5-4wobob boemovp65.4 08b p6p5-4boo5 15 306E53o polqopqop5 6epb-456-4Do 5-4o6b6qopo 60D5popp65 OZb obbobvpopo fiebPvoemob Pop000bbqo opooqqbgbo Eyeopoob662 pooyobygob 48p5ogogbo ovo-466.4poo Pv8b5voo66 55-4ovqopbq pq-eqb16yly 6.4pqopqq-ey boglogybeb perq6loPlqv lb-460065pp opb5p5qogy 6Pbqoo5v65 yE,155y66Te ObZ
ouqoo6povq bubaepoqop bopbbobqov qqp5opoq5p bpo666popq q5upbpopo5 orgoovvovy ovb5514.45-4 vqopobeogy y65.255bqpb bqbp6.4.4obb bepoye6goo OZI
Do65yopf)36 q655lo6P5q Pqobqvqovq q6poqqoopo -46v5.6qoqqo 55ppob-4331 pq56pyblE6 alopq6bOgo oempbvv5-46 bvbqobpbbq olbpobqbbq o5poo-466yo (Lss :pm m Oas) aauanbas appoatanu tqcto C1'9113 [L8S]
=
=
IL6tZ0/ZIOZS9/IDcl 68tZII/ZIOZ OM

. =
tll ASAANAISNAOgglIcININVNHAgADCIAAMNONAgdoggHSACIAAADIAgdDISHAFILCDIcINd dTHASd99113AVdDddDIFIDIUDSNdUMDIGANINScENHNANDIAIOIDISSSdAJAASSIS
AIDSSOIAVddlHADSEIVDSNUASAJAdgddAGNAIDOIVVIDDSISNSSddlcIAASdDNISV
SSAIAIIDOOMACHAS9S93NAHdINVDAAIAIVIMSIFIDSIMAIAAISISgaVILLANDOdNO
VANdIDAIVIIDDIAIMTIDOOdVONAMSIAIVANNAISOSVNDSANASSOOINAgVOSONIOAO
(1,9s :ON m Oas)aauanbas man oup.ue umto ARH rt,c9113 [5651 ,6Probb000 ofrebwobp6 qopErebuy5p 000P0P1OPO
OzSIoypoyobloo obbyboeo51 y5l6o5y051 35pa116.16o Byp665yo6y 065-46.6=5 oppovbbqbo ovolobvvob vovqb4=4.4 oqlobpobbo pbobvaebbq ofylbloopoo 00POOP6PPO PloPPoPu5P bDoo5voobb oppobp5p55 blbpbblboo 5oTeop6o6p opopygoglo bbfreeblbbq pqbqopuogo ooqbqbbyop ppbypoopbq ybpbbubbbo obypp000pb qopoyoy15q bbpopoobpb bb0000beop bbbppoobbp PO5P0qP0OP
OZOI 5v-25vbolpo p000bwobq oopbbyvoep obpbqbbepo bgbppopq5p bbppobbopv bqobecqove,5 voppobqobq boopogob-45 36261E6-465 booploopob poppoyqbPo Erebby6b5oo oo6PPooP6p voo6pEpovo blbbp58-46o 66opf)646op qbbloppogq bpuogbbpbo 000y55P5op oof)pfy4bovb .5q5.6-4E6-463 6.4oDp6-468p 5poopop66o ofreoqvblvo woovoybby y000byp000 0000llbloo glblboogoo 0E663566-4o OZL
EcqpEceb000p obl000bqoo 000pobqopp op000ebpyo pbobqobvfm oopf)P66.45 peovppovBE. 466yeoopop yobypoobyy ovoovv6q6o vo5q3-1.-eop qopp5vopop 0E651335pp bpobe000bq boo y5155-46 05ypere5loo bypplbloob bobpobpbpo 06g 5w5l0006p onoqlooPo 3615obbobp oppEraloobo 5636yopy66 were6l5ooe bgboopbeLo 000qloeloe b6e-eblbbqo obqobbbgoo oboobepeob bobbobeoDe obpbpyobeo beoppoobbl oppool.1616 pEreopoobbb pooeobplo 616e6o13716 00v3lbfyg03 3epbbb8oDb bbbloelDeb oqqqpqqbeb bbfxy-4-2,bb.4-4 ql1E,v4eq:Deo pooqqeb6pb 35-454peqq2 q6;epo56D2 op65p5q0.4.2 6p6qop55o5 uerqpee55.4P
ObZ
oylpqbqopo 625oPboqpv 5ov6bobooP lle5ovoq6u eceobbbpopq qbpebeoppb ael6vePpoe oebbbqqqqg egobogeoqe Bbbebbbgeb fylbyblgob5 bpeoybbqoo OZT
pobbpov536 16b6lo5pbq E-406-4-eqoee vbeoqqoqvo bvybbqoglo bbeyobgpoq ol6p5pb165 olopq5b6qo o5 556 5e5lo55561 oq6po61651 obpD5456po (E95 :ON m Ogs) aauanbas appoalanu mega SAnaH rt,E9H3 [176s]
19g :ON cii OHS ui umoqs aouonbos ppr ou!wr lump 1q2qoq uu 99g :oN cii Os u! umoqs opuonbos appoopnu u!rqo 1q2!1 alp Xq popoouo (g9g :0N ai Os) uo!2ai ziquturit uno lqSll saprqou! osir Xpoqgur 921 DIPoods-VH 17179113 an 179g :0N cll Os u! umoqs gouonbas p!or ou!un Limp Xnroq oip pur :ON al Os ui umoqs opumbas oppoolonu u!rqo Xnuoq otp Xq popoouo (z9c :ON CII
Ogs) uo0'al alqu!nik u!rqo Xnuati R sopniou! Xpoqpur DI oupads-vH 717E91J oq [E6s]
DIA.LANIDIDAAAHCISSSOMACOAACIVaDV3ANSIEILVINOSNS
DSJIMIDSdlICISNCIAANIAdVO9d)100AMHASNSDINHDO3IIIIVIODdVASgSddOIAASO
(655 :omui Ogs) aauanbas man ounue TA fb9N3 [Z651 =SDatc1VA.L}13AISDAIllACOSASNIISNMOIld.L
ISIA.SSVVANNNSONSdiligADVNAdSSCIV)IMVAIAVDdAKISMATLV)INVOlggSSdd TUASdVV3IdOOVVVOIA.LAN.I.DIDJAAHCISSSOMACOAACIVgGOVgANSIEILVINOSNS
DS4112dIDSOIGSNICIAA/VIAdVO0d-NOOAMHASNSOINHOODIIIIVIOOdVAS3SddOIAASO
(195 :ON ai Ogs) aauanbas ppe ounun um31112r1 a9113 II651 .r.
=
IL6ta/ZIOZS9II3.:1 68tZII/ZIOZ OM

LTVLHQDWLNGKEYKCKVSNICALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM
HEALHNHYTQKSLSLSPGK
[596] CR6344 VH amino acid sequence (SEQ ID NO: 562) QVQLVQSGAEVKKPGSSVRVSCKASGSIFRNYAMSWVRQAPGQGLEWMGGIIAIFGTPKYA
QKFQGRVTITADESTSTVYMELSGLRSEDTAMYYCARIPHYNFGSGSYFDYWGQGTLVTVSS
[597] CR6344 Light Chain nucleotide sequence (SEQ ID NO: 566) actgtgttga cacagccgcc ctcagtgtct ggggccccag ggcagagggt caccatctcc 60 tgcactggga gcagctccaa catcggggca ggttatgatg tacactggta ccagcagctt 120 ccaggaacag cccccaaact cctcatctat ggtaacaga atcggccctc aggggtccct 180 gaccgattct ctggctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcgga acatgggata gcagcctgag tgcttatgtc 300 ttcggaactg ggaccaaggt caccgtccta ggtgcggccg caggccagcc caaggccgct 360 cccagcgtga ccctgttccc cccctcctcc gaggagctgc aggccaacaa ggccaccctg 420 gtgtgcctca tcagcgactt ctaccctggc gccgtgaccg tggcctggaa ggccgacagc 480 agccccgtga aggccggcgt ggagaccacc acccccagca agcagagcaa caacaagtac 540 gccgccagca gctacctgag cctcaccccc gagcagtgga agagccaccg gagctacagc 600 tgccaggtga cccacgaggg cagcaccgtg gagaagaccg tggcccccac cgagtgcagc 660 [598] CR6344 Light Chain amino acid sequence (SEQ ID NO: 567) TVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRF
SGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAYVFGTGTKVTVLGAAAGQPKAAPSVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVE __ ITIPSKQSNNKYAASSYLS
LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
[599] CR6344 VL amino acid sequence (SEQ ID NO: 565) TVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKWYGNSNRPSGVPDRF
SGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAYVFGTGTKVTVLG
HA antibody epitopes [600] The invention relates to an isolated human HA antibody that is able to recognize and bind to an epitope in the HA2 subunit of the influenza haemagglutinin protein (HA) (also known as hemagglutinin(HA)), characterized in thatthe HA antibody has neutralizing activity against an influenza virus 5 including HA,of the H5 subtype. Examples of influenza strains that contain such a HA of the H5 subtype and that are important strains in view of pandemic threats are H5N1, H5N2, H5N8, and H5N9. Particularly preferred are HA
antibodies that at least neutralize the H5N1 influenza strain. Preferably, an HA antibody of the invention does not depend on an epitope in the HAI subunit of the HA
protein for binding to said HA protein.
[601] A number of the antibodies of the invention (such as CR6307 and CR6323) do not depend on conformational epitopes and recognize the HA2 epitope even in a reduced form (when used in western-blotting). This is an advantage over the antibodies from the art 115 , -because when a conformational change is induced in the HA protein due to whatever mutation in another part of the protein, such conformational change will not most likely hamper the binding of the antibodies of the present invention to the HA2 epitope, whereas antibodies that do depend on conformation might very well be unable to bind when such mutations occur.
[602] In another preferred embodiment, an HA antibody of the invention also has neutralizing activity against an influenza virus comprising HA of the H1 subtype, and preferably wherein the HA antibody also has neutralizing activity against influenza virus comprising HA of the H2, H6 and/or H9 subtype. The HA antibodies of the invention interact with an epitope present in the HA2 epitopes present in the H5, HI, H2, I-16, and H9 A.; .
subtypes (see, International Patent Application PCTIEP2007/059356, published as WO
2008/028946, the contents of which are incorporated by reference in their entirety), and it has been shown that the HA antibodies of the invention cross-neutralize between influenza subtypes because of this epitope-sharing.
[603] In another preferred aspect of the invention an HA antibody of the invention binds to an epitope that is selected from the group consisting of the amino acid sequence:
GVTNKVNSIIDK (SEQ ID NO: 198), GVTNKVNSIINK (SEQ ID NO: 283), 'GVTNKENSIIDK (SEQ ID NO: 202), GVTNKVNRIIDK (SEQ ID NO: 201), GITNKVNSVIEK (SEQ ID NO: 281), GITNKENSVIEK (SEQ ID NO: 257), GITNKVNSIIDK (SEQ ID NO: 225), and KITSKVNNIVDK (SEQ ID NO: 216). Certain HA antibodies of the invention, CR6261, CR6325, and CR6329 interact with the GVTNKVNSIIDK (SEQ ID NO: 198) epitope present in H5N1, and are not hampered by a mutation in the TGLRN (SEQ ID NO: 200) epitope in HAI that do influence the binding of CI79. Moreover, some FIA antibodies, such as CR6307 and CR6323 are not even hampered by a escape mutant, as disclosed in Okuno et al. (1993) With a valine ->
glutamic acid mutation at position 6 (exemplified by GVTNKENSIIDK (SEQ ID NO: 202)). This epitope is part of an extended alpha helix in the HA2 regitinjhe residues in this putative epitope that are predicted to be most solvent exposed are underlined in bold: GV-TNKENSIIDK
(SEQ ID
NO: 202). These amino acids would be most accessible to an HA antibody and thus may form the most important region of the epitope. Consistent with this notion the highlighted (bolded) amino acids are absolutely conserved in identity and position in all the sequences presented. This knowledge could be used to predict binding epitopes in influenza subtypes that do not carry the same sequence as above (i.e. H3, H7 and B strains).

=
=
HA Antibodies II
[604] The invention provides neutralizing human Monoclonal antibodies that bind influenza A virus and inhibit the influenza A virus from infecting a cell. Although neutralizing human monoclonal antibodies of the invention bind epitopes within proteins that are exposed on the surface of an influenza virus, the invention focuses on the relatively invariant Influenza hemagglutinin (HA) protein. A neutralizing MAb raised against an Influenza HA
protein, which is maintained in its native conformation, provides a superior therapy for all Influenza A strains because it is not dependent upon small changes to the amino acid sequence.
[605] The Influenza hemagglutinin (HA) protein is responsible for allowing the virus to recognize target cells through binding the monosaccharide sialic acid-containing receptors on the surface of the target cell prior to infection. Moreover, the Influenza HA
protein is responsible for allowing entry of the viral genome into the target cell by fusing the host endosomal membrane with the viral membrane.
[606] The Influenza hemagglutinin (HA) protein is a homotrimeric integral membrane glycoprotein found on the surface of the Influenza virus. Using the host cell's protein synthesis machinery, the Influenza HA protein is first synthesized as a single-chain precursor polypeptide (HAO) in the endoplasmic reticulum, where it is also assembled as a homotrimer.
The resulting HA homotrimer is subsequently exported to the cell surface via the Golgi network. HA homotrimers located on a cell surface are cleaved by a host-produced protease into two smaller peptide subunits: HAI and HA2. The HA2 subunit forms a long helical chain anchored to the viral membrane whereas the HAI subunit tops the HA2 subunit to form a large globule. The cleavage step, which converts the HAO precursor into the mature HA
protein containing HAI and HA2 subunits, is essential for the viral pathogenicity of Influenza. Structurally, the mature HA protein contains a central a-helix coil resulting in an overall cylindrical shape with three spherical heads. The HA protein, and specifically, the HA1 subunit of the mature HA protein, binds receptors containing glycans with terminal sialic acids on host cells. The way in which sialic acid is connected to galactose, for example, a2-3 linkages as in avian serotypes versus a2-6 linkages as in human serotypes, not only determine species specificity of an Influenza virus, but also prevents cross-species infection.
\
However, within certain serotypes of HA, such as HI and,H3, only two amino acid mutations in the framework sequence are required to convert species specificity from avian to human.

[607] To mediate infection, the Influenza HA protein first binds sialic acid-containing receptors present on the surface of the target cell. Consequently, the target cell membrane endocytoses or engulfs the Influenza virus. Once in,side theendosome, and upon the host cell's acidification of that compartment, the Influenza HA', protein partially unfolds revealing a very hydrophobic fusion peptide that inserts itself into the endosomal membrane. As the rest of the Influenza HA protein refolds, the fusion protein retracts and fuses the endosomal membrane with the viral membrane. Upon fusion of the cellular and viral membranes, the contents of the virus, including the viral genome, are released in the cytoplasm of the target cell.
[608] At least 16 different Influenza A hemagglutinin serotypes or antigens have been identified: H1-H16. Only HA serotypes H1-H3 normally mediate human Influenza infection.
However, Influenza strains thought to infect only certain avian or mammalian species can mutate to infect humans. As described above, only a few amino acids need to change along the length of the entire protein to enable Influenza to cross a species barrier. For instance, a single amino acid change in the sequence of the H5 subtype allowed an avian-specific Influenza strain to become infectious in humans (H5N1). A pandemic arose when an Influenza strain common to swine species, became lethal to humans (H1N1). In contrast to i Influenza A, Influenza B and C viruses each contaiii only one form of HA
protein.
[609] Specifically, the invention provides an isolaied fay' human monoclonal antibody, wherein said monoclonal antibody has the follOwirig characteristics: a) binds to an influenza A virus; b) binds to a cell contacted with influenza A; c) binds to an epitope of an influenza A
viral protein; and, optionally, d) neutralizes influenza A virus infection. An antibody that does not neutralize influenza A virus infection may be used, for instance, for a conjugate therapy. In certain aspects, this antibody binds to a eukaryotic cell.
Moreover, the cell is optionally a human cell.
[610] In another aspect, this antibody is isolated from a B-cell from a human donor.
Isolation of a fully human monoclonal antibody of the invention from a B-cell is performed using recombinant methods. Alternatively, or in addition, the isolated fully human monoclonal antibody of the invention is isolated from the supernatant of a plasma cell cultured either in vitro or ex vivo. Plasma cells also known as a differentiated B-cells, plasma B-cells, plasmacytes, or effector B-cells. The fully human monoclonal antibody isolated from either a B-cell or a plasma cell demonstrates neutralizing activity.
=

[611] Antibodies of the invention bind to an epitope of influenza A viral hemagglutinin (HA) protein. Exemplary HA epitopes to which the antibodies of the invention bind include a hemagglutinin precursor peptide (HAO), a HAI subunit, a HA2 subunit, a mature protein containing HAI and HA2, and a recombinant HA polypeptide. Alternatively, antibodies of the invention bind to an epitope within a hema.gglutinin precursor peptide (HAO), a HA]
subunit, a HA2 subunit, a mature protein containing HAI. and HA2, or a recombinant HA
polypeptide. Recombinant HA polypeptides are eneodekfor example, by the sequence of SEQ ID NO: 727, 728, 729, 730, 731, 732, 733, 734, 735736, 737, 738, 739, 740, 741, 742, 743, or 744.
[612] Antibodies of the invention bind to an epitope that is linear or non-linear. In certain aspects of the invention, a non-linear epitope is a discontinuous epitope.
[613] An antibody of the invention is TCN-522 (3212_112), TCN-521 (3280_D18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-528 (5087_P17), TCN-529 (5297_H01), TCN-530 (5248_Hl0a), TCN-531 (5091_H13), TCN-532 (5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-(5246_P19), TCN-536 (5095_NO1), TCN-537 (3194_D21), TCN-538 (3206_017), TCN-= (5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-546 (5089_L08), TCN-547 (5092_F1 1), TCN-548 (5092_P01), TCN-549 (5092_PO4), TCN-550 (5096_F06), TCN-551 (5243_DO1), TCN-552 (5249_123), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), TCN-557 (5081_A04), TCN-558 (5248_Hl0b), TCN-559 (5097_G08), TCN-560 (50-84_P1O), or TCN-504 (325I_K17).
[614] The invention further encompasses an antibody that binds the same epitope as TCN-522 (3212_112), TCN-521 (3280_018), TCN-523(5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-528 (5087_P17), TCN-529 (5297_H01), TCN-530 (5248_Hl0a), TCN-531 (5091_H13), TCN-532 (5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-535 (5246_P19), TCN-536 (5095_NO1), TCN-537 (3194_021), TCN-538 (3206 017), TCN-539 (5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_023), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-546 (5089_L08), TCN-547 (5092_F11), TCN-548 (5092_P01), TCN-549 (5092_PO4), TCN-550 (5096_F06), TCN-551 (5243_001), TCN-552 (5249_123), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), =

1,,t '=
=
/ =
=

CA 02827301 2013-08-13, TCN-557 (5081_A04), TCN-558 (5248_H10b), TCN-559 (5097_G08), TCN-560 =
(5084_P10), or TCN-504 (3251_K17).
[615] The invention provides an isolated fully human monoclonal anti-HA
antibody or fragment thereof, wherein said antibody includes a variable heavy chain (VH) region comprising CDRI and CDR2, wherein the VH region is encoded by a human IGHV1 (or specifically, IGHV1-18, IGHV1-2, IGHV1-69, IGHV1-8), IGHV2 (or specifically, 5) , IGHV3 (or specifically, IGHV3-30, IGHV3-33, IGHV3-49, IGHV3-53, 66, IGHV3-7), IGHV4 (or specifically, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-59, IGHV4-61), or IGHV5 (or specifically, IGHV5-51) VH germline sequence or an allele thereof, or a nucleic acid sequence that is homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 VH
germline gene sequence or an allele thereof. In one aspeci, the nucleic acid sequence that is homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 VH germline sequence is at least 75% homologous to the IGHV I, IGHV2, IGHV3, IGHV4, or IGHV5 VH germline sequence or an allele thereof. Exemplary alleles include, but are not limited to, IGHV1-18*01, IGHVI-2*02, IGHV1-2*04, IGHV I-69*01, IGHV1-69*05, IGHV1-69*06, IGHV1-= 69*12,IGHVI-8*01, IGHV2-5*10, IGHV3-30-3*01, IGHV3-30*03, IGHV3-30*18, IGHV3-33*05, IGHV3-49*04, IGHV3-53*01, IGHV3-66*03, IGHV3-7*01, IGHV4-31*03, IGHV4-31*06, IGHV4-34*01, IGHV4-34*02, IGHV4-34*03, IGHV4-34*12, IGHV4-39*01, IGHV4-59*01, IGHV4-59*03, IGHV4-61*01, IGHV4-61*08, and IGHV5-51*01.
[616] An antibody of the invention, or specifically, any antibody described herein, may be operably-linked to a therapeutic agent or a detectable label.
[617] The invention further provides a pharmaceutical composition including an antibody described herein and a pharmaceutical carrier. This composition optionally includes an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor. Exemplary anti-viral drugs include, but are not limited to, a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor and an M2 ion channel inhibitor. In one enibodiipent of the composition, the M2 ion channel inhibitor is amantadine or rimantadine. Aliernatively, or in addition, the neuraminidase inhibitor zanamivir or oseltamivir phosphate. The composition may also include a second anti-Influenza A antibody. The second anti-Influenza A
antibody is optionally an antibody described herein.
[618] The invention provides a method for stimulating an immune response in a subject, including administering to the subject the pharmaceutical composition described herein.

=
41, ;
[619] Moreover, the invention provides a method for the treatment of an Influenza virus infection in a subject, including administering to the subject the pharmaceutical composition described herein. This method further includes administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.
[620] The invention also provides a method for the prevention of an Influenza virus infection in a subject, including administering to the subject the pharmaceutical composition described herein prior to exposure of the subject to Influenza virus or infection. This method further includes administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor. This method may be a method of vaccination.
[621] The subject of these methods may have an Influenza infection or is predisposed to developing an Influenza virus infection. Subjects predisposed to developing an Influenza infection, or who may be at elevated risk for contracting an infection, are those subjects with compromised immune systems because of autoirnmune disease, those persons receiving immunosuppressive therapy (for example, following organ transplant), those persons afflicted with human immunodeficiency syndrome (HIV) or acquired immune deficiency syndrome (AIDS), certain forms of anemia that deplete or destroy White blood cells, those persons . , receiving radiation or chemotherapy, or those persons afflicted with an inflammatory disorder. Additionally, subject of extreme young or old age are at increased risk. Any person who comes into physical contact or close physical proximity with an infected individual has an increased risk of developing an Influenza virus infection. Moreover, a subject is at risk of contracting an influenza infection due to proximity to an outbreak of the disease, e.g. subject resides in a densely-populated city or in close proximity to subjects having confirmed or suspected infections of Influenza virus, or choice of employment, e.g.
hospital worker, pharmaceutical researcher, traveler to infected area, or frequent flier.
[622] According to the methods described herein, exemplary anti-viral drugs include, but are not limited to, a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor and an M2 ion channel. In one aspect of these methods, the M2 ion channel inhibitor is amantadine or rimantadine. Alternatively, or in addition, the neuraminidase inhibitor is zanamivir or oseltamivir phosphate.
[623] These methods optionally include administering;a second anti-Influenza A
antibody.
For example, the antibody is administered prior to- or after exposure to Influenza virus. In certain aspects of these methods, the antibody is administered at a dose sufficient to promote viral clearance or to eliminate Influenza A infected cells. The second antibody is optionally an antibody described herein [624] The invention further provides a method for determining the presence of a Influenza virus infection in a subject, including the steps of: (a) contacting a biological sample obtained from the subject with an antibody described herein or the,pharmaceutical composition described herein; (b) detecting an amount of the antibody that binds to the biological sample;
and (c) comparing the amount of antibody that binds .to the biological sample to a control value, and therefrom determining the presence of the Influenza virus in the subject.
[625] The invention provides a vaccine composition including an antibody described herein.
This composition optionally contains a pharmaceutical carrier.
[626] Alternatively, the invention provides a vaccine composition including an epitope of an antibody described herein. This composition optionally contains a pharmaceutical carrier.
[627] Vaccines of the invention are multivalent vaccines. The term "multivalent vaccine" is meant to describe a single vaccine that elicits an immune response either to more than one infectious agent, e.g. recombinant homotrimeric HAO proteins or fragments thereof derived from multiple strains of Influenza A (see, Table 9), or to several different epitopes of a molecule, e.g. a linear and a discontinuous epitope of the same recombinant homotrimeric HAO protein or fragment thereof derived from a single strain of Influenza A.
Alternatively, or = ..i =
in addition, the term multivalent vaccine is meant to desci-ibe the administration of a combination of human antibodies raised against moi-e than one infectious agent, e.g. a =
combination of HuMHA antibodies raised against reCombinant homotrimeric HAO
proteins or fragments thereof derived from multiple strains of Influenza A (see, Table 9).
[628] The invention provides a diagnostic kit including an antibody described herein.
[629] The invention provides a prophylactic kit including an antibody described herein or an epitope of an antibody described herein. Alternatively, or in addition, the invention provides a prophylactic kit including a vaccine composition described herein.
[630] In a preferred embodiment, the present invention provides fully human monoclonal antibodies specifically directed against the Influenza hemagglutinin glycoprotein, which neutralize influenza infection. Optionally, the antibody is isolated from a B-cell from a mammalian donor, and preferably, a human donor. In certain embodiments of the invention, the antibody is identified for its ability to bind an intact or whole Influenza virus.
Alternatively, or in addition, the antibody is identified isolated for its ability to bind to an epitope of a recombinant homotrimeric Influenza HAO protein or HA protein(s) isolated from f, , = 122 - = -=

multiple Influenza strains, or made as recombinant proteins such as those influenza A virus strains provided in Table 9. Alternatively, or in addition, the antibody is identified for its ability to inhibit or neutralize virus infection of susceptible eukaryotic cells. Exemplary neutralizing antibodies of this profile include, but are not limited to, those antibodies listed in Table 10. Alternatively, the monoclonal antibody is an antibody that binds to the same epitope as the antibodies provided in Table 10: In certain embodiments, neutralizing human monoclonal antibodies of the invention are anti-HA antibodies. A monoclonal anti-HA
antibody of the invention has one or more of the following characteristics: a) binds to an epitope in an HAI subunit of an Influenza hemagglutinin (HA) protein; b) binds to an epitope in the HA2 subunit of Influenza hemagglutinin (HA)protein; c) binds to an epitope in the extracellular domain of an Influenza hemagglutinin (HA) protein, consisting of an HAI
subunit and an HA2 subunit; d) binds to an epitope of a recombinant homotrimeric Influenza HAO protein; e) binds to an epitope of an Influenza HA protein expressed on an infected cell;
f) binds to an epitope of an Influenza HA protein expressed on a modified cell; g) binds to an Influenza virus; or h) inhibits virus infection of susceptible eukaryotic cells.
[631] Modified cells of the invention are transfected or transformed with a polynucleotide that encodes an Influenza HA protein, or any fragment thereof. The term "Influenza HA
protein fragment" is meant to describe any portion of the protein that is smaller or less than the entire protein. Polynucleotides and polypeptides of the invention do not always encode a functional Influenza HA protein.
[632] Infected cells of the invention are mammalian, and preferably human in origin.
Specifically, mammalian cells are infected with Influenza A virus in vivo, in vitro, in situ, ex vivo, in culture, and any combination thereof. Cellssare infected with active or inactive virions. Exemplary inactive virions display the FIA protein on their surfaces, however, they are replication-defective, and therefore, unable to propagate within the cell or subject.
[633] Epitopes of the human monoclonal antibodies of the invention include a transmembrane or integral membrane Influenza A protein. Specifically, epitopes of the human monoclonal antibodies of the invention comprise Influenza hemagglutinin (HA) protein.
[634] Epitopes of the human monoclonal antibodies of the invention include one or more subunits of an influenza hemagglutinin (HA) protein. HA proteins of the invention include hemagglutinin precursor proteins (HAO), the HAI subunit, the HA2 subunit, the mature protein containing the HA 1 and HA2 subunits, and a recombinant HA protein.
Recombinant -so.

CA 02827301 2013-08-13,, HA proteins contain SEQ ID NO: 726. Exemplary recombinant proteins include but, are not limited to, those proteins described by SEQ ID NO: 727-744.
[635] Epitopes of the human monoclonal antibodies of the invention are linear or non-linear. For instance, a non-linear epitope is discontinuous. Discontinuous epitopes are available for antibody binding only when the Influenza HA protein is maintained in its native homotrimeric conformation. When an antibody binds to a discontinuous epitope, the antibody binds to a three-dimensional surface of the target protein, i.e. the Influenza HA protein, upon which juxtaposed amino acids are alternatively exposed or masked.
[636] Recombinant homotrimeric HAO proteins of the invention are encoded by, for instance, sequences described by any one of SEQ ID NO: 727-744. In certain embodiments of the invention, the human monoclonal antibodies, or monoclonal anti-HA
antibodies, =,1 described herein bind membrane-bound or soluble recombinant homotrimeric Influenza HA
proteins. Alternatively, the monoclonal anti-FIFt. antibodies described herein bind membrane-bound and soluble recombinant homotrimeric Influenza HA proteins. In certain embodiments of the invention, the monoclonal anti-HA antibodies described herein bind and neutralize Influenza virus subtypes HI, H2, and H3. In other embodiments of the invention, the monoclonal anti-HA antibodies bind Influenza virus subtypes HI, H2, and H3, and neutralize one of these subtypes, such as HI, H2, or H3. In a specific embodiment, the monoclonal anti-HA antibodies bind Influenza subtypes 1-11N1, I-12N2, and I-13N2, and neutralize HINI.
[637] In one aspect, the HA precursor polypeptide (HAO) of the soluble and recombinant homotrimeric Influenza HA protein contains a trimerization domain (foldon) encoded in the phage T4 fibritin. An exemplary trimerization domain isolated from the phage T4 fibritin has the following sequence wherein a thrombin cleavage site is italicized and bolded, a T4 trimerization domain or sequence is underlined, a V5 tag is boxed, and a hexa.-histidine (His) tag is bolded:
SGRLVPRGSPGSGYIPEAPRDGOAYVRKIDGENVVLLSTFLGKPIPNPLLGLDSTGIFIHH
HHH (SEQ ID NO: 726).
[638] As used herein, the term "neutralizing antibody" is meant to describe an antibody that inhibits or prevents influenza A infection, inhibits or'prevents Influenza A
viral entry into a cell, inhibits or prevents influenza replication, inhibits or prevents influenza egress from a host cell, or reduces the Influenza A titer in a cell, biological sample, or subject. In a preferred embodiment, neutralizing antibodies of the invention prevent viral entry into the cytoplasmic compartment of host cells.

[639] The present invention provides fully human monoclonal antibodies that bind influenza virus and neutralize infection. In certain embodiments, the present invention provides fully human monoclonal neutralizing antibodies specific against the Influenza hemagglutinin =
protein. The antibodies are respectively referred to herein is human monoclonal anti-HA
(huMHA) antibodies.
[640] The Influenza hemagglutinin (HA) protein is a homotrimeric integral membrane glycOprotein found on the surface of the Influenza virus. To mimic the native conformation of this homotrimeric protein, the methods of the invention provide an isolated HA protein precursor that is operably-linked to a trimerization or foldon domain from the phage T4 fibritin protein (SGRLVPRGSPGSGYIPEAPRDGOAYVRKDGEWVLLSTFLGKPIPNPLLGLDSTGHHH
HHH (SEQ ID NO: 726)).
[641] The resultant recombinant homotrimeric foldon HA protein not only retains the native Influenza hemagglutinin homotrimeric conformation, but also becomes soluble, i.e. the protein is no longer bound to a viral or cellular membrane.. Specifically, these recombinant HA homotrimeric proteins lack an integral membrane or transmembrane domain. In certain embodiments, these recombinant HA homotrimeric proteins include HAI and HA2 subunits as well as a trimerization domain, the resultant reconibinant HA homotrimeric protein containing between 1-50, 50-100, 100-150, 150-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500,500-550, 550-600 amino acids (aa) or any length of amino acids in between. Preferably, these recombinant HA homotrimeric proteins contain between 565-575 amino acids (aa). Recombinant HA homotrimeric proteins further include a signal cleavage site at the N-terminus containing between 15-25 aa. Alternatively, or in addition, recombinant HA homotrimeric proteins further include a transmembrane domain positioned between amino acids 525-535 of HA depending on the influenza A virus subtype. In a preferred embodiment, the HA protein is derived from one or more strains of an Influenza A virus.
Recombinant HA homotrimeric proteins of the invention retain the native signal sequence to enable secretion. Moreover, recombinant HA homotrimeric proteins of the invention contain a same signal sequence, which is not derived from HA. Futhermore, signal sequences used with recombinant HA homotrimeric proteins of the-mvention include those signal sequences known in the art that allow efficient secretion of proteins, I such as the signal sequence of the immunoglobulin light kappa chain. Alternatively, .reebmbinant HA homotrimeric proteins, or the HAO precursors thereof, may have the native signal sequences in the expression constructs used by Immune Technology Corp. (http://www.immune-tech.com/).
Signal sequences are retained or manipultated to allow efficient secretion from, for instance, art-recognized cell lines maintained in vitro, e.g. 293 HEK cells.
[642] Recombinant HA homotrimeric proteins may retain a native HA1/HA2 protease cleavage site, which is critical for viral pathogenicity. In qne aspect of the invention, recombinant HA homotrimeric proteins contain aS.ubstituted HA1/HA2 protease cleavage site. For example, the recombinant HA protein encoded by SEQ ID NO: 737 does not have a native cleavage site, but rather a cleavage site substituted from another HA
protein.
Furthermore, these proteins optionally retain sialic acid-containing receptor binding sites within the HAI subunit.
[643] According to the methods of the invention, human antibodies obtained from blood, serum, plasma, or cerebral spinal fluid, are contacted to recombinant and soluble HA
homotrimers of the invention in vitro, wherein the recombinant and soluble HA
homotrimers act as targets for human antibody binding to confirm specificity of the isolated human antibody for an Influenza HA homotrimer in its native conformation. In general, the methods include obtaining serum or plasma samples from subjects or patients that have been infected with or vaccinated against an infectious agent. These serum or plasma samples are then = screened to identify those that contain antibodies specific for a particular polypeptide associated with the infectious agent, such as, e.g. a=Polypeptide specifically expressed on the surface of cells infected with the infectious agent,but nO1 uninfected cells.
In particular embodiments, the serum or plasma samples are screened by contacting the samples with a cell that has been transfected with an expression vector that expresses the polypeptide expressed on the surface of infected cells. In particular embodiments the serum or plasma samples are screened by contacting the samples with a recombinant protein which represents a particular protein of the infectious agent such as, e.g. hemagglutinin of the influenza A
virus. In particular embodiments the serum or plasma samples are screened by contacting the samples with a purified form of the infectious agent such as, e.g. intact whole virions of the influenza A virus. In particular embodiments, the serum or plasma samples are screened by contacting the samples with a live form of the infectious agent such as, e.g.
intact whole virions of the influenza A virus to determine the presence of serum antibodies that inhibit or = neutralize infection of susceptible cells. Exemplary susceptible cells are eukaryotic or mammalian cells, such as MDCK cells.
126 µ, =

[644] Once a subject or patient is identified as having serum or plasma containing an antibody specific for the infectious agent polypeptide or virus of interest, mononuclear and/or B cells obtained from the same subject or patient are used to identify a cell or clone thereof that produces the antibody, using any of the methods described herein or available in the art.
Once a B cell that produces the antibody is identified, cDNAs encoding the variable regions or fragments thereof of the antibody may be cloned using standard RT-PCR
vectors and primers specific for conserved antibody sequences, and subcloned into expression vectors used for the recombinant production of monoclonal antibodies specific for the infectious agent polypeptide of interest.
[645] More specifically, B cells are collected from a particular donor, i.e. a subject or patient is identified as having serum or plasma containing an antibody specific for HA, cultured, and antibody is secreted from these B cells into the culture medium.
The culture medium is separated from these B cells, the B cells are lysed, and then frozen for storage. The culture medium is then screened for antibody binding to various HA targets and/or inhibition/neutralization of infection in vitro. When a culture well is identified as having an antibody of the desired specificity, reverse-transcriptase polymerase chain reaction (RT-PCR) is applied to the B-cell lysate to amplify the antibody variable regions and subsequently clone, express, and test for binding and function of the recombinant antibody, [646] Human antibodies, such as the MAbs listed in Table 10, which bind the recombinant and soluble HA homotrimer and/or bind whole virions, and optionally inhibit or neutralize infection of live virus are recombinantly reproduced and formulated into a pharmaceutical composition for administration to a subject at risk of contacting an Influenza virus.
Furthermore, recombinant and soluble HA homotrirriers are derived from multiple strains of Influenza viruses, including multiple strains of influenza N virus. Exemplary human On antibodies specifically bind Influenza A, and may.be selected for an inability to bind influenza B and C virus strains.
[647] The invention further provides a novel process whereby full-length HA is expressed in mammalian cell lines, which allows for the identification of human antibodies that bind this cell-expressed HA. The huMHA antibodies have been shown to bind conformational determinants on the HA-transfected cells, as well as native HA, which can be isolated, or contacted to huMHA antibodies when presented either on Influenza infected cells or on Influenza A virus. Alternatively, or in addition, huMHA antibodies bind native HA, recombinant homotrimeric HA, purified virus, infected cells, linear peptide, synthetic HA

=
= =

peptide, HA transfected mammalian cells, and HA expressed on the surface of genetically altered bacteriophage virus, which are used for gene fragment display assays.
Thus, this invention has allowed for the identification and production of human monoclonal antibodies that exhibit novel specificity for a very broad range of Influenza A virus strains. These antibodies may be used prophylactically to prevent Influenza A infection, diagnostically to identify Influenza A infection and therapeutically to treat Influenza A
infection. Moreover, the epitopes to which huMHA antibodies of the invention bind are used. as vaccines to prevent influenza A infection.
[648] The huMHA antibodies of the invention has one or more of the following characteristics: a) binds to an epitope in an HA 1 subunit of an Influenza hemagglutinin (HA) protein; b) binds to an epitope in the HA2 subunit of Influenza hemagglutinin (HA) protein;
c) binds to an epitope in the extracellular domain of.an Influenza hemagglutinin (HA) protein, consisting of an HAI subunit and an HAZ subupit; d) binds to an epitope of a recombinant homotrimeric Influenza HAO proteine) binds to an epitope of an Influenza HA
= protein expressed on an infected cell; f) binds to an *tope of an Influenza HA protein expressed on a modified cell; g) binds to an Influenza virus; or h) inhibits virus infection of susceptible eukaryotic cells. The huMHA antibodies of the invention eliminate Influenza infected cells through immune effector mechanisms such as ADCC and/or CDC and promote direct viral clearance by binding to Influenza virions.
[649] Exemplary Influenza A strains used for screening human plasma samples, B
Cell Culture supernatants (BCC SN), and monoclonal transfection supernatants (MN
are shown in Table 8 below). Live strains were used for the neutralization assays described herein...
Inactivated strains were used for the virus binding assays described herein.
Recombinant homotrimeric HA protein was used in the trimeric HA binding assay.
t [650] Table 8 ==Virus Trimeric HA
Virus Subtype ' Neutralization nng binding A/California/WO') HI
A/Solomon Islands/3/06 HI
A/South Carolina/I/18 HI
=
A/Japan/305/57 H2 +
A/Wisconsin/67/05 H3 +
A/swine/Ontario/01911-2/99 H4 A/Vietnam/I203/04 H5 =
A/Indonesia/5/05 H5 A/Egypt/3300-NA MRU3/08 H5 A/common magpie/Hong Kong/5052/07 H5 A/Anhui/1/05 H5 A/chicicen/Vietnam/NCVD-016/08 H5 A/Hong Kong/156/97 H5 A/northern s hoveler/California/HKW Fl 15/07 H6 A/Netherlands/219/03 H7 A/duck/Yangzhou/02/05 H8 A/Hong Kong/2108/03 H9 A/Hong Kong/1073/99 H9 [651] Exemplary HA sequences include those sequences listed on Table 9 below.
=
=
- =

[652] Table 9 Type Cen Bank- Subtype 11A Sequence from &min SEQ ID NO:
Accession No.

A/California/(4/2009(I11Ni) SEQ ID NO: 727 A A BU99109 111 A/Solomon Islands/3/2006(111N1) SEQ ID NO: 728 A A Fll 7241 HI AiSouth Carolina/I/18 (HINI) SEQ ID NO: 729 A .AA A43 (85 112 Allapan/305/19.57(112N2) = SEQ ID NO: 730 A = A CF54576 113 A/W
isconsin/67/2005(113N2) .. sE0 ID NO: 731 AiSwinciOntario/01911-2/99.(114N6) SEQ ID NO: 732 ,4 A F028709 115 Ail Ione konsil 56/97 (115N 1) SEQ ID NO: 733 .

A/VietNaini1203/2004(115N1) SEQ 1 D NO: 734 A/Indonesia/5/2005(115N1) SEQ ID NO: 735 A AC106185 115 AiEgypt/3300-N A MUD/2008(l15Ni ) , SEQ ID NO: 736 A AC126242 115 A/common matt pie/Ilon g Kone./5052/2007(115N1) SEQ ID NO: 737 A/Anhui/1/2005(115N1) SCQ ID NO: 738 A AC007033 115 Aich icken/Viem am/NC:VD-016/2008(H 5N1) SI.7.0 ID NO: 739 A ACM1692 116 A/northern shoveler/Californ ill/lit:WEI 15/2007(116N1) SEQ ID NO: 740 = A AA R02640 117 A/Netherlands/219/03(117N7) SEQ ID NO: 741 A A131:32094 118 AiducklYanvhou/02/2005(118N4) SEQ ID NO: 742 AII1K/2108/2003(l19N2) SEQ ID NO: 743 A NC 004908 119 Alflong Kon gi I 073/99 (119N2) SEQ ID NO: 744 [653] In one embodiment, the huMHA antibodies of the invention bind to an HA
that wholly or partially includes the amino acid residues from position 1 to position 525 of Influenza hemagglutinin when numbered in accordance with SEQ ID NO: 7277744.
Alternatively, the monoclonal antibody is an antibody that binds to the same epitope as the mAbs listed in Table 10.
[654] Table 10 - -.
BCC well ID Theraclone ID BCC well ID Theraclone ID *BCC well ID Theraclone ID
BCC well ID Theraclone ID
3251_K17 TCN-504 5091_H13 TCN-531 5062_M11 TCN-541 _ TCN-3280_1)18 TCN-521 5262_H18 TCN-532 5079_A16 TCN-542 5249_123 TCN-552 ' 3212_112 TCN-522 5256_A17 TCN-533 5081_G23 TCN-543 5261_C18 5248_A17 TCN-523 5249_1302 TCN-534 5082_A19 TCN-544 5277_M05 5237_1321 TCN-524 5246_P19 TCN-535 5082_115 TCN-545 5246_L16 5084_C17 TCN-526 5095_NO1 TCN-536 5089_LO8 TCN-546 5089_K12 5086_006 TCN-527 3194_D21 TCN-537 5092_F11 TCN-547 5081_A04 TCN-557 5087_P17 TCN-528 3206_017 TCN-538 . 5092_PO1 TCN-548 5248_HlOb TCN-558 5297_HO1 TCN-529 5056_A08 TCN-539 5092_PO4 TCN-549 5097_G08 TCN-559 5248_HlOa TCN-530 5060_F05 TCN-540 5096_F06 TCN-550 _ TCN-[655] The antibodies of the invention are able to neutralize Influenza A.
Monoclonal = antibodies can be produced by known procedures, e.g., as described by R.
Kennet et al. in "Monoclonal Antibodies and Functional Cell Lines; Progress and Applications".
Plenum ..
, 130 = =
¨

Press (New York), 1984. Further materials and methods applied are based on known procedures, e.g., such as described in J. Virol. 67:6642-6647, 1993.
[656] These antibodies can be used as prophylactic or therapeutic agents upon appropriate formulation, or as a diagnostic tool.
[657] A "neutralizing antibody" is one that can neutralize the ability of that pathogen to initiate and/or perpetuate an infection in a host and/or in target cells in vitro. The invention provides a neutralizing monoclonal human antibody, wherein the antibody recognizes an antigen from an Influenza virus, which is preferably derived from the HA
protein. Preferably an antibody according to the invention is a novel monoclonal antibody referred to herein as TCN-522 (corresponding to BCC plate and well location 3212_112), TCN-521 (3280_D18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-528 (5087_P17), TCN-529 (5297_HOl), TCN-530 (5248_H10a), TCN-531 (5091_H13), TCN-532 (5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-(5246_P19), TCN-536 (5095_NO1), TCN-537 (3194_D21), TCN-538 (3206_017), TCN-(5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-546 (5089_L08), TCN-547 (5092_F1 1), TCN-548 (5092_P01), TCN-549 (5092_PO4), TCN-550 (5096_F06), TCN-551 (5243_DO1), TCN-552 (5249_123), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), TCN-557 (5081_A04), TCN-558 (5248_Hl0b), TCN-559 (5097_G08), TCN-560 (5084_P10), and TCN-504 (3251_K17).
These antibodies were initially isolated from human samples and are produced by the B cell cultures referred to as 3212_112, 3280_D18, 5248_A17, 5237_B21, 5084_C17, 5086_C06, 5087217, 5297_H01, 5248_H1 0a, 5091_H13;5262_H18, 5256_A17, 5249_B02, 5246_P19, 5095_NO1, 3194_D21, 3206_017, 5056_A08, 50661FO, 5062_M11, 5079_A16, 5081_G23, 5082_A19, 5082_115, 5089_L08, 5092_F11, 5092_PO1, 5.092204, 5096_F06, 5243_DOI, 5249_123, 5261_C18, 5277_M05, 5246_L16, 5089_K12; 5081_A04, 5248_H10b, 5097_G08, 5084_P10, and 3251_K17. These antibodies have broad neutralizing activity or broad binding activity for Influenza A in vitro.
[658] The CDRs of the antibody heavy chains are referred to as CDRH1, CDRH2 and CDRH3, respectively. Similarly, the CDRs of the antibody light chains are referred to as CDRL1, CDRL2 and CDRL3, respectively. The position of the CDR amino acids is defined according to the IMGT numbering system as: CDR1--IMGT positions 27 to 38, CDR2--IMGT positions 56 to 65 and CDR3--IMGT positions 105 to 117. (Lefranc, M P. et al. 2003 IMGT unique numbering for immunoglobulin and T cell receptor variable regions and Ig superfamily V-like domains. Dev Comp Immunol. 27(1):55-77; Lefranc, M P. 1997.
Unique database numbering system for immunogenetic analysis. Immunology Today, 18:509;
Lefranc, M P. 1999. The IMGT unique numbering for Immunoglobulins, T cell receptors and 1g-like domains. The Immunologist, 7:132-136.) [659] The sequences of the antibodies were determined, including the sequences of the variable regions of the Gamma heavy and Kappa or Lambda light chains of the antibodies designated. In addition, the sequence of each of the polynucleotides and polypeptides encoding the antibody sequences was determined for TCN-522 (3212_112), TCN-521 (3280_D18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-(5086_C06), TCN-528 (5087_P17), TCN-529 (5297_H01), TCN-530 (5248_Hl0a), TCN-531 (509 1_H13), TCN-532 (5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-535 (5246_P19), TCN-536 (5095_NO1), TCN-537.(3194_D21), TCN-538 (3206_017), TCN-539 (5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-(5089_L08), TCN-547 (5092_F1 1), TCN-548 (5092P01), TCN-549 (5092_PO4), TCN-(5096_F06), TCN-551 (5243_D01), TCN-552 (5249_123), TCN-553 (5261_C18), TCN-(5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), TCN-557 (5081_A04), TCN-558 (5248_H10b), TCN-559 (5097_G08), TCN-560 (5084_P10), and TCN-504 (3251_K17).
[660] Shown below are the polypeptide and polynucleotide sequences of the heavy and light chains, with the signal peptides at the N-terminus (or 5' end) and the constant regions at the C-terminus (or 3' end) of the variable regions, which are shown in bolded text.
[661] TCN-504 (3251_K17) heavy chain variable region nucleotide sequence:
CAGGTGCAACTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCCTCGGAGACCCTGTCCCTCACTTGCGCTGTCTCT
GGTGTCTCCATCAGCAATATTGATTTCTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTAGAATGGATT
GGCAATATCTATTATACGGGGATCACCTTCTACAACCCGTCCCTCAGCAGTCGAGTCGCCATATCCATTGACACC
TCCAAGAACCAGTTCTCCCTGACTCTGACTTCTGTGACCGCCGCAGACACGGCTATGTATTACTGTGCGAGACAT
TACGGTGACTCCGAGGCAATAAACGATGCCTTTGACATCTGGGGCCAAGGGACAATGCTCACCGTCTCGAGC
(SEQ ID NO: 745) [662] TCN-504 (3251_K17) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) , QVQLQESGPGLVKPSETLSLTCAVSGVSISNIDFYWGWIRQppGKGLEWIGNIYYTGITFYNPSLSSRV
AISIDTSKNQFSLTLTSVTAADTAMYYCARHYGDSEAINDAFDIWGQGTMLTVSS (SEQ ID NO: 746) [663] TCN-504 (3251_K17) gamma heavy chain Kabat CDRs:
CDR 1: NIDFYWG (SEQ ID NO: 747) CDR 2: NIYYTGITFYNPSLSS (SEQ ID NO: 748) =
CDR 3: HYGDSEAINDAFDI (SEQ ID NO: 749) _ .
[664] TCN-504 (3251_K17) gamma heavy chain. Chothia CDRs CDR 1: GVSISN (SEQ ID NO: 750) CDR 2: NIYYTGITF (SEQ ID NO: 751) CDR 3: HYGDSEAINDAFDI (SEQ ID NO: 749) [665] TCN-504 (3251_K17) light chain variable region nucleotide sequence:
GAGATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTGGCAATAGTTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTACGGT
GCATCCACCAGGGCCACTGGTATCCCACCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAATTCACTCTCACCATC
AGCAGCCTGCAGACTGAAGATTTTGCAGTTTATTACTGTCAACAATATATTAACTGGCGTCCGCTCAGTTTTGGC
GGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 752) [666] TCN-504 (3251_K17) light chain variable region amino acid sequence (KabatCDRs in bold, Chothia CDRs underlined) EIVMTQSPATLSVSPGERATLSCRASOSVGNSLAWYQQRPGQAPRLLIYGASTRATGIPPRFSGSGSGT
EFTLTISSLQTEDFAVYYCOOYINWRPLSEGGGTKVEIK (SEQ ID NO: 753) [667] TCN-504 (3251_K17) light chain Kabat CDRs:
CDR 1: RASQSVGNSLA (SEQ ID NO: 754) CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QQYINWRPLS (SEQ ID NO: 756) , =
[668] TCN-504 (3251_K17) light chain Chothia CDRs:' CDR 1: RASQSVGNSLA (SEQ ID NO: 754)=
CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QQYINVVRPLS (SEQ ID NO: 756) [669] TCN-521 (3280_D18) heavy chain variable region nucleotide sequence:
=
=
GAAGTGCAGTTGGTGCAGTCTGGAGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCGCCTGTGTAGTCTCT
GGGTTCACCGTCACCAGCAATTATATAACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTT
ATTTATAGTCATGGTCGCGCATATTATTCAGCCTCCGTGAATGGCCGATTCACCATCTCCAGACACACTTCCAAG
AACACAGTTTATCTTGAAATGAACAGCCTGAGACCTGAGGACACGGCCGTCTATTACTGTGCGGGCGGGGGCCTA
GTCGGTGGCTACGACGAATATTTCTTTGACTATTGGGGCCAGGGAACCCTGGCCACCGTCTCCTCA (SEQ ID
NO: 758) [670] TCN-521 (3280_D18) gamma heavy chain variable region amino acid sequence:
= (Kabat CDRs in bold, Chothia CDRs underlined) EVQLVQSGGGLVQPGGSLRLACVVSGFTVTSNYITWVRQAPGKGLEWVSVIYSHGRAYYSASVNGRF
TISRHTSKNTVYLEMNSLRPEDTAVYYCAGGGLVGGYDEYFFDYWGQGTLATVSS (SEQ ID NO: 759) [671] TCN-521 (3280_D18) gamma heavy chain Kabat CDRs:
CDR 1: SNYIT (SEQ ID NO: 760) CDR 2: VIYSHGRAYYSASVNG (SEQ ID NO: 761) CDR 3: GGLVGGYDEYFFDY (SEQ ID NO: 762) , [672] TCN-521 (3280_D18) gamma heavy chain Chothia CDRs:
CDR 1: GFTVTS (SEQ ID NO: 763) CDR 2: VIYSHGRAY (SEQ ID NO: 764) CDR 3: GGLVGGYDEYFFDY (SEQ ID NO: 762) [673] TCN-521 (3280_D18) light chain variable region nucleotide sequence:
GAAACTGTCTTGACGCAATCTCCAGGCACCTTGTCTTTGACTCCAGGGGAAAGAGCCACCCTCTCCTGCAGAGTC
GGTCAGAGTGTTAGCGGCAGCCACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT
GGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCGGTGGCAGTGTGTCTGGGACAGACTTCACTCTCACC
ATCAGCAGACTGGAGCCTGAAGATTCTGCAGTTTATTACTGTCAGCAGTATGGTGACTCACGATACACTTTTGGC
CAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 765) [674] TCN-521 (3280_D18) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) ETVLTQSPGTLSLTPGERATLSCRVGOSVSGSHLAWYQQKPGQAPRLLIYGASSRATGIPDRFGGSVSG
TDFTLTISRLEPEDSAVYYCOOYGDSRYTFGQGTKLEIK (SEQ ID NO: 766) [675] TCN-521 (3280_D18) Light chain Kabat CDRs:
CDR 1: RVGQSVSGSHLA (SEQ ID NO: 767) CDR 2: GASSRAT (SEQ ID NO: 768) CDR 3: QQYGDSRYT (SEQ ID NO: 769) [676] TCN-521 (3280_D18) Light chain Chothia CDRs:
CDR 1: RVGQSVSGSHLA (SEQ ID NO: 767) CDR 2: GASSRAT (SEQ ID NO: 768) CDR 3: QQYGDSRYT (SEQ ID NO: 769) [677] TCN-522 (3212_112) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTTTTGAAACCTTCGGAGACCCTGTCCCTCACCTGCACTGTGTCT
GGGGGGTCCCTCACTGATTACTCTTGGAACTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATCGGTGAC
ACCCTTCATAATGGCTACACCAACTACAACCCGTCCCTCAGGGGTCGAGTTTCCATCTCAATAGACACGTCCAAG
AACCAGGTCTCACTCAGGCTGACCTCTGTGACCGCCGCGGACACGGCTCTTTATTACTGTGCGAGAGGCTCAGGT
GGATATGGTGGCTTCGATTATTTTGGCAAGCTCCGGACATGGGACTTCTGGGGCCAGGGAACGCTGGTCACCGTC
TCCTCA (SEQ ID NO: 770) [678] TCN-522 (3212_112) gamma heavy ch'ain ./afiable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQQWGAGLLKPSETLSLTCTVSGGSLTDYSWNWIRQPPGKGLEWIGDTLHNGYTNYNPSLRGR
VSISIDTSKNQVSLRLTSVTAADTALYYCARGSGGYGGFDYFGKLRTWDFWGQGTLVTVSS (SEQ ID
NO: 771) [679] TCN-522 (3212_112) gamma heavy chain Kabat CDRs:
CDR 1: DYSWN (SEQ ID NO: 772) CDR 2: DTLHNGYTNYNPSLRG (SEQ ID NO: 773) CDR 3: GSGGYGGFDYFGKLRTWDF (SEQ ID NO: 774) [680] TCN-522 (3212_112) gamma heavy chain Chothia CDRs:
CDR 1: GGSLTD (SEQ ID NO: 775) CDR 2: DTLHNGYTN (SEQ ID NO: 776) CDR 3: GSGGYGGFDYFGKLRTWDF (SEQ ID NO: 774) [681] TCN-522 (3212_112) light chain variable region nucleotide sequence:
GACATTCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAAAAACCAGGGAACGCCCCTAAGCGCCTGATCTTTGGT
GCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACAATC
AGCAGCCTGCAGCCTGAGGACTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCGTACACTTTTGGCCAG
GGGACCAAGCTGGAGATCAAG (SEQ ID NO: 777) [682] TCN-522 (3212_112) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIQLTQSPSSLSASVGDRVTITCRASOGIRNDLGWYQQKPGNAPKRLIFGASSLOSGVPSRFSGSGSGT
EFTLTISSLQPEDFATYYCLOHNSYPYTFGQGTKLEIK (SEQ ID NO: 778) [683] TCN-522 (3212_112) Light chain Kabat CDRs:
CDR 1: RASQGIRNDLG (SEQ ID NO: 779) CDR 2: GASSLQS (SEQ ID NO: 780) CDR 3: LQHNSYPYT (SEQ ID NO: 781) [684] TCN-522 (3212_112)Light chain Chothia CDRs CDR 1: RASQGIRNDLG (SEQ ID NO: 779) CDR 2: GASSLQS (SEQ ID NO: 780) CDR 3: LQHNSYPYT (SEQ ID NO: 781) [685] TCN-523 (5248_A17) heavy chain variable region nucleotide sequence:
CAGGTGCAACTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCAGCTTCAGCAACTATGCCTTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ACCATCCCTCTACTTGGTACAACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTTCCGCGGACCAATTC
ACGAGCACAGCCTACATGGAGCTGGGCAGCCTGAGATCTGAAGACACGGCCGTGTATTACTGTACGAGACGGAAA
ATGACTACGGCTTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 782)=
[686] TCN-523 (5248_A17) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVKKPGSSVKVSCKASGGSFSNYAFSWVRQAPGQGLEWMGGTIPLLGTTNYAQKFQ
GRVTISADQFTSTAYMELGSLRSEDTAVYYCTRRKMTTAFDSWGQGTLVTVSS (SEQ ID NO: 783) [687] TCN-523 (5248_A17) gamma heavy chain Kabat CDRs: =
CDR 1: NYAFS (SEQ ID NO: 784) CDR 2: GTIPLLGTTNYAQKFQG (SEQ ID NO: 785) CDR 3: RKMTTAFDS (SEQ ID NO: 786) [688] TCN-523 (5248_A17)gamma heavy chain Chothia CDRs:
CDR 1: GGSFSN (SEQ ID NO: 787) CDR 2: GTIPLLGTTN (SEQ ID NO: 788) CDR 3: RKMTTAFDS (SEQ ID NO: 786) [689] TCN-523 (5248_A17)light chain variable region nucleotide sequence:
CAGCCTGTTCTGACTCAGCCACCTTCTGCATCAGCCTCCCTGGGAGCCTCGGTCACACTCACCTGCACCCTGAGC
AGCGCCTACAGTAATTATAAAGTGGACTGGTACCAGCAGAGACCAGGGAAGGGCCCCCGCTTTGTGATGCGAGTG
GGCACTGGTGGGATTGTGGGATCCAAGGGGGATGGCATCCCTGATCGCTTCTCAGTCTTGGGCTCAGGCCTGAAT
CGGTACCTGACCATCAAGAACATCCAGGAAGAGGATGAGAGTGACTACCACTGTGGGGCAGACCATGGCAGTGGG
AGCAACTTCGTGTCCCCTTACGTATTCGGCGGAGGGACCAAGCTGACCGTTCTA (SEQ ID NO: 789) [690] TCN-523 (5248_A17)light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) , QPVLTQPPSASASLGASVTLTCTLSSAYSNYKVDWYQQRPGKGPRFVMRVGTGGIVGSKGDGIPDRE
SVLGSGLNRYLTIKNIQEEDESDYHCGADHGSGSNFVSPYVFGGGTKLTVL (SEQ ID NO: 790) [691] TCN-523 (5248_A17)Light chain Kabat CDRs:
CDR 1: TLSSAYSNYKVD (SEQ ID NO: 791) CDR 2: VGTGGIVGSKGD (SEQ ID NO: 792) CDR 3: GADHGSGSNFVSPYV (SEQ ID NO: 793) [692] TCN-523 (5248_A17)Light chain Chothia CDRs:
CDR 1: TLSSAYSNYKVD (SEQ ID NO: 791) CDR 2: VGTGGIVGSKGD (SEQ ID NO: 792) CDR 3: GADHGSGSNFVSPYV (SEQ ID NO: 793) [693] TCN-563 (5237_B21) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGCGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAAGTCTCATGCACGGCTTCT
GGAGGCATCTTCAGGAAGAATGCAATCAGCTGGGTGCGACAGGCCCCTGGACAAGGCCTTGAGTGGATGGGAGGG
ATCATCGCAGTCTTTAACACAGCAAATTACGCGCAGAAGTTTCAGGGCAGAGTCAAAATTACCGCAGACGAATCC
GGGAATACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGTCACCCA
AAATATTTCTATGGTTCGGGGAGTTATCCGGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ
ID NO: 794) :
[694] TCN-563 (5237_B21) gamma heavy chain,variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLAQSGAEVKRPGSSVKVSCTASGGIFRKNAISWVRQAPGQGLEWMGGHAVFNTANYAQKFQG
RVKITADESGNTAYMELSSLRSDDTAVYYCASHPKYFYGSGSYPDFWGQGTLVTVSS (SEQ ID NO:
795) [695] TCN-563 (5237_B21)gamma heavy chain Kabat CDRs:
CDR 1: KNAIS (SEQ ID NO: 796) CDR 2: GIIAVFNTANYAQKFQG (SEQ ID NO: 797) CDR 3: HPKYFYGSGSYPDF (SEQ ID NO: 798) [696] TCN-563 (5237_B21)gamma heavy chain Chothia CDRs:
CDR 1: GGIFRK (SEQ ID NO: 799) CDR 2: GIIAVFNTAN (SEQ ID NO: 800) CDR 3: HPKYFYGSGSYPDF (SEQ ID NO: 798) [697] TCN-563 (5237_B21)light chain variable region nucleotide sequence:
CAATCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAAGC
AGCAGTGATGTTGGTGCTTCTAACTCTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCGTTATT
TATGATGTCACTGAGCGACCCTCAGGGGTCCCTCATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCGTCTCTGGGCTCCAGCCTGAGGACGAGGCTGATTATTTCTGCTGCGCATATGGAGGCAAATATCTTGTGGTC
TTCGGCGGAGGGACCAAGGTGACCGTCCTC (SEQ ID NO: 801) =

[698] TCN-563 (5237_B21)light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSALTQPRSVSGSPGQSVTISCTGSSSDVGASNSVSWYQQHPGKAPKLVIYDVTERPSGVPHRFSGSKS
GNTASLTVSGLQPEDEADYFCCAYGGKYLVVFGGGTKVTVL (SEQ ID NO: 802) [699] TCN-563 (5237_B21)light chain Kabat CDRs: =
CDR 1: TGSSSDVGASNSVS (SEQ ID NO: 803) CDR 2: DVTERPS (SEQ ID NO: 804) CDR 3: CAYGGKYLVV (SEQ ID NO: 805) [700] TCN-563 (5237_B21)light chain Chothia CDRs:
CDR 1: TGSSSDVGASNSVS (SEQ ID NO: 803) CDR 2: DVTERPS (SEQ ID NO: 804) CDR 3: CAYGGKYLVV (SEQ ID NO: 805) [701] TCN-526 (5084_C17)heavy chain variable region nucleotide sequence:
GAGGTGCTGATGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCGTGAGACTCTCCTGTGTAGCCTCT
GGATTCAGTTTCAGTAGTCATTGGATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAAC
ATAGAGGACGATGGAGGTGACAAGTACTATGTGGACTCTGTGAAGGGCCGATTCATTATCTCCAGAGACAACGCC
AAGAATTCAGTGTATCTGCAAATGAACAGCCTAAGAGCCGAGGACACGGCTGTGTATTTCTGTGCGAGAGGTTCG
GGGAGCTCTGATAGAAGTGATTATGACCCCCACTACTACTACTACTTGGACGTCTGGGGCAAAGGGGCCACGGTC
ACCGTCTCCTCA (SEQ ID NO: 806) [702] TCN-526 (5084_C17) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) EVLMVESGGGLVQPGGSVRLSCVASGFSFSSHVVMTWVRQAPGKGLEWVANIEDDGGDKYYVDSVK
GRFIISRDNAKNSVYLQMNSLRAEDTAVYFCARGSGSSDRSOYDPHYVYYLDVWGKGATVTVSS
(SEQ ID NO: 807) =
[703] TCN-526 (5084_C17) gamma heavy chain Kabat CDRs:
CDR 1: SHWMT (SEQ ID NO: 808) CDR 2: NIEDDGGDKYYVDSVKG (SEQ ID NO: 809) CDR 3: GSGSSDRSDYDPHYYYYLDV (SEQ ID NO: 810) [704] TCN-526 (5084_C17) gamma heavy chain Chothia CDRs:
CDR 1: .GFSFSS (SEQ ID NO: 811) CDR 2: NIEDDGGDKY (SEQ ID NO: 812) CDR 3: GSGSSDRSDYDPHYYYYLDV (SEQ ID NO: 810) [705] TCN-526 (5084_C17) light chain variable region nucleotide sequence:
GACATCCAGCTGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGAGCATTAGTAGGTATTTAAATTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGCTGTTTGCT
GCTTCTACTTTGCTAGATGGGGTCCCATCAAGATTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATC
AGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACGGAATCACAGTCCCTCGTGGACGTTCGGCCAA
GGGACCAGGGTGGAAATCAAA (SEQ ID NO: 813) [706] TCN-526 (5084_C17) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIQLTQSPSSLSASVGDRVTITCRASOSISRYLNWYQQKPGKAPKULFAASTLLDGVPSRFSGSGSGT
DFTLTISSLQPEDFATYYCORNHSPSWTFGQGTRVEIK (SEQ ID NO: 814) [707] TCN-526 (5084_C17) Light chain Kabat CDRs:
CDR 1: RASQSISRYLN (SEQ ID NO: 815) =
CDR 2: AASTLLD (SEQ ID NO: 816) CDR 3: QRNHSPSWT (SEQ ID NO: 817) [708] TCN-526 (5084_C17) Light chain Chothia CDRs: ' CDR 1: RASQSISRYLN (SEQ ID NO: 815) CDR 2: AASTLLD (SEQ ID NO: 816) CDR 3: QRNHSPSWT (SEQ ID NO: 817) ' [709] TCN-527 (5086_C06) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAAGAGTCGGGCCCGGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCAACTGCGCTGTCTCT
GGAGGCTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGCCCCCCGGGAAGGGACTGGAGTGGATTGGCTAT
ATCTCTTACAATGGGAGGCCCAAGTACAACCCCTCCCTCACGAGTCGAGTCACCATATCCGTCGACACGTCCAAG
GACCAGTTCTCCCTGGAGCTGCGCTCTGTGACCGCTGCGGACACGGCCCTTTATTACTGTGCGAGAGAAACGCGG
TTCGGGGAGTTATTATCTCCCTATGATGCTTTTGAAATCTGGGGCCAAGGGACAATGGTCACCGTCTCCTCA
(SEQ ID NO: 818) [710] TCN-527 (5086_C06) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSETLSLNCAVSGGSISNYVWSWIRQPPGKGLEWIGYISYNGRPKYNPSLTSRVTI
SVDTSKDQFSLELRSVTAADTALYYCARETREGELLSPYDAFEIWGQGTMVTVSS (SEQ ID NO: 819) [711] TCN-527 (5086_C06) gamma heavy chain Kabat CDRs:
CDR 1: NYYWS (SEQ ID NO: 820) CDR 2: YISYNGRPKYNPSLTS (SEQ ID NO: 821) CDR 3: ETRFGELLSPYDAFEI (SEQ ID NO: 822) [712] TCN-527 (5086_C06) gamma heavy chairithothia CDRs:
CDR 1: GGSISN (SEQ ID NO: 824) CDR 2: YISYNGRPK (SEQ ID NO: 823) =
CDR 3: ETRFGELLSPYDAFEI (SEQ ID NO: 822) [713] TCN-527 (5086_C06) light chain variable region nucleotide sequence:
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATGACTTGCCGGGCA
AGTCAGAACATTAGAAGCTATTTAAATTGGTATCAGCAGAGACCAGGGACAGCCCCTAAACTCCTGATCTATGCT
GCATCCACTTTACACAGTGGGGTCCCATCAAGGTTCAGTGGCGGTGGGTCTGGGACAGATTTCACTCTCACCATC
AATAATCTGCAACCTGAAGATTTTGCATCTTACTACTGTCAACAGAGTTACGATAACCCTCAGACGTTCGGCCAA
GGGACCAAGGTGGAAATCAAA (SEQ ID NO: 825) [714] TCN-527 (5086_C06) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIQMTQSPSSLSASVGDRVTMTCRASONIRSYLNWYQQRPGTAPKLLIYAASTLHSGVPSRFSGGGSG
TDFTLTINNLQPEDFASYYCOOSYDNPQTFGQGTKVEIK (SEQ ID NO: 826) [715] TCN-527 (5086_C06) Light chain Kabat CDRs:
CDR 1: RASQNIRSYLN (SEQ ID NO: 827) CDR 2: AASTLHS (SEQ ID NO: 828) CDR 3: QQSYDNPQT (SEQ ID NO: 829) [716] TCN-527 (5086_C06) Light chain Chothia CDRs:
CDR 1: RASQNIRSYLN (SEQ ID NO: 827) CDR 2: AASTLHS (SEQ ID NO: 828) CDR 3: QQSYDNPQT (SEQ ID NO: 829) [717] TCN-528 (5087_P17) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGCAGTCTGGGTCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCACCAATTATGACATCAACTGGATTCGACAGGCCCCTGGTCAAGGACTTGAGTGGATGGGCTGG
ATAAATCCCAACAGTGGAACCACGGGCTCTGCACAGAGGTTCCAGGGCAGAGTCACCATAACCGTGGACACCTCC
ATAACCACAGTCTACATGGAACTGAGCAGCCTGAGATCTGACGACACGGCCATTTACTACTGCGCGAGAGGCCGT
GAGCTCCTCCGGCTTCAACATTTTTTGACTGACTCCCAGTCCGAGAGGAGGGACTGCTTCGACCCCTGGGGCCAG
GGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 830)..
[718] TCN-528 (5087_P17) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGSEVKKPGASVKVSCKASGYTFTNYDINWIRQAPGQGLEWMGVVINPNSGTMSAQRFQG
RVTITVDTSITTVYMELSSLRSDDTAIYYCARGRELLRLOHFLTDSOSERRDCFDPWGQGTLVTVSS
(SEQ ID NO: 831) [719] TCN-528 (5087_P17) gamma heavy chain Kabat CDRs:
CDR 1: NYDIN (SEQ ID NO: 832) CDR 2: WINPNSGTTGSAQRFQG (SEQ ID NO: 833) CDR 3: GRELLRLQHFLTDSQSERRDCFDP (SEQ ID NO: 834) [720] TCN-528 (5087_P17) gamma heavy chain Chothia CDRs:
CDR 1: GYTFTN (SEQ ID NO: 835) CDR 2: WINPNSGTTG (SEQ ID NO: 836) CDR 3: GRELLRLQHFLTDSQSERRDCFDP (SEQ ID NO: 834) [721] TCN-528 (5087_P17) light chain variable region nucleotide sequence:
GATATCCAGATGACCCAGTCTCCTTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AATCAAGACATTGGCATTTATTTAAATTGGTATCAACAGAATCCAGGGAAAGTCCCTAAACTCCTGCTCCATGGT
GCGTCCAGTTTGCAGGGCGGGGTCCCATCAAGGTTCAGTGCCAGTGGATCTGGGACAGATTTCACTCTCACCATT
CACAGTCTACAACCTGAAGATTTAGCAACCTACTACTGTCAACAGAGTCGCCGTCTACCGTACACTTTTGGCCAG
GGGACCAGGGTGGAACTCAAA (SEQ ID NO: 837) ' [722] TCN-528 (5087_P17) light chain variable'region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIQMTQSPSSLSASVGDRVTITCRANODIGIYLNWYQQNPGKVPKLLLHGASSLOGGVPSRFSASGSG
TDFTLTIHSLQPEDLATYYCOOSRRLPYTFGQGTRVELK (SEQ ID NO: 838) =
[723] TCN-528 (5087_P17) Light chain Kabat CDRs:
CDR 1: RANQDIGIYLN (SEQ ID NO: 839) CDR 2: GASSLQG (SEQ ID NO: 840) CDR 3: QQSRRLPYT (SEQ ID NO: 841) [724] TCN-528 (5087_P17) Light chain Chothia CDRs:
CDR 1: RANQDIGIYLN (SEQ ID NO: 839) CDR 2: GASSLQG (SEQ ID NO: 840) CDR 3: QQSRRLPYT (SEQ ID NO: 841) [725] TCN-529 (5297_H01) heavy chain variable region nucleotide sequence:
CAGATCACCTTGAGGGAGTCTGGTCCTACGCTGGTGAAACCCACACAGACCCTCACGCTGACCTGCACCTTCTCT
GGGTTTTCACTCAGCACTAATGGAGTGAATGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGGAGTGGCTT
GCACTCATTTACTGGGATGATGATAAGCGCTACAGTCCGTCTCTGAAGAGAAGGCTCACCATCACCAAGGACACC
TCCAAAAACCAAGTGGTCCTTACACTGACCAACATGGACCCTGTAGATACAGCCACATATTACTGTGCACACAGA
CCCGACTTCTATGGTGACTTCGAGTACTGGGGCCCGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO:
842) [726] TCN-529 (5297_H01) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QITLRESGPTLVKPTQTLTLTCTFSGFSLSTNGVNVGWIRQPPGKALEWLALIYWDDDKRYSPSLKRR
LTITRDTSKNQVVLTLTNMDPVDTATYYCAHRPDFYGDFEYWGPGTLVTVSS (SEQ ID NO: 843) [727] TCN-529 (5297_H01) gamma heavy chain Kabat CDRs:
CDR 1: TNGVNVG (SEQ ID NO: 844) CDR 2: LIYWDDDKRYSPSLKR (SEQ ID NO: 845) CDR 3: RPDFYGDFEY (SEQ ID NO: 846) [728] TCN-529 (5297_H01)gamma heavy chain Chothia CDRs:
CDR 1: GFSLSTNG (SEQ ID NO: 847) =
CDR 2: LIYWDDDKR (SEQ ID NO: 848) CDR 3: RPDFYGDFEY (SEQ ID NO: 846) [729] TCN-529 (5297_H01) light chain variable region nucleotide sequence:
CAGTCTGCACTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCCGGACAGTCGATCACCATCTCCTGCACTGGAAGC
AGCAGTGACATTGGTGGTTATAACTATGTCTCCTGGTACCAACAACACCCAGGCAAGGCCCCCAAACTCATGATT
TACGATGTCAATAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACTATCTCTGGGCTCCAGACTGACGACGAGGCTGATTATTACTGCGGCTCATATACAGGCAGTCCTCATTATGTC
= TTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 849) [730] TCN-529 (5297_H01) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSALTQPASVSGSPGQSITISCTGSSSDIGGYNYVSWYQQHPGKAPKLMIYDVNNRPSGVSNRFSGSKS
GNTASLTISGLQTDDEADYYCGSYTGSPHYVFGTGTKVTVL (SEQ ID NO: 850) [731] TCN-529 (5297_H01) Light chain Kabat =
CDR 1: TGSSSDIGGYNYVS (SEQ ID NO: 851),.
CDR 2: DVNNRPS (SEQ ID NO: 852) CDR 3: GSYTGSPHYV (SEQ ID NO: 853) WO 2012/112489 =

[732] TCN-529 (5297_H01)Light chain Chothia CDRs:
CDR 1: TGSSSDIGGYNYVS (SEQ ID NO: 851) CDR 2: DVNNRPS (SEQ ID NO: 852) CDR 3: GSYTGSPHYV (SEQ ID NO: 853) , [733] TCN-530 (5248_Hl0a) heavy chain variable region nucleotide sequence:
CAGGTCCAACTGGTGCAATCTGOGGCTGAGGTGAGGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCCCCTTCATGAGTTATGCTATCGGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCAACCCTOTOTTTGGTAGACCGCACTACGCACAGAAGYTCCAGGGCAGAGTCACCATCGCCACGGACGACTCC
ACGAAGACATCGTACATGGAACTGAGTAGCCTGACGTCTGAGGACACGGGCATGTATTACTGTGCGAGTAGGTAT
AGTAGGTCGTCCCCAGGGACCTTTGAGTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ ID NO:
854) [734] TCN-530 (5248_Hl0a) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVRKPGSSVKVSCKASGGPFMSYAIGWVRQAPGQGLEWMGGINPVFGRPHYAQKFQ
GRVTIATDDSTKTSYMELSSLTSEDTGMYYCASRYSRSSPGTFESWGQGTLVTVSS (SEQ ID NO: 855) [735] TCN-530 (5248_Hl0a) gamma heavy chain Kabat CDRs:
CDR 1: SYAIG (SEQ ID NO: 856) CDR 2: GINPVFGRPHYAQKFQG (SEQ ID NO: 857) CDR 3: RYSRSSPGTFES (SEQ ID NO: 858) [736] TCN-530 (5248_Hl0a) gamma heavy chain Chothia CDRs:
CDR 1: GGPFMS (SEQ ID NO: 859) CDR 2: GINPVFGRPH (SEQ ID NO: 860) CDR 3: RYSRSSPGTFES (SEQ ID NO: 858) [737] TCN-530 (5248_H10a) light chain variable -region nucleotide sequence:
GAAATAGTGATGACGCAGTTTCCAGCCACCCTGTCTGTGTCTCCCGGGGAACGAGTCACCCTCTCCTGTAGGGCC
AGTCAGAGTGTTAGCAACAATTTAGCCTGGTACCAGCAAAAACCTGGCCAGCCTCCCAGGCTCCTCATCTATGAT
GCATCTACCAGGGCCACGGGIGTCCCAGCCAAGTTCAGTGGCACTGGGICTGGCACAGAGTTCACTCTCAGCATC
AGCAGCCTGCAGTCCGAAGATTTTGCAGTTTATTACTGTCAGCAGTATCACAACTGGCCTCCCTCGTACAGTTTT
GGCCTGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 861) [738] TCN-530 (5248_Hl0a) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVMTQFPATLSVSPGERVTLSCRASOSVSNNLAWYQQKPGQPPRLLIYDASTRATGVPAKFSGTGSGT
EFTLSISSLQSEDFAVYYCOOYHNWPPSYSFGLGTKLEIK (SEQ ID NO: 862) [739] TCN-530 (5248_H10a) Light chain Kabat CDRs:
CDR 1: RASQSVSNNLA (SEQ ID NO: 863) CDR 2: DASTRAT (SEQ ID NO: 864) CDR 3: QQYHNWPPSYS (SEQ ID NO: 865) [740] TCN-530 (5248_Hl0a) Light chain Chothia CDRs:
CDR 1: RASQSVSNNLA (SEQ ID NO: 863) CDR 2: DASTRAT (SEQ ID NO: 864) CDR 3: QQYHNVVPPSYS (SEQ ID NO: 865) =

[741] TCN-531 (5091_H13) heavy chain variable region nucleotide sequence:
GAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTGGTACAGCCAGGGCGGTCCCTGAAACTCTCCTGCACAGGTTCT
GGATTCACCTTTGGTGATTATGGTGTGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTC
ATTAGAACCAGACCTTGGGGTGGGACAGCAGATACCGCCGCGTCTGTGAAAGGCAGATTCACTATTTCAAGAGAT
GATTCCAAAAGTCTCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTTGTAGA
GATGCCCCTCCAAATGTGGAAGTGGCTTCTATGACCAACTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTC
ACCGTCTCCTCA (SEQ ID NO: 866) [742] TCN-531 (5091_H13) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) EVQLVESCGDLVQPGRSLKLSCTGSGFTFGDYGVTWVRQAPCKGLEWVGFIRTRPWGGTADTAASV
KGRFTISRDDSKSLAYLQMNSLKTEDTAVYYCCRDAPPNVEVASMTNWYFDLWGRGTLVTVSS
(SEQ ID NO: 867) .
[743] TCN-531 (5091_H13) gamma heavy chain Kabat CDRs:
CDR 1: DYGVT (SEQ ID NO: 868) CDR 2: FIRTRPWGGTADTAASVKG (SEQ ID NO: 869) CDR 3: DAPPNVEVASMTNVVYFDL (SEQ ID NO: 870) [744] TCN-531 (5091_H13) gamma heavy chain Chothia CDRs:
CDR 1: GFTFGD (SEQ ID NO: 871) CDR 2: FIRTRPWGGTAD (SEQ ID NO: 872) CDR 3: DAPPNVEVASMTNWYFDL (SEQ ID NO: 870) [745] TCN-531 (5091_H13) light chain variable region nucleotide sequence:
GACATCCAGCTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCG
AGTCAGGGCATTCTCAATTGTTTAGCCTGGTATCAGCAGAAACCGGGGAAAGTTCCTAACCTCCTGATGTATGCT
GCATCCACATTGCAGTCAGGGGTCCCATCTCGGTTCAGCGGCAGTGGATTTGGGACAGATTTCACTCTCACCATC
AGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAACGTATGGCGGTGTCTCTACTTTCGGCGGAGGG
ACCAAGGTGGAGATCAGA (SEQ ID NO: 873) [746] TCN-531 (5091_H13) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) ,}. =
DIQLTQSPSSLSASVGDRVTITCRASOGILNCLAWYQQKPGKVPNLLMYAASTLOSGVPSRFSGSGFG
TDFTLTISSLQPEDVATYYCQTYGGVSTFOGGTKVEIR (SEQ lb. NO: 874) [747] TCN-531 (5091_H13) Light chain Kabat CDRs:
CDR 1: RASQGILNCLA (SEQ ID NO: 875) CDR 2: AASTLQS (SEQ ID NO: 876) CDR 3: QTYGGVST (SEQ ID NO: 877) [748] TCN-531 (5091_H13) Light chain Chothia CDRs:
CDR 1: RASQGILNCLA (SEQ ID NO: 875) CDR 2: AASTLQS (SEQ ID NO: 876) CDR 3: QTYGGVST (SEQ ID NO: 877) , i [749] TCN-532 (5262_H18) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCTTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCGTCAGCAGTGAGACTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTAGAGTGGATT
GGATATATCTATTACATTGGGAACACCGACTACAGGCCCTCCCTCAAGAGTCGAGTCACCATATCACTGGACACG
TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTTTATTACTGTGCGAGAGGC
GCTTATTATGATAGTAGTGGTTACCCGGCTTTTTATATCTGGGGCCAAGGGACAATGGTCACCGTCTCCTCA
(SEQ ID NO: 878) [750] TCN-532 (5262_H18) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSETLSLTCTVSGGSVSSETYYWSWIRQPPGKGLEWIGYIYYIGNTDYRPSLKSR
VTISLDTSKNQFSLKLSSVTAADTAVYYCARGAYYDSSGYPAFYIWGQGTMVTVSS (SEQ ID NO: 879) [751] TCN-532 (5262_H18) gamma heavy chain Kabat CDRs:
CDR 1: SETYYWS (SEQ ID NO: 880) =
CDR 2: YIYYIGNTDYRPSLKS (SEQ ID NO: 881) CDR 3: GAYYDSSGYPAFYI (SEQ ID NO: 882) [752] TCN-532 (5262_H18) gamma heavy chain Chothia CDRs:
CDR 1: GGSVSSET (SEQ ID NO: 883) 2, CDR 2: YIYYIGNTD (SEQ ID NO: 884) CDR 3: GAYYDSSGYPAFYI (SEQ ID NO: 882) [753] TCN-532 (5262_H18) light chain variable region nucleotide sequence:
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGC
AGCTCCAACATCGGGTCAGATTATGATGTGCACTGGTACAAGCAACTTCCAGGAACAGCCCCCAAACTCCTCATC
TTTGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTG
GCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAATCCTATGACAGCAGCCTGAGTGGTTTT
CATGTCTTCGGAAGTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 885) [754] TCN-532 (5262_H18) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSVLTQPPSVSGAPGQRVTISCTGSSSNIGSDYDVHWYKQLPGTAPKLLIEGNSNRPSGVPDRFSGSKS
GTSASLAITGLQAEDEADYYCOSYDSSLSGFHVFGSGTKVTVL (SEQ ID NO: 886) [755] TCN-532 (5262_H18) Light chain Kabat CDRs:
CDR 1: TGSSSNIGSDYDVH (SEQ ID NO: 887) CDR 2: GNSNRPS (SEQ ID NO: 888) CDR 3: QSYDSSLSGFHV (SEQ ID NO: 889) [756] TCN-532 (5262_H18) Light chain Chothia CDRs:
CDR 1: TGSSSNIGSDYDVH (SEQ ID NO: 887).., CDR 2: GNSNRPS (SEQ ID NO: 888) CDR 3: QSYDSSLSGFEIV (SEQ ID NO: 889) =

[757] TCN-533 (5256_A17) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGACGTGAAGAAGCCTGGGTCCTCGGTGACGGTCTCCTGCAAGGCTTCT
GGAGGCAGCTTCAGCAACTATGGAATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGGGGA
ATCATCCCTCTCATTAATGCACCGAACTACGCACCGAAGTTCCAGGGCAGAGTGACGATTACCGCGGACATGTTC
TCGAATATAGTCTCCTTGCAGTTGACCAGCCTGAGAACTGACGACACGGCCGTGTATTATTGTGCGAGACGAAAA
ATGACTACGGCTATTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 890) [758] TCN-533 (5256_A17) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGADVKKPGSSVTVSCKASGGSFSNYGINWVRQAPGQGLEWMGGIIPLINAPNYAPKFQG
RVTITADMFSNIVSLQLTSLRTDDTAVYYCARRKMTTAIDYWGQGTLVTVSS (SEQ ID NO: 891) =
[759] TCN-533 (5256_A17) gamma heavy chain Kabat CDRs:
CDR 1: NYGIN (SEQ ID NO: 892) CDR 2: GIIPLINAPNYAPKFQG (SEQ ID NO: 893) CDR 3: RKMTTAIDY (SEQ ID NO: 894) =
[760] TCN-533 (5256_A17) gamma heavy chain Chothia CDRs:
CDR 1: GGSFSN (SEQ ID NO: 787) CDR 2: GIIPLINAPN (SEQ ID NO: 895) CDR 3: RKMTTAIDY (SEQ ID NO: 894) [761] TCN-533 (5256_A17) light chain variable region nucleotide sequence:
CAGCCTGTGTTGAGTCAGCCACCTTCTGCATCGGCCiCCCTGGGAGCCTCCGTCACACTCACCTGCAC
CCTGAGTAGCGGCTTCGATAATTATCAAGTGGCCTGGTACCAGCAGAGACCAGGGAAGGGCCCCCGCT
TTGTGATGCGGGTGGGCAATGGTGGGAATGTGGCTTCCAAGGGGGATGGCATTCCTGATCGTTTCTCA
GTCTCGGGCTCAGGCCTGAATCGGTACCTGACCATCAAGAACATCCAGGAAGACGATGAGAGTGACTA
TTATTGTGGGGCAGACCATGGCAGTGGGAACAACTTCGTGTCCCCTTATGTGTTTGGCGGAGGGACCA
AGCTGACCGTTCTA (SEQ ID NO: 896) [762] TCN-533 (5256_A17) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QPVLSQPPSASASLGASVTLTCTLSSGFDNYOVAWYQQRPGKGPRFVMRVGNGGNVASKG
DGIPDRFSVSGSGLNRYLTIKNIQEDDESDYYCGADHGSGNNFVSPYVFOGGTICLTVL (SEQ
75 NO: 897) [763] TCN-533 (5256_A17) Light chain Kabat CDRs:
CDR 1: TLSSGFDNYQVA (SEQ ID NO: 898) CDR 2: VGNGGNVASKGD (SEQ ID NO: 899) CDR 3: GADHGSGNNFVSPYV (SEQ ID NO: 900) [764] TCN-533 (5256_A17) Light chain Chothia CDRs:
CDR 1: TLSSGFDNYQVA (SEQ ID NO: 898) CDR 2: VGNGGNVASKGD (SEQ ID NO: 899) CDR 3: GADHGSGNNFVSPYV (SEQ ID NO: 900) =
.=
=

[765] TCN-534 (5249_B02) heavy chain variable region nucleotide sequence:
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCAGGGTCCTCGGTGAAGGTCTCCTGCAGGGAATCT
GGAGGCACCTTCAACGGCTACACTATCACCTGGGTGCGACAGGCCCCTGGGCAAGGCCTTGAGTGGATGGGAGGG
ATCATCCCTATGATGGGGACAGTCAACTACGCACAGAAGTTGCAGGGCAGAGTCACCATTACCACGGACTATTTC
ACGAAAACAGCCTACATGGATCTGAACAATTTAAGATCTGAAGACACGGCCATGTATTATTGTGTGAAAATCAGA
TATACTGGGCAGCAGCTGCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 901) [766] TCN-534 (5249_B02) gamma heavy chain priable region amino acid sequence:

(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVKKPGSSVKVSCRESCGTFNGYTITWVRQAPGQGLEWMGGIIPMMGTVNYAQKLQ
GRVTITTDYFIXTAYMDLNNLRSEDTAMYYCVKIRYTGOOLLWGQGTLVTVSS (SEQ ID NO: 902) [767] TCN-534 (5249_B02) gamma heavy chain Kabat CDRs:
CDR 1: GYTIT (SEQ ID NO: 903) CDR 2: GIIPMMGTVNYAQKLQG (SEQ ID NO: 904) CDR 3: IRYTGQQLL (SEQ ID NO: 905) [768] TCN-534 (5249_B02) gamma heavy chain Chothia CDRs: =
CDR 1: GGTFNG (SEQ ID NO: 906) CDR 2: GIIPMMGTVN (SEQ ID NO: 907) CDR 3: IRYTGQQLL (SEQ ID NO: 905) [769] TCN-534 (5249_B02) light chain variable region nucleotide sequence:
GACXTCCAGATGACCCAGTCTCCTTCCACCCTGTCGGCATCTATAGGAGACAGAGTCACCATCACTTGCCGGGCC
AGTCAGAGTATTGCAAGTTGGTTGGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAG
GCAGTTAATTTAGAAAGTGGGGICCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATC
AGCAGCCTGCAGCCCGATGATTTTGCAACTTATTTCTGCCAACATTATGGTACTATTTCTCAGACCTTCGGCGGA.
GGGACCAAGGTGGAGATCAAA (SEQ ID NO: 908) [770] TCN-534 (5249_B02) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) :T4 DIQMTQSPSTLSASIGDRVTITCRASOSIASWLAWYQQKPGKAPKWYEAVNLESGVPSRFSGSGSGT
DFILTISSLQPDDFATYFCOHYGTISOTFGGGTKV,EIK(SEQ ID NO: 909) [771] TCN-534 (5249_B02) Light chain Kabat CDRs:
CDR 1: RASQSIASWLA (SEQ ID NO: 910) CDR 2: EAVNLES (SEQ ID NO: 911) CDR 3: QHYGTISQT (SEQ ID NO: 912) [772] TCN-534 (5249_B02) Light chain Chothia CDRs:
CDR 1: RASQSIASWLA (SEQ ID NO: 910) CDR 2: EAVNLES (SEQ ID NO: 911) CDR 3: QHYGTISQT (SEQ ID NO: 912) 145 =.; .

CA 02827301 20,13-08-13 [773] TCN-535 (5246_P19) heavy chain variable region nucleotide sequence:
CAGGTCCAGCTGGTGCAATCTGGGAGTGAGGTGAAGAAGCCTGGGACCTCGGTGAAGGTCTCCTGCACGGCCTCT
GGAAGTGTCTTCACCAATTATGGAATTAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCCCTCTCTTTGGCGCAGCCAAGTACGCACAGAAATTCCAGGGCAGAGTCACCATCACAGCGGACGAATCC
ACGAAGACAGTCTACATGGAGCTGAGCAGGCTGACATCTAAAGACACGGCCATATATTTCTGTGCGAAGGCCCCC
CGTGTCTACGAGTACTACTTTGATCAGTGGGGCCAGGGAACCCCAGTCACCGTCTCCTCA (SEQ ID NO:
913) [774] TCN-535 (5246_P19) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGSEVKKPGTSVKVSCTASGSVFTNYGISWVRQAPGQGLEWMGGIIPLFGAAKYAQKFQG
RVTITADESTKTVYMELSRLTSKDTAIYFCAKAPRVYEYYFDOWGQGTPVTVSS (SEQ ID NO: 914) [775] TCN-535 (5246_P19) gamma heavy chain Kabat CDRs:
CDR 1: NYGIS (SEQ ID NO: 915) CDR 2: GIIPLFGAAKYAQKFQG (SEQ ID NO:.916) CDR 3: APRVYEYYFDQ (SEQ ID NO: 917) , =
=
[776] TCN-535 (5246_P19) gamma heavy chain Chothia CDRs:
CDR 1: GSVFTN (SEQ ID NO: 918) CDR 2: GIIPLFGAAK (SEQ ID NO: 919) CDR 3: APRVYEYYFDQ (SEQ ID NO: 917) [777] TCN-535 (5246_P19) light chain variable region nucleotide sequence:
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCAGTCAATTAGCCTGGTACCAGCAAAAACCTGGCCAGGCTCCCAGGCTCATCATCTAT
GGTGCGTCCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGAAGTGGGTCTGGGACAGACTTCACTCTCACC
ATCGGCAGACTGGAGCCTGAAGATTTTGCAGTGTTTTTCTGTCAGCAGTATAGTACCTCACCTCCGACGTTCGGC
CAAGGGACCAAGGTGGATTTCAAA (SEQ ID NO: 920) [778] TCN-535 (5246_P19) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVLTQSPGTLSLSPGERATLSCRASOSVSSSOLAWYQQKPGQAPRLIIYGASTRATGIPDRFSGSGSGT
DFTLTIGRLEPEDFAVFFCOOYSTSPPTEGQGTKVDEK (SEQ ID NO: 921) [779] TCN-535 (5246_P19) Light chain Kabat Cpults:
CDR 1: RASQSVSSSQLA (SEQ ID NO: 922) CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QQYSTSPPT (SEQ ID NO: 923) =
[780] TCN-535 (5246_P19) Light chain Chothia CDRs:
CDR 1: RASQSVSSSQLA (SEQ ID NO: 922) CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QQYSTSPPT (SEQ ID NO: 923) ..ei [781] TCN-536 (5095_NO1) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT
GGTGGGTCCTTCAGTGTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAGGGGGCTGGAGTGGATT
GGGGAAATCAGTCATGGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTGGACACG
ACCAAGAACCAGTTCTCCCTGAGACTGAGCTCTGTGACCGCCGCGGACACGGCCGTCTATTACTGTGCGAGAGGG
ACAGACCCTGACACGGAAGTATATTGTCGTGTTGGTAACTGCGCGGCCTTTGACTACTGGGGCCAGGGAAGCCTG
GTCACCGTCTCCTCA (SEQ ID NO: 924) [782] TCN-536 (5095_NO1) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSVSGYYWSWIRQPPGRGLEWIGEISHGGSTNYNPSLKS
RVTISVDTrKNQFSLRLSSVTAADTAVYYCARGTDPDTEVYCRVGNCAAFDYWGQGSLVTVSS (SEQ
ID NO: 925) [783] TCN-536 (5095_NO1) gamma heavy chain Kabat CDRs:
CDR 1: VSGYYWS (SEQ ID NO: 926) CDR 2: EISHGGSTNYNPSLKS (SEQ ID NO: 927) CDR 3: GTDPDTEVYCRVGNCAAFDY (SEQ ID NO: 928) [784] TCN-536 (5095_NO1) gamma heavy chain Chothia CDRs:
CDR 1: GGSFSVSG (SEQ ID NO: 929) CDR 2: EISHGGSTN (SEQ ID NO: 930) CDR 3: GTDPDTEVYCRVGNCAAFDY (SEQ NO: 928) [785] TCN-536 (5095_NO1) light chain variable region nucleotide sequence:
GAAATTATATTGGCGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAGAGAGCCACCCTCTCCTGCAGGGCC
AGCCAGTTTGTTAGCACCAGATCCCTGGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGACTCCTCATCTAT
GGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACGCTCACC
ATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTATGGTTACTCACCTAGGTACGCTTTT
GGCCAGGGGTCCAAGGTTGAGATCAAA (SEQ ID NO: 931) [786] TCN-536 (5095_NO1) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIILAQSPGTLSLSPGERATLSCRASOFVSTRSLAWYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQHYGYSPRYAFGQGSKVEIK (SEQ ID NO: 932) [787] TCN-536 (5095_N01) Light chain Kabat CDRs:
CDR 1: RASQFVSTRSLA (SEQ ID NO: 933) CDR 2: GASSRAT (SEQ ID NO: 768) CDR 3: QHYGYSPRYA (SEQ ID NO: 934) [788] TCN-536 (5095_NO1) Light chain Chothia CDRs:
CDR 1: RASQFVSTRSLA (SEQ ID NO: 933) CDR 2: GASSRAT (SEQ ID NO: 768) CDR 3: QHYGYSPRYA (SEQ ID NO: 934) =

=
[789] TCN-537 (3194_D21) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTCCAACAGTGGGGCTCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT
GGTGGGTCCTTCAGAGATGACTACTGGACCTGGATTCGCCAGCCCCCAGGCAAGGGGCTGGAGTGGATTGGGGAA
ATCAATCATAGTGGAAGAACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCCTG
AAACAGTTCTCCTTGAAGGTGATTTCTGTGACCGCCGCGGACACGGCTGTTTATTACTGTGCGAGAGGGACGAGC
CATGTTICCCGGTATTITGATTGGTTACCACCCACCAACTGGTTCGACCCCTGGGGCCAGGGAACCCAGGTCACC
GTCTCGAGC (SEQ ID NO: 935) [790] TCN-537 (3194_D21) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) =
QVQLQQWGSGLLKPSETLSLTCAVYGGSFRDDYWTWIRQPPGKGLEWIGEINHSGRTNYNPSLKSRV
TISVDTSLKQFSLKV ISVTAADTAVYYCARGTSHVSRYFDWLPPTNWFDPWGQGTQVTVSS (SEQ ID
= NO: 936) [791] TCN-537 (3194_D21) gamma heavy chain Kabat CDRs:
CDR 1: DDYWT (SEQ ID NO: 937) CDR 2: EINHSGRTNYNPSLKS (SEQ ID NO: 938) CDR 3: GTSHVSRYFDWLPPTNWFDP (SEQ ID NO: 939) [792] TCN-537 (3194_D21) gamma heavy chain Chothia CDRs:
CDR 1: GGSFRD (SEQ ID NO: 940) CDR 2: EINHSGRTN (SEQ ID NO: 941) CDR 3: GTSHVSRYFDWLPPTNWFDP (SEQ ID NO: 939) [793] TCN-537 (3194_D21) light chain variable region nucleotide sequence:
GACATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCGTCATGTAT
GGTGCAGCCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGCCAGACTTCACTCTCACC
ATCAGCAGACTGGAGCCTGAAGATTTTGCAATGTATTACTGTCAGCAGTATGGTAACTCACCGATCACCTTCGGC
CAAGGGACACGACTGGAGATCAAA (SEQ ID NO: 942) [7941 TCN-537 (3194_D21) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIVLTQSPGTLSLSPGERATLSCRASOSVSSSYLAWYQQKPGQAPRLVMYGAATRATGIPDRFSGSGS
GPDFTLTISRLEPEDFAMYYCOOYGNSPITFGQGTRLEIK (SEQ ID NO: 943) =
[795] TCN-537 (3194_D21) Light chain Kabat CDRs:
CDR 1: RASQSVSSSYLA (SEQ ID NO: 944) CDR 2: GAATRAT (SEQ ID NO: 945) CDR 3: QQYGNSPIT (SEQ ID NO: 946) [796] TCN-537 (3194_D21) Light chain Chothia CDRs:
CDR 1: RASQSVSSSYLA (SEQ ID NO: 944) CDR 2: GAATRAT (SEQ ID NO: 945) =
CDR 3: QQYGNSPIT (SEQ ID NO: 946) [797] TCN-538 (3206_017) heavy chain variable region nucleotide sequence:
CAGATCACCTTGAAGGAGTCTGGTCCTACACTGGTGAAACCCACACAGACCCTCACACTGACCTGCGTCTTCTCT
GGGTTCTCACTCAGCATTACTGGAGTGCGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGGAGTGGCTT
GCACTCATTTCTTGGGATGATGAAAAGCACTACAGCCCATCTCTGCAGAGTAGGCTCACCATCACCAAGGACACC
TCCAAAAACCAGGTGGTCCTTACAATGACCAACCTGGACCCTGTCGACACAGCCACATATTACTGTGCACGGTCA
ACCGACAGGGGCCACGTCTTACGATATTTTGGCTGGATGTTACCGGGTGATGCATTTGATGTCTGGGGCCAAGGG
ACAATGGTCACCGTCTCGAGC (SEQ ID NO: 947) [798] TCN-538 (3206_017) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) =
QITLKESGPTLVKPTQTLTLTCVESGESLSITGVRVGWIRQPPGKALEWLALISWDDEKHYSPSLQSRL
TITKDTSKNQVVLTMTNLDPVDTATYYCARSTDRGHVLRYFGWMLPGDAFDVWGQGTMVTVSS
(SEQ ID NO: 948) [799] TCN-538 (3206_017) gamma heavy chain Kabat CDRs:
CDR 1: ITGVRVG (SEQ ID NO: 949) CDR 2: LISWDDEKHYSPSLQS (SEQ ID NO: 950) CDR 3: STDRGHVLRYFGWMLPGDAFDV (SEQ ID NO: 951) [800] TCN-538 (3206_017) gamma heavy chain Chothia CDRs:
CDR 1: GFSLSITG (SEQ ID NO: 952) CDR 2: LISWDDEKH (SEQ ID NO: 953) CDR 3: STDRGHVLRYFGWMLPGDAFDV (SEQ ID NO: 951) [801] TCN-538 (3206_017) light chain variable region nucleotide sequence:
GACATCGTGATGACCCAGTCTCCAGACTTCCTGCCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCC
AGCCAGAGAGTTTTATACAGCTCCAACAATAAAAACTACTTAGCTTGGTACCAGCTGAAACCAGGGCAGCCTCCT
AAGTTGATCATTTATTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACA
GAATTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAACAATATTATAGTCGT
CCGTACACTTTTGGCCAGGGGACCAAGCTCGAGATCAAA (SEQ ID NO: 954) [802] TCN-538 (3206_017) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIVMTQSPDELPVSLGERATINCKSSORVLYSSNNKNYLAWYOLKPGQPPKLIIYWASTRESGVPDRES
GSGSGTEETLTISSLQAEDVAVYYCOOYYSRPYTEGQGTKLEIK (SEQ ID NO: 955) [803] TCN-538 (3206_017) Light chain Kabat CDRs:
CDR 1: KSSQRVLYSSNNKNYLA (SEQ ID NO: 956) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYYSRPYT (SEQ ID NO: 958) =
[804] TCN-538 (3206_017) Light chain Chothia CDRs:
CDR 1: KSSQRVLYSSNNKNYLA (SEQ ID NO: 956) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYYSRPYT (SEQ ID NO: 958) =

WO 2012/112489 =

=
[805] TCN-539 (5056_A08) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GAAATCACCTTCATTACCTATGCTATGCACTGGGTCCGCCAGGCCCCAGGCAAGGGGCTGGAGTGGGTGGCACTT
ATATCAGATGATGGAAGCAATAAATTCTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCC
AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGCTTATTACTGTGCGAGAGAAGGG
GTTTACTTTGATTCGGGGACTTATAGGGGCTACTTTGACTACTGGGGCCAGGAAACCCTGGTCACCGTCTCGAGC
(SEQ ID NO: 959) [806] TCN-539 (5056_A08) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVESGGGVVQPGRSLRLSCAASEITFITYAMHWVRQAPCKGLEWVALISDDGSNKFYADSVKG
RFTISRDNSKNTLYLQMNSLRAEDTAAYYCAREGVYFDSGTYRGYFDYWGQETLVTVSS (SEQ ID
NO: 960) [807] TCN-539 (5056_A08) gamma heavy chain Kabat CDRs:
CDR 1: TYAMH (SEQ ID NO: 961) CDR 2: LISDDGSNKFYADSVKG (SEQ ID NO: 962) CDR 3: EGVYFDSGTYRGYFDY (SEQ ID NO: =963) .=
[808] TCN-539 (5056_A08) gamma heavy chain Chothia CDRs:
CDR 1: EITFIT (SEQ ID NO: 964) =
CDR 2: LISDDGSNKF (SEQ ID NO: 965) CDR 3: EGVYFDSGTYRGYFDY (SEQ ID NO: 963) [809] TCN-539 (5056_A08) light chain variable region nucleotide sequence:
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGAT
GCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC
AGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCCACTGGCCTCCGATCACCTTCGGC
CAAGGGACACGACTGGAGATCAAA (SEQ ID NO: 966) [810] TCN-539 (5056_A08) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVLTQSPATLSLSPGERATLSCRASOSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTD
FTLTISSLEPEDFAVYYCOORSHWPPITFGQGTRLEIK (SEQ ID NO: 967) [811] TCN-539 (5056_A08) Light chain Kabat CDRs:
CDR 1: RASQSVSSYLA (SEQ ID NO: 968) CDR 2: DASNRAT (SEQ ID NO: 969) CDR 3: QQRSHWPPIT (SEQ ID NO: 970) [812] TCN-539 (5056_A08) Light chain Chothia CDRs:
CDR 1: RASQSVSSYLA (SEQ ID NO: 968) CDR 2: DASNRAT (SEQ ID NO: 969) CDR 3: QQRSHWPPIT (SEQ ID NO: 970) =

=
[813] TCN-540 (5060_F05) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTACAATCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGATTCACCTTCAGTAGCTACGCCATGCACTGGGTCCGCCAGGCTCAGGCAAGGGGCTGGAGTGGGTGGCTATT
ATATCATACGACGGAAATGATCAATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAGCTCC
AAAGTGTATCTCCAAATGCACAGGCTGAGACCTGAGGACACGGCTGTTTATTACTGTGCGAAAGAATTTGAAACT
AGTGGTTATTTTCATGGGAGTTTTGACTACTGGGGCCAGGGAATCCTGGTCACCGTCTCGAGC (SEQ ID NO:
971) [814] TCN-540 (5060_F05) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAIISYDGNDOYYTDSVKG
RFTISRDSSKVYLQMHRLRPEDTAVYYCAKEFETSGYFHGSFDYWGQGILVTVSS (SEQ ID NO: 972) [815] TCN-540 (5060_F05) gamma heavy chain Kabat CDRs:
CDR 1: SYAMH (SEQ ID NO: 973) CDR 2: IISYDGNDQYYTDSVKG (SEQ ID NO: 974) CDR 3: EFETSGYFHGSFDY (SEQ ID NO: 975) [816] TCN-540 (5060_F05) gamma heavy chain Chothia CDRs:
CDR I: GFTFSS (SEQ ID NO: 976) CDR 2: IISYDGNDQY (SEQ ID NO: 977) CDR 3: EFETSGYFHGSFDY (SEQ ID NO: 975) [817] TCN-540 (5060_F05) light chain variable tegion nucleotide sequence:
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACC
AGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCTTGATT
TATGAGGTCACTAATTGGCCCTCAGGGGTTTCTAATCGCTTCiCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACAATCTCTGGGCTCCAGGCTGAGGACGAGGCTGACTATTACTGCAGCTCATATGCGGGCAGCAGCACTTGGGTG
TTCGGCGGAGGGACCAGGGTGACCGTTCTA (SEQ ID NO: 978) [818] TCN-540 (5060_F05) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLLIYEVTNWPSGVSNRFSGSK
SGNTASLTISGLQAEDEADYYCSSYAGSSTWVFGGGTRVTVL (SEQ ID NO: 979) [819] TCN-540 (5060_F05) Light chain Kabat CDRs:
CDR 1: TGTSSDVGGYNYVS (SEQ ID NO: 980) CDR 2: EVTNWPS (SEQ ID NO: 981) CDR 3: SSYAGSSTWV (SEQ ID NO: 982) [820] TCN-540 (5060_F05) Light chain Chothia CDRs:
CDR 1: TGTSSDVGGYNYVS (SEQ ID NO: 980) CDR 2: EVTNVVPS (SEQ ID NO: 981) CDR 3: SSYAGSSTVVV (SEQ ID NO: 982) [821] TCN-541 (5062_M11) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAATAGTTACTACTGGAACTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGCTAT
ATCTATCACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATTTCGGTAGACACGTCCAAG
AACCAGTTCTCCCTGCAGCTGAGCTCTGTGACCGCCGCAGACACGGCCGTGTATTACTGTGCGAGACTCCGGACG
GACTACGGTGACCCCGACTCGGTATACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCG
AGC (SEQ ID NO: 983) [822] TCN-541 (5062_M11) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWNWIRQPPGKGLEWIGYIYHSGSTNYNPSLKSRVTI
SVDTSKNQFSLQLSSVTAADTAVYYCARLRTDYGDPDSVYYYGMDVWGQGTTVTVSS (SEQ ID NO:
984) [823] TCN-541 (5062_M11) gamma heavy chain Kabat CDRs:
CDR 1: SYYWN (SEQ ID NO: 985) CDR 2: YIYHSGSTNYNPSLKS (SEQ ID NO: 986) CDR 3: LRTDYGDPDSVYYYGMDV (SEQ ID NO: 987) [824] TCN-541 (5062_M11) gamma heavy chain Chothia CDRs:
CDR 1: GGSINS (SEQ ID NO: 988) CDR 2: YIYHSGSTN (SEQ ID NO: 989) CDR 3: LRTDYGDPDSVYYYGMDV (SEQ ID NO: 987) [825] TCN-541 (5062_M11) light chain variable region nucleotide sequence:
TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCCAGGACAGACGGCCAGGATCACCTGCTCTGGAGAT
GCATTGCCAAAGCAAAATGCTTATTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGCTGATATATAAAGAC
AGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGT-GGAGTCCAGGCAGAGGACGAGGCTGACTATTACTGTCAATCAGCAGACAGCAGTGGTACTTCTTGGGTGTTCGGC
GGAGGGACCAAACTGACCGTTCTA (SEQ ID NO: 990) =
[826] TCN-541 (5062_M1 1) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) SYELTQPPSVSVSPGQTARITCSGDALPKONAYWYQQKPGQAPVLLIYKDSERPSGIPERFSGSSSGTT
VTLTISGVQAEDEADYYCOSADSSGTSWVFGGGTKLTVL (SEQ ID NO: 991) [827] TCN-541 (5062_M11) Light chain Kabat CDRs:
CDR 1: SGDALPKQNAY (SEQ ID NO: 994) CDR 2: KDSERPS (SEQ ID NO: 995) CDR 3: QSADSSGTSWV (SEQ ID NO: 996) [828] TCN-541 (5062_M11) Light chain Chothia CDRs:
CDR 1: SGDALPKQNAY (SEQ ID NO: 994) CDR 2: KDSERPS (SEQ ID NO: 995) CDR 3: QSADSSGTSWV (SEQ ID NO: 996) =

[829] TCN-542 (5079_A16) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAGCAGTGGTAATTACTACTGGAACTGGGTCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATT
GGGTACATCTATTACAGAGGGAGCACCTTCTACAACCCGTCCCTCAAGAGTCGAGTGACCATATCAATAGACACG
TCTAAGAACCAGTTCTCCCTGAGGCTGAGCTCTGTGACGGCCGCGGACACGGCCGTGTATTACTGTGCGAAGGAT
ACAAGGTCGAGCCTAGACAATTACCAGTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC
(SEQ ID NO: 992) [830] TCN-542 (5079_A16) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGNYYWNWVRQHPGKGLEWIGYIYYRGSTFYNPSLKSR
VTISIDTSKNQFSLRLSSVTAADTAVYYCAKDTRSSLDNYOYGMDVWGQMTVTVSS (SEQ ID NO:
993) [831] TCN-542 (5079_A16) gamma heavy chain Kabat CDRs:
CDR 1: SGNYYWN (SEQ ID NO: 997) CDR 2: YIYYRGSTFYNPSLKS (SEQ ID NO: 998), CDR 3: DTRSSLDNYQYGMDV (SEQ ID NO: 999) [832] TCN-542 (5079_A16) gamma heavy chain Chothia CDRs:
CDR 1: GGSISSGN (SEQ ID NO: 1000) CDR 2: YIYYRGSTF (SEQ ID NO: 1001) CDR 3: DTRSSLDNYQYGMDV (SEQ ID NO: 999) [833] TCN-542 (5079_A16) light chain variable region nucleotide sequence:
CAGACTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGCTTCCAGC
ACTGGAGCAGTCACCAGTAGTTACTTTCCAAACTGGTTCCAGCAGAAACCTGGACAAGCGCCCAGGCCACTGATT
TATAGTACAACTATCAGACACTCCTGGACCCCGGCCCGATTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTG
ACACTGTCAGGTGTGCAGCCTGAGGACGAGGCTGACTATTACTGCCTGCTCTACTCTGGTGGTGATCCAGTGGCT
TTCGGCGGAGGGACCAAACTGACCGTTCTA (SEQ ID NO:. 1002) =
[834] TCN-542 (5079_A16) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QTVVTQEPS LTV S PGGTVTLTCASSTGA VTSSYFPNWFQQKPGQAPRPLIYSTTIRHSWTPARFSGSLL
GGKAALTLSGVQPEDEADYYCLLYSGGDPVAFGGGTKLTVL (SEQ ID NO: 1003) [835] TCN-542 (5079_A16) Light chain Kabat clDRs:
CDR 1: ASSTGAVTSSYFPN (SEQ ID NO: 1004) CDR 2: STTIRHS (SEQ ID NO: 1005) CDR 3: LLYSGGDPVA (SEQ ID NO: 1006) [836] TCN-542 (5079_A16) Light chain Chothia CDRs:
CDR 1: ASSTGAVTSSYFPN (SEQ ID NO: 1004) CDR 2: STTIRHS (SEQ ID NO: 1005) CDR 3: LLYSGGDPVA (SEQ ID NO: 1006) =
[837] TCN-543 (508 1_G23) heavy chain variable region nucleotide sequence:
CAGGTTCATCTGGTGCAGTCTGGAGCTGAGGTGAGGAAGCCTGGGGACTCAGTGAAGGTCTCCTGTAAGACTTCT
GGTTACACCTTTTCCACCTATCCTGTCGCCTGGGTGCGACAGGTCCCCGGACAAGGGCTTGAGTGGATGGGATGG
ATCAGCACTTACAATGGAAACACAAACTTTGCACAGAACTTCCAGGGCAGAGTCACCCTGACCACAGACACAACC
ACGAACACAGCCTACATGGAAGTGAGGAGCCTGAAATTTGACGACACGGCCGTCTATTACTGTGCGAGAGTGGAA
' GGCTCGTACAGGGATTTTTGGAATAATCAAAACAGATTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCG
AGC (SEQ ID NO: 1007) [838] TCN-543 (5081_G23) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVHLVQSGAEVRKPGDSVKVSCKTSGYTFSTYPVAWVRQVPGQGLEWMGWISTYNGNTNFAQNFQ
GRVTLTTIXITTNTAYMEVRSLKFDDTAVYYCARVEGSYRDFWNNONRFDPWGQGTLVTVSS (SEQ
ID NO: 1008) [839] TCN-543 (5081_G23) gamma heavy chain Kabat CDRs:
CDR 1: TYPVA (SEQ ID NO: 1009) CDR 2: WISTYNGNTNFAQNFQG (SEQ ID NO: 1010) CDR 3: VEGSYRDFWNNQNRFDP (SEQ ID NO:-.1011) [840] TCN-543 (5081_G23) gamma heavy chain Chothia CDRs:
CDR 1: GYTFST (SEQ ID NO: 1012) =
CDR 2: WISTYNGNTN (SEQ ID NO: 1013) CDR 3: VEGSYRDFWNNQNRFDP (SEQ ID NO: 1011) [841] TCN-543 (5081_G23) light chain variable region nucleotide sequence:
TCCTATGTACTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATTTCCTGTGGGGGAAGC
AACATTGGAGGGAAAAGTGTGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTCTATGATGAT
AGCGGCCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGGACACGGCCACCCTGACCATCAGC
AGGGTCGAAGCCGGGGATGAGGCCGACTATTTCTGTCAGGTGTGGGATAATTTCGGGGGAGTCTTCGGAACTGGG
ACCAAGGTCACCGTTCTA (SEQ ID NO: 1014) [842] TCN-543 (508 1_G23) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) SYVLTQPPSVSVAPGQTARISCGGSNIGGKSVHWYQQKPGQAPVLVVYDDSGRPSGIPERFSGSNSGD
TATLTISRVEAGDEADYFCOVWDNFGGVFGTGTKVTVL (SEQ ID NO: 1015) [843] TCN-543 (508 1_G23) Light chain Kabat CDRs:
CDR 1: GGSNIGGKSVH (SEQ ID NO: 1016) CDR 2: PDSGRPS (SEQ ID NO: 1017) CDR 3: QVWDNFGGV (SEQ ID NO: 1018) [844] TCN-543 (5081_G23) Light chain Chothia CDRs:
CDR 1: GGSNIGGKSVH (SEQ ID NO: 1016) CDR 2: DDSGRPS (SEQ ID NO: 1017) CDR 3: QVWDNFGGV (SEQ ID NO: 1018) [845] TCN-544 (5082_A19) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGGCTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
CGTGGCTCCATCGGTCATTACTTCTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGTTAT
ATCTCTTACAGTGGGAGCACCAAGTACAACCCCTCCCTCAGGAGTCGAGTCACCATATCAGTAGACACGTCCAAG

AACCAGTTCTCCCTGAATCTGAACTCTGTCACCGCTACGGACACGGCCCTATATTACTGTGCGAGAGAGGATTAC
GATATTTTGACTGGGGCGGGACCCGGTATGGAGGTCTGGGGCCAAGGGACCACGGTCACCGTCTCGAGC (SEQ
ID NO: 1019) [846] TCN-544 (5082_A19) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) =
QVQLQESGPGLVKPSETLSLTCTVSRGSIGHYFWSWIRQPPGKGLEWIGYISYSGSTKYNPSLRSRVTIS
VDTSKNQFS,LNLNSVTATDTALYYCAREDYDILTGAGPGMEVWGQGTTVTVSS (SEQ ID NO: 1020) [847] TCN-544 (5082_A19) gamma heavy chain Kabat CDRs:
CDR I: HYFWS (SEQ ID NO: 1021) CDR 2: YISYSGSTKYNPSLRS (SEQ ID NO: 1022) CDR 3: EDYDILTGAGPGMEV (SEQ ID NO: 1023) [848] TCN-544 (5082_A19) gamma heavy chain Chothia CDRs:
CDR 1: RGSIGH (SEQ ID NO: 1024) CDR 2: YISYSGSTK (SEQ ID NO:= 1025) CDR 3: EDYDILTGAGPGMEV (SEQ ID NO: 1023) [849] TCN-544 (5082_A19) light chain variable region nucleotide sequence:
CAGTCTATGTTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGGAGC
AGCTCCAACATCGGAAGTAATACTGTCAACTGGTTCAAACATCTCCCAGGAACGGCCCCCAAACTCCTCATCTAC
AGAAATGATCTGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCC
ATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAACATGGGATGACAGCCTGAATGGTTTTTAT
GTCTTCGGAACTGGGACCAAAGTCACCGTTCTA (SEQ ID NO: 1026) [850] TCN-544 (5082_A19) light chain variable.iregion amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSMLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWFICHLPGTAPKWYRNDLRPSGVPDRFSGSKSGT
SASLA1SGLQSEDEADYYCATWDDSLNGFYVFGTGTKVTVL (SEQ ID NO: 1027) [851] TCN-544 (5082_A19) Light chain Kabat CDRs:
CDR 1: StSSSNIGSNTVN (SEQ ID NO: 1028) = CDR 2: RNDLRPS (SEQ ID NO: 1029) CDR 3: ATWDDSLNGFYV (SEQ ID NO: 1030) [852] TCN-5/14 (5082_A19) Light chain Chothia CDRs:
CDR 1: SGSSSNIGSNTVN (SEQ ID NO: 1028) CDR 2: RNDLRPS (SEQ ID NO: 1029) CDR 3: ATWDDSLNGFYV (SEQ ID NO: 1030) [853] TCN-545 (5082_115) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCTCCTGCGCTGTCTTT
GGTGGGTCCTTCAGTGATTACTACTGGACCTGGATACGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGCGAA
ATCAAACATAGTGGAAGAACCAACTACAACCCGTCCCTTGAGAGTCGAGTCACCATATCAGTGGACACGTCCAAG
AACCAGTTTTCCCTGAAACTGAGTTCTGTGACCGCCGCGGACACGGCTATATATTATTGTGCGAGAGGGACAGAC
CCTGACACGGAGGGATATTGTCGTAGTGGTAGCTGCTCGGCCTTTGACTTCTGGGGCCAGGGAACCCTGGTCACC
GTCTCGAGC (SEQ ID NO: 1031) [854] TCN-545 (5082_115) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQQWGAGLLKPSETLSLSCAVFGGSFSDYYWTWIRQPPGKGLEWIGEIKHSGRTNYNPSLESRV
TISVDTSKNQFSLKLSSVTAADTAIYYCARGTDPDTEGYCRSGSCSAFDFWGQGTLVTVSS (SEQ ID
NO: 1032) [855] TCN-545 (5082_115) gamma heavy chain Kabat CDRs:
CDR 1: DYYWT (SEQ ID NO: 1033) CDR 2: EIKHSGRTNYNPSLES (SEQ ID NO: 1034) =
CDR 3: GTDPDTEGYCRSGSCSAFDF (SEQ ID ,NO: 1035) [856] TCN-545 (5082_115) gamma heavy chain Chothia CDRs:
CDR 1: GGSFSD (SEQ ID NO: 1036) CDR 2: EIKHSGRTN (SEQ ID NO: 1037) CDR 3: GTDPDTEGYCRSGSCSAFDF (SEQ ID NO: 1035) [857] TCN-545 (5082_115) light chain variable region nucleotide sequence:
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCACTTTGTGAACTACAGGTCCTTAGCCTGGTACCAGCAGACACCTGGCCAGGTTCCCAGGCTCCTCATCTAT
GGTGCGTCCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACC
ATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTTCTGTCAGCAGTATGGTGGCTCACCTAGGTACACTTTT
GGCCAGGGGACCAGGCTGGAGATCAAA (SEQ ID NO: 1038) [858] TCN-545 (5082_115) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVLTQSPGTLSLSPGERATLSCRASHEVNYRSLAWYQQTPGQVPRLLIYGASTRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYFCOOYGGSPRYTFGQGTRLEIK (SEQ ID NO: 1039) [859] TCN-545 (5082_115) Light chain Kabat CDRs:
CDR 1: RASHFVNYRSLA (SEQ ID NO: 1040) .
CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QQYGGSPRYT (SEQ ID NO: 1041) , =
[860] TCN-545 (5082_115) Light chain Chothia CDRs:
CDR 1: RASHFVNYRSLA (SEQ ID NO: 1040) CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QQYGGSPRYT (SEQ ID NO: 1041) [861] TCN-546 (5089_L08) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGGTGTCTAT
GGTGGGTCCCTCAGTGATTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGAGAA
ATCAATCATAGTGGAGGCACCAACTACAATCCGTCCCTCAAGAGACGAGTCACCATATCAGTAGACACGTCAAAG
AAGCAATTCTCCCTGAAGATGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGAGAGGGACAGAC
CCTGACACGGAAGTATATTGTCGTGCTGGTAACTGCGCGGCCTTTGACTTCTGGGGCCAGGGAACCCTGGTCACC
GTCTCGAGC (SEQ ID NO: 1042) CA 02827301 2013:08-13 =
[862] TCN-546 (5089_L08) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQQWGAGLLKPSETLSLTCGVYGGSLSDYYWSWIRQPPGKGLEWIGEINHSGGTNYNPSLKRRV
TISVDTSKKQESLKMNSVTAADTAVYYCARGTDPDTEVYCRAGNCAAFDFWGQGTLVTVSS (SEQ
ID NO: 1043) [863] TCN-546 (5089_L08) gamma heavy chain Kabat CDRs:
CDR 1: DYYWS (SEQ ID NO: 1044) CDR 2: EINHSGGTNYNPSLKR (SEQ ID NO: 1045) CDR 3: GTDPDTEVYCRAGNCAAFDF (SEQ ID NO: 1046) [864] TCN-546 (5089_L08) gamma heavy chain Chothia CDRs:
CDR 1: GGSLSD (SEQ ID NO: 1047) CDR 2: EINHSGGTN (SEQ ID NO: 1048) CDR 3: GTDPDTEVYCRAGNCAAFDF (SEQ ID NO: 1046) [865] TCN-546 (5089_L08) light chain variable region nucleotide sequence:
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAGAGAGCCACCCTCTCCTGCCGGGCC
AGTCACTTTGTTATAGGCAGGGCTGTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAC
GGTGCATCCAGCAGGGCCACTGGCATCCCGGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACC
ATCAGCAGACTGGAGACTGAAGATTTTGCTGTGTTTTACTGTCAGCACTATGGTAGCTCACCTAGGTACGCTTTT
GGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 1049) [866] TCN-546 (5089_L08) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVLTQSPGTLSLSPGERATLSCRASHEVIGRAVAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLETEDFAVFYCOHYGSSPRYAFGQGTKLEIK (SEQ ID NO: 1050) [867] TCN-546 (5089_L08) Light chain Kabat CDRs:
CDR 1: RASHFVIGRAVA (SEQ ID NO: 1051) CDR 2: GASSRAT (SEQ ID NO: 768) CDR 3: QHYGSSPRYAF (SEQ ID NO: 1052) [868] TCN-546 (5089_L08) Light chain Chothia CDRs:
CDR 1: RASHFVIGRAVA (SEQ ID NO: 1051) CDR 2: GASSRAT (SEQ ID NO: 768) CDR 3: QHYGSSPRYAF (SEQ ID NO: 1052) [869] TCN-547 (5092_F1 1) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTtCACAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGACTCCATTAGTAGTGTTGATCACTACTGGAGCTGGATCCGCCAACACCCAGTGAAGGGCCTGGAGTGGATT
GGGTTCATGTATTACAGTGCGAGCACCTATTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAACGGACACG
TCTAAGAACCAGTTCTCCCTGAGGCTGAGTTCTGTGACTGCCGCGGACACGGCCGTATATTACTGTGCGAGAGGC
ACTTGTGCTGGTGACTGCTCCCTTCACTACTACTACTACGGTTTGGACGTCTGGGGCCAAGGGAGGACGGTCACC
GTCTCGAGC (SEQ ID NO: 1053) [870] TCN-547 (5092_F11) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSQTLSLTCTVSGDSISSVDHYWSWIRQHPVKGLEWIGFMYYSASTYYNPSLKSR
VTISTDTSKNQFSLRLSSVTAADTAVYYCARGTCAGDCSLHYYYYGLDVWGQGRTVTVSS (SEQ ID
NO: 1054) [871] TCN-547 (5092_F1 1) gamma heavy chain Kabat CDRs:
CDR 1: SVDHYWS (SEQ ID NO: 1055) CDR 2: FMYYSASTYYNPSLKS (SEQ ID NO: 1056) CDR 3: GTCAGDCSLHYYYYGLDV (SEQ ID NO: 1057) =
[872] TCN-547 (5092_F11) gamma heavy chain Chothia CDRs:
CDR 1: GDSISSVD (SEQ ID NO: 1058) CDR 2: FMYYSASTY (SEQ ID NO: 1059) CDR 3: GTCAGDCSLHYYYYGLDV (SEQ ID NO: 1057) [873] TCN-547 (5092_F11) light chain variable region nucleotide sequence:
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCACAAACCAGGGAAAGCCCCTAAGGTCCTGATGTATGCT
GTATCCATTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGGCAGATTTCACTCTCACCATC
AGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTTCCCCGCTCACTTTCGGCGGA
GGGACCAAGGTGGAGATCAAA (SEQ ID NO: 1060) . -[874] TCN-547 (5092_F1 1) light chain variable =region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIQMTQSPSSLSASVGDRVTITCRASOSISSYLNWYQHKPGKAPKVLMYAVSILOSGVPSRFSGSGSGA
DFTLTISSLQPEDFATYYCOOSYSSPLTFGGGTKVEIK (SEQ ID NO: 1061) [875] TCN-547 (5092_F11) Light chain Kabat CDRs:
CDR 1: RASQSISSYLN (SEQ ID NO: 1062) CDR 2: AVSILQS (SEQ ID NO: 1063) CDR 3: QQSYSSPLT (SEQ ID NO: 1064) [876] TCN-547 (5092_F11) Light chain Chothia CDRs:
CDR 1: RASQSISSYLN (SEQ ID NO: 1062) CDR 2: AVSILQS (SEQ ID NO: 1063) CDR 3: QQSYSSPLT (SEQ ID NO: 1064) [877] TCN-548 (5092_P01) heavy chain variable region nucleotide sequence:
=
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
AGTGGCCCCATGAGTGATTATTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGCAT
=
GTCTCTGTCTCTCACGGAGGGAGGACCAAATCCAATCCCTCCGTCATGAGTCGAGTCACCATTTCAGTAGAAACG
TCCAAGAACCAATTCTCCCTGAAACTGACCTCCGTGACCGCTGCGGACACGGCCGTTTATTACTGTGCGAGATTA
AATTACTATGATAGAAGTGGTTATCATTCGCCTGACGGCCCCTCGAACAACTGGTTCGACCCCTGGGGCCAGGGA
ACCCTGGTCACCGTCTCGAGC (SEQ ID NO: 1065) [878] TCN-548 (5092_P01) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSETLSLTCTVSSGPMSDYYWSWIRQPPGKGLEWIGHVSYSHGGRTKSNPSVMS
RVTISVETSKNQFSLKLTS VTAADTAVYYCARLNYYDRSGYHSPDGPSNNWFDPWGQGTLVTVSS
(SEQ ID NO: 1066) [879] TCN-548 (5092_P01) gamma heavy chain Kabat CDRs:
CDR 1: DYYWS (SEQ ID NO: 1044) CDR 2: HVSVSHGGRTKSNPSVMS (SEQ ID NO: 1067) CDR 3: LNYYDRSGYHSPDGPSNNWFDP (SEQ ID NO: 1068) [880] TCN-548 (5092_P01) gamma heavy chain Chothia CDRs:
CDR 1: SGPMSD (SEQ ID NO: 1069) CDR 2: HVSVSHGGRTK (SEQ ID NO: 1070) CDR 3: LNYYDRSGYHSPDGPSNNWFDP (SEQ ID NO: 1068) [881] TCN-548 (5092_P01) light chain variable region nucleotide sequence:
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCC
AGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCT
AAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGAATCAGCGGCAGCGGGTCTGGGGCA
GATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTATTTTGCTACT
CCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 1071) [882] TCN-548 (5092_P01) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIVMTQSPDSLAVSLGERATINCKSSOSVLYSSNNKNAAWWQKPGQPPKWYWASTRESGVPDRI
SGSGSGADFTLTISSLQAEDVAVYYCOOYFATPRTFGQGTKVEIK (SEQ ID NO: 1072) [883] TCN-548 (5092_P01) Light chain Kabat CDRs:
CDR 1: KSSQSVLYSSNINTKNYLA (SEQ ID NO: 1073) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYFATPRT (SEQ ID NO: 1074) [884] TCN-548 (5092_P01) Light chain Chothia CDRs:
CDR 1: KSSQSVLYSSNNKNYLA (SEQ ID NO: 1073) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYFATPRT (SEQ ID NO: 1074) [885] TCN-549 (5092_PO4) heavy chain variable region nucleotide sequence:
CAGGTACAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAACCCTAACAGTGGTGACACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCC
ATCACCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATTCC
CCCTATAGCAGCAGCTGGTCCTTCTTTGACTACTGGGGCCAGGGACCCCTGGTCACCGTCTCGAGC (SEQ ID
NO: 1075) =

[886] TCN-549 (5092_PO4) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGDTNYAQKF
QGRVTMTRDTSITTAYMELSSLRSDDTAVYYCARDSPYSSSWSFFDYWGQGPLVTVSS (SEQ ID NO:
1076) [887] TCN-549 (5092_PO4) gamma heavy chain Kabat CDRs:
CDR 1: GYYMH (SEQ ID NO: 1077) CDR 2: WINPNSGDTNYAQKFQG (SEQ ID NO:.1078) CDR 3: DSPYSSSWSFFDY (SEQ ID NO: 1079) = .
[888] TCN-549 (5092_PO4) gamma heavy chain Chothia CDRs:
CDR 1: GYTFTG (SEQ ID NO: 1080) CDR 2: WINPNSGDTN (SEQ ID NO: 1081) CDR 3: DSPYSSSWSFFDY (SEQ ID NO: 1079) [889] TCN-549 (5092_PO4) light chain variable region nucleotide sequence:
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCC
AGCCAGAGTGTTTTATACAGCTCCAACAATAAGAGCCACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCT
AAGTTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACA
GATTTCACCCTCATCATCAGCAGCCTGCAGGCTGAGGATGTGGCAGTTTATTACTGTCAGCAATATTATTTTTCT
CCCCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 1082) [890] TCN-549 (5092_PO4) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIVMTQSPDSLAVSLGERATINCKSSOSVLYSSNNKSHLAWYQQKPGQPPKWYWASTRESGVPDRF
SGSGSGTDFTLIISSLQAEDVAVYYCOOYYFSPLTFGGGTKVEIK (SEQ ID NO: 1083) [891] TCN-549 (5092_PO4) Light chain Kabat CDRs:
CDR 1: KSSQSVLYSSNNKSHLA (SEQ ID NO: 1084) CDR 2: WASTRES (SEQ ID Na 957) CDR 3: QQYYFSPLT (SEQ ID NO: 1085) [892] TCN-549 (5092_PO4) Light chain Chothia,CDRs:
CDR 1: KSSQSVLYSSNNKSHLA (SEQ ID N61084) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYYFSPLT (SEQ ID NO: 1085) [893] TCN-550 (5096_F06) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGCCTCCATCAATAGTCACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTAT
GTCTATTACAGTGGGAGCACCACCTACAACCCCTCCCTCAAGAGTCGAGTCACCTTATCAGTAGATACGTCCAAG
AACCAGTTCTCCCTGAACCTGAGCTCTGTGACCGCCGCAGACACGGCCTTCTATTACTGTGCGAGACATCCCTAC
GATGTTTTGACTGGTTCCGGGGACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ
ID NO: 1086) , =

r =
=
[894] TCN-550 (5096_F06) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLQESGPGLVKPSETLSLTCTVSGASINSHYWSWIRQPPGKGLEWIGYVYYSGSTTYNPSLKSRVT
LSVDTSKNQFSLNISSVTAADTAFYYCARHPYDVLTGSGDWFDPWGQGTLVTVSS (SEQ ID NO:
1087) [895] TCN-550 (5096_F06) gamma heavy chain Kabat CDRs:
CDR 1: SHYWS (SEQ ID NO: 1088) CDR 2: YVYYSGSTTYNPSLKS (SEQ ID NO: 1089) CDR 3: HPYDVLTGSGDWFDP (SEQ ID NO: 1090) [896] TCN-550 (5096_F06) gamma heavy chain Chothia CDRs:
CDR 1: GASINSH (SEQ ID NO: 1091) CDR 2: YVYYSGSTT (SEQ ID NO: 1092) CDR 3: HPYDVLTGSGDWFDP (SEQ ID NO: 1090) [897] TCN-550 (5096_F06) light chain variable region nucleotide sequence:
TCCTATGTTCTGACTCAGGCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATTACCTGTGGGGGAAAT
GCCATTGGAAGTAAAAAAGTTCACTGGTACCAGCACAAGGCAGGCCAGGCCCCTGTACTCGTCGTCTATGATGAT
ACAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTTGGAGCACGGCCACCCTGACCATCAAC
AGGGTCGAAGCCGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATTTTACCATTGATCATGTGGTCTTCGGC
GGAGGGACCAAGCTGACCGTTCTA (SEQ ID NO: 1093) [898] TCN-550 (5096_F06) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) SYVLTQAPSVSVAPGQTARITCGGNAIGSKKVHWYQHKAGQAPVLVVYDDTDRPSGIPERFSGSNSW
STATLTINRVEAGDEADYYCOVVVDFTIDHVVFGGGTKLTVL (SEQ ID NO: 1094) [899] TCN-550 (5096_F06) Light chain Kabat CDRs:
CDR 1: GGNAIGSKKVH (SEQ ID NO: 1095) CDR 2: DDTDRPS (SEQ ID NO: 1096) CDR 3: QVWDFTIDHVV (SEQ ID NO: 1097) [900] TCN-550 (5096_F06) Light chain Chothia CDRs:
CDR 1: GGNAIGSKKVH (SEQ ID NO: 1095) CDR 2: DDTDRPS (SEQ ID NO: 1096) =
CDR 3: QVWDFTIDHVV (SEQ ID NO: 1097) , [901] TCN-551 (5243_D01) heavy chain variable region nucleotide sequence:
GAGGTGCAACTGGTTCAGTCTGGATCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTCT
GGCTACAGCTTTAGCAACTACTGGATCGGCTGGGTGCGCCACATGCCCGGGAAAGGCCTGGAATGGATGGGGATC
ATTTATCCTGGTGACTCTGATACCAGATACAGCCCGTCCTTCCAAGGCCAGGTCACCATGTCAGCCGACAAGTCC
AGCAGCACCGTCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATTTATTATTGTGCGAGACGGGGC
GGACATAGTTTTGGATATGGGTCGGGGGGGGACACGCACAGTGAATTCGACTCCTGGGGCCAGGGAACCCTGGTC
ACCGTCTCGAGC (SEQ ID NO: 1098) [902] TCN-551 (5243_DO1) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined);:':
EVQLVQSGSEVKKPGESLKISCKGSGYSFSNYVVIGWVRHMPGKGLEWMGHYPGDSDTRYSPSFQGQ
VTMSADKSSSTVYLQWSSLKASDTAIYYCARRGGHSFGYGSGGDTHSEFDSWGQGTLVTVSS (SEQ
ID NO: 1099) [903] TCN-551 (5243_DO1) gamma heavy chain Kabat CDRs:
CDR 1: NYWIG (SEQ ID NO: 1100) CDR 2: IIYPGDSDTRYSPSFQG (SEQ ID NO: 1101) CDR 3: RGGHSFGYGSGGDTHSEFDS (SEQ ID NO: 1102) [904] TCN-551 (5243_DO1) gamma heavy chain Chothia CDRs:
CDR 1: GYSFSN (SEQ ID NO: 1103) CDR 2: ITYPGDSDTR (SEQ ID NO: 1104) CDR 3: RGGHSFGYGSGGDTHSEFDS (SEQ ID NO: 1102) [905] TCN-551 (5243_D01) light chain variable region nucleotide sequence:
CAGTCTGTATTGACGCAGTCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGC
GACTCCAACATTGGTGATTATTTTGTATGTTGGTACCAGCACCTCCCAGGAAAACCCCCCCAACTCCTCATCTAT
GAAAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGC
ATCACCGGAATCCAGACCGGGGACGAGGCCGATTACTACTGCGCAACTTGGGATGGCAGCCTGAGTGCTTGGGTG
TTCGGCGGAGGGACCAAGCTGACCGTTCTA (SEQ ID NO; 1105) [906] TCN-551 (5243_DO1) light chain variable:region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSVLTQSPSVSAAPGQKVTISCSGSDSNIGDYFVCWYQHLPGKPPQLLIYENNKRPSGIPDRFSGSKSGT
SATLGITGIQTGDEADYYCATWDGSLSAWVFGGGTKLTVL (SEQ ID NO: 1106) [907] TCN-551 (5243_DO1) Light chain Kabat CDRs:
CDR 1: SGSDSNIGDYFVC (SEQ ID NO: 1107) CDR 2: ENNKRPS (SEQ ID NO: 1108) CDR 3: ATWDGSLSAWV (SEQ ID NO: 1109) [908] TCN-551 (5243_DO1) Light chain Chothia CDRs:
CDR 1: SGSDSNIGDYFVC (SEQ ID NO: 1107) CDR 2: ENNKRPS (SEQ ID NO: 1108) CDR 3: ATWDGSLSAWV (SEQ ID NO: 1109) [909] TCN-552 (5249_123) heavy chain variable region nucleotide sequence:
CAGGTCCAAGTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAGGGTCTCCTGCCAGGCTTCT
GGAGGCACCTTCATGAATTATGCTATCATTTGGGTGCGACGGGCCCCTGGACAAGGCCTTGAGTGGATGGGAGGG
ATCATCCCTGTCTTTCCTACACCAAACTACGCACAGATGTTCCAGGGCAGAGTCACGATTTCCACGGACGAATCC
AGGAGCACATCCTTCTTGGAACTGACCAACCTGAGATATGAGGACACGGCCGTTTATTACTGTGCGAGGCGAATT
TATCACGGTGGTAACTCCGGCTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ ID NO:
1110) [910] TCN-552 (5249_123) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQVVQSGAEVKKPGSSVRVSCQASGGTFMNYAIIWVRRAPGQGLEWMGGIIPVFPTPNYAQMFQG
RVTISTDESRSTSFLELTNLRYEDTAVYYCARRIYHGGNSGFDFWGQGTLVTVSS (SEQ ID NO: 1111) [911] TCN-552 (5249_123) gamma heavy chain Kabat CDRs:
CDR 1: NYAII (SEQ ID NO: 1112) CDR 2: GIIPVFPTPNYAQMFQG (SEQ ID NO:-1113) CDR 3: RIYHGGNSGFDF (SEQ ID NO: 1114) [912] TCN-552 (5249_123) gamma heavy chain Chothia CDRs:
CDR 1: GGTFMN (SEQ NO: 1115) CDR 2: GIIPVFPTPN (SEQ ID NO: 1116) CDR 3: RIYHGGNSGFDF (SEQ ID NO: 1114) [913] TCN-552 (5249_123) light chain variable region nucleotide sequence:
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTGGCAACTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGAT
TCATCCAACAGGGCCCCTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC
AGCAGCCTCGCGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAAGTGGCCTCCCATGTACAGTTTT
GGCCATGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 1117) [914] TCN-552 (5249_123) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVLTQSPAILSLSPGERATLSCRASOSVGNYLAWYQQKPGQAPRLLIYDSSNRAPGIPARFSGSGSGT
DETLTISSLAPEDFAVYYCOORSKWPPMYSFGHGTKLEIK (SEQ ID NO: 1118) [915] TCN-552 (5249_123) Light chain Kabat Cl?Rs:
CDR 1: RASQSVGNYLA (SEQ ID NO: 1119) CDR 2: DSSNRAP (SEQ ID NO: 1120) CDR 3: QQRSKWPPMYS (SEQ ID NO: 1121) [916] TCN-552 (5249_123) Light chain Chothia CDRs:
CDR 1: RASQSVGNYLA (SEQ ID NO: 1119) CDR 2: DSSNRAP (SEQ ID NO: 1120) CDR 3: QQRSKWPPMYS (SEQ ID NO: 1121) [917] TCN-553 (5261_C18) heavy chain variable region nucleotide sequence:
CAGGTCCAGGTGGTGCAGTCTGGGACTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCCAGACTTCT
GGAGGCAGGTTCATGAGTTATGCTATCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGC
ATCGTCCCTGTCTTCGGAACAGCAAACTACGCTCAGAAGTTCCAGGGCAGAGTCACGATCACCACGGACGATTCC
ACGCGCACAGCCTATATGGAGTTGAGCAGCCTGAGAAGTGAGGACACGGCCGTTTATTACTGTGGGTTCCGATAC
GGCTCTGGTTACGGGTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ ID NO: 1122) [918] TCN-553 (5261_C18) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQVVQSGTEVKKPGSSVKVSCQTSGGRFMSYAITWVRQAPGQGLEWMGGIVPVFGTANYAQKFQ
GRVTITTDDSTRTAYMELSSLRSEDTAVYYCGFRYGSGYGFDSWGQGTLVTVSS (SEQ ID NO: I 123) [919] TCN-553 (5261_C18) gamma heavy chain Kabat CDRs:
CDR 1: SYAIT (SEQ ID NO: 1124) CDR 2: GIVPVFGTANYAQKFQG (SEQ ID NO: 1125) CDR 3: RYGSGYGFDS (SEQ ID NO: 1126) [920] TCN-553 (5261_C18) gamma heavy chain Chothia CDRs:
CDR 1: GGRF/VIS (SEQ ID NO: 1127) =
CDR 2: GIVPVFGTAN (SEQ ID NO: 1128) CDR 3: RYGSGYGFDS (SEQ ID NO: 1126) [921] TCN-553 (5261_C18) light chain variable region nucleotide sequence:
GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGTAGCAGCTACTTAGCCTGGTATCAGAAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT
GGTGCTTCCACTAGGGCCACTGGCATCCCGGACCGGTTCACTGGCAGTGGGTCTGGGACAGACTTCACTCTCAGC
ATCAGTAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTTTGGTACCTCAGTCTTCACTTTCGGC
GGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 1129) [922] TCN-553 (5261_C18) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVLTQSPGTLSLSPGERATLSCRASOSVSSSYLAWYQKKPGQAPRLLIYGASTRATGIPDRFTGSGSGT
DFTLSISRLEPEDFAVYYCOHFGTSVFTFGGGTKVEIK (SEQ ID NO: 1130) [923] TCN-553 (5261_C18) Light chain Kabat CDRs:
CDR 1: RASQSVSSSYLA (SEQ ID NO: 944) CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QHFGTSVFT (SEQ ID NO: 1131) [924] TCN-553 (5261_C18) Light chain Chothia CDRs:
CDR 1: RASQSVSSSYLA (SEQ ID NO: 944) CDR 2: GASTRAT (SEQ ID NO: 755) CDR 3: QHFGTSVFT (SEQ ID NO: 1131) [925] TCN-554 (5277_M05) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGATCTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCACCGACTACTATATTCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAACCCTGAAAGTGGTGACACAAAGTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCC
ATCACCACAGCCTACATGGAGCTGGGTAGGCTGAGATCCGACGACACGGCCGTGTATTACTGTGCGAGAGATGTA
AGTACGACCTGGAGCTGGTTCGCCCCCTGGGGCCAGGGAAftCTGGTCACCGTCTCGAGC (SEQ ID NO:
1132) [926] TCN-554 (5277_M05) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGADLKKPGASVKVSCKASGYTFTDYYIHWVRQAPGQGLEWMGWINPESGDTKYAQKFQ
GRVTMTRDTSITTAYMELGRLRSDDTAVYYCARDVSTTWSWFAPWGQGTLVTVSS (SEQ ID NO:
1133) [927] TCN-554 (5277_M05) gamma heavy chain Kabat CDRs:
CDR 1: DYYIH (SEQ ID NO: 1134) CDR 2: WINPESGDTKYAQKFQG (SEQ ID NO: 1135) CDR 3: DVSTTWSWFAP (SEQ ID NO: 1136) [928] TCN-554 (5277_M05) gamma heavy chain Chothia CDRs:
CDR 1: GYTFTD (SEQ ID NO: 1137) CDR 2: WINPESGDTK (SEQ ID NO: 1138) CDR 3: DVSTTWSWFAP (SEQ ID NO: 1136) [929] TCN-554 (5277_M05) light chain variable region nucleotide sequence:
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCAGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAGGTCC
AGCCAGAGTATTTTCCACAACTCCAACAATGAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCT
AAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACA
GATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCGGTTTATTTCTGTCAGCAATATTATAATGCT
CCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 1139) [930] TCN-554 (5277_M05) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) DIVMTQSPDSLAVSLGERATINCRSSOSIEHNSNNENYLAWYQQKPGQPPKLLIYWASTRESGVPDRE
SGSGSGTDFTLTISSLQAEDVAVYFCQQYYNAPLTFGGGTKVE1K (SEQ ID NO: 1140) [931] TCN-554 (5277_M05) Light chain Kabat CDRs:
CDR 1: RSSQSIFHNSNNENYLA (SEQ ID NO: 1141) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYYNAPLT (SEQ ID NO: 1142) [932] TCN-554 (5277_M05) Light chain Chothia CDRs:
CDR 1: RSSQSIFHNSNNENYLA (SEQ ID NO: 1141) CDR 2: WASTRES (SEQ ID NO: 957) CDR 3: QQYYNAPLT (SEQ ID NO: 1142) [933] TCN-555 (5246_L16) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAGGTCTCATGCACGGCTTCT
GGAGGCATCTTCAGGAAGAATGCAATCAGCTGGGTGCGACAGGCCCCTGGACAAGGCCTTGAGTGGATGGGAGGG
ATCATCGCAGTCTTTAACACAGCAAATTACGCGCAGAAGTTCCAGAACAGAGTCAAAATTACCGCAGACGAGTCA
GGCAATACGGCCTACATGGAGCTGAGCAGCCTGACATCTGACGACACGGCCGTGTATTACTGTGCGAGTCACCCA
AAATATTTCTATGGTTCGGGGAGTTATCCGGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ
ID NO: 1143) [934] TCN-555 (5246_L16) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVKRPGSSVKVSCTASGGIFRKNAISWVRQAPGQGLEWMGGHAVENTANYAQKFQN
RVKITADESGNTAYMELSSLTSDDTAVYYCASHPKYFYGSGSYPDFWGQGTLVTVSS (SEQ ID NO:
1144) =
[935] TCN-555 (5246_L16) gamma heavy chain Kabat CDRs:
CDR 1: KNAIS (SEQ ID NO: 796) CDR 2: GIIAVFNTANYAQKFQN (SEQ ID NO: 797) CDR 3: HPKYFYGSGSYPDF (SEQ ID NO: 798) [936] TCN-555 (5246_L16) gamma heavy chain Chothia CDRs:
CDR 1: GGIFRK (SEQ ID NO: 799) CDR 2: GIIAVFNTAN (SEQ ID NO: 800) CDR 3: HPKYFYGSGSYPDF (SEQ ID NO: 798) [937] TCN-555 (5246_L16) light chain variable region nucleotide sequence:
CAATCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAATCACCATCTCCTGTACTGGTGGC
AGCAGTGATATTGGTGCTTCTAACTCTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCGTTATT
TTTGATGTCACTGAGCGACCCTCAGGGGTCCCGCATCGGTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCGTCTCTGGGCTCCAGCCTGACGACGAGGCTGATTATTTCTGCTGCGCATATGGAGGCAAATATCTTGTGGTC
TTCGGCGGAGGGACCAAGGTGACCGTTCTA (SEQ ID NO: 1145) [938] TCN-555 (5246_L16) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSALTQPRSVSGSPGQSITISCTGGSSDIGASNSVSWYQQHPGKAPKLVIFDVTERPSGVPHRFSGSKSG
NTASLTVSGLQPDDEADYFCCAYGGKYLVVFGGGTKVTVL (SEQ ID NO: 1146) [939] TCN-555 (5246_L16) Light chain Kabat CDRs:
CDR 1: TGGSSDIGASNSVS (SEQ ID NO: 1147) CDR 2: DVTERPS (SEQ ID NO: 804) CDR 3: CAYGGKYLVV (SEQ ID NO: 805) [940] TCN-555 (5246_L16) Light chain Chothia CDRs:
CDR 1: TGGSSDIGASNSVS (SEQ ID NO: 1147), CDR 2: DVTERPS (SEQ ID NO: 804) CDR 3: CAYGGKYLVV (SEQ ID NO: 805) [941] TCN-556 (5089_K12) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAACCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCATCGGCTATGATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAACGCTAAAAGAGGTGGCACAAACTATGCACAAAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCT
ATCAGCACAGCCTACATGGAGCTGAACAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGGGGTG
GGGTCACGAACTACGATTTTTGGAGTTCTCAACCCGGAATTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTC
TCGAGC (SEQ ID NO: 1148) [942] TCN-556 (5089_K12) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVKKPGASVKVSCKASGYTFIGYDMHWVRQAPGQGLEWMGVVINAKRGGTNYAQKF
QGRVTMTRDTSISTAYMELNSLRSDDTAVYYCARGVGSRTTIFGVLNPEFDYWGQGTLVTVSS (SEQ
ID NO: 1149) [943] TCN-556 (5089_K12) gamma heavy chain Kabat CDRs:
CDR 1: GYDMH (SEQ ID NO: 1150) CDR 2: WINAKRGGTNYAQKFQG (SEQ ID NO: 1151) CDR 3: GVGSRTTIFGVLNPEFDY (SEQ ID NO: 1152) [944] TCN-556 (5089_K12) gamma heavy chain Chothia CDRs:
CDR 1: GYTFIG (SEQ ID NO: 1153) CDR 2: WINAKRGGTN (SEQ ID NO: 1154) .=
CDR 3: GVGSRTTIFGVLNPEFDY (SEQ ID NO: 1152) [945] TCN-556 (5089_K12) light chain variable region nucleotide sequence:
CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGATCC
AGCAGTGACGTTGGTGGTTATGACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCCTGATT
TATGAGGTCACTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCGGGCAACTACAATCATGTC
TTCGGACCTGGGACCAAGGTCACCGTTCTA (SEQ ID NO: 1155) [946] TCN-556 (5089_K12) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QSALTQPPSASGSPGQSVTISCTGSSSDVGGYDYVSWIYQQHPGKAPKLLIVEVTKRPSGVPDRFSGSKS
GNTASLTVSGLQAEDEADYYCSSYAGNYNHVFGPGTKVTVL (SEQ ID NO: 1156) [947] TCN-556 (5089_K12) Light chain Kabat CDRs:
CDR 1: TGSSSDVGGYDYVS (SEQ ID NO: 1157) CDR 2: EVTKRPS (SEQ ID NO: 1158) CDR 3: SSYAGNYNHV (SEQ ID NO: 1159) [948] TCN-556 (5089_K12) Light chain Chothia CDRs:
CDR 1: TGSSSDVGGYDYVS (SEQ ID NO: 1157) CDR 2: EVTKRPS (SEQ ID NO: 1158) CDR 3: SSYAGNYNHV (SEQ ID NO: 1159) [949] TCN-557 (5081_A04) heavy chain variable region nucleotide sequence:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGACACACCTTCACCGGCTACTACATACACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAACCCTGACAGTGGTGCCACCAGTTCTGCACAGAACTTTCAGGGCAGGGTCACCATGACCGGGGACACGTCC
TCTAGCACAGCCTACATGGAGCTGAGTAGGCTGAGTTTTGACGACACGGCCGTCTATTACTGTGCGAGAGTACTG
TTTACCAGTCCTTTTGACTTCTGGGGTGAGGGAACCCTGGTCACCGTCTCGAGC (SEQ ID NO: 1160) [950] TCN-557 (5081_A04) gamma heavy chainariable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGAEVKKPGASVKVSCKASGHTFTGYVIHNVVRQAPGQGLEWMGWINPDSGATSSAQNFQ
GRVTMTGDTSSSTAYMELSRLSFDDTAVYYCARVLFTSPFDFWGEGTLVTVSS (SEQ ID NO: 1161) [951] TCN-557 (5081_A04) gamma heavy chain Kabat CDRs:
CDR 1: GYYIH (SEQ ID NO: 1162) CDR 2: WINPDSGATSSAQNFQG (SEQ ID NO: 1163) CDR 3: VLFTSPFDF (SEQ ID NO: 1164) [952] TCN-557 (5081_A04) gamma heavy chain Chothia CDRs:
CDR 1: GHTFTG (SEQ ID NO: 1165) CDR 2: WINPDSGATS (SEQ ID NO: 1166) CDR 3: VLFTSPFDF (SEQ ID NO: 1164) [953] TCN-557 (5081_A04) light chain variable region nucleotide sequence:
CAGGCTGTGGTGACTCAGGAGCCCTCACTGGCTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGGCTCCAGC
ACTGGAGCTGTCACCAGGGGTCATTATCCCTATTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGGGCACTCATT
TATGATAGTGCAGGCAACAGACACTCCTGGACTCCCGCCCGATTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCC
167 , 1%

CTGACCCTTTCGGGTGCGCAGCCTGAGGATGAGGCTGAGTATTACTGCTTGCTCTCCTATAGTGGTGTCTGGGTG
TTCGGCGGAGGGACGAAGCTGACCGTTCTA (SEQ ID NO: 1167) [954] TCN-557 (5081_A04) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QAVVTQEPSLAVSPGGTVTLTCGSSTGAVTRGHYPYWFQQKPGQAPRALIYDSAGNRHSWTPARFSG
SLLGOKAALTLSGAQPEDEAEYYCLLSYSGVVVVFGGOTKLTVL (SEQ ID NO: 1168) [955] =TCN-557 (5081_A04) Light chain Kabat CDRs:
CDR 1: GSSTGAVTRGHYPY (SEQ ID NO: 1169) CDR 2: DSAGNRHS (SEQ ID NO: 1170) CDR 3: LLSYSGVVVV (SEQ ID NO: 1171) [956] TCN-557 (5081_A04) Light chain Chothia CDRs:
CDR 1: GSSTGAVTRGHYPY (SEQ ID NO: 1169) CDR 2: DSAGNRHS (SEQ ID NO: 1170) CDR 3: LLSYSGVVVV (SEQ ID NO: 1171) [957] TCN-558 (5248_Hl0b) heavy chain variable region nucleotide sequence:
CAGGTCCAGCTGGTGCAATCTGGGAGTGAGGTGAAGAAGCCTGGGACCTCGGTGAAGGTCTCCTGCACGGCCTCT
GGAAGTGTCTTCACCAATTATGGAATTAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCCCTCTCTTTGGCGCAGCCAAGTACGCACAGAAATTCCAGGGCAGAGTCACCATCACAGCGGACGAATCC
ACGAAGACAGTCTACATGGAGCTGAGCAGGCTGACATCTAAAGACACGGCCATATATTTCTGTGCGAAGGCCCCC
CGTGTCTACGAGTACTACTItGATCAGTGGGGCCAGGGAACCCCAGTCACCGTCTCCTCA (SEQ ID NO:
1172) [958] TCN-558 (5248_Hl0b) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) QVQLVQSGSEVKKPGTSVKVSCTASGSVFINYGISWVRQAPGQGLEWMGGIIPLFGAAKYAQKFQG
RVTITADESTKTVYMELSRLTSKDTAIYFCAKAPRVYEYYFDOWGQGTPVTVSS (SEQ ID NO: 914) [959] TCN-558 (5248_H10b) gamma heavy chain Kabat CDRs:
CDR 1: NYGIS (SEQ ID NO: 915) CDR 2: GIIPLFGAAKYAQKFQG (SEQ ID NO: 916) CDR 3: APRVYEYYFDQ (SEQ ID NO: 917) =
[960] TCN-558 (5248_Hl0b) gamma heavy chainghothia CDRs:
= CDR 1: GSVFTN (SEQ ID NO: 918) CDR 2: GIIPLFGAAK (SEQ ID NO: 919) CDR 3: APRVYEYYFDQ (SEQ ID NO: 917) [961] TCN-558 (5248_H10b) light chain variable region nucleotide sequence:
GAAATAGTGATGACGCAGTTTCCAGCCACCCTGTCTGTGTCTCCCGGGGAACGAGTCACCCTCTCCTGTAGGGCC
AGTCAGAGTGTTAGCAACAATTTAGCCTGGTACCAGCAAAAACCTGGCCAGCCTCCCAGGCTCCTCATCTATGAT
GCATCTACCAGGGCCACGGGTGTCCCAGCCAAGTTCAGTGGCACTGGGTCTGGCACAGAGTTCACTCTCAGCATC
AGCAGCCTGCAGTCCGAAGATTTTGCAGTTTATTACTGTCAGCAGTATCACAACTGGCCTCCCTCGTACAGTTTT
GGCCTGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 1173) =
[962] TCN-558 (5248_H I Ob) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) EIVMTQFPATLSVSPGERVTLSCRASQSVSNNLAWYQQKPGQPPRLLIYDASTRATGVPAKFSGTGSGT
EFTLSISSLQSEDFAVYYCOOYHNWPPSYSFGLGTKLEIK (SEQ ID NO: 862) [963] TCN-558 (5248_Hl0b) Light chain Kabat CDRs:
CDR 1: RASQSVSNNLA (SEQ ID NO: 863) CDR 2: DASTRAT (SEQ ID NO: 864) CDR 3: QQYHNVVPPSYS (SEQ ID NO: 865) [964] TCN-558 (5248_Hl0b) Light chain Chothia CDRs:
CDR 1: RASQSVSNNLA (SEQ ID NO: 863) CDR 2: DASTRAT (SEQ ID NO: 864) CDR 3: QQYHNWPPSYS (SEQ ID NO: 865) [965] TCN-559 (5097_G08) heavy chain variable region nucleotide sequence:
CAAGAGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
AGAAAGTCCTTCATTGGCTACTATGTACACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAGCCCTGACAGTGATGCCACAAAGTACGCACAGAAGTTTCAGGGCTCCGTCATCATGACCAGGGACACGTCC
GTCAGCACAGTGTACATGGAGCTGAGTAGGCTGACATCTGAC-GACACGGCCCTTTATTACTGTCTCCTTTTTCGA
GGTGGAAACTCCCTCTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC (SEQ ID NO: 1174) [966] TCN-559 (5097_G08) gamma heavy chain variable region amino acid sequence:
= (Kabat CDRs in bold, Chothia CDRs underlined) QEQLVQSGAEVKKPGASVKVSCKASRKSFIGYYVHWVRQAPGQGLEWIVIGWISPDSDATKYAQKFQ
GSVIMTRDTSVSTVYMELSRLTSDDTALYYCLLFRGGNSLSWGQGTLVTVSS (SEQ ID NO: 1175) [967] TCN-559 (5097_G08) gamma heavy chain Kabat CDRs:
CDR 1: GYYVH (SEQ ID NO: 1176) CDR 2: WISPDSDATKYAQKFQG (SEQ ID NO: 1177) CDR 3: FRGGNSLS (SEQ ID NO: 1178) [968] TCN-559 (5097_G08) gamma heavy chain Chothia CDRs:
CDR 1: RKSFIG (SEQ ID NO: 1179) CDR 2: WISPDSDATK (SEQ ID NO: 1180) CDR 3: FRGGNSLS (SEQ ID NO: 1178) [969] TCN-559 (5097_G08) light chain variable region nucleotide sequence:
CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACCCTCACCTGTGGCTCCAGC
ACTGGACCTGTCACCAGTGGTCATTATCCCTACTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGGACATTGATT
TCTGCTACATCCAACACACACTCCTGGACACCTGCCCGCTTCTCAGGCTCCCTCCTTGGGGGCAGAGCTGCCCTG
ACCCTTTCGGGTGCGCAGCCTGAGGATGAGGCTGACTATTATTGCTTTCTCTCCTACAGTGGTGCTTGGGTGTTC
GGCGGAGGGACCACGCTGACaGTTCTA (SEQ ID NO: 1181) [970] TCN-559 (5097_G08) light chain variable region amino acid sequence (Kabat CDRs in bold, Chothia CDRs underlined) QAVVTQEPSLTVSPGGTVTLTCGSSTGPVTSGHYPYWFQQKPGQAPRTLISATSNTHSWTPARFSGSL
LGGRAALTLSGAQPEDEADYYCFLSYSGAWVFGGGTTLTVL (SEQ ID NO: 1182) [971] TCN-559 (5097_G08) Light chain Kabat CDRs:
CDR 1: GSSTGPVTSGHYPY (SEQ ID NO: 1183) CDR 2: ATSNTHS (SEQ ID NO: 1184) CDR 3: FLSYSGAWV (SEQ ID NO: 1185) [972] TCN-559 (5097_G08) Light chain Chothia CDRs:
CDR 1: GSSTGPVTSGHYPY (SEQ ID NO: 1183) CDR 2: ATSNTHS (SEQ ID NO: 1184) CDR 3: FLSYSGAWV (SEQ ID NO: 1185) [973] TCN-560 (5084_P10) heavy chain variable region nucleotide sequence:
GAGGTGCAGCTGGTGGAATCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGATTTATCTTTAGAAATTACTGGATGAGCTGGGTCCGGCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAAC
ATAAAACAAGATGGAAGAGAGAAGTACTATGTGGACTCTCTGAGGGGCCGAGTCAACATCTCCAGAGACAACGCC
GAGAACTCATTGTATCTGCACATGAACAGCCTGAGAGTCGAGGACACGGCTGTTTATTTCTGTGCGAGAGCTCGG
ATGGTGGTGGTTACTGGCGATGGTTTTGATGTCTGGGGCCATGGGACAATGGTCACCGTCTCGAGC (SEQ ID
NO: 1186) [974] TCN-560 (5084_P10) gamma heavy chain variable region amino acid sequence:
(Kabat CDRs in bold, Chothia CDRs underlined) EVQLVESGGGLVQPGGSLRLSCAASGFIFRNYWMSWVRQAPGKGLEWVANIKODGREKYYVDSLR
GRVNISRDNAENSLYLHMNSLRVEDTAVYFCARARMV'VVTGDGFDVWGFIGTMVTVSS (SEQ ID
NO: 1187) [975] TCN-560 (5084_P10) gamma heavy chain Kabat CDRs:
CDR 1: NYWMS (SEQ ID NO: 1188) CDR 2: NIKQDGREKYYVDSLRG (SEQ ID NO: 1189) =
CDR 3: ARMVVVTGDGFDV (SEQ ID NO: 1190) [976] TCN-560 (5084_P10) gamma heavy chain'Chothia CDRs:
CDR 1: GFIFRN (SEQ ID NO: 1191) CDR 2: NIKQDGREKY (SEQ ID NO: 1192) CDR 3: ARMVVVTGDGFDV (SEQ ID NO: 1190) [977] TCN-560 (5084_P10) light chain variable region nucleotide sequence:
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGAATATTAAGAGGTATTTCAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCT
GCATCCAATTTAGAAAATGGGGTCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATC
AGCAGTCTGCAACCTGAGGATTTTGCGACTTATTACTGTCAGCAGAGTTTCAGTAAATCGTGGACATTCGGCCAA
GGGACCAACGTGGACATCAAA (SEQ ID NO: 1193) [978] TCN-560 (5084_P1 O) light chain variable region amino acid sequence (Kabat CDRs in bold,. Chothia CDRs underlined) DIQMTQSPSSLSASVGDRVTITCRASONIKRYFNAVYQQKPGKAPKLLIYAASNLENGVPSRFSGSGSGT
DFITTISSLQPEDFATYYCOCISFSKSWTFGQGTNVDIK (SEQ ID NO: 1194) [979] TCN-560 (5084_P10) Light chain Kabat CDRs:
CDR 1: RASQNIKRYFN (SEQ ID NO: 1195) CDR 2: AASNLEN (SEQ ID NO: 1196) CDR 3: QQSFSKSWT (SEQ ID NO: 1197) 170 ' [980] TCN-560 (5084_P10) Light chain Chothia CDRs:
CDR 1: RASQNIKRYFN (SEQ ID NO: 1195) CDR 2: AASNLEN (SEQ ID NO: 1196) CDR 3: QQSFSKSWT (SEQ ID NO: 1197) [981] The invention provides an isolated fully human monoclonal anti-HA
antibody or fragment thereof, wherein said antibody includes a variable heavy chain (VH) region comprising CDR1 and CDR2, wherein the VH region is encoded by a human IGHV1 (or specifically, IGHV1-18, IGHV1-2, IGHV1-69, IGHV1-8), IGHV2 (or specifically, 5) , IGHV3 (or specifically, IGHV3-30, IGHV3-33, IGHV3-49, IGHV3-53, 66, IGHV3-7), IGHV4 (or specifically, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-59, IGHV4-6I), or IGHV5 (or specifically, IGHV5-51) VH germline sequence or an allele thereof, or a nucleic acid sequence that is homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 VH
germline gene sequence or an allele thereof. In one aspect, the nucleic acid sequence that is homologous to the IGHVI, IGHV2, IGHV3, IGHV4, or IGHV5 VH germline sequence is at least 75% homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 VH germline sequence or an allele thereof. Exemplary alleles include, but are not limited to, IGHV1-18*01, IGHV1-2*02, IGHV1-2*04, IGHV1-69*01, IGHV1-69*05, IGHV1-69*06, IGHV1-69*12, IGHV1-8*01, IGHV2-5*10, IGHV3-30-3*01, IGHV3-30*03, IGHV3-30*18, IGHV3-33*05, IGHV3-49*04, IGHV3-53*01, IGHV3-66*03, IGHV3-7*01, IGHV4-31*03, IGHV4-31*06, IGHV4-34*01, IGHV4-34*02, IGHV4-34*03, IGHV4-34*12, IGHV4-39*01, IGHV4-59*01, IGHV4-59*03, IGHV4-61*61, IGHV4-61*08, and IGHV5-51*01.
Exemplary sequences for each allele are provided below.' [982] IGHV1-18*01 nucleotide sequence (SEQ ID,NO: 1198) CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCC
ACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGA
[983] IGHV1-2*02 nucleotide sequence (SEQ ID NO: 1199) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCC
ATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGA
[984] IGHV1-2*04 nucleotide sequence (SEQ ID NO: 1200) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
ATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCTGGGTCACCATGACCAGGGACACGTCC
ATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGA

c!

[985] IGHV1-69*01 nucleotide sequence (SEQ ID NO: 1201) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCC
ACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGA
[986] IGHV1-69*05 nucleotide sequence (SEQ ID NO: 1202) CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCACGGACGAATCC
ACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGA
[987] IGHV1-69*06 nucleotide sequence (SEQ ID NO: 1203) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCC
ACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGA
[988] IGHV1-69*12 nucleotide sequence (SEQ ID NO:.1204) CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCC
ACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGA
[989] IGHV1-8*01 nucleotide sequence (SEQ ID NO: 1205) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGATACACCTTCACCAGTTATGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGATGG
ATGAACCCTAACAGTGGTAACACAGGCTATGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGAACACCTCC
ATAAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGG
[990] IGHV2-5*10 nucleotide sequence (SEQ ID NO: 1206) CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACAGACCCTCACGCTGACCTGCACCTTCTCT
GGGTTCTCACTCAGCACTAGTGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGGAGTGGCTT
GCACTCATTTATTGGGATGATGATAAGCGCTACAGCCCATCTCTGAAGAGCAGGCTCACCATCACCAAGGACACC
TCCAAAAACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGTGCACGG
[991] IGHV3-30-3*01 nucleotide sequence (SEQ ID NO: 1207) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGATTCACCTTCAGTAGCTATGCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT
ATATCATATGATGGAAGCAATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCC
AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGA
[992] IGHV3-30*03 nucleotide sequence (SEQ ID NO: 1208) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT
ATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGi':GAAGGGCCGATTCACCATCTCCAGAGACAATTCC
AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGA
[993] IGHV3-30*18 nucleotide sequence (SEQ ID NO: 1209) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT
ATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCC
AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAAAGA

[994] IGHV3-33*05 nucleotide sequence (SEQ ID NO: 1210) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCT
GGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT
ATATCATATGATGGAAGTAATAAATACTATGCAGACTtCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCC
AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGA
[995] IGHV3-49*04 nucleotide sequence (SEQ ID NO: 1211) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTCTCCTGTACAGCTTCT
GGATTCACCTTTGGTGATTATGCTATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTC
ATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGAT , GATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTACTAGA
GA
[996] IGHV3-53*01 nucleotide' sequence (SEQ ID NO: 1212) GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGATCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGGTTCACCGTCAGTAGCAACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTT
ATTTATAGCGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAG
AACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGA
[997] IGHV3-66*03 nucleotide sequence (SEQ ID NO: 1213) CAGGTGCAGCTGGTGCAGTCTGGCCATGAGGTGAAGCAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGTTACAGTTTCACCACCTATGGTATGAATTGGGTGCCACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
TTCAACACCTACACTGGGAACCCAACATATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCATGGACACCTCT
GCCAGCACAGCATACCTGCAGATCAGCAGCCTAAAGGCTGAGGACATGGCCATGTATTACTGTGCGAGATA
[998] IGHV3-7*01 nucleotide sequence (SEQ ID NO: 1214) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCT
GGATTCACCTTTAGTAGCTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAAC
ATAAAGCAAGATGGAAGTGAGAAATACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCC
AAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGA
[999] IGHV4-31*03 nucleotide sequence (SEQ ID NO: 1215) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATT
GGGTACATCTATTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACG
TCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGA
[1000] IGHV4-31*06 nucleotide sequence (SEQ ID NO: 1216) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAGCAGTGGTAGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATT
GGGTACATCTATTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACG
TCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTG
[1001] IGHV4-34*01 nucleotide sequence (SEQ ID NO: 1217) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAGCAGTAGTAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATT
GGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACACG
TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGACA
[1002] IGHV4-34*02 nucleotide sequence (SEQ ID NO: 1218) CAGGTGCAGCTACAACAGTGGGGCGCAGGACTGTTGAAGCatTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT
GGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAA
ATCAATCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAG
AACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGG

[1003] IGHV4-34*03 nucleotide sequence (SEQ ID NO: 1219) CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT
GGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAA
ATCAATCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAG
AACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTG
[1004] IGHV4-34*12 nucleotide sequence (SEQ 10.NO: 1220) CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTAT

ATCATTCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAG
AACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGA
[1005] IGHV4-39*01 nucleotide sequence (SEQ ID NO: 1221) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAGCAGTAGTAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATT
GGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACACG
TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGACA
[1006] IGHV4-59*01 nucleotide sequence (SEQ ID NO: 1222) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTAAAGACTGGAGGGGTCTCTGAGACTCTCCTGTGCAGCCTC
TGGATTCACCTTCAGTAGCTCTGCTATGCACTGGGTCCACCACTCCAGGAAAGGGTTTGGAGTGGGTCTCAGT
TATTAGTACAAGTGGTGATACCGTACTCTACACAGACTCTGTGAAGGGCTGATTCACCATCTCTAGAGACAATGC
CCAGAATTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGACGACATGGCTGTGTATTACTGTGTGAAAGA
[1007] IGHV4-59*03 nucleotide sequence (SEQ ID NO: 1223) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCATCAGTAGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTAT
ATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAG
AACCAATTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCG
[1008] IGHV4-61*01 nucleotide sequence (SEQ ID NO: 1224) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCGTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCT
GGTGGCTCCGTCAGCAGTGGTAGTTACTACTGGAGCTGGATC.CGGCAGCCCCCAGGGAAGGGACTGGAGTGGATT
GGGTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACG
TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGA
[1009] IGHV4-61*08 nucleotide sequence (SEQ ID NO: 1225) CAGGTGCAGCTGGTGCAGTCTGGCCATGAGGTGAAGCAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT
GGTTACAGTTTCACCACCTATGGTATGAATTGGGTGCCACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG
TTCAACACCTACACTGGGAACCCAACATATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCATGGACACCTCT
GCCAGCACAGCATACCTGCAGATCAGCAGCCTAAAGGCTGAGGACATGGCCATGTATTACTGTGCGAGATA
[1010] IGHV5-51*01 nucleotide sequence (SEQ ID NO: 1226) GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGG,TTCT
GGATACAGCTTTACCAGCTACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGATC
ATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCC
ATCAGCACCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGACA
[1011] In certain embodiments of the invention, the antibody further includes a variable light chain (VL) region encoded by a human IGKV1 (or specifically, IGKV1-17, IGKV1-27, IGKV1-39, IGKV1D-39, IGKV1-5), IGKV2 (or specifically, IGKV2-30), IGKV3 (or specifically, IGKV3-11, IGKV3-15, IGKV3-20), IGKV4 (or specifically, IGKV4-1, 1), IGLV1 (or specifically, IGLV1-40, IGLV1-44, IpLV1-55), IGLV2 (or specifically, IGLV2-11, IGLV2-14, IGLV2-8), IGLV3 (or specifically, IGLV3-21 or IGLV3-25), (or specifically, IGLV7-43 or IGLV7-46), or IGLV9 (or specifically, IGLV9-49) or an allele thereof. VL germline gene sequenceIGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 or an allele thereof, or a nucleotide acid sequence that is homologous to the IGKV1, IGKV2, IGKV3, IGKV4, IGLV I , IGLV2, IGLV3, IGLV7, or IGLV9 VL gerrriline gene sequence or an allele thereof. Furthermore, the nucleic acid sequence that is homologous to the IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 VL gerrnline sequence or an allele thereof is at least 65%
homologous to the IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or =
IGLV9 VL gerrnline sequence or an allele thereof.
=
[1012] IGKV1-17*01 nucleotide sequence (SEQ ID NO: 1227) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCT
GCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATC
AGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCC
[1013] IGKV1-27*01 nucleotide sequence (SEQ ID NO: 1228) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCG
AGTCAGGGCATTAGCAATTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATGCT
GCATCCACTTTGCAATCAGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATC
AGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAAGTATAACAGTGCCCCTCC
[1014] IGKV1-39*01 nucleotide sequence (SEQ ID NO: 1229) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCT
GCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATC
AGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCC
[1015] IGKV1D-39*01 nucleotide sequence (SEQ ID NO: 1230) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCT
GCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGAGTGGATCTGGGACAGATTTCACTCTCACCATC
AGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCC
[1016] IGKV1-5*03 nucleotide sequence (SEQ ID NO: 1231) GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTdTAGGAGACAGAGTCACCATCACTTGCCGGGCC
AGTCAGAGTATTAGTAGCTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAG
GCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATC
AGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCTCC
[1017] IGKV2-30*02 nucleotide sequence (SEQ ID NO: 1232) GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCT
AGTCAAAGCCTCGTACACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGG
CGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGAT
TTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCT
CC

=
[1018] IGKV3-11*01 nucleotide sequence (SEQ ID NO: 1233) GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGAT
GCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC
AGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCC
[1019] IGKV3-15*01 nucleotide sequence (SEQ ID NO: 1234) GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGT
GCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATC
AGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGICAGCAGTATAATAACTGGCCTCC
= [1020] IGKV3-20*01 nucleotide sequence (SEQ ID NO: 1235) =
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT
GGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACC
ATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACCTCC
[1021] IGKV4-1*01 nucleotide sequence (SEQ ID NO: 1236) GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCC
AGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCT
AAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACA
GATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACT
CCTCC
[1022] IGLV1-40*01 nucleotide sequence (SEQ ID NO: 1237) CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGC
AGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAACTCCTCATC
TATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTG
GCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGCAGCCTGAGTGGTTC
[1023] IGLV1-44*01 nucleotide sequence (SEQ ID NO: 1238) CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGC
AGCTCCAACATCGGAAGTAATACTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTAT
AGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCC
ATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAATGGTCC
[1024] IGLV1-51*02 nucleotide sequence (SEQ ID NO: 1239) CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGC
AGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATCTAT
GAAAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGC
ATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATAGCAGCCTGAGTGCTGG
[1025] IGLV2-11*01 nucleotide sequence (SEQ ID NO: 1240) CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACC
AGCAGTGATGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATT
TATGATGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCATCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCAGCTACACTTTC
[1026] IGLV2-14*01 nucleotide sequence (SEQ ID NO: 1241) CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACC
AGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATT
TATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCAGCAGCACTCTC

[1027] IGLV2-8*01 nucleotide sequence (SEQ ID NO: 1242) CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACC

TATGAGGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAGCAACAATTTC
[1028] IGLV3-21*02 nucleotide sequence (SEQ ID NO: 1243) TCCTATGAGCTGACACAGCTACCCTCGGTGTCAGTGTCCCCAGGACAGACAGCCAGGATCACCTGCTCTGGAGAT
GTACTGGGGGAAAATTATGCTGACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGAGTTGGTGATATACGAAGAT
AGTGAGCGGTACCCTGGAATCCCTGAACGATTCTCTGGGTCCACCTCAGGGAACACGACCACCCTGACCATCAGC
AGGGTCCTGACCGAAGACGAGGCTGACTATTACTGTTTGTCTGGGGATGAGGACAATCC
[1029] IGLV3-25*03 nucleotide sequence (SEQ ID NO: 1244) TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCCAGGACAGACGGCCAGGATCACCTGCTCTGGAGAT
GCATTGCCAAAGCAATATGCTTATTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTGATATATAAAGAC
AGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGT
GGAGTCCAGGCAGAAGACGAGGCTGACTATTACTGTCAATCAGCAGACAGCAGTGGT
[1030] IGLV7-43*01 nucleotide sequence (SEQ ID NO: 1245) CAGACTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGCTTCCAGC
ACTGGAGCAGTCACCAGTGGTTACTATCCAAACTGGTTCCAGCAGAAACCTGGACAAGCACCCAGGGCACTGATT
TATAGTACAAGCAACAAACACTCCTGGACCCCTGCCCGGTTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTG
ACACTGTCAGGTGTGCAGCCTGAGGACGAGGCTGAGTATTACTGCCTGCTCTACTATGGTGGTGCTCAG
[1031] IGLV7-46*01 nucleotide sequence (SEQ ID NO: 1246) CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGGCTCCAGC
ACTGGAGCTGTCACCAGTGGTCATTATCCCTACTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGGACACTGATT
TATGATACAAGCAACAAACACTCCTGGACACCTGCCCGGTTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTG
ACCCTTTCGGGTGCGCAGCCTGAGGATGAGGCTGAGTATTACTGCTTGCTCTCCTATAGTGGTGCTCGG
[1032] IGLV7-46*02 nucleotide sequence (SEQ ID NO: 1247) CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGGGACAGTCACTCTCACCTGTGGCTCCAGC
ACTGGAGCTGTCACCAGTGGTCATTATCCCTACTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGGACACTGATT
TATGATACAAGCAACAAACACTCCTGGACACCTGCCCGGTTCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTG
ACCCTTTTGGGTGCGCAGCCTGAGGATGAGGCTGAGTATTACTGCTTGCTCTCCTATAGTGGTGCTCGG
[1033] IGLV9-49*01 nucleotide sequence (SEQ ID NO: 1248) CAGCCTGTGCTGACTCAGCCACCTTCTGCATCAGCCTCCCTGGGAGCCTCGGTCACACTCACCTGCACCCTGAGC
AGCGGCTACAGTAATTATAAAGTGGACTGGTACCAGCAGAGACCAGGGAAGGGCCCCCGGTTTGTGATGCGAGTG
GGCACTGGTGGGATTGTGGGATCCAAGGGGGATGGCATCCCTGATCGCTTCTCAGTCTTGGGCTCAGGCCTGAAT
CGGTACCTGACCATCAAGAACATCCAGGAAGAGGATGAGAGTGACTACCACTGTGGGGCAGACCATGGCAGTGGG
AGCAACTTCGTGTAACC
[1034] IGLV9-49*03 nucleotide sequence (SEQ ID NO: 1249) CAGCCTGTGCTGACTCAGCCACCTTCTGCATCAGCCTCCCTGGGAGCCTCGGTCACACTCACCTGCACCCTGAGC
AGCGGCTACAGTAATTATAAAGTGGACTGGTACCAGCAGAGACCAGGGAAGGGCCCCCGATTTGTGATGCGAGTG
GGCACTGGTGGGATTGTGGGATCCAAGGGGGATGGCATCCCTGATCGCTTCTCAGTCTTGGGCTCAGGCCTGAAT
CGGTACCTGACCATCAAGAACATCCAGGAAGAGGATGAGAGTGACTACCACTGTGGGGCAGACCATGGCAGTGGG
AGCAACTTCGTGTAACC
[1035] The heavy chain of an isolated monoclonal anti-hemagglutinin (HA) antibody (i.e., anti-hemagglutinin antibody of the invention) is derived from a germ line V
(variable) gene ,, =

such as, for example, the IGHVI, IGHV2, IGHV3, IGHV4, or IGHV5 germline gene or an allele thereof.
[1036] The HA antibodies of the invention include a variable heavy chain (VH) region encoded by a human IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 germline gene sequence or an allele thereof. A IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 germline gene sequence is shown, e.g., in SEQ ID NOs: 457 to 485. The HA antibodies of the invention include a VH
region that is encoded by a nucleic acid sequence that is at least 75%
homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 germline gene sequence or an allele thereof.
Preferably, the nucleic acid sequence is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%
homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 germline gene sequence or an allele thereof, and more preferably, at least 98%, 99% homologous to the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 germline gene sequence or an allele thereof. The VH
region of the HA antibody is at least 75% homologous to the amino acid sequence of the VH region encoded by the IGHV1, IGHV2, IGHV3, IGHV4, or IGHV5 VH germline gene sequence or an allele thereof. Preferably, the amino acid sequence of VH region of the HA
antibody is at least 75%, 80%, 85%, 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the 75%, 80%, 85%, 90%, 95%, 96%, 97% germline gene sequence or an allele thereof, and more preferably, at least 98%, 99% homologous to the sequence encoded by the 75%, 80%, 85%, 90%, 95%, 96%, 97% germline gene sequence or an allele thereof.
[1037] The HA antibodies of the invention also include a variable light chain (VL) region encoded by a human IGKV1, IGKV2, IGKV3, IG04, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof.' A htim' an IGKV1, IGKV2, IGKV3, IGKV4, IGLV I, IGLV2, IGLV3, IGLV7, or IG09 VL germline gene sequence, or an allele thereof is shown, e.g., at SEQ ID NOs: 486 to 508. Alternatively, the HA
antibodies include a IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 VL region that is encoded by a nucleic acid sequence that is at least 65% homologous to the IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof. Preferably, the nucleic acid sequence is at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% homologous to the IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof, and more preferably, at least 98%, 99% homologous to the IGKV1, IGKV2, IGKV3, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof. The VL region of the HA antibody is at least 65% homologous to the amino acid sequence of the . , =

VL region encoded the IGKV1, IGKV2, IGKV3, IGKV4, IGLV I, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof. Preferably, the amino acid sequence of VL region of the HA antibody is at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof, and more preferably, at least 98%, 99% homologous to the sequence encoded by the IGKV1, IGKV2, IGKV3, IGKV4, IGLV1, IGLV2, IGLV3, IGLV7, or IGLV9 germline gene sequence or an allele thereof.
HA Antibodies III ;.
[1038] The present invention relates to an immunogen capable of inducing antibodies against a target peptide of the stem region of hemagglutinn protein of an influenza virus. The immunogen is a peptide or a synthetic peptide. In particular, the immunogen of this invention comprises one or more epitopes or epitope units. Optionally, the immunogen further comprises a general immune stimulator. These immunogens of the present invention are capable of inducing antibodies against influenza A virus to prevent infection by the virus.
[1039] In one aspect the invention provides an immunogen having an epitope or epitope unit recognized by a protective monoclonal antibody having the specificity for the stem region of hemagglutinn protein of an influenza virus.
[1040] The antibody binds both the HAI and HA2 peptide. In some embodiments the epitope is recognized by monoclonal antibody D7, D8, F10, G17, H40, A66, D80, E88, E90, or H98 or a monoclonal antibody that competes with the binding of monoclonal antibody D7, D8, F10, G17, 1-140, A66, D80, E88, E90, or H98 to the HA protein. Preferably, the epitope is the FIO epitope.
[1041] In some embodiments the hemagglutinin protein is in the neutral pH
conformation.
[1042] The immunogen is a peptide or a synthetic=peptide.
[1043] In some aspects the immunogen is a conjugate having one or more peptides or peptide fragments that are spatially positioned relative to each other so that they together form a non-linear sequence which mimics the tertiary structure of an F10 epitope.
Optionally, the one or more peptides or peptide fragments are linked to a backbone. The conjugate competes with the binding of monoclonal antibody F10 to the HA protein.

s;
[1044] The e conformation of the epitope is defined by amino acid residues 18, 38, 39, 40 and 291 of HAI and 18, 19, 20, 21, 38, 41, 42, 45, 49, 52, 53, and 56 of HA2 when the hemagglutinin in the neutral pH conformation.
[1045] In some embodiments the immunogen is a peptide having one or more of the following amino acid sequences.
[1046] [Xaadm-Xaar-Xaa2- [Xaadp, wherein, preferably, Xaai is S, T, F H or Y
and Xaa 2 is H, Y, M, L or Q. Most preferably, Xaai is Y. Most preferably, Xaa2 is H.
[1047] EXaadm-Xaai-Xaa2- [Xaadp, wherein, preferably, Xaai is H, Q, Y, S, D, N
or T and Xaa2 of is Q, E, K, I , V, M, E, R or T. Most preferably, Xaal is H. Most preferably, Xaa2 is Q.
[1048] [Xaadm-Xaai-Xaa2-Xaa3-Xaa4- [Xaadp, wherein, preferably, Xaai is I, V, M, or L;
Xaa2 is D, N, H, Y, D, A,S or E, Xaa3 is G or A, and Xaa4 is W, R, or G. Most preferably, Xaai is V; Xaa2 is D, Xaa3 is G, and Xaa4 is W.
[1049] [Xaa0],õ-Xaai-[Xaaoll Xaa2-Xaa3-[Xaaolq Xaa4-[Xapol, Xaa5-[Xaa0L-Xaa6 Xaa7 -[XaaoL -Xaa8 -[Xaaolp, and [Xaaolm-Xaaj-[Xaaolq Xaa2-Xaa3-[Xaaolq Xaa4-[Xaa01,-Xaa5-, [Xaaolq-Xaa6 Xaa7 -[Xaads -[Xaaslt -[Xaao]p, wherein, preferably Xaal is K, Q, R, N, L, G, F, H or Y; Xaa2 is S or T, Xaa3 is Q or P; Xaa4 is F, V, I, M, L, or T; Xaa5 is I, T, S, N, Q, D, or A; Xaa6 is I, V, M, or L; Xaa7 is N, S, T, or D and Xaa8 is I, F,V, A, or T.
Most preferably, Xaai is K; Xaa2 is T, Xaa3 is Q; Xaa4 is I ; Xaa5 is T ; Xaa6 is V; Xaa7 is N, and Xaa8 is I.
[1050] For all of the preceding sequences, m, and p are independently 0 or 1-100, preferably about 1-90, 1-80, 1-70, 1-60, 1-50, 1-40, 1-30, 1-20 or 1-10; q is 2, r is 3, s is 0 or 2, and t is 0 or 1, and Xaao, is independently any amino acid. Preferably s is 2 and t is 1.
[1051] In some aspects of the inventions, one or more amino acids are D- amino acids.
[1052] Optionally, the immunogen further comprises an adjuvant or is conjugated to a carrier.
[1053] In various aspects the invention includes a composition containing the immunogen together with one or more pharmaceutically acceptable excipients, diluents, and/or adjuvants.
In some embodiments the composition further comprises an anti-influenza antibody of antigen binding fragment thereof. Preferably, the antibodY is monoclonal antibody D7, D8, F10, G17, H40, A66, D80, E88, E90, or H98 or a monoclonal antibody that competes with the binding of monoclonal antibody D7, D8, F10, G17, H40, A66, D80, E88, E90, or H98 to the HA protein. Also provided by the invention are nucleic acids encoding the immunogens of the invention and composition comprising the nucleic acids.

[1054] The invention further comprises a method preventing a disease or disorder caused by an influenza virus by administering to person at risk of suffering from said disease or disorder an immunogen composition described herein. Optionally, the method includes further administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor. The anti-viral drug is a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 ion channel. The M2 ion channel inhibitor is amantadine or, rimantadine. The neuraminidase inhibitor zanamivir, or oseltamivir phosphate.
[1055] In another aspect the method includes further administering one or more antibodies specific to a Group I influenza virus and or a Group II influenza virus. The antibody is administered at a dose sufficient to neutralize the influenza virus.
[1056] Administration is prior to or after exposure to influenza virus.
[1057] Also disclosed are methods of treating subjects and methods of screening and producing antibodies. For example, disclosed is a method of treating a subject suffering or at risk of influenza infection, the method comprising administering to the subject one or more of the disclosed antibodies, such as the disclosed HA stem antibodies. For example, disclosed is a method of treating a subject, the method comprising administering to the subject the stem region of influenza hemagglutinin in the neutral pH conformation in isolation from other components of influenza virus, wherein the subject produtes an immune response to the stem region. For example, disclosed is a method of treatink a subject, the method comprising administering to the subject the stem region of influenza hemagglutinin in the neutral pH
conformation in isolation from the head region of hemagglutinin, wherein the subject produces an immune response to the stem region. For example, disclosed is a method of treating a subject, the method comprising administering to the subject influenza hemagglutinin in the neutral pH conformation in isolation from other components of influenza virus, wherein the head region of the hemagglutinin is modified to reduce the antigenicity of the head region, wherein the subject produces an immune response to the stem region. For example, disclosed is a method, the method comprising screening antibodies reactive to hemagglutinin for binding to hemagglutinin immobilized on a surface, thereby identifying antibodies of interest. For example, disclosed is a method comprising screening antibodies reactive to hemagglutinin for binding to the stem region of influenza hemagglutinin in the neutral pH conformation in isolation from the head region of hemagglutinin, thereby identifying antibodies of interest. For example, disclosed is a method , =
comprising screening antibodies reactive to hemagglutinin for binding to influenza hemagglutinin in the neutral pH conformation in isolation from other components of influenza virus, wherein the head region of the hemagglutinin is modified to reduce the antigenicity of the head region, thereby identifying antibodies of interest.
[1058] In some forms, the head region of the hemagglutinin can be modified by removing or replacing glycosylation sites. In some forms, the head region of the hemagglutinin can be modified by adding glycosylation sites. In some forms, the head region of the hemagglutinin can be modified by removing all or a portion of the head region.
[1059] In some forms, the disclosed antibodies, disclosed hemagglutinins, and disclosed methods can produce an immune reaction in a subject. For example, in some forms, the subject can produce an immune response that prevents or reduces the severity of an influenza infection. In some forms, the immune response can be reactive to influenza viruses within a subtype. In some forms, the immune response can be reactive to influenza viruses in each subtype within a cluster. In some forms, the immune response can be reactive to influenza viruses in each cluster within a group. In some forms, the immune response can be reactive to all influenza viruses in each subtype within a group. In some forms, the immune response can be reactive to influenza viruses within group 1.
[1060] In some forms, the disclosed methods can further comprise screening the antibodies of interest for competing with antibody F10 for binding to hemagglutinin, thereby identifying F10-competing antibodies. In some forms, the hemagglutinin can be hemagglutinin from a group 2 influenza virus. In some forms, the hemagglutinin can be hemagglutinin from a group 1 influenza virus. In some forms, the disclosed methods can further comprising . producing the identified antibodies. Also disclosed are antibodies produced by the disclosed t methods. Also disclosed are antibodies identified by the disclosed methods.
[1061] The disclosed compositions and methods are based upon the discovery of monoclonal antibodies which neutralize the influenza virus, e.g. influenza A virus. The influenza A virus is a Group I influenza A virus such as a H1 cluster influenza virus. The HI
cluster influenza virus is an Hla cluster or an H lb cluster. The monoclonal antibody is fully human. In some forms, the monoclonal antibody can be a bivalent antibody, a monovalent antibody, a single chain antibody or fragment thereof. Specifically, such monoclonal can bind to an epitope on the stem region of the hemagglutinin protein (HA), such as HAI or HA2 polypeptide. The epitope can be non-linear.
[1062] The epitope can comprise both the HAI and HA2. The epitope can be non-linear. In .L1 .4.
=

=
some forms the epitope can comprise the amino acid position 18, 38, 40, 291 of the Hal polypeptide and the amino acid at position 18, 19, 20, 21, 38, 41, 42, 45, 49, 52, 53 and 56 of the HA2 polypeptide.
[1063] The disclosed compositions and methods are further based upon the discovery of a protocol for generating broadly neutralizing human antibodies that target a highly conserved epitope in the stem region of HA. Using the trimeric H5 ectodomain expressed in baculovirus which produces shorter N-glycans and uncharged mannoses absorbed on a plastic surface, allowed for the dominant presentation of the stem epitope while masking the normally immunodominat globular head. Accordingly, also disclosed is a method of producing an isolated antibody that specifically binds a pathogenic enveloped virus by exposing a single chain or Fab expression library to a membrane fusion protein of the virus, identifying an antibody in the library that specifically binds said protein'and isolating the antibody from the library. The fusion protein can be immobilized on a solid surface, e.g.
plastic. In some forms the fusion protein can have modified glycosylations compared to a wild type fusion protein.
For example, the fusion can be produced in a non-mammalian cell, such as an insect cell. The fusion protein can be, for example, a trimeric hemagglutinin (HA) protein.
[1064] Also disclosed is a method of vaccinating a subject against pathogenic enveloped virus such as an influenza virus by administering to the subject, for example, a membrane fusion protein (e.g., a trimeric hemagglutinin (HA) protein coated) or embedded in a biologically compatible matrix. In some forms the fusion protein can have modified glycosylations compared to a wild type fusion protein.
[1065] Also disclosed is a composition comprising a monoclonal antibody as described herein and kits containing the composition in one or more containers and instructions for use.
The invention further provides a method of screening a compound for binding to an FIO
antibody by contacting said F10 antibody with à compound of interest and detecting a compound-antibody complex. Also included in the invention are the compound identified by the method and their use as immunogens.
[1066] High affinity, cross-subtype, broadly-neutralizing human anti-HA mAbs have been identified. Sepcifically, a human Ab phage display library and H5 hemagglutinin (HA) ectodomain was used to select ten neutralizing mAbs (nAbs) with a remarkably broad range among Group 1 influenza viruses, including the H5N1 "bird flu" and the H1N1 "Spanish flu"
and "Swine flu" strains. These nAbs inhibit the post-attachment fusion process by recognizing a novel and highly conserved neutralizing epitope within the stem region at a 183 =
=

=
point where key elements of the conformational change - the fusion peptide and the exposed surface of helix aA - are brought into close apposition. The crystal structure of one mAb (mAbF10) bound to H5N1 HA reveals that oniy the heavy chain inserts into a highly conserved pocket in the HA stem region, inhibiting the conformational changes required for membrane fusion. It has been discovered that nAbs targeting this pocket can provide broad protection against both seasonal and pandemic influenza A infections. The crystal structure further revealed that the epitope to which the F10 mAb is defined by amino acid residues 18, 38, 39, 40 and 291 of HAI and 18, 19, 20, 21, 38, 41, 42, 45, 49, 52, 53, and 56 of HA2.
This epitope is referred to herein as the Fl 0 epitope. Structural and sequence analysis of all 16 HA subtypes points to the existence of only two variants of this epitope, corresponding to the two phylogenetic groupings of HA (Groups 1 and 2). This discovery indicates that a small cocktail of nAbs derived from a subset of each group can provide broad protection against both seasonal and pandemic influenza.
[1067] Remarkably, nAbs were isolated that utilize the same VH germline gene, IGHV1-69*01, and encode a CDR3 loop containing a tyrosine at an equivalent position to Y102, from a non-immune library. This indicates that broad anti-HA cross-immunity pre-exists in the H5-naive population, possibly due to previous exposure to H1, and, for library donors born before 1968, H2 subtypes. The recurrent use of this germline VH
segment, the commonality of the CDR3 tyrosine introduced through N insertion and/or germline D gene assembly, and the promiscuous use of VL genes by the discovered nAbs discovered indicate that the precursor frequency of rearranged VH segments that could recognize this epitope is significant. This indicates that with suitable exposure to the FIO epitope identified here, these broad-spectrum nAbs can be readily induced in vivo. These discoveries led to the disclosed simple solution to provide universal protection against virus subtypes in both groups.
[1068] Three unique anti-HA-1 scFvs were identified by sequencing analysis of the 58 HA-1 positive clones. These scFvs were designated as 38B and IC. The VH and VL
amino acid sequence of 2A is shown herein. Ten unique anti-HAO scFvs were identified by sequencing analysis of the 97 HAO positive clones. These scFvs were designated as 7, 8, 10, 17, 40, 66, 80, 88, 90, and 98. Six different VH and 10 different VL genes were revealed.
Some scFvs shared the same VH gene. Five out of the six different VH genes belonged to the IGHVI-69 gene family. Three out of ten VL genes were kappa chain:2A scFv is a moderate neutralizing antibody, 38B and 1C are non-neutralizing antibodies. Ten scFvs, 7, 8, 10, 17, 40, 66, 80, 88, 90, and 98 are potent neutralizing antibodies. The nucleic acid and amino acid sequence of the neutralizing influenza antibodies are provided below. Methods of making these antibodies are disclosed in PCT/US2009/054950 (Publication No. WO 2010/027818), the entire contents of which are incorporated herein by reference.
[1069] Antibody 2A: Variable Region nucleic acid sequences [1070] VH chain of 2A (SEQ ID NO: 1305) =
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCACCTTCAGTGACAATGCTATCAGCTGGGTGCGACAGGCCCCAGGACAAGGGCTTGAGTGGATGGGGGGC
ATCATTCCTATCTTTGGAAAACCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACTGCGGACGAATCC
ACGAGCACAGCCTACATGGACCTGAGGAGCCTGAGATCTGAGGACACGGCCGTTTATTACTGTGCGAGAGATTCA
GACGCGTATTACTATGGTTCGGGGGGTATGGACGTCTGGGGCCAAGGCACCCTGGTCACCGTCTCCTCA
[1071] VL chain of 2A (SEQ ID NO: 1306) CTGCCTGTGCTGACTCAATCATCCTCTGCCTCTGCTTCCCTGGGATCCTCGGTCAAGCTCACCTGCACTCTGAGC
AGTGGGCATAGTAACTACATCATCGCATGGCATCAACAGCAGCCAGGGAAGGCCCCTCGGTACTTGATGAAGGTT
AATAGTGATGGCAGCCACACCAAGGGGGACGGGATCCCTGATCGCTTCTCAGGCTCCAGCTCTGGGGCTGACCGC
TACCTCACCATCTCCAACCTCCAGTCTGAGGATGAGGCTAGTTATTTCTGTGAGACCTGGGACACTAAGATTCAT
GTCTTCGGAACTGGGACCAAGGTCTCCGTCCTCAG
[1072] Antibody 2A: Variable Region amino acid sequences [1073] VH chain of 2A (SEQ ID NO: 1307) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSDNAISWVRQAPGQGLEWMGGIIPIFGKPNYAQ
KFQGRVTITADESTSTAYMDLRSLRSEDTAVYYCARDSDAYYYGSGGMDVWGQGTLVTVS
=
[1074] VL chain of 2A (SEQ ID NO: 1308) . =
LPVLTQSSSASASLGSSVKLTCTLSSGHSNYIIAWHQQQF'GKAPRYLMKVNSDGSHTKGDGE
PDRFSGSSSGADRYLT ISNLQSEDEASYFCETWDTK I HVFGTGTKVSVL
[1075] Antibody D7: Variable Region nucleic acid sequences [1076] VH chain of D7 (SEQ ID NO: 1309) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTCCT
GGAGGTATCTTCAACACCAATGCTTTCAGCTGGGTCCGACAGGCCCCTGGACAAGGTCTTGAGTGGGTGGGAGGG
GTCATCCCTTTGTTTCGAACAGCAAGCTACGCACAGAACGTCCAGGGCAGAGTCACCATTACCGCGGACGAATCC
ACGAACACAGCCTACATGGAGCTTACCAGCCTGAGATCTGCGGACACGGCCGTGTATTACTGTGCGAGAAGTAGT
GGTTACCATTTTAGGAGTCACTTTGACTCCTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCA
[1077] VL chain of D7 (SEQ ID NO: 1310) AATTTTATGCTGACTCAGCCCCACTCTGTGTCGGCGTCTCCGGGGAAGACGGTGACCATCTCCTGCACCGGCAGC
AGTGGCAACATTGCCGCCAACTATGTGCAGTGGTACCAACAACGTCCGGGCAGTGCCCCCACTACTGTGATCTAT
GAGGATGACCGAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGCTCCATCGACAGGTCCTCCAACTCTGCCTCC
CTCACCATCTCAGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCAGACTTATGATACCAACAATCATGCT
GTGTTCGGAGGAGGCACCCACCTGACCGTCCTC

[1078] Antibody H98: Variable Region nucleic acid sequences [1079] VH chain of H98 (SEQ ID NO: 1311) CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTCCT
GGAGGTATCTTCAACACCAATGCTTTCAGCTGGGTCCGACAGGCCCCTGGACAAGGTCTTGAGTGGGTGGGAGGG
GTCATCCCTTTGTTTCGAACAGCAAGCTACGCACAGAACGTCCAGGGCAGAGTCACCATTACCGCGGACGAATCC
ACGAACACAGCCTACATGGAGCTTACCAGCCTGAGATCTGCGGACACGGCCGTGTATTACTGTGCGAGAAGTAGT
GGTTACCATTTTAGGAGTCACTTTGACTCCTGGGGCC.TGGGAACCCTGGTCACCGTCTCCTCA
[1080] VL chain of H98 (SEQ ID NO: 1312) TCCTATGAGCTGACTCAGCCACCCTCAGCGTCTGGGAAACACGGGCAGAGGGTCACCATCTCTTGTTCTGGAGGC
ACCTCCAACATCGGACGTAATCATGTTAACTGGTACCAGCAACTCCCAGGAACGGCCCCCAAACTCCTCATCTAT
AGTAATGAACAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAATCTGGCACCTCCGCCTCCCTGGCC
GTGAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCATcATGGGATGACAACTTGAGTGGTTGGGTG
TTCGGCGGAGGGACCAAGCTGACCGTCCTA
[1081] Antibody D7 and H98: Variable Region chain amino acid sequences [1082] VH chain of D7 and H98 (SEQ ID NO: 1313) QVQLVQSGAEVKKPGSSVKVSCKAPGGIFNTNAFSWVRQAPGQGLEWVGGVIPLFRTASYA
QNVQGRVT I TADESTNTAYMELTSLRSADTAVYYCARSSGYH FRSHFDSWGLGTLVTVSS
[1083] VL chain of D7 (SEQ ID NO: 1314) NFMLTQPHSVSASPGKTVTISCTGSSGNIAANYVQWYQQRPGSAPTTVIYEDDRRPSGVPDRF
SGSIDRS SNS ASLTIS GLKTEDEADYYCQTYDTNNHA V FGGGTHLTVL
[1084] VL chain of H98 (SEQ ID NO: 1315) SYELTQPPSASGKHGQRVTISCSGGTSNIGRNHVNWYQQLPGTAPKWYSNEQRPSGVPDRF
SGSKSGTSASLAVSGLQSEDEADYYCASWDDNLSGWVFGGGTKLTVL
[1085] Antibody D8: Variable Region nucleic acid sequences [1086] VH chain of D8 (SEQ ID NO: 1316) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCT
GGAGGCACCTTCAGCGCTTATGCTTTCACCTGGGTGCGGCAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGC
ATCACCGGAATGTTTGGCACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAACTC
ACGAGCACAGCCTACATGGAGTTGAGCTCCCTGACATCTGAAGACACGGCCCTTTATTATTGTGCGAGAGGATTG
TATTACTATGAGAGTAGTCTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG
[1087] VL chain of D8 (SEQ ID NO: 1317) CAGTCTGTGCTGACTCAGCCACCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACC
AGCAGTGACGTTGGTGGTTATAACTCTGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATT
TATGAGGTCACTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGCCTCCAAGTCTGGCAACACGGCCTCCCTG
ACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTTCTGCTGCTCATATGCAGGCCACAGTGCTTATGTC
TTCGGAACTGGGACCAAGGTCACCGTCCTG
[1088] Antibody D80: Variable Region nucleic acid sequences [1089] VH chain of D80 (SEQ ID NO: 1318) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAGGGCTTCT
GGAGGCACCTTCAGCGCTTATGCTTTCACCTGGGTGCGGCAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGC

=

=
ATCACCGGAATGTTTGGCACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAACTC
ACGAGCACAGCCTACATGGAGTTGAGCTCCCTGACATCTGAAGACACGGCCCTTTATTATTGTGCGAGAGGATTG
TATTACTATGAGAGTAGTCTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG
[1090] VK chain of D80 (SEQ ID NO: 1319) GAAATTGTGCTGACTCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTCTTAGCAGCAAGTACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT
GGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACCCTCACC
ATCAGTAGACTGGAGCCTGAAGATTTTGCAGTGTATTCCTGTCAGCAGTATGATGGCGTACCTCGGACGTTCGGC
CAAGGGACCACGGTGGAAATCAAA
[1091] Antibody D8 and D80: Variable Region chain amino acid sequences [1092] VH chain of D8 and D80 (SEQ ID NO: 1320) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSAYAFTWVRQAPGQGLEWMGGITGMFGTANY

[1093] VL chain of D8 (SEQ ID NO: 1321) QSVLTQPPSASGSPGQSVTISCTGTSSDVGGYNSVSWYQQHPGKAPKLMIYEVTKRPSGVPD
RFSASKSGNTASLTVSGLQAEDEADYFCCSYAGHSAYVFGTGTKVTVL
[1094] VK chain of D80 (SEQ ID NO: 1322) EIVLTQSPGTLSLSPGERATLSCRASQSLSSKYLAWYQQKPGQAPRLLIYGASSRATG
IPDRFSGSGSGTDFILTISRLEPEDFAVYSCQQYDGVPRTFGQGTTVEIK
[1095] Antibody F10: Variable Region nucleic acid sequences [1096] VH chain of F10 (SEQ ID NO: 1323) CAGGTGCAGCTGGTGCAGTCAGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCACGTCCTCT
GAAGTCACCTTCAGTAGTTTTGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGCTGGGAGGG
ATCAGCCCTATGTTTGGAACACCTAATTACGCGCAGAAGTTCCAAGGCAGAGTCACCATTACCGCGGACCAGTCC
ACGAGGACAGCCTACATGGACCTGAGGAGCCTGAGATCTGAGGACACGGCCGTGTATTATTGTGCGAGATCTCCT
TCTTACATTTGTTCTGGTGGAACCTGCGTCTTTGACCATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1097] VL chain of F10 (SEQ ID NO: 1324) CAGCCTGGGCTGACTCAGCCACCCTCGGTGTCCAAGGGCTTGAGACAGACCGCCACACTCACCTGCACTGGGAAC
AGCAACAATGTTGGCAACCAAGGAGCAGCTTGGCTGCAGCAGCACCAGGGCCACCCTCCCAAACTCCTATCCTAC
AGGAATAATGACCGGCCCTCAGGGATCTCAGAGAGATTCTCTGCATCCAGGTCAGGAAACACAGCCTCCCTGACC
ATTACTGGACTCCAGCCTGAGGACGAGGCTGACTATTACTGCTCAACATGGGACAGCAGCCTCAGTGCTGTGGTA
TTCGGCGGAGGGACCAAGCTGACCGTCCTA
[1098] Antibody E90: Variable Region nucleic acid sequences [1099] VH chain of E90 (SEQ ID NO: 1325) ;
CAGGTACAGCTGCAGCAGTCAGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCACGTCCTCT
GAAGTCACCTTCAGTAGTTTTGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGCTGGGAGGG
ATCAGCCCTATGTTTGGAACACCTAATTACGCGCAGAAGTTCCAAGGCAGAGTCACCATTACCGCGGACCAGTCC
ACGAGGACAGCCTACATGGACCTGAGGAGCCTGAGATCTGAGGACACGGCCGTGTATTATTGTGCGAGATCTCCT
TCTTACATTTGTTCTGGTGGAACCTGCGTCTTTGACCATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1100] VL chain of E90 (SEQ ID NO: 1326) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCA
AGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCT

GCATCCAGTTTGCAAAGAGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGACTTCACTCTCACCATT
AGCAGCCTGCAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGATAGTTCACCGTACACTTTTGGCCAG
GGGACCAAGGTAGAGATCAAA
[1101] Antibody F10 and E90 Variable Region amino acid sequences [1102] VH chain of FIO and E90 (SEQ ID NO: 1327) QVQLVQSGAEVKKPGS SVKVSCTSSEVTFSSFAISWVRQAPGQGLEWLGGISPMFGT
PNYAQKFQGRVTITADQSTRTAYMDLRSLRSEDTAVYYCARSPSYICSGGTCVFDHWGQGT
LVTVSS
[1103] VL chain of FIO (SEQ ID NO: 1328) QPGLTQPPSVSKGLRQTATLTCTGNSNNVGNQGAAWLQQHQGHPPKLLSYRNNDRPSGISER
FSASRSGNTASLTITGLQPEDEADYYCSTWDSSLSAVVFGGGTKLTVL
[1104] VL chain of E90 (SEQ ID NO: 1329) SGSGTDFTLTISSLQPEDFAVYYCQQYDSSPYTFGQGTKVEIK
[1105] Antibody G17: Variable Region nucleic acid sequences [1106] VH chain of G17 (SEQ ID NO: 1330) CAGGTGCAGCTGGTGCAATCTGGGGCTGAAGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGACTTCT
GGAGTCACCTTCAGCAGCTATGCTATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG
ATCATCGGTGTCTTTGGTGTACCAAAGTACGCGCAGAACTTCCAGGGCAGAGTCACAATTACCGCGGACAAACCG
ACGAGTACAGTCTACATGGAGCTGAACAGCCTGAGAGCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGCCC
GGGTACTACGTAGGAAAGAATGGTTTTGATGTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
[1107] VL chain of G17 (SEQ ID NO: 1331) TCCTATGAGCTGACTCAGCCACCCTCGGTGTCCAAGGGCTTGAGACAGACCGCCATACTCACCTGCACTGGAGAC
AGCAACAATGTTGGCCACCAAGGTACAGCTTGGCTGCAACAACACCAGGGCCACCCTCCCAAACTCCTATCCTAC
AGGAATGGCAACCGGCCCTCAGGGATCTCAGAGAGATTCTCTGCATCCAGGTCAGGAAATACAGCCTCCCTGACC
ATTATTGGACTCCAGCCTGAGGACGAGGCTGACTACTACTGCTCAGTATGGGACAGCAGCCTCAGTGCCTGGGTG
TTCGGCGGAGGGACCAAGCTGACCGTCCTA
[1108] Antibody G17 Variable Region amino acid sequences =
[1109] VH chain of G17 (SEQ ID NO: 1332) *
QVQLVQSGAEVKKPGASVKVSCKTSGVTFSS YAISWVRQAPGQGLEWMGGIIGVFGVPKYA
QNFQGRVTITADKPTSTVYMELNSLRAEDTAVYYCAREPGYYVGKNGFDVWGQGTMVTVS
[1110] VL chain of GI7 (SEQ ID NO: 1333) SYELTQPPS VSKGLRQTAILTCTGDSNNVGHQGTAWLQQHQGHPPKLLS YRNGNRPSGISER
FSASRSGNTASLTIIGLQPEDEADYYCSVWDSSLSAWVFGGGTKLTVL
[1111] Antibody H40: Variable Region nucleic acid sequences [1112] VH chain of H40 (SEQ ID NO: 1334) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAGGAAGCCTGGGGCCTCAGTGAAGGTCTCATGTAAGGCTTCT
GGATACACCTTCACCGGTTATTATATTCACTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGTTGG
ATCAACCCTATGACTGGTGGCACAAACTATGCACAGAAGTTTCAGGTCTGGGTCACCATGACCCGGGACACGTCC
ATCAACACAGCCTACATGGAGGTGAGCAGGCTGACATCTGACGACACGGCCGTGTATTACTGTGCGAGGGGGGCT
188 , TCCGTATTACGATATTTTGACTGGCAGCCCGAGGCTCTTGATATCTGGGGCCTCGGGACCACGGTCACCGTCTCC
TCA
[1113] VL chain of H40 (SEQ ID NO: 1335) CAGCCTGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGCATTCCCTGTGGGGGGAAC
AACATTGGAGGCTACAGTGTACACTGGTACCAACAAAAGCCGGGCCAGGCCCCCCTCTTGGTCATTTATGACGAT
AAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCGCCAACTCTGGGAGCACGGCCACCCTGACAATCAGC
AGGGTCGAAGCCGGGGATGAGGGCGACTACTACTGTCAGGTGTGGGATAGTGGTAATGATCGTCCGCTGTTCGGC
GGAGGGACCAAGCTGACCGTCCTA
[1114] Antibody H40: Variable Region amino acid sequences =
[1115] VH chain of H40 (SEQ ID NO: 1336) =
QVQLVQSGAEVRKPGASVKVSCKASGYTFTGYYIHWVRQAPGQGLEWMGWINPMTGGTN
YAQKFQVWVTMTRDTSINTAYMEVSRLTSDDTAVYYCARGASVLRYFDWQPEALDIWGLG
TTVTVSS
[1116] VL chain of H40 (SEQ ID NO: 1337) QPVLTQPPSVSVAPGQTASIPCGGNNIGGYSVHWYQQKPGQAPLLVIYDDKDRPSGIPERFSG
ANSGSTATLTISRVEAGDEGDYYCQVWDSGNDRPLFGGGTKLTVL
[1117] Antibody A66 Variable Region nucleic acid sequences [1118] VH chain of A66 (SEQ ID NO: 1338) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGCTCCTCGGTGAAGGTTTCCTGCAAGGCTTCT
GGAGGCCCCTTCAGCATGACTGCTTTCACCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTGGG
ATCAGCCCTATCTTTCGTACACCGAAGTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCC
ACGAACACAGCCAACATGGAGCTGACCAGCCTGAAATCTGAGGACACGGCCGTGTATTACTGTGCGAGAACCCTT
TCCTCCTACCAACCGAATAATGATGCTTTTGCTATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
[1119] VK chain of A66 (SEQ ID NO: 1339) GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC
AGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGAT
GCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATC
AGCAGACTGGAGCCTGAAGATTTTGCAGTCTATTTCTGTCAGCAGTATGGTAGCTCACCTCAATTCGGCCPOGGG
ACACGACTGGAGATTAAA
[1120] Antibody A66 Variable Region amino aci&sequences [1121] VH chain of A66 (SEQ ID NO: 1340) QVQLVQSGAEVKKPGSSVKVSCKASGGPFSMTAFTWLRQAPGQGLEWMGGISPIFRTPKYA
QKFQGRVTITADESTNTANMELTSLKSEDTAVYYCARTLSSYQPNNDAFAIWGQGTMVTVS
[1122] VK chain of A66 (SEQ ID NO: 1341) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSG
SGSGTDFTLT I SRLEPEDFAVYFCQQYGSSPQFGQGTRLEIK
[1123] Antibody E88 Variable Region nucleic acid sequences [1124] VH chain of E88 (SEQ ID NO: 1342) CAGGTGCAGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGCTCCTCGGTGAAGGTTTCCTGCAAGGCTTCT
GGAGGCCCCTTCAGCATGACTGCTTTCACCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTGGG

=
=

ATCAGCCCTATCTTTCGTACACCGAAGTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCC
ACGAACACAGCCAACATGGAGCTGACCAGCCTGAAATCTGAGGACACGGCCGTGTATTACTGTGCGAGAACCCTT
TCCTCCTACCAACCGAATAATGATGCTTTTGCTATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
[1125] VL chain of E88 (SEQ ID NO: 1343) CTGCCIGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGC
AGCTCCAACATCGGAAGTAATACTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTAT
AGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAGGTCAGGCACCTCAGCCTCCCTGGCC
ATCATTGGACTCCGGCCTGAGGATGAAGCTGATTATTACTGTCAGTCGTATGACAGCAGGCTCAGTGCTTCTCTC
TTCGGAACTGGGACCACGGTCACCGTCCTC
[1126] Antibody E88 Variable Region amino acid sequences [1127] VH chain of E88 (SEQ ID NO: 1344) QVQLVQSGAEVKKPGSSVKVSCKASGGPFSMTAFTWLRQAPGQGLEWMGGISPIFRTPKYA
QKFQGRVTITADESTNTANMELTSLKSEDTAVYYCARTLSSYQPNNDAFAIWGQGTMVTVS
[1128] VL chain of E88 (SEQ ID NO: 1345) ' LPVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKWYSNNQRPSGVPDRFS
GSRSGTSASLAIIGLRPEDEADYYCQSYDSRLSASLFGTGTTVTVL
[1129] The amino acid sequences of the heavy and light chain complementary determining regions of the neutralizing influenza antibodies are shown below in Table 18.

=

[1130] Table 18 ID ID ID
NO: = NO: NO:

QN

QG
Fl 0/E90 HEAVY SFAIS 600 QG DH

QV EALDI

AI

AI

MDV

YVA

YVQ

NSVS

QGAA

QGTA

A

LA

VN

HVN

A
Antibodies [1131] Unless otherwise defined, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures utilized in connection with, and techniques of, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well known and commonly used in the art. Standard techniques are used for recombinant DNA, .oligonucleotidc synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein.
The practice of the present invention will employ, Unless indicated specifically to the contrary, conventional methods of virology, immunology, microbiology, molecular biology and recombinant DNA techniques within the skill of the art, many of which are described below for the purpose of illustration. Such techniques are explained fully in the literature.
See, e.g., Sambrook, et al. Molecular Cloning: A Laboratory Manual (2nd Edition, 1989);
Maniatis et al. Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A
Practical Approach, vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984);
Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., 1985); Transcription and Translation (B. Hames & S. Higgins, eds., 1984); Animal Cell Culture (R.
Freshney, ed., 1986); Perbal, A Practical Guide to Molecular Cloning (1984).
[1132] The nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
[1133] The following definitions are useful in understanding the present invention:
[1134] The term "antibody" (Ab) as used herein includes monoclonal antibodies, polyclonal = i antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein.
[1135] An "isolated antibody" is one that has been separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody is purified: (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99%
by weight;
(2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator; or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain.
Isolated antibody includes the antibody in situ within". recombinant cells since at least one =

=

=
component of the antibody's natural environment will not be present.
Ordinarily, however, isolated antibody will be prepared by at least one purification step.
[1136] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM
antibody consists of 5 of the basic heterotetramer unit along with an additional polypeptide called J chain, and therefore contain 10 antigen binding sites, while secreted IgA antibodies can polymerize to form polyvalent assemblages comprising 2-5 of the basic 4-chain units along with J chain. In the case of IgGs, the 4-chain unit is generally about,150,000 daltons. Each L
chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L
chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and y chains and four CH domains for Ix and E isotypes. Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain (CL) at its other end. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CH1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site.
For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, Conn., 1994, page 71, and Chapter 6.
[1137] The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (x) and lambda (X), based on the amino acid sequences of their constant domains (CL). Depending on the amino acid sequence of the constant domain of their heavy õ
chains (CH), immunoglobulins can be assigned to different classes or isotypes.
There are five , = , .
classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated alpha (q), delta (8), epsilon (c), gamma (y) and mu ( ), respectively. The y and q classes are further divided into subclasses on the basis of relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
[1138] The term "variable" refers to the fact that certain segments of the V
domains differ extensively in sequence among antibodies. The V domain mediates antigen binding and =
defines specificity of a particular antibody for its particular antigen.
However, the variability = is not evenly distributed across the 110-amino acid span of the variable domains. Instead, the 1.4 V regions consist of relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability called "hypervariable regions" that are each 9-12 amino acids long. The variable domains of native heavy and light chains each comprise four FRs, largely adopting a 13-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the 13-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity.(ADCC).
[1139] The term "hypervariable region" when used herein refers to the amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region generally comprises amino acid residues from a "complementarity determining region" or "CDR" (e.g., around about residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the VL, and around about 31-35 (H1), 50-65 (H2) and 95-102 (H3) in the VH when numbered in accordance with the Kabat numbering system; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.
Public Health Service, National Institutes of Health, Bethesda, Md. (1991));
and/or those residues from a "hypervariable loop" (e.g., residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the VL, and 26-32 (H1), 52-56 (H2) and 95-101 (H3) in the VH when numbered in accordance with the Chothia numbering system; Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));
and/or those residues from a "hypervariable loop"/CDR (e.g., residues 27-38 (L1), 56-65 (L2) and 105-120 (L3) in the VL, and 27-38 (H1), 56-65 (H2) and 105-120 (H3) in the VH when numbered in accordance with the IMGT numbering system; Lefranc, M.P. et al.
Nucl. Acids Res. 27:209-212 (1999), Ruiz, M. e al. Nucl. Acids Res. 28:219-221 (2000)).
Optionally the . , antibody has symmetrical insertions at one or more'of the following points 28, 36 (L1), 63, , 74-75(L2) and 123 (L3) in the VL, and 28, 36 (H1),.63, 74175 (H2) and 123 (H3) in the VH
when numbered in accordance with AHo; Honneger,'A. and Plunkthun, A. J. Mol.
Biol.
309:657-670 (2001)).
[1140] By "germline nucleic acid residue" is meant the nucleic acid residue that naturally occurs in a germline gene encoding a constant or variable region. "Germline gene" is the DNA found in a germ cell (i.e., a cell destined to become an egg or in the sperm). A

"germline mutation" refers to a heritable change in a particular DNA that has occurred in a germ cell or the zygote at the single-cell stage, and When transmitted to offspring, such a mutation is incorporated in every cell of the body. A'gerMline mutation is in contrast to a somatic mutation which is acquired in a single body cell. In some cases, nucleotides in a germline DNA sequence encoding for a variable region are mutated (i.e., a somatic mutation) and replaced with a different nucleotide.
[1141] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations that include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. The modifier "monoclonal" is not to be construed as .f ==
requiring production of the antibody by any particular method. For example, the monoclonal antibodies useful in the present invention may be irepared by the hybridoma methodology first described by Kohler et al., Nature, 256:495 (1975), or may be made using recombinant DNA methods in bacterial, eukaryotic animal or plant cells (see, e.g., U.S.
Pat. No.
4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example.
[1142] The monoclonal antibodies herein include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl.
Acad. Sci. USA, 81:6851-6855 (1984)). The present invention provides variable domain antigen-binding sequences derived from human antibodies. Accordingly, chimeric antibodies of primary interest herein include antibodies having one or more human antigen binding sequences (e.g., CDRs) and containing one or more sequences derived from a non-human antibody, e.g., an FR or C region sequence. In addition, chimeric antibodies of primary interest herein include those comprising a human variable domain antigen binding sequence of one antibody class or subclass and another sequence, e.g., FR or C region sequence, derived from another antibody class or subclass. Cl-imeric antiboliies of interest herein also include those containing variable domain antigen-binding sequences related to those described herein or derived from a different species, such as a non-human primate (e.g., Old World Monkey, Ape, etc). Chimeric antibodies also include primatized and humanized antibodies.
[1143] Furthermore, chimeric antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. For further details, see Jones et al., Nature 321:522-525 (1986);
Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct.
Biol. 2:593-596 (1992).
[1144] A "humanized antibody" is generally considered to be a human antibody that has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization is traditionally performed following the method of Winter and co-workers (Jones et al.., Nature, 321:522-525 (1986); Reichmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting import hypervariable region sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S.
Pat. No. 4,816,567) wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
[1145] A "human antibody" is an antibody containing only sequences present in an antibody naturally produced by a human. However, as used herein, human antibodies may comprise residues or modifications not found in a naturally occurring human antibody, including those modifications and variant sequences described herein. These are typically made to further refine or enhance antibody performance.
[1146] An "intact" antibody is one that comprises an antigen-binding site as well as a CL and at least heavy chain constant domains, CH 1, CH 2 and CH 3. The constant domains may be if;

native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variant thereof. Preferably, the intact antibody has one or more effector functions.
[1147] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab.),), and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No.
5,641,870; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fcagments.
[1148] The phrase "functional fragment or analog'' of an antibody is a compound having qualitative biological activity in common with a full-length antibody. For example, a functional fragment or analog of an anti-IgE antibody is one that can bind to an IgE
immunoglobulin in such a manner so as to prevent or substantially reduce the ability of such molecule from having the ability to bind to the high affinity receptor, FcERI.
[1149] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH 1).
Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment that roughly corresponds to two disulfide linked Fab fragments having divalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having additional few residues at the carboxy terminus, of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
[1150] The "Fc" fragment comprises the carboxy-terminal portions of both H
chains held together by disulfides. The effector functions of antibodies are determined by sequences in =
the Fc region, which region is also the part recognized by Fc receptors (FcR) found on certain types of cells.

[1151] "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (three loops each from the H and L
chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
[1152] "Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain.
Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the sFv to form the desired Structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994);
Borrebaeck 1995, infra.
[1153] The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the VH
and VL domains such that inter-chain but not intra-chain pairing of the V
domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites.
Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains.
Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc.
Natl. Acad. Sci. USA, 90:6444-6448 (1993).
[1154] As used herein, an antibody that "internalizes" is one that is taken up by (i.e., enters) the cell upon binding to an antigen on a mammalian cell (e.g., a cell surface polypeptide or receptor). The internalizing antibody will of course,include.antibody fragments, human or chimeric antibody, and antibody conjugates. For certairoherapeutic applications, internalization in vivo is contemplated. The number of antibody molecules internalized will be sufficient or adequate to kill a cell or inhibit its growth, especially an infected cell.
Depending on the potency of the antibody or antibody conjugate, in some instances, the uptake of a single antibody molecule into the cell is sufficient to kill the target cell to which the antibody binds. For example, certain toxins are highly potent in killing such that internalization of one molecule of the toxin conjugated to the antibody is sufficient to kill the infected cell.
[1155] As used herein, an antibody is said to be "immunospecific," "specific for" or to "specifically bind" an antigen if it reacts at a detectable level with the antigen, preferably with an affinity constant, Ka, of greater than or equal to about 104 M-1, or greater than or equal to about 105 M-1, greater than or equal to about 106 M-1, greater than or equal to about 107 M-1, or greater than or equal to 108 M. Affinity of an antibody for its cognate antigen is also commonly expressed as a dissociation constant KD, and in certain embodiments, HuM2e antibody specifically binds to M2e if it binds with a KD of less than or equal to 10-4 M, less than or equal to about 10-5 M, less than or equal to about 10-6 M, less than or equal to 10-7 M, or less than or equal to 10-8 M. Affinities of antibodies can be readily determined using conventional techniques, for example, those described by Scatchard et al.
(Ann. N.Y. Acad.
S'ci. USA 51:660 (1949)).
[1156] Binding properties of an antibody to antigens, cells or tissues thereof may generally be determined and assessed using immunodetectiommethods including, for example, immunofluorescence-based assays, such as immuno-histo.chemistry (IHC) and/or fluorescence-activated cell sorting (FACS). 4'1 [1157] An antibody having a "biological characteristic" of a designated antibody is one that possesses one or more of the biological characteristics of that antibody which distinguish it from other antibodies. For example, in certain embodiments, an antibody with a biological characteristic of a designated antibody will bind the same epitope as that bound by the designated antibody and/or have a common effector function as the designated antibody.
[1158] The term "antagonist" antibody is used in the broadest sense, and includes an antibody that partially or fully blocks, inhibits, or neutralizes a biological activity of an epitope, polypeptide, or cell that it specifically binds. Methods for identifying antagonist antibodies may comprise contacting a polypeptide or cell specifically bound by a candidate antagonist antibody with the candidate antagonist antibody and measuring a detectable change in one or more biological activities normally associated with the polypeptide or cell.
[1159] An "antibody that inhibits the growth of infected cells" or a "growth inhibitory"
antibody is one that binds to and results in measurable growth inhibition of infected cells 199 =

expressing or capable of expressing an M2e epitope bound by an antibody.
Preferred growth inhibitory antibodies inhibit growth of infected cells by greater than 20%, preferably from about 20% to about 50%, and even more preferably, by greater than 50% (e.g., from about 50% to about 100%) as compared to the appropriate control, the control typically being infected cells not treated with the antibody being tested. Growth inhibition can be measured at an antibody concentration of about 0.1 to 30 g/m1 or about 0.5 nM to 200 nM in cell culture, where the growth inhibition is determined 1-10 days after exposure of the infected cells to the antibody. Growth inhibition of infected cells in vivo can be determined in various ways known in the art. The antibody is growth inhibitory in vivo if administration of the antibody at about 1 g/kg to about 100 mg/kg body weight results in reduction the percent of infected cells or total number of infected cells within about 5 days to 3 months from the first administration of the antibody, preferably within about 5 to 30 days.
[1160] An antibody that "induces apoptosis" is one which induces programmed cell death as determined by binding of annexin V, fragmentation of DNA, cell shrinkage, dilation of endoplasmic reticulum, cell fragmentation, and/or formation of membrane vesicles (called apoptotic bodies). Preferably the cell is an infected cell. Various methods are available for evaluating the cellular events associated with apoptosis. For example, phosphatidyl serine (PS) translocation can be measured by annexin binding; DNA fragmentation can be evaluated through DNA laddering; and nuclear/chromatin condensation along with DNA
fragmentation can be evaluated by any increase in hypodiploid cells. Preferably, the antibody that induces apoptosis is one that results in about 2 to 50 fold, preferably about 5 to 50 fold, and most preferably about 10 to 50 fold, induction of annexin binding relative to untreated cell in an annexin binding assay.
[1161] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.
[1162] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) present on certain cytotoxic J.
11' cells (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The antibodies "arm" the cytotoxic cells and are required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC
assay, such as that described in U.S. 134t. No. 5,500,362 or U.S. Pat. No. 5,821,337 may be performed.
Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al., PNAS (USA) 95:652-656 (1998). , [1163] "Fe receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody.
In certain embodiments, the FcR is a native sequence human FcR. Moreover, a preferred FcR
is one that binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FCyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the = cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)).
FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991);
Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995).
Other FcRs, including those to be identified in the future, are encompassed by the term "FcR"
herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)). , [1164] "Human effector cells" are leukocytes that express one or more FcRs and perform effector functions. Preferably, the cells express at least FcyRIII and perform ADCC effector function. Examples of human leukocytes that mediate ADCC include PBMC, NK
cells, * WO 2012/112489 , monocytes, cytotoxic T cells and neutrophils; with PBMCs and NK cells being preferred. The effector cells may be isolated from a native source, e.g., from blood.
[1165] "Complement dependent cytotoxicity" or "CDC" refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C lq) to antibodies (of the appropriate subclass) that are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J.
Immunol. Methods 202:163 (1996), may be performed.
[1166] The terms "influenza A" and "Influenzavirus A" refer to a genus of the Orthomyxoviridae family of viruses. Influenzavirus A includes only one species: influenza A
virus which cause influenza in birds, humans, pigs, and horses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon. Some isolates of influenza A virus cause severe disease both in,domestic poultry and, rarely, in humans.
.. =
[1167] A "mammal" for purposes of treating n infection, refers to any mammal, including humans, domestic and farm animals, and zoo, sports,, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human.
[1168] "Treating" or "treatment" or "alleviation" refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully "treated" for an infection if, after receiving a therapeutic amount of an antibody according to the methods of the present invention, the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of infected cells or absence of the infected cells; reduction in the percent of total cells that are infected; and/or relief to some extent, one or more of the symptoms associated with the specific infection; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disme are readily measurable by routine procedures familiar to a physician.

[1169] The term "therapeutically effective amount" refers to an amount of an antibody or a drug effective to "treat" a disease or disorder in a subject or mammal. See preceding definition of "treating."
[1170] "Chronic" administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the.initial therapeutic effect (activity) for an extended period of time. "Intermittent" administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
[1171] Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
[1172] "Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH
buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine;
monosaccharides, disaccharides, and other carbohydrates including glucose,:mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTm polyethylene glycol (PEG), and PLURONICSTM.
[1173] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g., At2I1, 1131, 1125, y90, Re186, Re 188, sm153, Bi212, p32 and radioactive isotopes of Lu), chemotherapeutic agents e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents, enzymes and fragments thereof such as nucleolytic enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof, and the various antitumor or anticancer agents disclosed below. Other cytotoxic agents are described below.
, [1174] A "growth inhibitory agent" when used herein refers to a compound or composition which inhibits growth of a cell, either in vitro or in vivo. Examples of growth inhibitory agents include agents that block cell cycle progression, such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vinca alkaloids (vincristine, vinorelbine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest GI also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouraci1, and ara-C. Further information can be found in The Molecular Basislbf Cancer, Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et al. (W B Saunders: Philadelphia, 1995), especially p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERETm, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL , Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.
[1175] "Label" as used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody. The label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.
[1176] The term "epitope tagged" as used herein refers to a chimeric polypeptide comprising a polypeptide fused to a "tag polypeptide." The tag, polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused. The tag polypeptide is also preferably fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).
[1177] A -small molecule'. is defined herein to have a molecular weight below about 500 Daltons.

WO 2012/112489=

[1178] The terms "nucleic acid" and "polynucleotide" are used interchangeably herein to refer to single- or double-stranded RNA, DNA, or mixed polymers.
Polynucleotides may include genomic sequences, extra-genomic and plasmid sequences, and smaller engineered gene segments that express, or may be adapted to express polypeptides.
[1179] An "isolated nucleic acid" is a nucleic acid that is substantially separated from other gcnomc DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term embraces a nucleic acid sequence that has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by heterologous systems. A substantially pure nucleic acid includes isolated forms of the nucleic acid. Of course, this refers to the nucleic acid as originally isolated and does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man.
=
[1180] The term "polypeptide" is used in its conventional meaning, i.e., as a sequence of amino acids. The polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms may be used interchangeably herein unless specifically indicated otherwise.
This term also does not refer to or exclude post-expression modifications of the polypeptide, for example, = glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art. both naturally occurring and non-naturally occurring. A
polypeptide may be an entire protein, or a subsequence thereof. Particular polypeptides of interest in the context of this invention are amino acid subsequences comprising CDRs and being capable of binding an antigen or Influenza A-infected cell.
[1181] An "isolated polypeptide" is one that has been identified and separated and/or = recovered from a component of its natural environment. In preferred embodiments, the isolated polypeptide will be purified (1) to greater than 95% by weight of polypeptide as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain.
Isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment, will not be present.
Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.
[1182] A "native sequence" polynucleotide is one'that has the same nucleotide sequence as a polynucleotide derived from nature. A "native sequence" polypeptide is one that has the same =
amino acid sequence as a polypeptide (e.g., antibody) derived from nature (e.g., from any species). Such native sequence polynucleotides and polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.
[1183] A polynucleotide "variant," as the term is used herein, is a polynucleotide that typically differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants may be naturally occurring_ or may be synthetically generated, for example, by modifying one or more of the polynucleotide sequences of the invention and evaluating one or more biological activities of the encoded polypeptide as described herein and/or using any of a number of techniques well known in the art.
[1184] A polypeptide "variant," as the term is useditierein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein irone or more substitutions, deletions, additions and/or insertions. Such variants may be naturally occurring or may be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptide as described herein and/or using any of a number of techniques well known in the art.
[1185] Modifications may be made in the structure of the polynucleotides and polypeptides of the present invention and still obtain a functional molecule that encodes a variant or derivative polypeptide with desirable characteristics. When it is desired to alter the amino acid sequence of a polypeptide to create an equivalent, or even an improved, variant or portion of a polypeptide of the invention, one skilled in the art will typically change one or more of the codons of the encoding DNA sequence.
[1186] For example, certain amino acids may be substituted for other amino acids in a protein structure without appreciable loss of its ability to bind other polypeptides (e.g., antigens) or cells. Since it is the binding capacity arid nature of a protein that defines that protein's biological functional activity, certain amino acidsequence substitutions can be made in a protein sequence, and, of course, its underlying DNA oding sequence, and nevertheless =

obtain a protein with like properties. It is thus contemplated that various changes may be made in the peptide sequences of the disclosed compositions, or corresponding DNA
sequences that encode said peptides without appreciable loss of their biological utility or activity.
[1187] In many instances, a polypeptide variant will contain one or more conservative substitutions. A "conservative substitution" is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged.
[1188] In making such changes, the hydropathic index of amino acids may be considered.
The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (Kyte and Doolittle, 1982).
These values are:
isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8);
cysteine/cystine (+2.5);
methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5);
glutamine (-3.5);
aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and,arginine (-4.5).
[1189] It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i.e. still obtain a biological functionally equivalent protein. In making such changes, the substitution of amino acids whose hydropathic indices are within 2 is preferred, those within 1 are particularly preferred, and those within 0.5 are even more particularly preferred. It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U. S. Patent 4,554,101 states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein.
=

=
=
[1190] As detailed in U. S. Patent 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0 1);
glutamate (+3.0 I); serine (+0.3); asparagine (+0.2); glutamine (+0.2);
glycine (0);
threonine (-0.4); proline (-0.5 1); alanine (-0.5); histidine (-0.5);
cysteine (-1.0);
methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3);
phenylalanine (-2.5); tryptophan (-3.4). It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent, and in particular, an immunologically equivalent protein. In such changes, the substitution of amino acids whose hydrophilicity values are within 2 is preferred, those within 1 are particularly preferred, and those within 0.5 are even more particularly preferred. =
[1191] As outlined above, amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine;
glutamine and asparagine; and valine, leucine and isoleucine.
[1192] Amino acid substitutions may further be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gln, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. A variant may also, or alternatively, contain nonconservative changes. In a preferred embodiment, variant polypeptides differ from a native sequence by substitution, deletion or addition of five amino acids or fewer. Variants may also (or alternatively) be modified by, for example, the deletion or addition of amino acids that have minimal influence on the immunogenicity, secondary structure and hydropathic nature of the polypeptide.

=

.ti, =
r.
[1193] Polypeptides may comprise a signal (or leader) sequence at the N-terminal end of the protein, which co-translationally or post-translationally directs transfer of the protein. The polypeptide may also be conjugated to a linker or other sequence for ease of synthesis, purification or identification of the polypeptide (e.g., poly-His), or to enhance binding of the polypeptide to a solid support. For example, a polypeptide may be conjugated to an immunoglobulin Fc region.
[1194] When comparing polynucleotide and polypeptide sequences, two sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A
"comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a j reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
[1195] Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins ¨ Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M. (1989) CABIOS 5:151-153; Myers, E.W. and Muller W.
(1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 11:105; Santou, N.
Nes, M.
(1987) Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy ¨ the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci.
USA 80:726-730.
[1196] Alternatively, optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970)J. Mol. Biol.
48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad.
Sci. USA 85:
=
2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.
[11971 One preferred example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al.
(1990)J. Mol. Biol. 215:403-410, respectively. BLAST and BLAST 2.0 can be used, for example with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides of the invention. Software for performing BLAST analyses =
is publicly available through the National Center for Biotechnology Information.
[1198] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues;
always >0) and N
(penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignmentscore falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands.
[1199] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T
and X determine the sensitivity and speed of the alignment.
[1200] In one approach, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window orComparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, =
dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying tkie=results by 100 to yield the percentage of sequence identity. ' [1201] "Homology" refers to the percentage of reSidues in the polynucleotide or polypeptide sequence variant that are identical to the non-variant Sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology.
In particular embodiments, polynucleotide and polypeptide variants have at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%
polynucleotide or polypeptide homology with a polynucleotide or polypeptide described herein.
=
[1202] "Vector" includes shuttle and expression vectors. Typically, the plasmid construct will also include an origin of replication (e.g., the ColE1 origin of replication) and a selectable marker (e.g., ampicillin or tetracycline resistance), for replication and selection, respectively, of the plasmids in bacteria. An "expression vector" refers to a vector that contains the necessary control sequences or regulatory elements for expression of the antibodies including antibody fragment of the invention, in bacterial or eukaryotic cells.
Suitable vectors are disclosed below.
[1203] As used in this specification and the appended claims, the singular forms "a," "an"
and "the" include plural references unless the content clearly dictates otherwise.
;
[1204] The present invention includes human monoclonal anti-influenza antibodies comprising a polypeptide of the present invention, as well as fragments and variants thereof.
In one embodiment, the antibody is an antibody designated herein as TCN-032 (8110), 21B15, TCN-031 (23K12), 3241_023, 3244_110, 3243_107, 3259_121, 3245_019, 3244_H04, 3136_005, 3252_C13, 3255_106, 3420_123, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B11, 3242_P05, TCN-522 (3212_112), TCN-521 (3280_D18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-(5087_P17), TCN-529 (5297_H01), TCN-530 (5248_H10), TCN-531 (5091_H13), TCN-(5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-535 (5246_P19), TCN-(5095_N01), TCN-537 (3194_D21), TCN-538 (3206_017), TCN-539 (5056_A08), TCN-.

= -=

540 (5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-544 (5082_A19), TCN-545 (5082_115), TCN-546 (5089_L08), TCN-547 (5092_F11), TCN-548 (5092_P01), TCN-549 (5092_PO4), TCN-550 (5096_F06), TCN-551 (5243_DO1), TCN-552 (5249_123), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), TCN-557 (5081_A04), TCN 558 (5248_Hl0b), TCN-559 (5097_G08), TCN-560 (5084_P10), TCN-504 (3251_K17), SC06-141, SC06-255, SC06-257, SC06-260, SC06-261, SC06-262, SC06-268, SC06-272, SC06-296, SC06-301, SC06-307, SC06-310, SC06-314, SC06-323, SC06-325, SC06-327, SC06-328, SC06-329, SC06-331, SC06-332, SC06-334, SC06-336, SC06-339, SC06-342, SC06-343, SC06-344, CR6141, CR6255, CR6257, CR6260, CR6261, CR6262,'CR6268, CR6272, CR6296, CR6301, CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, CR6329, CR6331, CR6332, CR6334, CR6336, CR6339, CR6342, CR6343, Or CR6344. These antibodies preferentially bind to or specifically bind to influenza A infected cells as compared to uninfected control cells of the same cell type.
[1205] In particular embodiments, the antibodies of the present invention bind to the M2 or HA protein. In certain embodiments, the present invention provides human anti-influenza antibodies that bind to epitopes within M2e or HA that are only present in the native conformation, i.e., as expressed in cells. In particular embodiments, these antibodies fail to specifically bind to an isolated M2e polypeptide, e.g., the 23 amino acid residue M2e fragment or an isolated HA polypeptide. It is understood that these antibodies recognize non-linear (i.e. conformational) epitope(s) of the M2 or HA peptide or protein.
[1206] These specific conformational epitopes within the M2 or HA protein, and particularly within M2e, may be used as vaccines to prevent the development of influenza infection within a subject.
=
[1207] As will be understood by the skilled artisan:general description of antibodies herein and methods of preparing and using the same also apply tO individual antibody polypeptide constituents and antibody fragments.
[1208] The antibodies of the present invention may be polyclonal or monoclonal antibodies.
However, in preferred embodiments, they are monoclonal. In particular embodiments, antibodies of the present invention are fully human antibodies. Methods of producing polyclonal and monoclonal antibodies are known in the art and described generally, e.g., in U.S. Patent No. 6,824,780. Typically, the antibodies of the present invention are produced , recombinantly, using vectors and methods available in the art, as described further below.
Human antibodies may also be generated by in vitro activated B cells (see U.S.
Pat. Nos.
5,567,610 and 5,229,275).
[1209] Human antibodies may also be produced in transgenic animals (e.g., mice) that are capable of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production.
Transfer of the human germ-line immunoglobulin gene array into such germ-line mutant mice results in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al., Proc.
Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993);
Bruggemann et al., Year in Immuno., 7:33 (1993); U.S. Pat. Nos. 5,545,806, 5,569,825, 5,591,669 (all of GenPharm); U.S. Pat. No. 5,545,807; and WO 97/17852. Such animals may be genetically engineered to produce human antibodies comprising a polypeptide of the present invention.
[1210] In certain embodiments, antibodies of the present invention are chimeric antibodies that comprise sequences derived from both human and non-human sources. In particular embodiments, these chimeric antibodies are humanized or primatizedTM. In practice, humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
[1211] In the context of the present invention, chimeric antibodies also include fully human antibodies wherein the human hypervariable region.or one or more CDRs are retained, but one or more other regions of sequence have been replaced by corresponding sequences from a non-human animal.
[1212] The choice of non-human sequences, both light and heavy, to be used in making the' chimeric antibodies is important to reduce antigenicity and human anti-non-human antibody responses when the antibody is intended for human therapeutic use. It is further important that chimeric antibodies retain high binding affinity.for the antigen and other favorable biological properties. To achieve this goal, according to a preferred method, chimeric antibodies are prepared by a process of analysis of the parental sequences and various conceptual chimeric products using three-dimensional models of the parental human and non-human sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational Structures of selected candidate immunoglobulin sequences. Inspection of these &Splays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so =
that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the hypervariable region residues are directly and most substantially involved in influencing antigen binding.
[1213] As noted above, antibodies (or immunoglobulins) can be divided into five different classes, based on differences in the amino acid sequences in the constant region of the heavy chains. All immunoglobulins within a given class have very similar heavy chain constant regions. These differences can be detected by sequence studies or more commonly by serological means (i.e. by the use of antibodies directed to these differences). Antibodies, or fragments thereof, of the present invention may be any class, and may, therefore, have a gamma, mu, alpha, delta, or epsilon heavy chain. 'A gamma chain may be gamma 1, gamma 2, gamma 3, or gamma 4; and an alpha chain mayThe alpha 1 or alpha 2.
[1214] In a preferred embodiment, an antibody of the present invention, or fragment thereof, is an IgG. IgG is considered the most versatile immunoglobulin, because it is capable of carrying out all of the functions of immunoglobulin molecules. IgG is the major Ig in serum, and the only class of Ig that crosses the placenta. IgG also fixes complement, although the IgG4 subclass does not. Macrophages, monocytes, PMN's and some lymphocytes have Fc receptors for the Fc region of IgG. Not all subclasses bind equally well; IgG2 and IgG4 do not bind to Fc receptors. A consequence of binding to the Fc receptors on PMN's, monocytes and macrophages is that the cell can now internalize the antigen better. IgG
is an opsonin that enhances phagocytosis. Binding of IgG to Fc receptors on other types of cells results in the activation of other functions. Antibodies of the present invention may be of any IgG
subclass. =
214 ;==

[1215] In another preferred embodiment, an antibody, or fragment thereof, of the present invention is an IgE. IgE is the least common serum Ig since it binds very tightly to Fc receptors on basophils and mast cells even before interacting with antigen. As a consequence of its binding to basophils an mast cells. IgE is involved in allergic reactions. Binding of the allergen to the IgE on the cells results in the release of various pharmacological mediators that result in allergic symptoms. IgE also plays a role in parasitic helminth diseases.
Eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminths results in killing of the parasite. IgE does not fix cOmplement.
[1216] In various embodiments, antibodies of the;present invention, and fragments thereof, comprise a variable light chain that is either kappa or lambda. The lamba chain may be any of subtype, including, e.g., lambda 1, lambda 2, lambda 3, and lambda 4.
[1217] As noted above, the present invention further provides antibody fragments comprising a polypeptide of the present invention. In certain circumstances there are advantages of using antibody fragments, rather than whole antibodies. For example, the smaller size of the fragments allows for rapid clearance, and may lead to improved access to certain tissues, such as solid tumors. Examples of antibody fragments include: Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies; single-chain antibodies; and multispecific antibodies formed from antibody fragments. =
=
[1218] Various techniques have been developed for the production of antibody fragments.
Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Wipphysical Methods 24:107-117 (1992);
and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScEv antibody fragments can all be expressed in and secreted from E. coli, thus allowing the facile production of large amounts of these fragments. Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al., Bio/Technology 10:163-167 (1992)).
According to another approach, F(ab')2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab'), fragment with increased in vivo half-life comprising a salvage receptor binding epitope residues are described in U.S. Pat. No. 5,869,046.
Other techniques for the production of antibody fragments will be apparent to the skilled practitioner.

, fi.
[1219] In other embodiments, the antibody of choice is a single chain Fv fragment (scFv).
See WO 93/16185; U.S. Pat. Nos. 5,571,894; and 5,587,458. Fv and sFy are the only species with intact combining sites that are devoid of constant regions. Thus, they are suitable for reduced nonspecific binding during in vivo use. sFy fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an sFv. See Antibody Engineering, ed. Borrebaeck, supra. The antibody fragment may also be a "linear antibody", e.g., as described in U.S. Pat. No. 5,641,870 for example. Such linear antibody fragments may be monospecific or bispecific.
[1220] In certain embodiments, antibodies of the present invention are bispecific or multi-specific. Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes. Exemplary bispecific antibodies may bind to two different epitopes of a single antigen. Other such antibodies may combine a first.antigen binding site with a binding site for a second antigen. Alternatively, an anti-M2e arm may be combined with an arm that =
binds to a triggering molecule on a leukocyte, such as a T-cell receptor molecule (e.g., CD3), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRIII (CD16), so as to focus and localize cellular defense mechanisms to the infected cell.
Bispecific antibodies may also be used to localize cytotoxic agents to infected cells.
These antibodies possess an M2e-binding arm and an arm that binds the cytotoxic agent (e.g., saporin, anti-interferon-a, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten).
Bispecific antibodies can be prepared as full length.antibodies or antibody fragments (e.g., F(ab.), bispecific antibodies). WO 96/16673 describes a bispecific anti-ErbB2/anti-FcyRIII
antibody and U.S. Pat. No. 5,837,234 discloses a bispecific anti-ErbB2/anti-FcyRI antibody.
A bispecific anti-ErbB2/Fca antibody is shown in W098/02463. U.S. Pat. No.
5,821,337 teaches a bispccific anti-ErbB2/anti-CD3 antibody.
[1221] Methods for making bispecific antibodies are known in the art.
Traditional production of full length bispecific antib6dies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (Millstein et al., Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure.
Purification of the correct molecule, which is usually done by affinity chromatography steps, is rather cumbersome, and the product yields are low. Similar procedures are disclosed in WO 93/08829, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).
[1222] According to a different approach, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. Preferably, the fusion is with an Ig heavy chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CHI) containing the site necessary for light chain bonding, present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host cell. This provides for greater flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yield of the desired bispecific antibody. It is, however, possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios have no significant affect on the yield of the desired chain combination.
[1223] In a preferred embodiment of this approach, the bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. It was found that this asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation. This approach is disclosed in WO 94/04690. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).
[1224] According to another approach described in U.S. Pat. No. 5,731,168, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heteroclimers that are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH 3 domain. In this,method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.
[1225] Bispecific antibodies include cross-linked or "heteroconjugate"
antibodies. For example, one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360, WO 92/200373, and EP 03089). Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, along with a number of cross-linking techniques.
[1226] Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science, 229: 81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab'), fragments. These fragments are reduced in the presence of the dithiol complexing agent, sodium arsenite, to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB
derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents 'for the selective immobilization of enzymes.
[1227] Recent progress has facilitated the direct recovery of Fab'-SH
fragments from E. coli, which can be chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med., 175: 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab.)2 molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T
cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
218 , [1228] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol., 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers.
The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci.
USA, 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a VH connected -to a VL by a linker that is too short to allow pairing between the two domains on the same chain. Accordingly, the VH
and VL
domains of one fragment are forced to pair with the complementary VL and VH
domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See Gruber et al., J. Immunol., 152:5368 (1994).
[1229] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147: 60 (1991). A
multivalent antibody may be internalized (and/or catabolized) faster than a bivalent antibody by a cell expressing an antigen to which the antibodies bind. The antibodies of the present invention can be multivalent antibodies with three or more antigen binding sites (e.g., tetravalent antibodies), which can be readily produced by recombinant expression of nucleic acid encoding the polypeptide chains of the antibody. The multivalent antibody can comprise a dimerization domain and three or more antigen binding sites. The preferred dimerization domain comprises (or consists of) an Fc region or a hinge region. ,In this scenario, the antibody will comprise an Fc region and three or more antigen binding sites amino-terminal to the Fc region. The preferred multivalent antibody herein comprises (or consists of) three to about eight, but preferably four, antigen binding sites. The multivalent antibody comprises at least one polypeptide chain (and preferably two polypeptide chains), wherein the polypeptide chain(s) comprise two or more variable domains. For instance, the polypeptide chain(s) may comprise VD1-(X1)n -Fc, wherein VD1 is a first variable domain, VD2 is a second variable domain, Fc is one polypeptide chain of an Fc region, X1 and X2 represent an , =
amino acid or polypeptide, and n is 0 or 1. For instanee, the polypeptide chain(s) may comprise: VH-CH linker-VH-C1-11-Fc region chain; or VH-CH 1-VH-CH 1-Fc region chain. The multivalent antibody herein preferably further comprises at least two (and preferably four) light chain variable domain polypeptides. The multivalent antibody herein may, for instance, comprise from about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides contemplated here comprise a light chain variable domain and, optionally, further comprise a CL domain.
' [1230] Antibodies of the present invention further include single chain antibodies.
[1231] In particular embodiments, antibodies of the present invention are internalizing antibodies.
[1232] Amino acid sequence modification(s) of the aniibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid s'equence variants of the antibody may be prepared by introducing appropriate nucleotide changes into a polynucleotide that encodes .
the antibody, or a chain thereof, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution may be made to arrive at the final antibody, provided that the final construct possesses the desired characteristics. The amino acid changes also may alter post-translational processes of the antibody, such as changing the number or position of glycosylation sites. Any of the variations and modifications described above for polypeptides of the present invention may be included in antibodies of the present invention.
[1233] A useful method for identification of certain residues or regions of an antibody that are preferred locations for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells in Science, 244:1081-1085 (1989). Here, a residue or group of target residues are identified (e.g., charged residues such as arg, asp, his, lys, and glu) and replaced by a neutral or negatively charged amino acid (most preferably alanine or polyalanine) to affect the interaction of the amino.acids wih PSCA antigen.
Those amino acid locations demonstrating functional sensitivity'tothe substitutions then are refined by introducing further or other variants at, or for, the sites of substitution.
Thus, while the site for introducing an amino acid sequence variation is predetermined, the nature of the mutation per se need not be predetermined. For example, to analyze the performance of a mutation at a given site, ala scanning or random mutagenesis is conducted at the target codon or region and the expressed anti- antibody variants are screened for the desired activity.
[1234] Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptide's containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
Examples of terminal insertions include an antibody with an N-terminal methionyl residue or the antibody fused to a cytotoxic polypeptide. Other insertional variants of an antibody include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide that increases the serum half-life of the antibody.
[1235] Another type of variant is an amino acid substitution variant. These variants have at least one amino acid residue in the antibody molecule replaced by a different residue. The sites of greatest interest for substitutional mutagenesis include the hypervariable regions, but FR alterations are also contemplated. Conservative and non-conservative substitutions are contemplated.
[1236] Substantial modifications in the biological properties of the antibody are accomplished by selecting substitutions that differ,significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
[1237] Any cysteine residue not involved in maintaining the proper conformation of the antibody also may be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, cysteine bond(s) may be added to the antibody to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment).
[1238] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody. Generally, the resulting variant(s) selected for further development will have improved biological properties relative to the parent antibody from which they are generated. A convenient way for generating such substitutional variants involves affinity maturation using phage display. Briefly, several hypervariable region sites (e.g., 6-7 sites) are mutated to generate all possibleamino_substitutions at each site. The 221 , antibody variants thus generated are displayed in a monovalent fashion from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle. The phage-displayed variants are then screened for their biological activity (e.g., binding affinity) as herein disclosed. In order to identify candidate hypervariable region sites for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues contributing significantly to antigen binding. Alternatively, or additionally, it may be beneficial to analyze a crystal structure of the antigen-antibody complex to identify contact points between the antibody and an antigen or infected cell. Such contact residues and neighboring residues are candidates for substitution according to the techniques elaborated herein. Once such variants are generated, the panel of variants is subjected to screening as described herein and antibodies with superior properties in one or more relevant assays may bc selected for further development.
[1239] Another type of amino acid variant of the antibody alters the original glycosylation pattern of the antibody. By altering is meant deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that are not present in the antibody.
[1240] Glycosylation of antibodies is typically either N-linked or 0-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X
is any amino acid except proline, are the recognition sequences for enzymatic attachment of the = carbohydrate moiety to the asparagine side chain. Thus; ttie presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site.
0-linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although hydroxyproline or 5-hydroxylysine may also be used.
[1241] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for 0-linked glycosylation sites).

=

[1242] The antibody of the invention is modified with respect to effector function, e.g., so as to enhance antigen-dependent cell-mediated cyotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antibody. This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody. Alternatively or additionally, cysteine residue(s) may be introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med. 176:1191-1195 (1992) and Shopes, B. J. Immunol. 148:2918-2922 (1992). Homodimeric antibodies with enhanced anti-infection activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al., Cancer Research 53:2560-2565 (1993). Alternatively, an antibody can be engineered which has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et a/.,.Anti-Cancer Drug Design 3:219-230 (1989).
[1243] To increase the serum half-life of the antibody, one may incorporate a salvage receptor binding epitope into the antibody (especially an antibody fragment) as described in U.S. Pat. No. 5,739,277, for example. As used herein, the term "salvage receptor binding epitope" refers to an epitope of the Fc region of an IgG molecule (e.g., IgGI, IgG2, IgG3, or IgG4) that is responsible for increasing the in vivo serum half-life of the IgG molecule.
[1244] Antibodies of the present invention may also be modified to include an epitope tag or label, e.g., for use in purification or diagnostic applications. The invention also pertains to therapy with immunoconjugates comprising an antibody conjugated to an anti-cancer agent such as a cytotoxic agent or a growth inhibitory agent. Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above.
11245] Conjugates of an antibody and one or more small molecule toxins, such as a calicheamicin, maytansinoids, a trichothene, and CC1065; and the derivatives of these toxins that have toxin activity, are also contemplated herein.
[1246] In one preferred embodiment, an antibody (full length or fragments) of the invention is conjugated to one or more maytansinoid molecules. Maytansinoids are mitototic inhibitors that act by inhibiting tubulin polymerization. Maytansine was first isolated from the east African shrub Maytenus serrata (U.S. Pat. No. 3,896,111). Subsequently, it was discovered that certain microbes also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (U.S. Pat. No. 4,151,042). Synthetic maytansinol and derivatives and analogues thereof are disclosed, for example, in U.S. Pat. Nos. 4,137,230; 4,248,870; 4,256,746;
4,260,608;
4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; 4,313,946;
4,315,929;
4,317,821; 4,322,348; 4,331,598; 4,361,650; 4,364,866; 4,424,219; 4,450,254;
4,362,663;
and 4,371,533.
[1247] In an attempt to improve their therapeutic index, rnaytansine and maytansinoids have been conjugated to antibodies specifically binding to tumor cell antigens.
Immunoconjugates containing maytansinoids and their therapeutic use are disclosed, for example, in U.S. Pat.
Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 Bl. Liu et al., Proc. Natl.
Acad. Sci. USA 93:8618-8623 (1996) described immunoconjugates comprising a maytansinoid designated DM I linked to the monoclonal antibody C242 directed against human colorectal cancer. The conjugate was found to be highly cytotoxic towards cultured colon cancer cells, and showed antitumor activity in an in vivo tumor growth assay.
[1248] Antibody-maytansinoid conjugates are prepared by,chemically linking an antibody to a maytansinoid molecule without significantly diminishing the biological activity of either the antibody or the maytansinoid molecule. An average of 3-4 maytansinoid molecules conjugated per antibody molecule has shown efficacy in enhancing cytotoxicity of target cells without negatively affecting the function or solubility of the antibody, although even one molecule of toxin/antibody would be expected to enhance cytotoxicity over the use of naked antibody. Maytansinoids are well known in the art and can be synthesized by known techniques or isolated from natural sources. Suitable maytansinoids are disclosed, for example, in U.S. Pat. No. 5,208,020 and in the other patents and nonpatent publications referred to hereinabove. Preferred maytansinoids are maytansinol and maytansinol analogues modified in the aromatic ring or at other positions of the maytansinol molecule, such as various maytansinol esters.
[1249] There are many linking groups known in the art for making antibody conjugates, including, for example, those disclosed in U.S. Pat. No. 5,208,020 or EP
Patent 0 425 235 B1, and Chari et al., Cancer Research 52: 127-131, (1992). =The linking groups include disufide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, or esterase labile groups, as disclosed in the above-identified patents, disulfide and thioether groups being preferred.
[1250] Immunoconjugates. may be made using a variety of bifunctional protein coupling agents such as N-succinimidy1-3-(2-pyridyldithio)propionate (SPDP), succinimidy1-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), 'active esters (such as diSuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyphexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoy1)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Particularly preferred coupling agents include N-succinimidy1-3-(2-pyridyldithio)propionate (SPDP) (Carlsson et al., Biochem. J.
173:723-737 [19781) and N-succinimidy1-4-(2-pyridylthio)pentanoate (SPP) to provide fora disulfide linkage. For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzy1-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026. The linker may be a "cleavable linker"
facilitating release of the cytotoxic drug in the cell. For example, an acid-labile linker, Cancer Research 52 127-131 (1992); U.S. Pat. No. 5,208,020) may be used.
[1251] Another immunoconjugate of interest comprises an antibody conjugated to one or more calicheamicin molecules. The calicheamicirf.family of antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. For the preparation of conjugates of the calicheamicin family, see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, 5,877,296 (all to American Cyanamid Company). Another drug that the antibody can be conjugated is QFA
which is an antifolate. Both calicheamicin and QFA have intracellular sites of action and do not readily cross the plasma membrane. Therefore, cellular uptake of these agents through antibody mediated internalization greatly enhances their cytotoxic effects.
[1252] Examples of other agents that can be conjugated to the antibodies of the invention include BCNU, streptozoicin, vincristine and 5-fluorouracil, the family of agents known collectively LL-E33288 complex described in U.S. Pat. Nos. 5,053,394, 5,770,710, as well as esperamicins (U.S. Pat. No. 5,877,296).

=

[1253] Enzymatically active toxins and fragments thereof that can be used include, e.g., diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin and the tricothecenes.
See, for example, WO 93/21232.
[1254] The present invention further includes an initnunoconjugate formed between an antibody and a compound with nucleolytic activity (e.g., a ribonuclease or a DNA
endonuclease such as a deoxyribonuclease; DNase).
[1255] For selective destruction of infected cells, the antibody includes a highly radioactive atom. A variety of.radioactive isotopes are available for the production of radioconjugated anti-PSCA antibodies. Examples include At211, /131, /125, y90, Re186, Re188, smI53, Bi212, P32, Pb212 and radioactive isotopes of Lu. When the conjugate is used for diagnosis, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.
[1256] The radio- or other label is incorporated in the conjugate in known ways. For example, the peptide may be biosynthesized or may be synthesized by chemical amino acid = synthesis using suitable amino acid precursors involving, for example, fluorine-19 in place of hydrogen. Labels such as tc99m or 1123, Reim,88 ' Rel- .and In111 can be attached via a cysteine residue in the peptide. Yttrium-90 can be attached via a lysine residue. The IODOGEN
method (Fraker et al. (1978) Biochem. Biophys. Res. Commun. 80: 49-57 can be used to incorporate iodine-123. "Monoclonal Antibodies in Irnmunoscintigraphy"
(Chatal,CRC Press 1989) describes other methods in detail.
[1257] Alternatively, a fusion protein comprising the antibody and cytotoxic agent is made, e.g., by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.
= 226 4if =
I.

=
[1258] The antibodies of the present invention are also used in antibody dependent enzyme mediated prodrug therapy (ADET) by conjugating the antibody to a prodrug-activating enzyme which converts a prodrug (e.g., a peptidyl chemotherapeutic agent, see W081/01143) to an active anti-cancer drug (see, e.g., WO 88/07378 and U.S.
Pat. No.
4,975,278).
[1259] The enzyme component of the immunoconjugate useful for ADEPT includes any enzyme capable ofacting on a prodrug in such a way so as to covert it into its more active, cytotoxic.form. Enzymes that are useful in the method of this invention include, but are not limited to, alkaline phosphatase useful for converting phosphate-containing prodrugs into free drugs; arylsulfatase useful for converting sulfate-containing prodrugs into free drugs;
cytosine deaminase useful for converting non-toxic 5-fluorocytosine into the anti-cancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases and cathepsins (such as cathepsins B and L), that are useful for converting peptide-containing prodrugs -into free drugs; D-alanylcarboxypeptidases, useful for converting prodrugs that contain D-amino acid substituents; carbohydrate-cleaving enzymes such as13-galactosidase and neuraminidase useful for converting glycosylated prodrugs into free drugs; I3-lactamase useful for converting drugs derivatized with 13-lactams into free drugs; and penicillin amidases, such as penicillin V amidase or penicillin G
amidase, useful for converting drugs derivatized at their amine nitrogens with phenoxyacetyl or phenylacetyl groups, respectively, into free drugs. Alternatively, antibodies with enzymatic activity, also known in the art as "abzymes", can be used to convert the prodrugs of the invention into free active drugs (see, e.g., Massey, Nature 328: 457-458 (1987)). Antibody-abzyme conjugates can be prepared as described herein for delivery of the abzyme to a infected cell population.
[1260] The enzymes of this invention can be covalently bound to the antibodies by techniques well known in the art such as the use of the heterobifunctional crosslinking reagents discussed above. Alternatively, fusion proteins comprising at least the antigen binding region of an antibody of the invention linked to at least a functionally active portion of an enzyme of the invention can be constructed ,using recombinant DNA
techniques well known in the art (see, e.g., Neuberger et al., Nature, 312: 604-608 (1984).
[1261] Other modifications of the antibody are contemplated herein. For example, the antibody may be linked to one of a variety of nonproteinaceous polymers, e.g., polyethylene =

glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol. The antibody also may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980).
[1262] The antibodies disclosed herein are also formulated as immunoliposomes.
A
"liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant that is useful for delivery of a drug to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82:3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77:4030 (1980); U.S. Pat. Nos. 4,485,045 and 4,544,545; and W097/38731 published Oct. 23, 1997. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.
[1263] Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired a diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem. 257: 286-288 (1982) via a disulfide interchange reaction. A
chemotherapeutic agent is optionally contained within the liposome. See Gabizon et al., J.
National Cancer Inst. 81(19)1484 (1989).
[1264] Antibodies of the present invention, or fragments thereof, may possess any of a variety of biological or functional characteristics. In certain embodiments, these antibodies are Influenza A specific or M2 protein specific antibodies, indicating that they specifically bind to or preferentially bind to Influenza A or the M2 protein thereof, respectively, as compared to a normal control cell. In particular eml3odithents, the antibodies are HuM2e antibodies, indicating that they specifically bind to aM2evprotein, preferably to an epitope of the M2e domain that is only present when the M2 protein is expressed in cells or present on a virus, as compared to a normal control cell.
[1265] In particular embodiments, an antibody of the present invention is an antagonist antibody, which partially or fully blocks or inhibits a biological activity of a polypeptide or cell to which it specifically or preferentially binds. In other embodiments, an antibody of the present invention is a growth inhibitory antibody, which partially or fully blocks or inhibits the growth of an infected cell to which it binds. In another embodiment, an antibody of the present invention induces apoptosis. In yet another embodiment, an antibody of the present invention induces or promotes antibody-dependent cell-mediated cytotoxicity or complement dependent cytotoxicity.
Methods of Identifying and Producing Antibodies Specific for Influenza Virus [1266] The present invention provides novel methods for the identification of human anti-influenza antibodies raised against the M2e protein, as exemplified in Example 4, and for the identification of human anti-influenza antibodies raised against the HA
protein, as exemplified in Example 13. These methods may be readily adapted to identify antibodies specific for other polypeptides expressed on the cell surface by infectious agents, or even polypeptides expressed on the surface of an.infectious agent itself.
[1267] In general, the methods include obtaining serum samples from patients that have been infected with or vaccinated against an infectious agent. These serum samples are then screened to identify those that contain antibodies specific for a particular polypeptide associated with the infectious agent, such as, e.g., a polypeptide or protein specifically expressed on the surface of cells infected with the infectious agent, but not uninfected cells.
In particular embodiments, the serum samples arecreened by contacting the samples with a cell that has been transfected with an expression vector that expresses the polypeptide expressed on the surface of infected cells.
[1268] Once a patient is identified as having serum containing an antibody specific for the infectious agent polypeptide of interest is identified, mononuclear and/or B
cells obtained from the same patient are used to identify a cell or clone thereof that produces the antibody, =
using any of the methods described herein or available in the art. Once a B
cell that produces the antibody is identified, cDNAs encoding the variable regions or fragments thereof of the antibody may be cloned using standard RT-PCR vectors and primers specific for conserved antibody sequences, and subcloned in to expression vectors used for the recombinant production of monoclonal antibodies specific for the infectious agent polypeptide of interest.

1,1 1 =

[1269] In one embodiment, the present invention provides a method of identifying an antibody that specifically binds influenza A-infected cells, comprising:
contacting an Influenza A virus or a cell expressing the M2 protein with a biological sample obtained from a patient having been infected by Influenza A; determining an amount of antibody in the biological sample that binds to the cell; and comparing the amount determined with a control value, wherein if the value determined is at least two-fold greater than the control value, an antibody that specifically binds influenza A-infected cells is indicated.
[1270] In various embodiments, the cells expressing an M2 or HA protein are cells infected with an Influenza A virus or cells that have been transfected with a polynucleotide that expressed the M2 or HA protein. Alternatively, the cells may express a portion of the M2 protein that includes the M2e domain and enough additional M2 sequence that the protein remains associated with the cell and the M2e domain is presented on the cell surface in the same manner as when present within full length M2 protein. Methods of preparing an M2 or HA expression vector and transfecting an appropriate cell, including those described herein, may be readily accomplished, in view of the M2 and HA sequences being publicly available.
See, for example, the Influenza Sequence Database (ISD) (flu.lanl.gov on the World Wide Web, described in Macken et al., 2001, "The value of a database in surveillance and vaccine selection" in Options for the Control of Influenza IV. A.D.M.E., Osterhaus &
Hampson (Eds.), Elsevier Science, Amsterdam, pp. 103-106) and the Microbial Sequencing Center (MSC) at The Institute for Genomic Research (TIGR) (tignorg/msc/infl_a_virus.shtml on the World Wide Web).
[1271] The M2e- or HA-expressing cells or virus described above are used to screen the biological sample obtained from a patient infected with influenza A for the presence of antibodies that preferentially bind to the cell expressing the M2 or HA
polypeptide using standard biological techniques. For example, in certain e'mbodiments, the antibodies may be labeled, and the presence of label associated with the cell 'detected, e.g., using FMAT or FACs analysis. In particular embodiments, the biological sample is blood, serum, plasma, bronchial lavage, or saliva. Methods of the present invention may be practiced using high throughput techniques.
[1272] Identified human antibodies may then be characterized further. For example the particular conformational epitopes with in the M2e or HA protein that are necessary or sufficient for binding of the antibody may be determined, e.g., using site-directed mutagenesis of expressed M2e or HA polypeptides. These methods.may be readily adapted =

. , =
to identify human antibodies that bind any protein expressed on a cell surface. Furthermore, these methods may be adapted to determine binding of the antibody to the virus itself, as opposed to a cell expressing recombinant M2e or HA, or infected with the virus.
[1273] Polynucleotide sequences encoding the antibodies, variable regions thereof, or antigen-binding fragments thereof may be subcloned into expression vectors for the recombinant production of human monoclonal anti-M2e or anti-HA antibodies. In one embodiment, this is accomplished by obtaining mononuclear cells from the patient from the serum containing the identified human monoclonal anti-M2e or anti-HA antibody was obtained; producing B cell clones from the mononuclear cells; inducing the B
cells to become antibody-producing plasma cells; and screening the supernatants produced by the plasma cells to determine if it contains the human monoclonal anti-M2e or anti-HA
antibody. Once a B cell clone that produces a human monoclonal anti-M2e or anti-HA antibody is identified, reverse-transcription polymerase chain reaction (RT-PCR) is performed to clone the DNAs encoding the variable regions or portions thereof of the human monoclonal anti-M2e or anti-HA antibody. These sequences are then subcloned into expression vectors suitable for the recombinant production of human monoclonal anti-M2e or anti-HA antibodies. The binding specificity may be confirmed by determining the recombinant antibody's ability to bind cells expressing M2e or HA polypeptide or protein.
[1274] In particular embodiments of the methods described herein, B cells isolated from peripheral blood or lymph nodes are sorted, e.g., based on their being CD19 positive, and plated, e.g., as low as a single cell specificity per well, e.g., in 96, 384, or 1536 well configurations. The cells are induced to differentiate into antibody-producing cells, e.g., plasma cells, and the culture supernatants are harvested and tested for binding to cells expressing the infectious agent polypeptide on their surface using, e.g., FMAT
or FACS
analysis. Positive wells are then subjected to whole well RT-PCR to amplify heavy and light chain variable regions of the IgG molecule expressed by the clonal daughter plasma cells.
The resulting PCR products encoding the heavy and light chain variable regions, or portions thereof, are subcloned into human antibody expression vectors for recombinant expression.
The resulting recombinant antibodies are then testedto confirm their original binding specificity and may be further tested for pan-specificity across various strains of isolates of the infectious agent.
[1275] Thus, in one embodiment, a method of identifying human monoclonal anti-M2e or anti-HA antibodies is practiced as follows. First, full length or approximately full length M2 or HA cDNAs are transfected into a cell line for expression of M2 or HA
protein. Secondly, individual human plasma or sera samples are tested for antibodies that bind the cell-expressed M2 or HA. And lastly, MAbs derived from plasma- or serum-positive individuals are characterized for binding to the same cell-expressed M2 or HA. Further definition of the fine specificities of the MAbs can be performed at this point: ' [1276] These methods may be practiced to identif3, a variety of different HuM2e antibodies, including antibodies specific for (a) epitopes in a linear M2e peptide, (b) common epitopes in multiple variants of M2e, (c) conformational determinants of an M2 homotetramer, and (d) common conformational determinants of multiple variants of the M2 homotetramer. The last category is particularly desirable, as this specificity is perhaps specific for all A strains of influenza.
[1277] These methods may be practiced to identify a variety of different human monoclonal anti-HA antibodies, including antibodies specific for (a) epitopes in a linear HA peptide, (b) common epitopes in multiple variants of HA, (c) conformational determinants Ian HA
protein or homotrimer, and (d) common conformational determinants of multiple variants of the HA protein or homotrimer. The last category is particularly desirable, as this specificity is perhaps specific for all A strains of influenza.
[1278] Polynucleotides that encode the human monoclonal anti-M2e or anti-HA
antibodies or =
portions thereof of the present invention may be iolated from cells expressing human monoclonal anti-M2e or anti-HA antibodies, according to methods available in the art and described herein, including amplification by polymerase chain reaction using primers specific for conserved regions of human antibody polypeptides. For example, light chain and heavy chain variable regions may be cloned from the B cell according to molecular biology techniques described in WO 92/02551; U.S. Patent No. 5,627,052; or Babcook et al., Proc.
Natl. Acad. Sci. USA 93:7843-48 (1996). In certain embodiments, polynucleotides encoding all or a region of both the heavy and light chain variable regions of the IgG
molecule expressed by the clonal daughter plasma cells expressing the human monoclonal anti-M2e or anti-HA antibody are subcloned and sequenced. The sequence of the encoded polypeptide may be readily determined from the polynucleotide sequence.
[1279] Isolated polynucleotides encoding a polypeptide of the present invention may be subcloned into an expression vector to recombinantly produce antibodies and polypeptides of the present invention, using procedures known in the art and described herein.

[1280] Binding properties of an antibody (or fragment thereof) to M2e or infected cells or tissues may generally be determined and assessed using immunodetection methods including, for example, immunofluorescence-based assays, such as immuno-histochemistry (IHC) and/or fluorescence-activated cell sorting (FACS). Immunoassay methods may include controls and procedures to determine whether antibodies bind specifically to M2e from one or more specific strains of Influenza A, and do not recognize or cross-react with normal control cells.
[1281] Following pre-screening of serum to identify patients that produce antibodies to an infectious agent or polypeptide thereof, e.g., M2 or HA, the methods of the present invention typically include the isolation or purification of B cells from a biological sample previously obtained from a patient or subject. The patient or subject may be currently or previously diagnosed with or suspect or having a particular disease or infection, or the patient or subject may be considered free or a particular disease or infection. Typically, the patient or subject is a mammal and, in particular embodiments, a human. The biological sample may be any sample that contains B cells, including but not limited to, lymph node or lymph node tissue, pleural effusions, peripheral blood, ascites, tumor tissue, or cerebrospinal fluid (CSF). In various embodiments, B cells are isolated from different types of biological samples, such as a biological sample affected by a particular disease or infection. However, it is understood that any biological sample comprising B cells may be used for any of the embodiments of the .present invention.
[1282] Once isolated, the B cells are induced to produce antibodies, e.g., by culturing the B
cells under conditions that support B cell proliferation or development into a plasmacyte, plasmablast, or plasma cell. The antibodies are then screened, typically using high throughput techniques, to identify an antibody that specifically binds to a target antigen, e.g., a particular tissue, cell, infectious agent, or polypeptide. In certain embodiments, the specific antigen, e.g., cell surface polypeptide bound by the antibody is not known, while in other embodiments, the antigen specifically bound by the antibody is known.
[1283] According to the present invention, B cells may be isolated from a biological sample, e.g., a tumor, tissue, peripheral blood or lymph node sample, by any means known and available in the art. B cells are typically sorted by FACS based on the presence on their surface of a B cell-specific marker, e.g., CD19, CD138, and/or surface IgG.
However, other methods known in the art may be employed, such as, e.g., column purification using CD19 magnetic beads or IgG-specific magnetic beads, followed by elution from the column.

, =
However, magnetic isolation of B cells utilizing any marker may result in loss of certain B
cells. Therefore, in certain embodiments, the isolated cells are not sorted but, instead, phicol-purified mononuclear cells isolated from tumor are directly plated to the appropriate or desired number of specificities per well.
[1284] In order to identify B cells that produce an infectious agent-specific antibody, the B
cells are typically plated at low density (e.g., a single cell specificity per well, 1-10 cells per well, 10-100 cells per well, 1-100 cells per well, less than 10 cells per well, or less than 100 cells per well) in multi-well or microtitre plates, e.g., in 96, 384, or 1536 well configurations.
When the B cells are initially plated at a density greater than one cell per well, then the methods of the present invention may include the step of subsequently diluting cells in a well identified as producing an antigen-specific antibody, until a single cell specificity per well is achieved, thereby facilitating the identification of the B cell that produces the antigen-specific antibody. Cell supernatants or a portion thereof and/or cells may be frozen and stored for future testing and later recovery of antibody polynucleotides.
[1285] In certain embodiments, the B cells are cultured under conditions that favor the production of antibodies by the B cells. For example, the B cells may be cultured under conditions favorable for B cell proliferation and differentiation to yield antibody-producing plasmablast, plasmacytes, or plasma cells. In particular embodiments, the B
cells are cultured in the presence of a B cell mitogen, such as lipopolysaccharide (LPS) or CD40 ligand. In one specific embodiment, B cells are differentiated to antibody-producing cells by culturing them with feed cells and/or other B cell activators, such as CD40 ligand.
[1286] Cell culture supernatants or antibodies obtained therefrom may be tested for their ability to bind to a target antigen, using routine methods available in the art, including those described herein. In particular embodiments, culture supernatants are tested for the presence of antibodies that bind to a target antigen using high- throughput methods.
For example, B
cells may be cultured in multi-well microtitre dishes, such that robotic plate handlers may be used to simultaneously sample multiple cell supernatants 'and test for the presence of antibodies that bind to a target antigen. In particular embodiments, antigens are bound to beads, e.g., paramagnetic or latex beads) to facilitate the capture of antibody/antigen complexes. In other embodiments, antigens and antibodies are fluorescently labeled (with different labels) and FACS analysis is performed to identify the presence of antibodies that bind to target antigen. In one embodiment, antibody binding is determined using FMATTm analysis and instrumentation (Applied Biosystems, Foster City, CA). FMATTm is a fluorescence macro-confocal platform for high-throughput screening, which mix-and-read, [1287] In the context of comparing the binding of an antibody to a particular target antigen (e.g., a biological sample such as infected tissue or cells, or infectious agents) as compared to a control sample (e.g., a biological sample such as uninfected cells, or a different infectious agent), in various embodiments, the antibody is considered to preferentially bind a particular target antigen if at least two-fold, at least three-fold, at least five-fold, or at least ten-fold more antibody binds to the particular target antigen as compared to the amount that binds a control sample.
[1288] Polynucleotides encoding antibody chains, variable regions thereof, or fragments thereof, may be isolated from cells utilizing any means available in the art.
In one embodiment, polynucleotides are isolated using polymerase chain reaction (PCR), e.g., reverse transcription-PCR (RT-PCR) using oligonucleotide primers that specifically bind to heavy or light chain encoding polynucleotide sequences or complements thereof using routine procedures available in the art. In one embodiment, positive wells are subjected to ,)r whole well RT-PCR to amplify the heavy and light chain variable regions of the IgG
molecule expressed by the clonal daughter plasma cells. These PCR products may be sequenced.
[1289] The resulting PCR products encoding the heavy and light chain variable regions or portions thereof are then subcloned into human antibody expression vectors and recombinantly expressed according to routine procedures in the art (see, e.g., US Patent No.
7,112,439). The nucleic acid molecules encoding a tumor-specific antibody or fragment thereof, as described herein, may be propagated and expressed according to any of a variety of well-known procedures for nucleic acid excision, ligation, transformation, and transfection. Thus, in certain embodiments expression of an antibody fragment may be preferred in a prokaryotic host cell, such as Escherichia coli (see, e.g., Pluckthun et al., Methods Enzymol. 178:497-515 (1989)). In certain other embodiments, expression of the antibody or an antigen-binding fragment thereof may be preferred in a eukaryotic host cell, .
including yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris); animal cells (including mammalian cells);,or plant cells. Examples of suitable animal cells include, but are not limited to, myel&, COS, CHO, or hybridoma cells.
Examples of plant cells include tobacco, corn, so)ibean, and rice cells. By methods known to those having ordinary skill in the art and based on the present disclosure, a nucleic acid vector may be designed for expressing foreign sequences in a particular host system, and then polynucleotide sequences encoding the tumor-specific antibody (or fragment thereof) may be inserted. The regulatory elements will vary according to the particular host.
[1290] One or more replicable expression vectors containing a polynucleotide encoding a variable and/or constant region may be prepared and used to transform an appropriate cell line, for example, a non-producing myeloma cell line, such as a mouse NSO line or a bacterium, such as E.coli, in which production of the antibody will occur. In order to obtain efficient transcription and translation, the polynucleotide sequence in each vector should include appropriate regulatory sequences, particularly a promoter and leader sequence operatively linked to the. variable domain sequence. Particular methods for producing antibodies in this way are generally well known and routinely used. For example, molecular biology procedures are described by Sambrook et al. (Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, New York, 1989; see also Sambrook et al., 3rd ed., Cold Spring Harbor Laboratory, New York, (2001)). While not required, in certain embodiments, regions of polynucleotides encoding the recombinant antibodies may be sequenced. DNA
sequencing can be performed as described in Sanger et al. (Proc. Natl. Acad. Sci. USA
74:5463 (1977)) and the Amersham International plc sequencing handbook and including improvements thereto.
[1291] In particular embodiments, the resulting recombinant antibodies or fragments thereof are then tested to confirm their original specificity and may be further tested for pan-. ==
specificity, e.g., with related infectious agents. In particular embodiments, an antibody identified or produced according to methods described herein is tested for cell killing via antibody dependent cellular cytotoxicity (ADCC) or apopto`sis, and/or well as its ability to =
internalize.
Polynucleotides [1292] The present invention, in other aspects, provides polynucleotide compositions. In preferred embodiments, these polynucleotides encode a polypeptide of the invention, e.g., a region of a variable chain of an antibody that binds to Influenza A, M2, M2e, or HA (soluble or recombinant). Polynucleotides of the invention are single-stranded (coding or antisense) or double-stranded DNA (genomic, cDNA or synthetic) or RNA molecules. RNA
molecules include, but are not limited to, HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns.
Alternatively, or in addition, coding or non-coding sequences are present within a =

polynucleotide of the present invention. Also altematively, or in addition, a polynucleotide is linked to other molecules and/or support materials of the invention.
Polynucleotides of the invention are used, e.g., in hybridization assays to detect the presence of an Influenza A
antibody in a biological sample, and in the recombinant production of polypeptides of the invention.
[1293] Therefore, according to another aspect of the present invention, polynucleotide compositions are provided that include some or all of a polynucleotide sequences set forth herein, complements of these polynucleotide sequences, and degenerate variants of these polynucleotide sequences. In certain preferred embodiments, the polynucleotide sequences set forth herein encode polypeptides capable .of preferentially binding a Influenza A-infected cell as compared to a normal control uninfected cell, including a polypeptide having a sequence set forth herein. Furthermore, the invention includes all polynucleotides that encode any polypeptide of the present invention.
[1294] In other related embodiments, the invention provides polynucleotide variants having substantial identity to the sequences set forth herein, for example those comprising at least 70% sequence identity, preferably at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or higher, sequence identity compared to a polynucleotide sequence of this invention, as determined using the methods described herein, (e.g., BLAST analysis using standard parameters). One skilled in this art will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning, and the like.
[1295] Typically, polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions, preferably such that the immunogenic binding properties of the polypeptide encoded by the variant polynucleotide is not Substantially diminished relative to a polypeptide encoded by a polynucleotide sequence specifically set forth herein.
In additional embodiments, the present invention provides polynucleotide fragments comprising various lengths of contiguous stretches of sequence identical to or complementary to one or more of the sequences disclosed herein. For example, polynucleotides are provided by this invention that comprise at least about 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 400, 500 or 1000 or more contiguous nucleotides of one or more of the sequences disclosed herein as well as all intermediate lengths there between. As used herein, the term "intermediate lengths" is meant to describe any length between the quoted values, such as 16, =
=
17, 18, 19, etc.; 21, 22, 23, etc.; 30, 31, 32, etc.; 50, 51, 52, 53, etc.;
100, 101, 102, 103, etc.;
150, 151, 152, 153, etc.; including all integers through 200-500; 500-1,000, and the like.
[1296] In another embodiment of the invention, polynucleotide compositions are provided that are capable of hybridizing under moderate to high stringency conditions to a polynucleotide sequence provided herein, or a fragment thereof, or a complementary sequence thereof. Hybridization techniques are well known in the art of molecular biology.
For purposes of illustration, suitable moderately stringent conditions for testing the hybridization of a polynucleotide of this invention with other polynucleotides include prewashing in a solution of 5 X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0);
hybridizing at 50 C-60 C, 5 X SSC, overnight; followed by washing twice at 65 C for 20 minutes with each of 2X, 0.5X and 0.2X SSC containing 0.1% SDS. One skilled in the art will understand that the stringency of hybridization can be readily manipulated, such as by altering the salt content of the hybridization solution and/or the temperature at which the hybridization is performed. For example, in another embodiment, suitable highly stringent hybridization conditions include those described above, with the exception that the temperature of hybridization is increased, e.g., to 60-65 C or 65-70 .
[1297] In preferred embodiments, the polypeptide encoded by the polynucleotide variant or fragment has the same binding specificity (i.e., specifically or preferentially binds to the same epitope or Influenza A strain) as the polypeptide encoded by the native polynucleotide. In certain preferred embodiments, the polynucleotides described above, e.g., polynucleotide variants, fragments and hybridizing sequences, encode polypeptides that have a level of binding activity of at least about 50%, preferably at least about 70%, and more preferably at least about 90% of that for a polypeptide sequence specifically set forth herein.
[1298] The polynucleotides of the present invention, or fragments thereof, regardless of the length of the coding sequence itself, may be combined with other DNA
sequences, such as promoters, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length may vary considerably. A
nucleic acid fragment of almost any length is employed, with the total length preferably being limited by the ease of preparation and use in the irjtended recombinant DNA
protocol. For example, illustrative polynucleotide segments With total lengths of about 10,000, about 5000, about 3000, about 2,000, about 1,000, about 500, about 200, about 100, about 50 base pairs in length, and the like, (including all intermediate lengths) are included in many implementations of this invention.

[1299] It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are multiple nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless; polynucleotides that encode a polypeptide of the present invention but which vary due to differences in codon usage are specifically contemplated by the invention. Further, alleles of the genes including the polynucleotide sequences provided herein are within the scope of the invention. Alleles are =
endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).
[1300] In certain embodiments of the present invention, mutagenesis of the disclosed polynucleotide sequences is performed in order to alter one or more properties of the encoded polypeptide, such as its binding specificity or binding strength. Techniques for mutagenesis are well-known in the art, and are widely used to create variants of both polypeptides and polynucleotides. A mutagenesis approach, such as site-specific mutagenesis, is employed for the preparation of variants and/or derivatives of the polypeptides described herein. By this approach, specific modifications in a polypeptide sequenee are made through mutagenesis of the underlying polynucleotides that encode them. These techniques provides a straightforward approach to prepare and test sequence variants, for example, incorporating one or more of the foregoing considerations, by introducing one or more nucleotide sequence changes into the polynucleotide.
[1301] Site-specific mutagenesis allows the production of mutants through the use of specific oligonucleotide sequences include the nucleotide sequence of the desired mutation, as well as a sufficient number of adjacent nucleotides, to provide a primer sequence of sufficient size and sequence complexity to fcirm a stable duplex on both sides of the deletion junction being traversed. Mutations are employed in a selected polynucleotide sequence to improve, alter, decrease, modify, or otherwise change the properties of the polynucleotide itself, and/or alter the properties, activity, composition, stability, or primary sequence of the encoded polypeptide.
[1302] In other embodiments of the present invention, the polynucleotide sequences provided herein are used as probes or primers for nucleic acid hybridization, e.g., as PCR primers. The ability of such nucleic acid probes to specifically hybridize to a sequence of interest enable 239 õ , =
them to detect the presence of complementary sequences in a given sample.
However, other uses are also encompassed by the invention, such as the use of the sequence information for the preparation of mutant species primers, or primers for use in preparing other genetic constructions. As such, nucleic acid segments of the invention that include a sequence region of at least about 15 nucleotides long contiguous sequence that has the same sequence as, or is complementary to, a 15 nucleotide long contiguous sequence disclosed herein is particularly useful. Longer contiguous identical or complementary sequences, e.g., those of about 20, 30, 40, 50, 100, 200, 500, 1000 (including all intermediate lengths) including full length sequences, and all lengths in between, are also used in certain embodiments.
[1303] Polynucleotide molecules having sequence regions consisting of contiguous nucleotide stretches of 10-14, 15-20, 30, 50, or even of 100-200 nucleotides or so (including intermediate lengths as well), identical or complementary to a polynucleotide sequence disclosed herein, are particularly contemplated as hybridization probes for use in, e.g., Southern and Northern blotting, and/or primers for use in, e.g., polymerase chain reaction (PCR). The total size of fragment, as well as the size of the complementary stretch(es), ultimately depends on the intended use or application of the particular nucleic acid segment.
Smaller fragments are generally used in hybridization embodiments, wherein the length of the contiguous complementary region may be varied, such as between about 15 and about 100 nucleotides, but larger contiguous complementarity stretches may be used, according to the length complementary sequences one wishes to detect.
[1304] The use of a hybridization probe of about 15-25 nucleotides in length allows the formation of a duplex molecule that is both stable arid selective. Molecules having contiguous complementary sequences over stretches greater than 12 bases in length are generally preferred, though, in order to increase stability and selectivity of the hybrid, and thereby improve the quality and degree of specific hybrid molecules obtained.
Nucleic acid molecules having gene-complementary stretches of 15 to 25 contiguous nucleotides, or even longer where desired, are generally preferred.
[1305] Hybridization probes are selected from any portion of any of the sequences disclosed herein. All that is required is to review the sequences set forth herein, or to any continuous portion of the sequences, from about 15-25 nucleotides in length up to and including the full length sequence, that one wishes to utilize as a probe or primer. The choice of probe and primer sequences is governed by various factors. For example, one may wish to employ primers from towards the termini of the total sequence.

CA 02827301 2013708-13, WO 2012/112489 = =

, [1306] Polynucleotide of the present invention, or fragments or variants thereof, are readily prepared by, for example, directly synthesizing the fragment by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer. Also, fragments are obtained by application of nucleic acid reproduction technology, such as the PCRTM
technology of U. S. Patent 4,683,202, by introducing selected sequences into recombinant vectors for recombinant production, and by other recombinant DNA techniques generally known to those of skill in the art of molecular biology.
Vectors, Host Cells and Recombinant Methods [1307] The invention provides vectors and host cells comprising a nucleic acid of the present invention, as well as recombinant techniques for the production of a polypeptide of the present invention. Vectors of the invention include those capable of replication in any type of cell or organism, including, e.g., plasmids, phage, cosmids, and mini chromosomes. In various embodiments, vectors comprising a polynucleotide of the present invention are vectors suitable for propagation or replication of the polynucleotide, or vectors suitable for expressing a polypeptide of the present invention. Such vectors are known in the art and commercially available.
[1308] Polynucleotides of the present invention are synthesized, whole or in parts that are then combined, and inserted into a vector using routine molecular and cell biology techniques, including, e.g., subcloning the polynucleotide into a linearized vector using appropriate restriction sites and restriction enzymes. Polynucleotides of the present invention are amplified by polymerase chain reaction using oligonucleotide primers complementary to each strand of the polynucleotide. These primers also include restriction enzyme cleavage sites to facilitate subcloning into a vector. The replicable vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, and one or more marker or selectable genes.
[1309] In order to express a polypeptide of the present iiiV-ention, the nucleotide sequences encoding the polypeptide, or functional equivalents', are inserted into an appropriate expression vector, i.e., a vector that contains the necessary elements for the transcription and translation of the inserted coding sequence. Methods well known to those skilled in the art are used to construct expression vectors containing sequences encoding a polypeptide of interest and appropriate transcriptional and translational control elements.
These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic 241 .

= =
recombination. Such techniques are described, for example, in Sambrook, J., et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Plainview, N.Y., and Ausubel, F. M. et al. (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York. N.Y.
[1310] A variety of expression vector/host systems are utilized to contain and express polynucleotide sequences. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA
expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with virus expression vectors (e.g., baculovirus); plant cell systems transformed with virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems.
Within one embodiment, the variable regions of a gene expressing a monoclonal antibody of interest are amplified from a hybridoma cell using nucleotide primers. These primers are synthesized by one of ordinary skill in the art, or may be purchased from commercially available sources (see, e.g., Stratagene (La Jolla, California), which sells primers for amplifying mouse and human variable regions. The primers are used to amplify heavy or light chain variable regions, which are then insertd into vectors such as ImmUnOZAPTM H or ImmUnOZAPTM L (Stratagene), respectively. These vectors are then introduced into E. coli, =
yeast, or mammalian-based systems for expression. Large amounts of a single-chain protein containing a fusion of the VH and VL domains are produced using these methods (see Bird et al., Science 242:423-426 (1988)).
[1311] The "control elements" or "regulatory sequences" present in an expression vector are those non-translated regions of the vector, e.g., enhancers, promoters, 5' and 3' untranslated regions, that interact with host cellular proteins to carry out transcription and translation.
Such elements may vary in their strength and specificity. Depending on the vector system and host utilized, any number of suitable transcription and translation elements, including constitutive and inducible promoters, is used.
[1312] Examples of promoters suitable for use with prokaryotic hosts include the phoa promoter,13-lactamase and lactose promoter systems, alkaline phosphatase promoter, a tryptophan (trp) promoter system, and hybrid promoters, such as the tac promoter. However, other known bacterial promoters are suitable. Promoters for use in bacterial systems also usually contain a Shine-Dalgarrio sequence operably linked to the DNA encoding the polypcptide. Inducible promoters such as the hybrid lacZ promoter of the PBLUESCRIPT

phagemid (Stratagene, La Jolla, Calif.) or PSPORT1 plasmid (Gibco BRL, Gaithersburg, MD) and the like are used.
[1313] A variety of promoter sequences are known for eukaryotes and any are used according to the present invention. Virtually all eukaryotic genes have an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated.
Another sequence found 70 to 80 bases upstream Trorn the start of transcription of many genes is a CNCAAT region where N may be any nucleotide. At the 3 end of most eukaryotic genes is an AATAAA sequence that may be the signal for addition of the poly A
tail to the 3' end of the coding sequence. All of these sequences are suitably inserted into eukaryotic expression vectors.
[1314] In mammalian cell systems, promoters from mammalian genes or from mammalian viruses are generally preferred. Polypeptide expression from vectors in mammalian host cells aer controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (e.g., Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus (CMV), a retrovirus, hepatitis-B virus and most preferably Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems. If it is necessary to generate a cell line that contains multiple copies of the sequence encoding a polypeptide, Vectors based on SV40 or EBV may =
be advantageously used with an appropriate selectable marker. One example of a suitable ;= , -expression vector is pcDNA-3.1 (Invitrogen, Carlsbad, CA), which includes a CMV
promoter.
[1315] A number of viral-based expression systems are available for mammalian expression of polypeptides. For example, in cases where an adenovirus is used as an expression vector, sequences encoding a polypeptide of interest may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader =
sequence. Insertion in a non-essential El or E3 region of the viral genome may be used to obtain a viable virus that is capable of expressing the polypeptide in infected host cells (Logan, J. and Shenk, T. (1984) Proc. Natl. Acad. Sci. 81:3655-3659). In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells.
[1316] In bacterial systems, any of a number of expression vectors are selected depending upon the use intended for the expressed polypeptide:: For example, when large quantities are 243.

desired, vectors that direct high level expression of fusion proteins that are readily purified are used. Such vectors include, but are not limited to, the multifunctional E.
coli cloning and expression vectors such as BLUESCRIPT (Stratagene), in which the sequence encoding the polypeptide of interest may be ligated into the vector in frame with sequences for the amino-terminal Met and the subsequent 7 residues of13-galactosidase, so that a hybrid protein is produced; pIN vectors (Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem.
264:5503-5509); and the like. pGEX Vectors (Promega, Madison, WI) are also used to express foreign polypeptides as fusion proteins with glutathione S-tr,ansferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption to glutathione-agarose beads followed by elution in the presence:of free glutathione.
Proteins made in such systems are designed to include heparin, thrombin, or factor XA protease cleavage sites so that the cloned polypeptide of interest can be released from the GST moiety at will.
[1317] In the yeast, Saccharomyces cerevisiae, a number of vectors containing constitutive or inducible promoters such as alpha factor, alcohol oxidase, and PGH are used.
Examples of other suitable promoter sequences for use with yeast hosts include the promoters for 3-phosphoglycerate kinase or other glycolytic enzymes, such as enolase, glyceraldehyde-3-phosphate dehydrogcnase, hexolcinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase. For reviews, see Ausubel et al.
(supra) and Grant et al. (1987) Methods Enzymol. 153:516-544. Other yeast promoters that are inducible promoters having the additional advantage of transcription controlled by growth conditions include the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with'n'itrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,6.57. Yeast enhancers also are athiantageously used with yeast promoters.
[1318] In cases where plant expression vectors are used, the expression of sequences =
encoding polypeptides are driven by any of a number of promoters. For example, viral promoters such as the 35S and 19S promoters of CaMV are used alone or in combination with the omega leader sequence from TMV (Takamatsu, N. (1987) EMBO J. 6:307-311.
Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters are used (Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Broglie, R.
et al. (1984) Science 224:838-843; and Winter, J., et al. (1991) Results Probl. Cell Differ.
/7:85-105).

qi These constructs can be introduced into plant cells by direct DNA
transformation or pathogen-mediated transfection. Such techniques are described in a number of generally available reviews (see, e.g., Hobbs, S. or Murry, L. E. in McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York, N.Y.; pp. 191-196).
[1319] An insect system is also used to express a polypeptide of interest. For example, in one such system, Autographa californicq nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes in Spodoptera frugiperda cells or in Trichoplusia larvae. The sequences encoding the polypeptide are cloned into a non-essential region of the virus, such as the polyhedrin gene, and placed under control of the polyhedrin promoter.
Successful insertion of the polypeptide-encoding sequence renders the polyhedrin gene inactive and produce recombinant virus lacking coat protein. The recombinant viruses are then used to infect, for example, S. frugiperda cells or Trichoplusia larvae, in which the polypeptide of interest is expressed (Engelhard, E. K. et al. (1994) Proc. Natl. Acad. Sci.
91 :3224-3227).
[1320] Specific initiation signals are also used to achieve more efficient translation of sequences encoding a polypeptide of interest. Such signals include the ATG
initiation codon and adjacent sequences. In cases where sequences encoding the polypeptide, its initiation codon, and upstream sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed.
However, in cases where only coding sequence, or a portion thereof, is inserted, exogenous translational control signals including the ATG initiation codon are provided. Furthermore, the initiation codon is in the correct reading frame to ensure correct translation of the inserted polynucleotide.
Exogenous translational elements and initiation codons are of various origins, both natural and synthetic.
[1321] Transcription of a DNA encoding a polypeptide of the invention is often increased by inserting an enhancer sequence into the vector. Many enhancer sequences are known, including, e.g., those identified in genes encoding globin, elastase, albumin, a-fetoprotein, and insulin. Typically, however, an enhancer from a eukaryotic cell virus is used. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the =
cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. See also Yaniv, Nature 297:17-18 (1982) on enhancing elements for activation of eukaryotic promoters. The enhancer is spliced into the vector at a position 5' or 3' to the polypeptide-encoding sequence, but is preferably located at a site 5' from the promoter.

[1322] Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular ,organisms) typically also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are comrnonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding anti-PSCA
antibody. One useful transcription termination component is the bovine growth hormone polyadenylation region. See W094/11026 and the expression vector disclosed therein.
[1323] Suitable host cells for cloning or expressing the DNA in the vectors herein are the prokaryote, yeast, plant or higher eukaryote cells described above. Examples of suitable prokaryotes for this purpose include eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. lichemformis 41P disclosed in DD 266,710 published 12 Apr. 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. One preferred E. coli cloning host is E. coli 294 (ATCC 31,446), although other strains such as E. eoli B, E. coli X1776 (ATCC
31,537), and E. coli W3110 (ATCC 27,325) are suitable. These examples are illustrative rather than limiting. .õ
[1324] Saccharomyces cerevisiae, or common baker's yeast, is the most commonly used among lower eukaryotic host microorganisms. However, a number of other genera, species, and strains are commonly available and used herein, such as Schizosaccharomyces pombe;
Kluyveromyces hosts such as, e.g., K lactis, K. fragilis (ATCC 12,424), K.
bulgaricus (ATCC
16,045), K wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC
36,906), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris. (EP
183,070); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa;
Schwanniotnyces such as Schwanniomyces occidentalis; and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts such as A. nidulans and A.
niger.
[1325] In certain embodiments, a host cell strain is chosen for its ability to modulate the expression of the inserted sequences or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are not limited to, acetylation, . =
carboxylation. glycosylation, phosphorylation, lipidation,t and acylation.
Post-translational processing that cleaves a "prepro" form of the protein is also used to facilitate correct insertion, folding and/or function. Different host cells such as CHO, COS, HeLa, MDCK, HEK293, and WI38, which have specific cellular machinery and characteristic mechanisms for such post-translational activities, are chosen to ensure the correct modification and processing of the foreign protein.
[1326] Methods and reagents specifically adapted for the expression of antibodies or fragments thereof are also known and available in the art, including those described, e.g., in U.S. Patent Nos. 4,816,567 and 6,331,415. In various embodiments, antibody heavy and light chains, or fragments thereof, are expressed from the same or separate expression vectors. In one embodiment, both chains are expressed in the same cell, thereby facilitating the formation of a functional antibody or fragment thereof.
[1327] Full length antibody, antibody fragments, and antibody fusion proteins are produced in bacteria, in particular when glycosylaticin and Fc effector function are not needed, such as when the therapeutic antibody is conjugated to a cytotoxic agent (e.g., a toxin) and the immunoconjugate by itself shows effectiveness in infected cell destruction.
For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos.
5,648,237, 5,789,199, and 5,840,523, which describes translation initiation region (TIR) and signal sequences for optimizing expression and secretion. After expression, the antibody is isolated from the E. coli cell paste in a soluble fraction and can be purified through, e.g., a protein A
or G column depending on the isotype. Final purification can be carried out using a process similar to that used for purifying antibody expressed. e.g., in CHO cells.
[1328] Suitable host cells for the expression of glyebsylated polypeptides and antibodies are derived from multicellular organisms. Examples of inveitebrate cells include plant and insect cells. Numerous baculoviral strains and variants and.corresponding permissive insect host cells from hosts such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopicius (mosquito), Drosophila melanogaster (fruitfly), and Bombyx mori have been identified. A variety of viral strains for transfection are publicly available, e.g., the L-1 variant of Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV, and such viruses are used as the virus herein according to the present invention, particularly for transfection of Spodoptera frugiperda cells. Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco are also utilized as hosts.
[1329] Methods of propagation of antibody polypeptides and fragments thereof in vertebrate cells in culture (tissue culture) are encompassed by the invention. Examples of mammalian host cell lines used in the methods of the invention are monkey kidney CV1 line transformed 247 .

by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells/-DHFR
(CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV I ATCC CCL 70);
African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL
3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep 02, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TR1 cells (Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cells; F54 cells; and a human hepatoma line (Hep G2). =
[1330] Host cells are transformed with the above-described expression or cloning vectors for polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.
[1331] For long-term, high-yield production of recombinant proteins, stable expression is generally preferred. For example, cell lines that stably express a polynucleotide of interest are transformed using expression vectors that contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells are allowed to grow for 1-2 days in an enriched media before they are switched to selective media. The purpose of the selectable marker is to confer resistance to selection, and its presence allows growth and recovery of cells that successfully express the introduced sequences. Resistant clones of stably =
transformed cells are proliferated using tissue culture techniques appropriate to the cell type.
, -[1332] A plurality of selection systems are used to' recover transformed cell lines. These include, but are not limited to, the herpes simplex virus thymidine kinase (Wigler, M. et al.
(1977) Cell 11:223-32) and adenine phosphoribosyltr'ansferase (Lowy, I. et al.
(1990) Cell 22:817-23) genes that are employed in tk- or aprt- cells, respectively. Also, antimetabolite, antibiotic or herbicide resistance is used as the basis for selection; for example, dhfr, which confers resistance to methotrexate.(Wigler, M. et al. (1980) Proc. Natl. Acad.
Sci. 77:3567-70); npt, which confers resistance to the aminoglycosides, neomycin and G-4I8 (Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14); and als or pat, which confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively (Murry, supra). Additional selectable genes have been described. For example, trpB allows cells to utilize indole in place of tryptophan, and hisD allows cells to utilize histinol in place of histidine (Hartman, S.
C. and R. C. Mulligan (1988) Proc. Natl. Acad. Sci. 85:8047-51). The use of visible markers has gained popularity with such markers as anthocyanins, beta-glucuronidase and its substrate GUS, and luciferase and its substrate luciferin, being widely used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system (Rhodes, C. A. et al. (1995) Methods Mol. Biol.
55:121-131).
[1333] Although the presence/absence of marker gene expression suggests that the gene of interest is also present, its presence and expression is confirmed. For example, if the sequence encoding a polypeptide is inserted within a marker gene sequence, recombinant cells containing sequences are identified by the absence of marker gene function.
Alternatively, a marker gene is placed in tandem with a polypeptide-encoding sequence under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
[1334] Alternatively, host cells that contain and express a,desired polynucleotide sequence are identified by a variety of procedures known to those of skill in the art.
These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations and protein bioassay or immunoassay techniques which include, for example, membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein.
[1335] A variety of protocols for detecting and measuring the expression of polynucleotide-encoded products, using either polyclonal or monoclonal antibodies specific for the product are known in the art. Nonlimiting examples include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on a given polypeptide is preferred for some applications, but a competitive binding assay may also be employed. These and other assays are described, among other places, in Hampton, R. et al. (1990; Serological Methods, a Laboratory Manual, APS Press, St Paul. Minn.) and Maddox, D. E. et al. (1983; J. Exp. Med.
158:1211-1216).
[1336] Various labels and conjugation techniques:are known by those skilled in the art and are used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides include oligolabeling, nick translation, end-labeling or PCR amplification using a labeled nucleotide.

Alternatively, the sequences, or any portions thereof are cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and are used to synthesize RNA probes invitro by addition of an appropriate RNA
polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures are conducted using a variety of commercially available kits. Suitable reporter molecules or labels, which are used include, but are not limited to, radionuclideg, enzymes, fluorescent, chemilurninescent, or chromogenic agents as well as substrates, cofactors, inhibitors, magnetic particles, and the like.
[1337] The polypeptide produced by a recombinant cell is secreted or contained intracellularly depending on the sequence and/or the vector used. Expression vectors containing polynucleotides of the invention are designed to contain signal sequences that direct secretion of the encoded polypeptide through a prokaryotic or eukaryotic cell membrane.
[1338] In certain embodiments, a polypeptide of the invention is produced as a fusion polypeptide further including a polypeptide domain that facilitates purification of soluble proteins. Such purification-facilitating domains include, but are not limited to, metal chelating peptides such as histidine-tryptophan ='modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized immunoglobulin, and the domain utilized in the FLAGS extension/affinity purification system (Amgen, Seattle, WA). The inclusion of cleavable linker sequences such as those specific for Factor XA or enterokinase (Invitrogen. San Diego, CA) between the purification domain and the encoded polypeptide are used to facilitate purification. An exemplary expression vector provides for expression of a fusion protein containing a polypeptide of interest and a nucleic acid encoding 6 histidine residues preceding a thioredoxin or an enterokinase cleavage site. The histidine residues facilitate purification on IMIAC
(immobilized metal ion affinity chromatography) as described in Porath, J. et al. (1992, Prot.
Exp. Purif. 3:263-281) while the enterokinase cleavage site provides a means for purifying the desired polypeptide from the fusion protein. A discussion of vectors used for producing fusion proteins is provided in Kroll, D. J. et al. (1993; DNA Cell Biol.
/2:441-453).
[1339] In certain embodiments, a polypeptide of the present invention is fused with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
The heterologous signal sequence selected preferably is one that is recognized and processed (i.e., , =
250 , WO 2012/112489= =

cleaved by a signal peptidase) by the host cell. For prokaryotic host cells, the signal sequence is selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders. For yeast secretion, the signal sequence is selected from, e.g., the yeast invertase leader, a factor leader (including Saccharomyces and Kluyverornyces a factor leaders), or acid phosplmtase leader, the C. albicans glucoamylase leader, or the signal described in WO 90/13646. In mammalian cell expression, mammalian signal sequences as well as viral secretory leaders, for example, the herpes simplex gD signal, are available.
[1340] When using recombinant techniques, the paypeptide or antibody is produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the polypeptide or antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, are removed, for example, by centrifugation or ultrafiltration. Carter et al., Bio/Technology 10:163-167 (1992) describe a procedure for isolating antibodies that are secreted to the periplasmic space of E. coli.
Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min. Cell debris is removed by centrifugation. Where the polypeptide or antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. Optionally, a protease inhibitor such as PMSF is included in any of the foregoing steps to inhibit proteolysis and antibiotics are included to prevent the growth of adventitious contaminants.
[1341] The polypeptide or antibody composition pre'pared from the cells are purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the preferred purification technique.
The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the polypeptide or antibody.
Protein A is used to purify antibodies or fragments thereof that are based on human 72, or 74 heavy chains (Lindmark et al., J. Immunol. Meth. 62:1-13 (1983)). Protein G is recommended for all mouse isotypes and for human 73 (Guss et al., EMBO J. 5:15671575 (1986)). The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available.
Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose.
Where the polypeptide or antibody comprises a CH 3 domain, the Bakerbond ABXTM
resin (J.

=
=:

T. Baker, Phillipsburg, N.J.) is useful for purification. Other techniques for protein purification such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSETM -chromatography on an anion or cation exchange .resin (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available depending on the polypeptide or antibody to be recovered.
[1342] Following any preliminary purification step(s), the mixture comprising the polypeptide or antibody of interest and contaminants are subjected to low pH
hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5-4.5, preferably performed at low salt concentrations (e.g., from about 0-0.25M salt).
Pharmaceutical Compositions [1343] The invention further includes pharmaceutical formulations including a polypeptide, antibody, or modulator of the present invention, at a desired degree of purity, and a pharmaceutically acceptable carrier, excipient, or stabilizer (Remingion's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). In certain embodiments, pharmaceutical formulations are prepared to enhance the stability of the polypeptide or antibody during storage, e.g., in the form of lyophilized formulations or aqueous solutions.
[1344] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include, e.g., buffers such as acetate, Tris, phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol;
alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides;
proteins, such as serum albumin, gelatin, or imfriunoglobujins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine,-glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; torkifiers such as trehalose and sodium chloride; sugars such as sucrose, mannitol, trehalose or sorbitol;
surfactant such as polysorbate; salt-forming counter-ions such as sodium; metal complexes (e.g.
Zn-protein = complexes); and/or non-ionic surfactants such as TWEENTm, PLURONICSTM or polyethylene glycol (PEG). In certain embodiments, the therapeutic formulation preferably comprises the polypeptide or antibody at a concentration 6f between 5-200 mg/ml, preferably between 10-100 mg/ml.
[1345] The formulations herein also contain one or thore additional therapeutic agents suitable for the treatment of the particular indication, e.g., infection being treated, or to prevent undesired side-effects. Preferably, the additional therapeutic agent has an activity complementary to the polypeptide or antibody of the resent invention, and the two do not adversely affect each other. For example, in addition to the polypeptide or antibody of the invention, an additional or second antibody, anti-viral agent, anti-infective agent and/or cardioprotectant is added to the formulation. Such molecules are suitably present in the pharmaceutical formulation in amounts that are effective for the purpose intended.
[1346] The active ingredients, e.g., polypeptides and antibodies of the invention and other therapeutic agents, are also entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in.Remingion's Pharrnaceutical Sciences 16th edition, Osol, A. Ed. (1980).
[1347] Sustained-release preparations are prepared. Suitable examples of sustained-release preparations include, but are not limited to, semi-permeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Nonlimiting examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTm (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxyburyric acid.
[1348] Formulations to be used for in vivo administration are preferably sterile. This is readily accomplished by filtration through sterile filtration membranes.
Diagnostic Uses .
[1349] Antibodies and fragments thereof, and therapeutic compositions, of the invention specifically bind or preferentially bind to infected cells or tissue, as compared to normal control cells and tissue. Thus, these influenza A antibodies are used to detect infected cells or tissues in a patient, biological sample, or cell population, using any of a variety of diagnostic and prognostic methods, including those described herein. The ability of an anti-M2e or anti-HA specific antibody to detect infected cells depends upon its binding specificity, which is readily determined by testing its ability to bind to infected cells or tissues obtained from different patients, and/or from patients infected with different strains of Influenza A.
[1350] Diagnostic methods generally involve contacting a biological sample obtained from a patient, such as, e.g., blood, serum, saliva, urine, sputum, a.cell swab sample, or a tissue biopsy, with an Influenza A, e.g., human monoclonal anti-M2e or anti-HA
antibody, and determining whether the antibody preferentially binds to the sample as compared to a control sample or predetermined cut-off value, thereby indicating the presence of infected cells. In particular embodiments, at least two-fold, three-fold, or five-fold more human monoclonal anti-M2e or anti-HA antibody binds to an infected cell as compared to an appropriate control normal cell or tissue sample. A pre-determined cut-off value is determined, e.g., by averaiing the amount of human monoclonal anti-M2e or anti-HA antibody that binds to several different appropriate control samples under the same conditions used to perform the diagnostic assay of the biological sample being tested. Alternatively, or in addition, a hemagglutinin (HA) protein is substituted for an Influenza virus in the above method. The HA protein is presented on the surface of a virus, host cell (e.g. any mammalian cell), or in a recombinant and soluble form. In the HA version O'f this diagnostic method, the control =
protein is a denatured HA protein, a linear HA peptide, an. unrelated protein of similar size and shape, but dissimilar sequence, or a pre-determined cut-off value.
[1351] Bound antibody is detected using procedures described herein and known in the art.
In certain embodiments, diagnostic methods of the invention are practiced using human monoclonal anti-M2e or anti-HA antibodies that are conjugated to a detectable label, e.g., a = fluorophore, to facilitate detection of bound antibody. However, they are also practiced using methods of secondary detection of the human monoclonal anti-M2e or anti-HA
antibody.
These include, for example, RIA, ELISA, precipitation, agglutination, complement fixation and immuno-fluorescence.
[1352] In certain procedures, the human monoclonal anti-M2e or anti-HA
antibodies are labeled. The label is detected directly. Exemplary labels that are detected directly include, but are not limited to, radiolabels and fluorochromes. Alaternatively, or in addition, labels are moieties, such as enzymes, that must be reacted or derivatized to be detected.
Nonlimiting 254 =
=

examples of isotope labels are 99Tc, it, 131/, 12.5/, 3H, 3213 a -- is S. Fluorescent materials that are used include, but are not limited to, for example, fluorescein and its derivatives, rhodamine and its derivatives, auramine, dansyl, umbelliferone, luciferia, 2,3-dihydrophthalazinediones, horseradish peroxidase, alkaline phosphatase, lysozyme, and glucose-6-phosphate dehydrogenase.
[1353] An enzyme label is detected by any of the currently utilized colorimetric, spectrophotometric, fluorospectro-photometric or gasometric techniques. Many enzymes which are used in these procedures are known and utilized by the methods of the invention.
Nonlimiting examples are peroxidase, alkaline phosphatase, P-glucuronidase, P-D-glucosidase, P-D-galactosidase, urease, glucose oxidase plus peroxidase, galactose oxidase plus peroxidase and acid phosphatase.
[1354] The antibodies are tagged with such labels by known methods. For instance, coupling agents such as aldehydes, carbodiimides, dimaleirnide, imidates, succinimides, bid-diazotized benzadine and the like are used to tag the antibodies with the above-described fluorescent, chemiluminescent, and enzyme labels. An enzyme is typically combined with an antibody using bridging molecules such as carbodiimides, periodate, diisocyanates, glutaraldehyde and the like. Various labeling techniques are described in Morrison, Methods in Enzymology 32b, 103 (1974), Syvanen et al., J. Biol. Chem. 284, 3762 (1973) and Bolton and Hunter, Biochem J. 133, 529(1973).
[1355] Human monoclonal anti-M2e or anti-HA antibodies of the present invention are capable of differentiating between patients with and patients without an Influenza A
infection, and determining whether or not a patient has an infection, using the representative assays provided herein. According to one method, a biological sample is obtained from a patient suspected of having or known to have an influenza A infection. In preferred embodiments, the biological sample includes cells. from the patient. The sample is contacted with a human monoclonal anti-M2e or anti-HA antibody, e.g., for a time and under conditions sufficient to allow the human monoclonal anti-M2e or anti-HA
antibody to bind to infected cells present in the sample. For instance, the sample is contacted with a human monoclonal anti-M2e or anti-HA antibody for 10 seconds, 30 seconds, 1 minute, 5 minutes, minutes, 30 minutes, 1 hour, 6 hours, 12 hours, 24 hours, 3 days or any point in between.
The amount of bound human monoclonal anti-M2e or anti-HA antibody is determined and compared to a control value, which may be, e.g., a pre-determined Value or a value determined from normal tissue sample. An increased amount of antibody bound to the = .t .1 '1 patient sample as compared to the control sample is indicative of the presence of infected cells in the patient sample.
[1356] In a related method, a biological sample obtained from a patient is contacted with a human monoclonal anti-M2e or anti-HA antibody for a time and under conditions sufficient to allow the antibody to bind to infected cells. Bound antibody is then detected, and the presence of bound antibody indicates that the sample contains infected cells.
This embodiment is particularly useful when the human monoclonal anti-M2e or anti-HA antibody does not bind normal cells at a detectable level.
[1357] Different human monoclonal anti-M2e or anti-HA antibodies possess different binding and specificity characteristics. Depending upon these characteristics, particular human monoclonal anti-M2e or anti-HA antibodies are used to detect the presence of one or more strains of Influenza A. For example, certain antibodies bind specifically to only one or several strains of Influenza virus, whereas others bind to all or a majority of different strains of Influenza virus. Antibodies specific for only one strain of Influenza A are used to identify the strain of an infection.
[1358] In certain embodiments, antibodies that bind to an infected cell preferably generate a signal indicating the presence of an infection in at least about 20% of patients with the infection being detected, more preferably at least about 30% of patients.
Alternatively, or in addition, the antibody generates a negative signal indicating the absence of the infection in at least about 90% of individuals without the infection being detected. Each antibody satisfies the above criteria; however, antibodies of the present invention are used in combination to improve sensitivity.
[1359] The present invention also includes kits useful in performing diagnostic and prognostic assays using the antibodies of the present invention. Kits of the invention include a suitable container comprising a human monoclonal anti-M2e or anti-HA
antibody of the invention in either labeled or unlabeled form. In addition, when the antibody is supplied in a labeled form suitable for an indirect binding assay, the kit further includes reagents for performing the appropriate indirect assay. For exaMple, the kit includes one or more suitable containers including enzyme substrates or derivatizing agents, depending on the nature of the label. Control samples and/or instructions are also included.
Therapeutic/ Prophylactic Uses [1360] Passive immunization has proven to be an effective and safe strategy for the prevention and treatment of viral diseases. (See Keller et al., Clin.
Microbiol. Rev. 13:602-14 =

(2000); Casadevall, Nat. Biotechnol. 20:114 (2002); Shibata et al., Nat. Med.
5:204-10 (1999); and Igarashi et al., Nat. Med. 5:211-16 (1999), each of which are incorporated herein by reference)). Passive immunization using human monoclonal antibodies provide an immediate treatment strategy for emergency proppylaxis and treatment of influenza [1361] Human monoclonal anti-M2e or anti-HA antibodies and fragments thereof, and therapeutic compositions, of the invention specifically bind or preferentially bind to infected cells, as compared to normal control uninfected cells and tissue. Thus, these human monoclonal anti-M2e or anti-HA antibodies are used to selectively target infected cells or tissues in a patient, biological sample, or cell population. In light of the infection-specific binding properties of these antibodies, the present invention provides methods of regulating (e.g., inhibiting) the growth of infected cells, methods of killing infected cells, and methods of inducing apoptosis of infected cells. These methods include contacting an infected cell with a human monoclonal anti-M2e or anti-HA antibody of the invention. These methods are practiced in vitro, ex vivo, and in vivo.
[1362] In various embodiments, antibodies of the invention are intrinsically therapeutically active. Alternatively, or in addition, antibodies of the invention are conjugated to a cytotoxic agent or growth inhibitory agent, e.g., a radioisotope or toxin, which is used in treating infected cells bound or contacted by the antibody.' [1363] In one embodiment, the invention provides methods of treating or preventing infection in a patient, including the steps of providing a human monoclonal anti-M2e or anti-HA antibody of the invention to a patient diagnosed with, at risk of developing, or suspected of having an Influenza A infection. The methods of the invention are used in the first-line treatment of the infection, follow-on treatment, or in the treatment of a relapsed or refractory infection. Treatment with an antibody of the invention is a stand alone treatment.
Alternatively, treatment with an antibody of the invention is one component or phase of a combination therapy regime, in which one or more additional therapeutic agents are also used =
to treat the patient.
[1364] Subjects at risk for an influenza virus -related diseases or disorders include patients who have come into contact with an infected person or who have been exposed to the influenza virus in some other way. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the influenza virus -related disease or disorder, such that a disease or disorder is prevented or, alternatively, delayed in its progression.
;, 257 :

[1365] In various aspects, the human monoclonal anti-M2e or anti-HA is administered substantially contemporaneously with or following infection of the subject, i.e., therapeutic treatment. In another aspect, the antibody provides a therapeutic benefit. In various aspects, a therapeutic benefit includes reducing or decreasing progression, severity, frequency, duration or probability of one or more symptoms or complications of influenza infection, virus titer, virus replication or an amount of a viral protein of one or more influenza strains. still another aspect, a therapeutic benefit includes hastening or accelerating a subject's recovery from influenza infection.
[1366] Methods for preventing an increase in influenza virus titer, virus replication, virus proliferation or an amount of an influenza viral protein in a subject are further provided. In one embodiment, a method includes administering to the subject an amount of a human monoclonal anti-M2e or anti-HA antibody effective to prevent an increase in influenza virus titer, virus replication or an amount of an influenza viral protein of one or more influenza strains or isolates in the subject.
[1367] Methods for protecting a subject from infection or decreasing susceptibility of a subject to infection by one or more influenza strains/isolates or subtypes, i.e., prophylactic methods, are additionally provided. In one embodiment, a method includes administering to the subject an amount of human monoclonal anti-M2e or anti-HA antibody that specifically binds influenza M2 or HA, respectively, effective to protect the subject from infection, or effective to decrease susceptibility of the subject to infection, by one or more influenza strains/isolates or subtypes.
[1368] Optionally, the subject is further administered with a second agent such as, but not limited to, an influenza virus antibody, an anti-viral drug such as a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 ion channel inhibitor, a viral entry inhibitor or a viral attachment inhibitor. The M2 ion channel inhibitor is for example amantadine or rimantadine. The neuraminidase inhibitor for example zanamivir, or oseltamivir phosphate:
[1369] Symptoms or complications of influenza infection that can be reduced or decreased include, for example, chills, fever, cough, sore throat, nasal congestion, sinus congestion, nasal infection, sinus infection, body ache, head ache, fatigue, pneumonia, bronchitis, ear infection, ear ache or death.
[1370] For in vivo treatment of human and non-human patients, the patient is usually administered or provided a pharmaceutical formulation including a human monoclonal anti-M2e or anti-HA antibody of the invention. When used for in vivo therapy, the antibodies of the invention are administered to the patient in therapeutically effective amounts (i.e., amounts that eliminate or reduce the patient's viral burden). The antibodies are administered to a human patient, in accord with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneCous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. The antibodies may be administered parenterally, when possible, at the target cell site, or intravenously. Intravenous or subcutaneous administration of the antibody is preferred in certain embodiments. Therapeutic compositions of the invention are administered to a patient or subject systemically, parenterally, or locally.
[1371] For parenteral administration, the antibodies are formulated in a unit dosage injectable form (solution, suspension, emulsion) in association with a pharmaceutically acceptable, parenteral vehicle. Examples of such vehicles are water, 'saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate are also used. Liposomes are used as carriers. The vehicle contains minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. The antibodies are typically formulated in such vehicles at concentrations of about 1 mg/ml to 10 mg/ml.
[1372] The dose and dosage regimen depends upon a variety of factors readily determined by a physician, such as the nature of the infection and the characteristics of the particular cytotoxic agent or growth inhibitory agent conjugated to the antibody (when used), e.g., its therapeutic index, the patient, and the patient's history. Generally, a therapeutically effective amount of an antibody is administered to a patient. In particular embodiments, the amount of antibody administered is in the range of about 0.1 mg/kg to about 50 mg/kg of patient body weight. Depending on the type and severity of the infection, about 0.1 mg/kg to about 50 mg/kg body weight (e.g., about 0.1-15 mg/kg/dose) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. The progress of this therapy is readily monitored by conventional methods and assays and based on criteria known to the physician or other persons of skill in the art.
[1373] In one particular embodiment, an immunoconjugate including the antibody conjugated with a cytotoxic agent is administered to the patient. Preferably, the immunoconjugate is internalized by the cell, resulting in increased therapeutic efficacy of the immunoconjugate in killing the cell to which it binds. In one embodiment, the cytotoxic agent targets or interferes with the nucleic acid in the infected cell. Examples of such cytotoxic agents are described above and include, but are not limited to, maytansinoids, calicheamicins, ribonucleases and DNA endonucleases.
[1374] Other therapeutic regimens are combined with the administration of the HuM2e antibody of the present invention. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities. Preferably such combined therapy results in a synergistic therapeutic effect.
[1375] In certain embodiments, it is desirable to combine administration of an antibody of the invention with another antibody directed against another antigen associated with the infectious agent.
[1376] Aside from administration of the antibody protein to the patient, the invention provides methods of administration of the antibody by gene therapy. Such administration of nucleic acid encoding the antibody is encompassed by the expression "administering a therapeutically effective amount of an antibody". See, for'example, PCT Patent Application Publication W096/07321 concerning the use of gene therapy to generate intracellular antibodies.
[1377] In another embodiment, human monoclonal anti-M2e or anti-HA antibodies of the invention are used to determine the structure of bound antigen, e.g., conformational epitopes, the structure of which is then used to develop a vaccine having or mimicking this structure, e.g., through chemical modeling and SAR methods. Such a vaccine could then be used to prevent Influenza A infection.
[1378] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheetare incorporated herein by reference, in their entirety.
1. .

EXAMPLES
Example 1: Screening and Characterization of M2e-specific Antibodies Present in Human Plasma Using Cells Expressing Recombinant M2e Protein [1379] Fully human monoclonal antibodies specific for M2 and capable of binding to influenza A infected cells and the influenza virus itself were identified in patient serum, as described below.
Expression of M2 in Cell Lines [1380] An expression construct containing the M2 full length cDNA, corresponding to the derived M2 sequence found in Influenza subtype H3N2, was transfected into 293 cells.
[1381] The M2 cDNA is encoded by the following polynucleotide sequence and SEQ
ID
NO: 53:
ATGAGTCTTCTAACCGAGGTCGAAACGCCTATCAGAAACGAATGGGGGTGCAGATGCAACGATTCAAGTGATCCTCTT

GTTGTTGCCGCAAGTATCATTGGGATCCTGCACTTGATATTGTGGATTCTTGATCGTCTTTTTTTCAAATGCATTTAT

CGTCTCTTTAAACACGGTCTGAAAAGAGGGCCTTCTACGGAAGGAGTACCAGAGTCTATGAGGGAAGAATATCGAAAG

GAACAGCAGAGTGCTGTGGATGCTGACGATAGTCATTTTGTCAACATAGAGCTGGAG
[1382] The cell surface expression of M2 was confirmed using the anti-M2e peptide specific MAb 14C2. Two other variants of M2, from A/Hong Kong/483/1997 (HK483) and AJVietnam/1203/2004 (VN1203), were used for subsequent analyses, and their expression was determined using M2e-specific monoclonal antibodies of the present invention, since 14C2 binding may be abrogated by the various amino acid substitutions in M2e.
Screening of Antibodies in Peripheral Blood . =
[1383] Over 120 individual plasma samples were tested for antibodies that bound M2. None of them exhibited specific binding to the M2e peptide. However, 10% of the plasma samples contained antibodies that bound specifically to the 293-M2 H3N2 cell line.
This indicates that the antibodies could be categorized as binding to conformational determinants of an M2 homotetramer, and binding to conformational determinants of multiple variants of the M2 homotetramer; they could not be specific for the linear M2e peptide.
Characterization of Anti-M2 MAbs [1384] The human MAbs identified through this process proved to bind to conformational epitopes on the M2 homotetramer. They bound to the original 293-M2 transfectant, as well as to the two other cell-expressed M2 variants. The 14C2 MAb, in addition to binding the M2e peptide, proved to be more sensitive to the M2 variant sequences. Moreover, 14C2 does not readily bind influenza virions, while the conformation specific anti-M2 MAbs did.

=
=

[1385] These results demonstrate that the methods of the invention provide for the identification of M2 MAbs from normal human immune responses to influenza without a need for specific immunization of M2. If used for immunotherapy, these fully human MAbs have the potential to be better tolerated by patients that humanized mouse antibodies.
Additionally, and in contrast to 14C2 and the Gemini Biosciences MAbs, which bind to linear M2e peptide, the MAbs of the invention bind to conformational epitopes of M2, and are specific not only for cells infected with A strain influenza, but also for the virus itself.
Another advantage of the MAbs of the invention is that they each bind all of the M2 variants yet tested, indicating that they are not restricted to a specific linear amino acid sequence.
Example 2: Identification of M2-Specific Antibodies [1386] Mononuclear or B cells expressing three of the MAbs identified in human serum as described in Example 1 were diluted into clonal populations and induced to produce antibodies. Antibody containing supernatants were screened for binding to 293 FT cells stably transfected with the full length M2E protein from influenza strain Influenza subtype H3N2. Supernatants which showed positive staining/binding were re-screened again on 293 FT cells stably transfected with the full length M2E protein from influenza strain Influenza subtype H3N2 and on vector alone transfected cells as a control.
[1387] The variable regions of the antibodies were then rescue cloned from the B cell wells whose supernatants showed positive binding. Transient transfections were performed in 293 FT cells to reconstitute and produce these antibodies. Reconstituted antibody supernatants were screened for binding to 293 FT cells stably transfected with the full length M2E protein as detailed above to identify the rescued anti-M2E antibodies. Three different antibodies were -tt ;
identified: 8i10, 21B15 and 23K12. A fourth additional antibody clone was isolated by the rescue screens, 4C2. However, it was not unique and had the exact same sequence as clone ti 8i10 even though it came from a different donor than clone 8i10.
[1388] The sequences of the kappa and gamma variable regions of these antibodies are provided below.

, , , =
Clone 8i10 (corresponds to TCN-032):
[1389] The Kappa LC variable region of the anti M2 clone 8i10 was cloned as Hind III to BsiW1 fragment (see below), and is encoded by the following polynucleotide sequences, and SEQ ID NO: 54 (top) and SEQ ID NO: 55 (bottom):
Hindi!
AAGCTTCCACCATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGTG
TTCGAAGGTGGTACCTGTACTCCCAGGAGCGAGTCGAGGACCCCGAGGACGATGAGACCGAGGCTCCAC
CCAGATGTGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCA
GGTCTACACTGTAGGTCTACTGGGTCAGAGGTAGGAGGGACAGACGTAGACATCCTCTGTCTCAGTGGT
TCACTTGCCGGGCGAGTCAGAACATTTACAAGTATTTAAATTGGTATCAGCAGAGACCAGGGAAAGCCC
AGTGAACGGCCCGCTCAGTCTTGTAAATGTTCATAAATTTAACCATAGTCGTCTCTGGTCCCTTTCGGG
CTAAGGGCCTGATCTCTGCTGCATCCGGGTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGAT
GATTCCCGGACTAGAGACGACGTAGGCCCAACGTTTCACCCCAGGGTAGTTCCAAGTCACCGTCACCTA
CTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAAC
GACCCTGTCTAAAGTGAGAGTGGTAGTGGTCAGACGTTGGACTTCTAAAACGTTGAATGATGACAGTTG
BsiWI
AGAGTTACAGTCCCCCTCTCACTTTCGGCGGAGGGACCAddGTGGAGATCAAACGTACG
TCTCAATGTCAGGGGGAGAGTGAAAGCCGCCTCCCTGGTCCCACCTCTAGTTTGCATGC
[1390] The translation of the 8i10 Kappa LC variable region is as follows, polynucleotide sequence (above, SEQ ID NO: 54, top) and amino acid sequence (below, corresponding to residues 1-131 of SEQ ID NO: 56):
Hinc1111 AAGCTTCCACCATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGTG
MDMR V L AOL L GL L L LWL R
G
CCAGATGTGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCA
A R CD I OM TOSPS S L S A S V
GDR V T
TCACTTGCCGGGCGAGTCAGAACATTTACAAGTATTTAAATTGGTATCAGCAGAGACCAGGGAAAGCCC
I TCR A S ON I Y K LNWY DOR P
GK A
CTAAGGGCCTGATCTCTGCTGCATCCGGGTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGAT
PK GL IS A A SGL OSGV P SR F
S GS G
CTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAAC
SG TDF TL T I TS LOP E DF
A TY VC() BsiWI
AGAGTTACAGTCCCCCTCTCACTTTCGGCGGAGGGACCAGGGTGGAGATCAAACGTACG
OS YSPP L TF GGG TR V E I K
R T
[1391] The amino acid sequence of the 8i10 Kappa.LC variable region is as follows, with specific domains identified below (CDR sequences defined according to Kabat methods):
MDMRVLAQLLGLLLLWLRGARC VK leader (SEQ ID NO: 57) DIQMTQSPSSLSASVGDRVTITC FR1 (SEQ ID NO: 58) RASQNIYKYLN CDR1(SEQ ID NO: 59) WYQQRPGKAPKGLIS FR2 (SEQ ID NO: 60) AASGLOS CDR2 (SEO ID NO: 61) GVPSRFSGSGSGTDFTLTITSLQPEDFATYYC FR3(SEQIDNO:62) OQSYSPPLT CDR3 (SEQ ID NO: 63) ' =FGGGTRVEIK = FR4 (SEQ ID NO:
64) R T Start of Kappa constant region [1392] The following is an example of the Kappa LC variable region of 8i10 cloned into the expression vector pcDNA3.1 which already contained the Kappa LC constant region (upper = polynucleotide sequence corresponds to SEQ ID NO: 65, lower polynucleotide sequence corresponds to SEQ ID NO: 66, amino acid sequence corresponds to SEQ ID NO:
56). Bases in black represents pcDNA3.1 vector sequences, underlined bases represent the cloned = antibody sequences. The antibodies described herein have also been cloned into the expression vector pCEP4.
=
taid (r) Pnrit 040) Wain! at 0) TCGAT=ihTTAATACCACTC&CIATAGGi7,13--,CCCANGCTGGCTAGCGTTT APiiii.C.TTAA. GC T
TCCA CCATGGACA TGAG GGT CC T C
A4-4717TAATTATOCTIAGTTIECCATCCTTC-MtraCriPicX*IgCr.4.7AMITTCANTT C.; It AGG __ TrfrIT"r.., 7472.7TT:Ce AGG AC
G CT C AGCT CCT GGG GCT CCTG CTACTC TGG CTC CGAG TG C CA GA'r GTGACA'r CCA GA
T GAC CCAGTCT
mC GAG TCGA GGA CCC CGAGGAC GAT GAGA CC GAG GCT C.: CAC cGT CTA.CAC TG TA
GGTCTA CT G GG T C AGP.
MI _________ A
CA'r CCTC CC T GTC -rGc ATCT GTAGGA GAC AGA GT CA CCA TCACTT GCC GG GC GAG TCA
GAA CATT TA C
.G G TA GGAG GGACAGACG TAGA CAT CCT CTGlyr CAGT GGTAGT GRAcGGCCcGCTcP.GI'crT
GTAAATG
M-17¨.4 4 ______________________ zatr __________________________________ tt rr,.n.x.vrt r A AGT Arrr sTATCA.C. cAC, AGA CCA C;GG B.AAG CCC CTAAGG GCC 'MAT cpc TGC 'FCC AT CC GGC;
.T T CA TAAA TT'r ?AC CAT .A.GTC GTC TCT GGT CCC TTTC GGG GAT TCC CGG ACTA GAG
A CG ACG TAGG CCC
Krot v ______ tir P
'1"r GC A.A.AG TGG GG CCC ATCAAGG TTC AGT GGC AGTG GAT CTG GGA CA G ATrr CAC
TCT CAC CAT C ACC
=A AC G "1"1"FC ACC C CA GGG TAG'I"VCC AAG ' r ctA c.c. 'I' CAC C TA GAC CC' I
T.A.AA G'rG AGA GT G GTAG TGG
µ. V a v V Yvttr v Tot. Z t..r r __ I I 7 1 P. GT C GCA C C TGAIAGA T`1"1"r GC A ACT TAC TAc: TGrc .n..n.c AGA r ACA GT CC
CCC TCT CAC TT TC GGC
'I' CA G ACC' TGG A C' l'TCT AAA_A cur C, AcAn TTGTC'IrC.A.; Tar c.z. ___ AGA (!;TGA.:,:AG G
________________________________________________________ 2: = P t &Ma G GAG GG.A.0 CAG GGTGGAGATCAP.A.CiF.17- Tt .777. 7-717 .C. CTC CCTC:C7PC CCA CC:TM-CT TT-trAG =-=
- - - = T¨ ¨Ft r tenr''...Pa"S".''...r.."7. K
hu Kappa constant PIACT.17477.17117171.77.717:4.-1.717277,r77-=(-17.77,17-=.11,-.Th,..17.4.7.:VAA-7171.74.77,71V-1,74.77.7-..;,-,TAA.17477.77.7..z..;717.-47:717',.
=====r'-.
:AT,Critc.:71.=::.:N5Ch5C.V.Eal-TtIL: C,G7IGA.,-;111-,AACK:Ar-34-",71'is.CfaitcsAiW:j\CAi-i,GTC
707,3"cr(W:h0TC;TCIT.YSTCATfrift7.517 CUITTCCTITiGhTOTGr3C-NSIC:GTCGTGGIACTfiCt {,z;fi.; ITT LiTTT (AG
1:11¨t,5r r í U
gi;fs ,?sr58-EL .4.5K a 0.---sr'-rsr-r=-=
D.1111844 Mot r I Elinagarl (Ian Tb.c. 77 777:;F%?.:377-,CCCF=.T''.'A71,T,-:l;C7 _.F.:"3,77.7:17,7 7,77CFs.:7=_211.74,-.1:771: Fv,,,4,37 ATG-.5.-_,GACCCTMAZ-ri.450:
771C-riaker.P.i-leTCCCALWA-CT c17:Cird3r...M.PCTT
) n ____________________ Ir-9^-1.¨Itt r ____ rr rj z =
[1393] The 8i10 Gamma HC variable region was cloned as a Hind III to Xho 1 fragment, and is encoded the following polynucleotide sequences, and SEQ ID NO: 67 (top) and SEQ ID
NO: 68 (bottom).
HindlIl AAGCTTCCACCATGAAACACCTGTGGTTCTTCCTTCTCCTGGTGGCAGCTCCCAGCTGGGT
TTCGAAGGTGGTACTTTGTGGACACCAAGAAGGAAGAGGACCACCGTCGAGGGTCGACCCA
CCTGTCCCAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTG
GGACAGGGTCCACGTTAACGTCCTCAGCCCGGGTCCTGACCACTTCGGAAGCCTCTGGGAC
TCCCTCACCTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGC
AGGGAGTGGACGTGACAGAGACCAAGCAGGTAGTCATTAATGATGACCTCGACCTAGGCCG
AGTCCCCAGGGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTA
TCAGGGGTCCCITCCCTGACCTCACCTAACCCAAATAGATAATGCCACCTITGTGGTTCAT
CAATCCCTCCCTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTCTCC
GTTAGGGAGGGAGTTCTCGGCGCAGTGGTATAGTGTTCTGTGAAGGTTCTCAGTCCAGAGG
CTGACGATGAGCTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCTGTGCGAGAGCGTCTT
GACTGCTACTCGAGACACTGGCGACGCCTTAGCCGGCAGATAAAGACACGCTCTCGCAGAA
Xhol GTAGTGGTGGTTACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAG
CATCACCACCAATGACATAGGAACTGATGACCCCGGTCCCTTGGGACCAGTGGCAGAGCTC
[1394] The translation of the 8i10 Gamma HC is as follows, polynucleotide sequence (above, SEQ ID NO: 67, top) and amino acid sequence (below, corresponding to residues 1-138 of SEQ ID NO: 69):
HindlII
AAGCTTCCACCATGAAACACCTGTGGTTCTTCCTTCTCCTGGTGGCAGCTCCCAGCTGGGTC
MK HLWF F L L L V A A PSWV
CTGTCCCAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTG
L SOY O L OES GP GL V K P
SE T L
TCCCTCACCTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGG
SL TC T V SGSS I S N Y Y
WSW I R
CAGTCCCCAGGGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAG
OSP GK GLEW I GF I Y Y GGN
TK
TACAATCCCTCCCTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTC
YN=PSLK SR V T !SOD TSK SOV
TCCCTGACGATGAGCTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCTGTGCGAGAGCG
SL TMSS V T A A ES A V Y F C
A R A
>31o1 TCTTGTAGTGGTGGTTACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTC
S CS GG Y C I L D WGQG T L
v T V
TCGAG
265 .- s.

CA 02827301 2013-08-13 , [1395] The amino acid sequence of the 8i10 Gamma HC is as follows with specific domains identified below (CDR sequences defined according to Kabat methods):
MKHLWFFLLLVAAPSWVLS VH leader (SEC) ID NO: 70) QVQLOESGPGLVKPSETLSLTCTVSGSSIS FR1 (SEQ ID NO: 71) NYYWS CDR1(SEQ ID NO: 72) WIRQSPGKGLEWIG FR2 (SEQ ID NO: 73) FIYYGGNTKYNPSLKS CDR2 (SEQ ID NO: 74) RVTISQDTSKSQVSLTMSSVTAAESAVYFCAR FR3(SEQIDNO:75) ASCSGGYCILD CDR3 (SEQ ID NO: 76) =
YWGQGTLVTVS = FR4 (SEQ ID NO: 77) YVVGQGTLVTVSS Long FR4 (SEQ ID NO: 266) [1396] The following is an example of the Gamma HC variable region of 8i10 cloned into the expression vector pcDNA3.1 which already contained the Gamma HC constant region (upper polynucleotide sequence corresponds to SEQ ID NO: 78, lower polynucleotide sequence corresponds to SEQ ID NO: 79, amino acid sequence corresponds to SEQ
ID NO:
69). Bases in black represents pcDNA3.1 vector sequences, underlined bases represent the = CA 02 82 7 3 01 2 013- 0 8-13 Prnal alat Mel Mal 6na a I falai ..". 4.4.. rs, A A.,..t.;;4_,A4:. :AA%
;4; COTTCCACC AT GA AAC AC CTGT G GT T
RETGIATIV:TITAATTATGCMGAGFCATAITCCITITMOTTCCACIIIAWGCMATTTGAAT TCGA AGGT
C,C7rACT TT GTCGACACC AA
_____________________________________________________________ 111 CTTC CTTCTCCTGGTGGCAGCTCCCAGCTCGCJTCCTGTOCCAGGTQCAATTGCAGGAGTCCJGGCCCA
i. !. 0 _________________________________ IN*4.===========.a-====-=-9====-**----4*=41======-====t===¨=-0.--.===*4=-=-=-==9====--6----0¨=
GGACTGGTGAAGCÇTTÇGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTTCGTCCATCAGTAATT .
=
.tr.T AA
I AC P.1.1(A.t.A.71.1.747A-C*CTZTXC.r. t..1 CJ-0..1. ,trA 1/4.17-.4t7C.:171/47:7r.".
'6 CV -4 C ___ '4 61 ___________________ 0----6 ____ 6 __ AC.TACTGGAGCTGGATCCC,GCACITCCCC:AGGCAAGGGACTGGAGTGGATTGGCTTTATCTATTACGC
- T.Z7.-,A1",17,7i171:71' TkTirT7=t7.7.717.7177=i;i7.777.7.777 717.777177Arr:7177A7.77.77,77-.71õ.r.. CA70-7, 1-=,-,717,714T=
T ___________________ w ===
ta TGGA AACACCAAGTACAATC CCTCCCTCAAGAGCCGC GTCACCATATCACAAGACACTTCCAACJACJT
T Tr.77.1:777C7CT CTTIA7,-GC7r.C7C;C=TT17 ______________________________________ uCC7C7CCT,737,71777-7.77C717-C77.71-CA=L1C7-C
______________________________________________________________________________ e CAGGTCTCCCTGAr-7GATGAGCTCTGTGACCGCTGC:GGAATCGGCCGTCTATTTCTGTGCGAGAGCGT
LALUGLI' At.. T C.;.4A(,grArTiAAA.4c.C=7:TT-A=CrZCATXTr1/4r1/4.A.61-0:..
AL:CZ:7(7'r_ A
11.- ¨Q¨Vm---!.3-7.*T¨µ1*-73. V1 A. 3-7/k *Ad 03311 CTTGTAGTGGTGGTTACTGT ATCCTTGACTACTC;CJGGCCAGGGAACCCTGGTCACCGTGICAGW.;a:Ta.P.
A-"th7:7.- CA-C.17:rA c1=7;...7 Auk:, A A-L AIT=C k._ (4(, .TTLr.LUC:77; fc,crtõ.
c, 6.4 Vi". 6. ' 4 " __ 6 CCAA.:,:r_=C=C:AlrCOTCTTCCCCCT:===..";CACCeTC"C=rb".":ri.ALACCACATiC2C.1..:(;'3 CA:AGCC.*:=,..:1=,7;c:;,:',..."Trk-="..7,1>C,14A.2.-;::;,,:i.rkt:'1= T
v ______________________________ fl .4 .3 f T 11TTT t Ia t v 631',31-r:GTIAN:Tekw.;17 Ga-c,TCAc '.1.1;r:c.;G:C.TC:7ACRf:*C1-1-07c C;Crr CTCCTACAGTO:TCAG G.; C pr:TC.Ccr, rGGIGACCGTG7.7C.T.Cr:
e 4==...,1JATLI-ILTUAUT
laTii.....A1,1TY: 11.11 L rl.TiTT* 11.T.T1-}11.3dwIJAW'w . TS .1. .11.,T, =Tay- .T.
r, .T/7 IV. W
A,3,:.:47,Criµ.::::;ChlACCCAt3AC:r_=TAr.'k'N'T=C;:"AACCZCIAATCAC:AAGCCCAXA_ACAC
CAASGVIL:A.CAAr:;A".;;GTT,WR=-Cr.AAATC.Tri3T.31.,'.==AAAACTCACArAT
0.1 s t, = ___________ 1 T ..446"-14 - =4 ri Ca-VV.:11:c ::AP.:,..;-,.:XC,",.P.,,..;(1=Xl:AcCuTCA I GA
= = . 2.11. .11:1 At. -2.1V,1_=2l2',.., IT 1 TEr3le L WI 1..r.1.'1 J 1 Tk=Jr.I.T.J1Tit_ 1 ,T, laliAL
its..:1j.frr CD.y.rralel V V V U V r, Pf t V 'tS T V U to V t V V si A lc T = =
TT E
111 ttµ 1.1k it!...r...1..rOACI.V.Atit..44,41.P.A.
A' P.A1 t,1 .. ,A..4 INCF.t.1 I. T1.1:1, ra Act, t -= AT I., I
- beTWVV41/ L 1 V 1. 1.1 1,1 Ca i .1' RCRV ^ V it ':AA = ; :T r 7- 'T = ; I-. 14,. ;AA = '7:4, =
= : _; = = ==
lEtt II Siaa 'COOP PEPCVY TIPP-S7-E-E M7t F0-V5 LI r..".
-; '" IT. ; 1.; %LAT '; 'A :IA
W., CI -1, AittiLei I IA at. ',I ==. P.' L.=,...1 t .1.-i 31'1.. k1. 1,.,t r J.,: 0_fir 71.'1401 AVL Ns* =
TC:1_171-"TD:1:11-TATA.1.:AAG"."1:CAXG'iti;LACAAGA;CAL;,:i`Gf;CP.,A.J..;,...;CLAkc.:;TC
TC=I'CA::=,;i:T.Y:,.: PLAR.:=:_=ATi.;AG=1;.:TC1'.
= Tc;_;:r L;k1GTC;C:ti t.T. f 47¨W t..r T.. Ia 11¨tt = T. t V 41-41-6¨A 1. 6 6 tr¨v--r¨

lavt DWI (23.341 Xbat (7326 I Pa-al t23451 AGAP1741.:177171X17,71'.GTCTrX:';13(31'ARAT.;ArSTIr.:17,W;C:r1:e2f.-3TITA.u.A17:7.-;t1. AT,7A,...:07'IrGAZTL:T al T VrAiTITGCCAr;CCA TCTGT rimer .;c:
. = , , = -., " A t tA= = = ru... =r-t=
: "MATTI -"IAA 73T''143,-iIIT'';ITAtIN"A,A..-AAA'' s is .=
[1397] The framework 4 (FR4) region of the Gamma HC normally ends with two serines (SS), so that the full framework 4 region should be WGQGTLVTVSS (SEQ ID NO:
80). The =

accepting Xho 1 site and one additional base downstream of the Xhol site in the vector, in which the Gamma HC constant region that the Gamma HC variable regions are cloned, supplies the last bases, which encode this final aminp acid of framework 4.
However, the original vector did not adjust for the silent mutation made when the Xhol site (CTCGAG, SEQ ID NO: 81) was created and contained an "A" nucleotide downstream of the Xho I site, which caused an amino acid change at the end of framework 4: a serine to arginine (S to R) substitution present in all the working Gamma HC clones. Thus, the full framework 4 region reads WGQGTLVTVSR (SEQ ID NO: 82) . Future constructs are being created wherein the base downstream of the Xho 1 site is a "C" nucleotide. Thus, the creation of the Xho 1 site used for cloning of the Gamma HC variable region sequences in alternative embodiments is a silent mutation and restores the framework 4 amino acid sequence to its proper WGQGTLV
TVSS (SEQ ID NO: 80). This is true for all M2 Gamma HC clones described herein.
Clone 21B15:
[1398] The Kappa LC variable region of the anti M2 clone 21B15 was cloned as Hind III to BsiW1 fragment, and is encoded by the following polynucleotide sequences and SEQ ID NO:
83 and SEQ ID NO: 84:
Hindi!!
AAGCTTCCACCATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGTGC
TTCGAAGGTGGTACCTGTACTCCCAGGAGCGAGTCGAGGACCCCGAGGACGATGAGACCGAGGCTCCACG
CAGATGTGACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATC
GTCTACACTGTAGGTCCACTGGGTCAGAGGTAGGAGGGACAGACGTAGACATCCTCTGTCTCAGTGGTAG
ACTTGCCGCGCGAGTCAGAACATTTACAAGTATTTAAATTGGTATCAGCAGAGACCAGGGAAAGCCCCTA
TGAACGGCGCGCTCAGTCTTGTAAATGTTCATAAATTTAACCATAGTCGTCTCTGGTCCCTTTCGGGGAT
AGGGCCTGATCTCTGCTGCATCCGGGTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGG
TCCCGGACTAGAGACGACGTAGGCCCAACGTTTCACCCCAGGGTAGTTCCAAGTCACCGTCACCTAGACC
GACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGT
CTGTCTAAAGTGAGAGTGGTAGTGGTCAGACGTTGGACTTCTAAAACGTTGAATGATGACAGTTGTCTCA
BWI
TACAGTCCCCCTCTCACTTTCGGCGGAGGGACCAGGGTGGATATCAAACGTACG
ATGTCAGGGGGAGAGTGAAAGCCGCCTCCCTGGTCCCACCTATAGTTTGCATGC
.-[1399] The translation of the 21B15 Kappa LC variable region is as follows, polynucleotide sequence (above, SEQ ID NO: 83, top) and amino acid sequence (below, corresponding to SEQ ID NO: 298):
Htndlli AAGCTTCCACCATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGT
MDMR V L A OL LGL L L LWLR
G
GCCAGATGTGACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC
ATCACTTGCCGCGCGAGTCAGAACATTTACAAGTATTTAAATTGGTATCAGCAGAGACCAGGGAAAGCC
I TCR AS ON I VI< V L NWV OOR PGK A
CCTAAGGGCCTGATCTCTGCTGCATCCGGGTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGA
PK GL IS A A SGL OS GV p S R
F SGSG
TCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAA
SG TDF T L T I TS LOP EDF A
T Y V CO
BsiWI
CAGAGTTACAGTCCCCCTCTCACTTTCGGCGGAGGGACCAGGGTGGATATCAAACGTACG
OS YSPP L TF GGG TR V D I K R
T
[1400] The amino acid sequence of the 21B15 Kappa LC variable region is as follows, with specific domains identified below (CDR sequences defined according to Kabat methods):
MDMRVLAQLLGLLLLWLRGARC VK leader (SEC) ID NO:57) DIQVTQSPSSLSASVGDRVTITC FR1 (SEQ ID NO:58) RASQNIYKYLN CDR1 (SEQ ID NO:59) WYQQRPGKAPKGL IS FR2 (SEQ ID NO: 60) AASGLQS CDR2 (SEQ ID NO: 61) GVPSRFSGSGSGTDFTLTITSLQPEDFATYYC FR3(SEQIDNO:62) COSYSPPLT CDR3 (SEQ ID NO: 63) FGGGTRVDIK FR4 (SEQ ID NO: 64) RT Start of Kappa constant region [1401] The primer used to clone the Kappa LC variable region extended across a region of diversity and had wobble base position in its design. Thus, in the framework 4 region a D or E amino acid could occur. In some cases, the amino acid in this position in the rescued antibody may not be the original parental amino acid that was produced in the B cell. In most kappa LCs the position is an E. Looking at the clone above (21B15) a D in framework 4 (DIKRT) (SEQ ID NO: 544) was observed. However, looking at the surrounding amino acids, this may have occurred as the result of the primer and may be an artifact. The native antibody from the B cell may have had an E in this position.

= .,.

[1402] The 21B15 Gamma HC variable region was cloned as a Hind III to Xho 1 fragment, and is encoded by the following polynucleotide sequences and SEQ ID NO: 85 (top), and SEQ ID NO: 86 (bottom):
Hindi!!
AAGCTTCCACCATGAAACACCTGTGGTTCTTCCTTCTCCTGGTGGCAGCTCCCAGCTGGGTCC
TTCGAAGGTGGTACTTTGTGGACACCAAGAAGGAAGAGGACCACCGTCGAGGGTCGACCCAGG
TGTCCCAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCC
ACAGGGTCCACGTTAACGTCCTCAGCCCGGGTCCTGACCACTTCGGAAGCCTCTGGGACAGGG
TCACCTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCCC
AGTGGACGTGACAGAGACCAAGCAGGTAGTCATTAATGATGACCTCGACCTAGGCCGTCAGGG
CAGGGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCCT
GTCCCTTCCCTGACCTCACCTAACCCAAATAGATAATGCCACCTTTGTGGTTCATGTTAGGGA
CCCTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTCTCCCTGACGATGA
GGGAGTTCTCGGCGCAGTGGTATAGTGTTCTGTGAAGGTTCTCAGTCCAGAGGGACTGCTACT
GCTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCTGTGCGAGAGCGTCTTGTAGTGGTGGTT
CGAGACACTGGCGACGCCTTAGCCGGCAGATAAAGACACGCTCTCGCAGAACATCACCACCAA
Xhol ACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAG
TGACATAGGAACTGATGACCCCGGTCCCTTGGGACCAGTGGCAGAGCTC
[1403] The translation of the 21B15 Gamma HC is as follows, polynucleotide sequence (above, SEQ ID NO: 87, top) and amino acid sequence (below, corresponding to residues 1-138 of SEQ ID NO: 69):
HindIll AAGCTTCCACCATGAAACACCTGTGGTTCTTCCTTCTCCTGGTGGCAGCTCCCAGCTGGGTC
MK HLWF F L L L V A A PSWV
CTGTCCCAGGTGCAATTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC
!ULM OL OESGPGL V K P SE T L S
^ CTCACCTGCACTGTCTCTGGTTCGTCCATCAGTAATTACTACTGGAGCTGGATCCGGCAGTCC
L TC T V S GS S I SNY Y WS W I
R OS
^ CCAGGGAAGGGACTGGAGTGGATTGGGTTTATCTATTACGGTGGAAACACCAAGTACAATCCC
IP GK GL EW I GF I Y YGGN TK
YNP
TCCCTCAAGAGCCGCGTCACCATATCACAAGACACTTCCAAGAGTCAGGTCTCCCTGACGATG
IS LK SR V T ISO=D TSK S 0 V S L
T M
AGCTCTGTGACCGCTGCGGAATCGGCCGTCTATTTCTGTGCGAGAGCGTCTIGTAGTGGTGGT
IS S v T A A ES A V YF C A R A
S CS GG
Xhol ^ TACTGTATCCTTGACTACTGGGGCCAGGGAACCCTGQTCACCGTCTCGAG
LDYWGOGT'L'µV T V S
.=
[1404] The amino acid sequence of the 21B15 Gamma HC is as follows, with specific domains identified below (CDR sequences defined according to Kabat methods):
MKHLWFFLLLVAAPSWVLS VH leader (SEQ ID NO: 70) QVQLQESGPGLVKPSETLSLTCTVSGSSIS FR1 (SEQ ID NO:71) NYYWS CDR1 (SEQ ID NO: 72) CA 02827301 2013-08-13 ' WIRQSPGKGLEWIG FR2 (SEQ ID NO: 73) FIYYGGNTKYNPSLKS CDR2 (SEQ ID NO: 74) RVTISQDTSKSQVSLTMSSVTAAESAVYFCAR FR3(SEQIDNO:75) ASCSGGYCILD CDR3 (SEQ ID NO: 76) YWGQGTLVTVS FR4 (SEQ ID NO: 77) YWGQGTLVTVSS Lang FR4 (SEQ ID NO: 266) Clone 23KI2 (corresponds to TCN-031):
[1405] The Kappa LC variable region of the anti M2 clone 23K12 was cloned as Hind III to BsiW1 fragment (see below), and is encoded by the following polynucleotide sequences SEQ
ID NO: 88 (top) and SEQ ID NO: 89 (below).
Hindlil AAGCTTCCACCATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGG
TTCGAAGGTGGTACCTGTACTCCCAGGAGCGAGTCGAGGACCCCGAGGACGATGAGACCGAGGCTCC
TGCCAGATGTGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTC
ACGGTCTACACTGTAGGTCTACTGGGTCAGAGGTAGGAGGGACAGACGTAGACATCCTCTGTCTCAG
ACCATCACTTGCCGGACAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGA
TGGTAGTGAACGGCCTGTTCAGTCTCGTAATCGTCGATAAATTTAACCATAGTCGTCTTTGGTCCCT
AAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGG
TTCGGGGATTTGAGGACTAGATACGACGTAGGTCAAACGTTTCACCCCAGGGTAGTTCCAAGTCACC
CAGTGGATCTGGGACAGATTTCACTCTCACCATCKGCGGTCTGCAACCTGAAGATTTTGCAACCTAC
GTCACCTAGACCCTGTCTAAAGTGAGAGTGGTAGTCGCCAGACGTTGGACTTCTAAAACGTTGGATG
BsiWI
TACTGTCAACAGAGTTACAGTATGCCTGCCTTTGGCCAGGGGACCAAGCTGGAGATCAAACGTACG
ATGACAGTTGTCTCAATGTCATACGGACGGAAACCGGTCCCCTGGTTCGACCTCTAGTTTGCATGC
[1406] The translation of the 23K12 Kappa LC variable region is as follows, polynucleotide sequence (above, SEQ ID NO: 90, top) and amino acid sequence (below, corresponding to SEQ ID NO: 91).
Hindi!!
AAGCTTCCACCATGGACATGAGGGTCCTCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGG
MDMR V L AOL L GL L L LWLRG
TGCCAGATGTGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTC
i AR CD I OM TOSPS S L $ A S
V GDR V
ACCATCACTTGCCGGACAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGA
iT I TCR TS OS IS S Y LNWY OOK P G
AAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGG
iK A PK L L I Y A A SS L OS G V P
SR F SG
CAGTGGATCTGGGACAGATTTCACTCTCACCATCA-GCGGTCTGCAACCTGAAGATTTTGCAACCTAC
SGS G T OF TL T I,SG'L OP EDF A
T Y
BsiWI
TACTGTCAACAGAGTTACAGTATGCCTGCCTTTGGCCAGGGGACCAAGCTGGAGATCAAACGTACG
gy c O O S Y S M F, A F G oc TK L
E iK R

[1407] The amino acid sequence of the 23K12 Kappa LC variable region is as follows, with specific domains identified below (CDR sequences defined according to Kabat methods):
MDMRVLAQLLGLLLLWLRGARC VK leader (SE0 ID NO: 57) DIQMTQSPSSLSASVGDRVTITC FR1 (SEQ ID NO:58) RTSQSISSYLN CDR1 (SEQ ID NO: 92) WYQQKPGKAPKLLIY FR2 (SEO ID NO: 93) AASSLOSGVPSRF CDR2 (SEQ ID NO: 94) SGSGSGTDFTLTISGLQPEDFATYYC FR3 (SEQ ID NO: 95) QQSYSMPA CDR3 (SEQ ID NO: 96) FGQGTKLEIK FR4 (SEQ ID NO: 114) RT Start of Kappa LC constant region [1408] The 23K12 Gamma HC variable region was cloned as a Hind III to Xho 1 fragment, and is encoded by the following polynucleotide sequences and SEQ ID NO: 97 (top) and SEQ ID NO: 98 (bottom).
Fitnc1111 AAGCTTCCACCATGGAGTTGGGGCTGTGCTGGGTTTTCCTTGTTGCTATTTTAAAAGGTGTCCAGT
TTCGAAGGTGGTACCTCAACCCCGACACGACC.CAAAAGGAACAACGATAAAATTTTCCACAGGTCA
GTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAATCTCCT
CACTCCACGTCGACCACCTCAGACCCCCTCCGAACCAGGTCGGACCCCCCAGGGACTCTTAGAGGA
GTGCAGCCTCTGGATTCACCGTCAGTAGCAACTACATGAGTTGGGTCCGCCAGGCTCCAGGGAAGG
CACGTCGGAGACCTAAGTGGCAGTCATCGTTGATGTACTCAACCCAGGCGGTCCGAGGTCCCTTCC
GGCTGGAGTGGGTCTCAGTTATTTATAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCA
CCGACCTCACCCAGAGTCAATAAATATCACCACCATCGTGTATGATGCGTCTGAGGCACTTCCCGT
GATTCTCCTTCTCCAGAGACAACTCCAAGAACACAGTGTTTCTTCAAATGAACAGCCTGAGAGCCG
CTAAGAGGAAGAGGTCTCTGTTGAGGTTCTTGTGTCACAAAGAAGTTTACTTGTCGGACTCTCGGC
AGGACACGGCTGTGTATTACTGTGCGAGATGTCTGAGCAGGATGCGGGGTTACGGTTTAGACGTCT
TCCTGTGCCGACACATAATGACACGCTCTACAGACTCGTCCTACGCCCCAATGCCAAATCTGCAGA
xho GGGGCCAAGGGACCACGGTCACCGTCTCGAG
CCCCGGTTCCCTGGTGCCAGTGGCAGAGCTC
[1409] The translation of the 23K12 Gamma HC variable region is as follows, polynucleotide sequence (above, SEQ ID NO: 99, top), and amino acid sequence (below, corresponding to SEQ ID NO: 100):

Hindu' AAGCTTCCACCATGGAGTTGGGGCTGTGCTGGGTTTTCCTTGTTGCTATTTTAAAAGGTGTCCAG
ME L GL CO/ V F L V A I L K
GV
TGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAATCTCC
ICE V OL V ESGGGL V OP GGS
LR IS
TGTGCAGCCTCTGGATTCACCGTCAGTAGCAACTACATGAGTTGGGTCCGCCAGGCTCCAGGGAAG

GGGCTGGAGTGGGTCTCAGTTATTTATAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGC

V K
AGATTCTCCTTCTCCAGAGACAACTCCAAGAACACAGTGTTTCTTCAAATGAACAGCCTGAGAGCC
.11=IF SF S R DNSK N 7 V F L OMNS L
R A
^ GAGGACACGGCTGTGTATTACTGTGCGAGATGTCTGAGCAGGATGCGGGGTTACGGTTTAGACGTC
iED 7 A V Y VC A R C L SR MR G Y
GL D V
^ TGGGGCCAAGGGACCACGGTCACCGTCTCGAG

[1410] The amino acid sequence of the 23K12 Gamma HC variable region is as follows, with specific domains identified below (CDR sequences defined according to Kabat methods):
MELGLCWVFLVAILKGVQC VH leader (SEQ ID NO: 101) EVQLVESGGGLVQPGGSLRISCAASGFTVS FR1 (SEQ ID NO: 102) SNYMS CDR1 (SEO ID NO: 103) WVRQAPGKGLEWVS FR2 (SEQ ID NO: 104) /IYSGGSTYYADSVK CDR2 (SEQ ID NO: 105) GRFSFSRDNSKNTVFLQMNSLRAEDTAVYYCARFR3(SEQIDNO:106) CLSRMRGYGLDV CDR3 (SEQ ID NO: 107) WGQGTTVTVS FR4 (SEQ ID NO: 108) WGOGTTVTV SS Long FR4 (SEO ID NO: 111) =.

=
Example 3: Identification of Conserved Antibody Variable Regions [1411] The amino acid sequences of the three antibody Kappa LC and Gamma HC
variable regions were aligned to identify conserved regions and residues, as shown below.
[1412] Amino acid sequence alignment of the Kappa LC variable regions of the three clones (SEQ ID NOs 673-675, respectively, in oe order of appearance):
=

Tramhtionofmp73 AS TMDMR.V LA QL LGLLLL WL RG AR CD 1 Q V T QSPS SL

Transhtionofrap147 AS TMECIAR V LA QL LG'LLLL WL RG AR CDI Q MT QS PS SL

Trma.a=itionofrap137 AS TMDMRV LA QL LGLLLL WL RG AR CDI Q MT QS PS SL

Translationofrap73 S A SV GDRV II T C RA SQN I YK YL NWYQQR P GKAPK GL

Tramlationofrap147 SA SVGDRV TI T C RA SQNI YK YL NWYQQR P GKAPK GL

Tr2nstationofmp137 S A S V GDRV TI T C RT SQSI S S YL NWYQQK P GKAPK LL

Translationofmp73 I S AA SGLQ SG V P SR FSGS GS GT DF IL TI T S LQPE DF

. L-9 Translationofrap147 .1 S 'A :A SGLQ,SG VP SR FSGS GS GT DF IL TI
T S LQPE DF..=
=

Trans1ationoimp137 I Y AA SS LQ SG VP SR FSGS GS GT DF TLTI S GLQPE DF

Translationafrap73 AT.YYCQQS YSPP LT FGGGTR VD 1 KRT

Tramlationofnm147 AT YYCQQS-YS P P LT FGGG T R VE I K RI

Trans1ationofmp137 AT YYCQQS YSM? = AFGQG T K LE 1 KRT

,4z [1413] Amino acid sequence alignment of the Gamma HC variable regions of the three clones (SEQ ID NOs 676-678, respectively, in order of appearance):

20 =
Translation of rap SI 21B15 A S T M KHL WF F L L L V =A A P
S WV L S Q VQLQES
-Translation of mg145 23K12 AS TM EL GL CWVF L V AI
LKG V QC E VQLVES
= TranAltionofmp153SI10 AS TM KHLWFF L L L VAAP S WV L S O VQLOES

TranliztionampS1 21B15 GP GL VKPS ET L S L T CT
VSGS S I S NYYWSW oe Tramiztionofmp145 23K12 GGGL VQPGGS L RI S CA
ASGF T P S SNYMSW
Tratulationamp153SII0 GP GL V-KPS E I L S L T CT VSGS S I S NYYWSW

SO
õ
TrainktionempS121B15 I R QS PGKGLE W I G F I YYGGNT K Y NPSL KS
Tranilationemp145 23K12 V R.Q A PGKGLE.WVS V I
YSGGS T YY ADSVKG
Tramlationofmp1538110 I R.QS PGKGLE WI G F I YYGGNT K Y NPSL KS

TranslationampS1211315 R.V T I SQDT SK'S QV S LT MSS V T A A ES AV YF
Tramiationaimp145 23K12 RF SF SRDNSKNT V F
LQMNS L R A E DT AV YY
Tranthrion env 153 8I10 R. V T I S -Q D¨T S K S -Q V S L T
M S S V T A A ES AV YF
120 . 130 = Tramiz-tionnimpS12.1B15 C AR A SCSGGYC I L D YWGQTL VT V S
Tranalationofmp145 23K12 C ARC LSRMRGYGL D VWGQT
TVTV S
Translation of mp 153 SI10 C A R A S CS G GY C I L D
YWGQT L V T V S
=
=
=
=
=
=

[1414] Clones 8110 and 21B15 came from two different donors, yet they have the same exact Gamma HC and differ in the Kappa LC by only one amino acid at position 4 in the framework 1 region (amino acids M versus V, see above), (excluding the D versus E wobble position in framework 4 of the Kappa LC).
[1415] Sequence comparisons of the variable regions of the antibodies revealed that the heavy chain of clone 8i10 was derived from germline sequen'ce IgHV4 and that the light chain was derived from the germline sequence IgKV I.
[1416] Sequence comparisons of the variable regions of the antibodies revealed that the heavy chain of clone 21B15 was derived from germline sequence IgHV4 and that the light chain was derived from the germline sequence IgKV1.
[1417] Sequence comparisons of the variable regions of the antibodies revealed that the heavy chain of clone 23K12 was derived from germline sequence IgHV3 and that the light chain was derived from the germline sequence IgKV1.
Example 4: Production and characterization of M2 Antibodies [1418] The antibodies described above were produced in milligram quantities by larger scale transient transfections in 293 PEAK cells. Crude un-purified antibody supernatants were used to examine antibody binding to influenza A/Puerto Rico/8/1932 (PR8) virus on ELISA plates, and were compared to the binding of the control antibody 14C2, which was also produced by larger scale transient transfection. The anti-M2 recombinant human monoclonal antibodies bound to influenza while the control antibody did not (Figure 9). -[1419] Binding was also tested on MDCK cells infected with the PR8 virus (Figure 10). The control antibody 14C2 and the three anti M2E clones: 8110, 21B15 and 23K12, all showed specific binding to the M2 protein expressed on the surface of PR8-infected cells. No binding was observed on uninfected cells.
[1420] The antibodies were purified over protein A columns from the supernatants. FACs analysis was performed using purified antibodies at a concentration of 1 ug per ml to examine the binding of the antibodies to transiently transfected 293 PEAK cells expressing the M2 proteins on the cell surface. Binding was measured testing binding to mock transfected cells and cells transiently transfected with the Influenza subtype H3N2, A/Vietnam/1203/2004 (VN1203), or A/Hong Kong/483/1997 HK483 M2 proteins. As a positive control the antibody 14C2 was ;' .

used. Unstained and secondary antibody alone controls helped determined background. Specific staining for cells transfected with the M2 protein was observed for all three clones. Furthermore, all three clones bound to the high path strains ANietnam/1203/2004 and A/Hong Kong/483/1997 M2 proteins very well, whereas the positive control 14C2 which bound well to H3N2 M2 protein, bound much weaker to the A/Vietnam/I203/2004 M2 protein and did not bind the A/Hong Kong/483/1997 M2 protein. See Figure 11.
[1421] Antibodies 21B15, 23K12, and 8110 bound to the surface of 293-HEK cells stably expressing the M2 protein, but not to vector transfected cells (see Figure 1).
In addition, binding of these antibodies was not competed by the presence of 5 mg/ml 24-mer M2 peptide, whereas the binding of the control chimeric mouse V-region/human IgG I kappa 14C2 antibody (hul4C2) generated against the linear M2 peptide was completely inhibited by the M2 peptide (see Figure 1). These data confirm that these antibodies bind to conformational epitopes present in M2e expressed on the cell or virus surface, as opposed to the linear M2e peptide.
Example 5: Viral Binding of human anti-influenza monoclonal antibodies [1422] UV-inactivated influenza A virus (A/PR/8/34) (Applied Biotechnologies) was plated in 384-well MaxiSorp plates (Nunc) at 1.2 pg/ml in PBS, with 25 l/well, and was incubated at 4 C
overnight. The plates were then washed three times with PBS, and blocked with I% Nonfat dry milk in PBS, 50 l/well, and then were incubated at room temp for 1 hr. After a second wash with PBS, MAbs were added at the indicated concentrations in triplicate, and the plates were incubated at room temp for 1 hour. After another wash with PBS, to each well was added 25 I
of a 1/5000 dilution of horseradish peroxidase (HRP) conjugated goat anti-human IgG Fc (Pierce) in PBS/1% Milk, and the plates were left at room temp for 1 hr. After the final PBS
wash, the HRP substrate 1StepTM Ultra-TMB-ELISA Oierce) was added at 25 l/well, and the reaction proceeded in the dark at room temp. The assaY was'stopped with 25 til/well IN H2SO4, and light absorbance at 450 nm (A450) was read on a SpectroMax Plus plate reader. Data are normalized to the absorbance of MAb 8110 binding at10 g/ml. Results are shown in Figures 2A
and 2B.

=
Example 6: Binding of Human Anti-Influenza Monoclonal Antibodies to Full-Length M2 Variants [1423] M2 variants (including those with a high pathology phenotype in vivo) were selected for analysis. See Figure 3A for sequences.
[1424] M2 cDNA constructs were transiently transfected in HEK293 cells and analyzed as follows: To analyze the transient transfectants by FACS, cells on 10 cm tissue culture plates were treated with 0.5 ml Cell Dissociation Buffer (Invitrogen), and harvested.
Cells were washed in PBS containing 1% FBS, 0.2% NaN3 (FACS buffer), and resuspended in 0.6 ml FACS buffer supplemented with 100 jig/m1 rabbit IgG. Each transfectant was mixed with the indicated MAbs at 1 Kg/m1 in 0.2 ml FACS buffer, with 5 x 105 to 106 cells per sample. Cells were washed three times with FACS buffer, and each sample was resuspended in 0.1 ml containing 1 g/ml alexafluor (AF) 647-anti human IgG H&L (Invitrogen). Cells were again washed and flow cytometry was performed on a FACSCanto device (Becton-Dickenson). The data is expressed as a percentage of the mean fluorescence of the M2-D26 transient transfectant.
Data for variant binding are representative of 2 experiments. Data for alanine mutants are average readouts from 3 separate experiments with standard error. Results are shown in Figure 3B and 3C.
Example 7: Alanine Scanning Mutagenesis to Evaluate M2 Binding [1425] To evaluate the antibody binding sites, alanine was substituted at individual amino acid positions as indicated by site-directed mutagenesis.
[1426] M2 cDNA constructs were transiently transfected in HEK293 cells and analyzed as described above in Example 6. Results are shown in Figure 4A and 4B. Figure 8 shows that the epitope is in a highly conserved region of the amino terminus of the M2 polypeptide. As shown in Figures 4A, 4B and Figure 8, the epitope includes the serine at position 2, the threonine at position 5 and the glutamic acid at position 6 of the M2 polypeptide.
Example 8: Epitope Blocking [1427] To determine whether the MAbs 8110 and 23K12 bind to the same site, M2 protein representing influenza strain A/HK1483/1997 sequence was stably expressed in the CHO
(Chinese Hamster Ovary) cell line DG44. Cells were 'treated with Cell Dissociation Buffer (Invitrogen), and harvested. Cells were washed in PBS containing 1% FBS, 0.2%
NaN3 (FACS

buffer), and resuspended at 107 cells/ml in FACS buffer supplemented with 100 g/m1 rabbit IgG. The cells were pre-bound by either MAb (or the 2N9 control) at 10 g/m1 for 1 hr at 4 C, and were then washed with FACS buffer. Directly conjugated AF647-8110 or -23K12 (labeled with the AlexaFluor0 647 Protein Labeling kit (Invitrogen) was then used to stain the three pre-blocked cell samples at 1 g/m1 for 106 cells per sample. Flow cytometric analyses proceeded as before with the FACSCanto. Data are average readouts from 3 separate experiments with _ standard error. Results are shown in Figure 5.
Example 9: Binding of human anti-influenza monoclonal antibodies to M2 Variants and Truncated M2 Peptides [1428] The cross reactivity of mAbs 8i10 and 23K12 to other M2 peptide variants was assessed by ELISA. Peptide sequences are shown in Figures 6A and 6B. Additionally, a similar ELISA
assay was used to determine binding activity to M2 truncated peptides.
[1429] In brief, each peptide was coated at 2 pg/mL to a flat bottom 384 well plate (Nunc) in 25 L/ well of PBS buffer overnight at 4 C. Plates were washed three times and blocked with 1%
MilkJPBS for one hour at room temperature. After washing three times, MAb titers were added and incubated for one hour at room temperature. Diluted HRP conjugated goat anti-human immunoglobulin FC specific (Pierce) was added to ede1i well after washing three times. Plates were incubated for one hour at room temperature and,ashed three times. 1-StepTm Ultra-TMB-ELISA (Pierce) was added at 25 l/well, and the reaction proceeded in the dark at room temp.
The assay was stopped with 25 l/well 1N H2SO4, and light absorbance at 450 nm (A450) was read on a SpectroMax Plus plate reader. Results are shown in Figures 6A and 6B.
Example 10: In Vivo Evaluation of the Ability of Human Anti-Influenza Monoclonal Antibodies to Protect From Lethal Viral Challenge [1430] The ability of antibodies, 23K12 and 8110, to protect mice from lethal viral challenge with a high path avian influenza strain was tested.
[1431] Female BALB/c mice were randomized into 5 groups of 10. One day prior (Day -1 (minus one)) and two days post infection (Day +2 (plus two), 200 ug of antibody was given via 200 ul intra-peritoneal injection. On Day 0 (zero), an approximate LD90 (lethal dose 90) of 279 =

ANietnam/1203/04 influenza virus, in a volume of 30 1 was given intra-nasally. Survival rate was observed from Day 1 through Day 28 post-infection. Results are shown in Figure 7.
[1432] Example 11: Characterization of M2 Antibodies TCN-032 (8I10), 211315, (23K12),3241 G23,3244 I10, 3243 J07,3259 J21,3245 019, 3244 H04,3136 G05, 3252 C13,3255 J06,3420 123, 3139 P23,3248 P18,3253 P10,3260 D19,3362 B11, and 3242 P05.
FACS
[1433] Full length M2 cDNA (A/Hong Kong/483/97) Were synthesized (Blue Heron Technology) and cloned into the plasmid vector pcDNA3.1 which was then transfected into CHO cells with Lipofectamine (Invitrogen) to create a stable pool of CHO-HK M2-expressing cells. For the panel of anti-M2 Mobs, 20 I samples of supernatant from transient transfections from each of the IgG heavy and light chain combinations was used to stain the stable cell line. Bound anti-M2 mabs were visualized on viable cells with Alexafluor 647-conjugated goat anti-Human IgG H&L antibody (Invitrogen). Flow cytometry was performed with a FACSCanto, and analysis on the accompanying FACSDiva software (Becton Dickenson).
ELISA
[1434] Purified Influenza A (A/Puerto Rico/8/34) inactivated by 13-propiolactone (Advanced Biotechnologies, Inc.) was biotinylated (EZ-Link Sulfo-NHS-LC-Biotin, Pierce) and adsorbed for 16 hours at 4 C to 384-well plates in 25 1 PBS that were pre-coated with neutravidin (Pierce). Plates were blocked with BSA in PBS, samples of supernatant from transient transfections from each of the IgG heavy and light chain combinations were added at a final dilution of 1:5, followed by HRP-conjugated goat anti-human Fc antibody (Pierce), and developed with TMB substrate (ThermoFisher).
[1435] The results of this analysis are shown below in Table 2.

=
Et =

WO 2012/112489. PCT/US2012/024971 . ,.
. , , -[1436] Table 2.
FACS Virus Sequence ID M2-HK ELISA
Transfection no.BCC well ID Gamma Light MFI OD A450 -322 3241G23 G4_005 K1_004 1697 3.02 _ 352 3244_110 G4_007 K2_006 434 3.01 339 3243_107 G4_007 K1_007 131 2.94 336 3259_121 G4_005 K2_005 1673 2.40 348 3245_019 G3_004 K1_001 919 3.51 345 3244_H04 G3_003 K1_006 963 3.31 346 Pos Cont (HC) Pos Cont (LC) 754 2.69 347 Neg Cont (HC) Neg Cont (LC) 11 0.15 374 3136_G05 G4_007 K1_007 109 ND
386 3252_C13 G4_013 K1_002 449 ND
390 3255_106 G4_013 K2_007 442 ND
' 400 3420_123 G4_004 K1_003 112 ND
432 3139_P23 G4_016 K1_007a 110 1.02 412 3248_P18 G4_009 K1_006 967 0.56 413 3253_P10 G4_007 K1_004 43 0.50 434 3260_D19 G3_004a K2_001 846 2.46 439 3362_B11 G4_010a K1_007 218 1.83 408 3242_P05 G3_005 K2_004 596 0.50 451 Pos Cont (HC) Pos Cont (LC) 1083 1.87 452 Neg Cont (HC) Neg Cont (LC) 6 0.05 Positive control: supernatant from tranisent transfection with the IgG heavy and light chain combination of mAb 8110 .
Negative control: supernatant from tranisent transfection with the IgG heavy and light chain combination of mAb 2N9 .
MFI= mean fluorescence intensity Example 12: Human Antibodies Reveal a Protective Epitope that is Highly Conserved Among Human and Non-Human Influenza A Viruses , [1437] Influenza remains a serious public health threai7throughout the world.
Vaccines and .
antivirals are available that can provide protection from infection. However, new viral strains emerge continuously because of the plasticity of the influenza genome which necessitates annual reformulation of vaccine antigens, and resistance to antivirals can appear rapidly and become entrenched in circulating virus populations. In addition, the spread of new pandemic strains is difficult to contain due to the time required to engineer and manufacture effective vaccines.

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims (29)

1. A composition comprising:
(a) an isolated human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) an isolated human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus.
2. The composition of claim 1, wherein said isolated human monoclonal antibody that specifically binds an epitope of the M2e polypeptide is TCN-032 (8110), 21B15, (23K12), 3241_G23, 3244_I10, 3243_J07, 3259_J21, 3245_O19, 3244_H04, 3136_G05, 3252_C13, 3255_J06, 3420_I23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B11, or 3242_P05.
3. The composition of claim 1, wherein said isolated human antibody that specifically binds an epitope of the HA glycoprotein is TCN-522 (3212_I12), TCN-521 (3280_D18), (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-(5087_P17), TCN-529 (5297_H01), TCN-530 (5248_H10), TCN-531 (5091_H13), TCN-(5262_H18), TCN-533 (5256_A17), TCN-534 (5249_B02), TCN-535 (5246_P19), TCN-(5095_N01), TCN-537 (3194_D21), TCN-538 (3206_O17), TCN-539 (5056_A08), TCN-(5060_F05), TCN-541 (5062_M11), TCN-542 (5079_A16), TCN-543 (5081_G23), TCN-(5082_A19), TCN-545 (5082_I15), TCN-546 (5089_L08), TCN-547 (5092_F11), TCN-(5092_P01), TCN-549 (5092_P04), TCN-550 (5096_F06), TCN-551 (5243_D01), TCN-(5249_I23), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_116), TCN-(5089_K12), TCN-557 (5081_A04), TCN 558 (5248_H10b), TCN-559 (5097_G08), TCN-(5084_P10), TCN-504 (3251_K17), SC06-141, SC06-255, SC06-257, 5C06-260, 5C06-261, SC06-262, SC06-268, SC06-272, 5C06-296, 5C06-301, 5C06-307, 5C06-310, 5C06-314, 5C06-323, SC06-325, SC06-327, SC06-328, SC06-329, SC06-331, SC06-332, SC06-334, SC06-336, SC06-339, SC06-342, SC06-343, SC06-344, CR6141, CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6272, CR6296, CR6301, CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, CR6329, CR6331, CR6332, CR6334, CR6336, CR6339, CR6342, CR6343, CR6344, 2A, D7, D8, F10, G17, H40, A66, D80, E88, E90, or H98.
4. The composition of claim 1, wherein said epitope of the HA glycoprotein is GVTNKVNSIIDK (SEQ ID NO: 198), GVTNKVNSIINK (SEQ ID NO: 283), GVTNKENSIIDK (SEQ ID NO: 202), GVTNKVNRIIDK (SEQ ID NO: 201), GITNKVNSVIEK (SEQ ID NO: 281), GITNKENSVIEK (SEQ ID NO: 257), GITNKVNSIIDK
(SEQ ID NO: 225), and KITSKVNNIVDK (SEQ ID NO: 216).
5. The composition of claim 1, wherein said epitope of the M2e polypeptide is a discontinuous epitope.
6. The composition of claim 1, wherein said epitope of the M2e polypeptide comprises, a) the amino acid at positions 2, 5, and 6 of MSLLTEVETPTRNEWGCRCNDSSD
(SEQ ID NO: 1); or b) the amino acid at positions 2, 5, and 6 of SLLTEV (SEQ ID NO: 42).
7. A composition comprising:
(a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each comprise three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR comprises the following amino acid sequences:
VH CDR1: SEQ ID NOs: 247, 571, 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251, 242, or 222;
VH CDR2: SEQ ID NOs: 248, 572, 587, 592, 598, 604, 610, 616, 628, 634, 638, 644, 650, 655, 659, 665, 671, 306, 249, 307, or 221;
VH CDR3: SEQ ID NOs: 568, 573, 588, 593, 599, 605, 611, 617, 629, 635, 639, 645, 651, 656, 660, 666, 672, 725, 246, 290, or 220;
VL CDR1: SEQ ID NOs: 569, 574, 577, 580, 583, 589, 594, 612, 618, 621, 624, 640, 646, 652, 661, 667, 285, 289, 245, 224, or 219;

VL CDR2: SEQ ID NOs: 570, 575, 578, 581, 584, 590, 595, 601, 607, 613, 619, 622, 625, 631, 653, 662, 668, 305, 223, or 231;
VL CDR3: SEQ ID NOs: 289, 576, 579, 582, 585, 591, 596, 602, 608, 614, 620, 623, 626, 632, 636, 642, 648, 654, 657, 663, 669, 308, 250, 227, or 280; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each comprise three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR comprises the following amino acid sequences:
VH CDR1: SEQ ID NOs: 72, 103, 179, 187, 203, 211, 228, 252, 260, 268, 284, 293, or 301;
VH CDR2: SEQ ID NOs: 74, 105, 180, 188, 204, 212, 229, 237, 253, 261, 269, 285, or 294;
VH CDR3 SEQ ID NOs: 76, 107, 181, 189, 197, 205, 213, 230, 238, 254, 262, 270, 286, or 295;
VL CDR1: SEQ ID NOs: 59, 92, 184, 192, 208, 192, 233, 241, 265, or 273;
VL CDR2: SEQ ID NOs: 61, 94, 185, 193, 209, 217, 226, 234, 258, 274, or 282;
and VL CDR3: SEQ ID NOs: 63, 96, 186, 194, 210, 218, 243, 259, 267, 275, 291, or 300.
8. A composition comprising:
(a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each comprise three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR comprises the following amino acid sequences:
VH CDR1: SEQ ID NOs: 247, 571, 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251, 242, or 222;
VH CDR : SEQ ID NOs: 248, 572, 587, 592, 598, 604, 610, 616, 628, 634, 638, 644, 650, 655, 659, 665, 671, 306, 249, 307, or 221;
VH CDR : SEQ ID NOs: 568, 573, 588, 593, 599, 605, 611, 617, 629, 635, 639, 645, 651, 656, 660, 666, 672, 725, 246, 290, or 220;
VL CDR : SEQ ID NOs: 569, 574, 577, 580, 583, 589, 594, 612, 618, 621, 624, 640, 646, 652, 661, 667, 285, 289, 245, 224, or 219;
VL CDR2: SEQ ID NOs: 570, 575, 578, 581, 584, 590, 595, 601, 607, 613, 619, 622, 625, 631, 653, 662, 668, 305, 223, or 231;

VL CDR3: SEQ ID NOs: 289, 576, 579, 582, 585, 591, 596, 602, 608, 614, 620, 623, 626, 632, 636, 642, 648, 654, 657, 663, 669, 308, 250, 227, or 280; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each comprise three complementarity determining regions 1 to 3 (CDR1-3), and wherein each CDR comprises the following amino acid sequences:
VH CDR1: SEQ ID NOs: 109, 112, 182, 190, 206, 214, 239, 255, 263, 271, 287, 296, or 304;
VH CDR2: SEQ ID NOs: 110, 113, 183, 191, 207, 215, 232, 240, 256, 264, 272, 288, or 297;
VH CDR3 SEQ ID NOs: 76, 107, 181, 189, 197, 205, 213, 230, 238, 254, 262, 270, 286, or 295;
VL CDR1: SEQ ID NOs: 59, 92, 184, 192, 208, 192, 223, 241, 265, or 273;
VL CDR2: SEQ ID NOs: 61, 94, 185, 193, 209, 217, 226, 234, 258, 274, or 282;
and VL CDR3: SEQ ID NOs: 63, 96, 186, 194, 210, 218, 243, 259, 267, 275, 291, or 300.
9. A composition comprising:
(a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) domain, wherein the VH domain comprises the following amino acid sequences: SEQ ID NOs 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349, 353, 357, 361, 365, 369, 373, 377, 381, 385, 389, 393, 397, 401, 405, 409, 199, 417, 423, 429, 435, 441, 447, 453, 459, 465, 471, 477, 483, 489, 495, 501, 507, 513, 519, 525, 531, 537, 543, 550, 556, or 562, and a light chain variable (VL) domain, wherein the VL
domain comprises the following amino acid sequences: SEQ ID NOs 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 366, 370, 374, 378, 382, 386, 390, 394, 398, 402, 406, 410, 414, 420, 426, 432, 438, 444, 450, 456, 462, 468, 474, 480, 486, 492, 498, 504, 510, 516, 522, 528, 534, 540, 547, 553, 559, or 565; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, comprising a heavy chain variable (VH) domain, wherein the VH domain comprises the following amino acid sequences: SEQ ID NOs 44, 277, 276, 50, 236, 235, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, or 176, and a light chain variable (VL) domain, wherein the VL domain comprises the following amino acid sequences:
SEQ ID NOs 46, 292, 52, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, or 178.
10. A multivalent vaccine composition comprising the composition of claim 7, 8, or 9.
11. A multivalent vaccine composition comprising the composition of claim 1.
12. A pharmaceutical composition comprising the composition of claim 1, 7, 8, or 9 and a pharmaceutical carrier.
13. A method for stimulating an immune response in a subject, comprising administering to the subject the composition of claim 12.
14. A method for the treatment of an influenza virus infection in a subject in need thereof, comprising administering to said subject the composition of claim 12.
15. The method of claim 14, wherein the subject has been exposed to an influenza virus.
16. The method of claim 15, wherein the subject has not be diagnosed with an influenza infection.
17. A method for the prevention of an influenza virus infection in a subject in need thereof, comprising administering to said subject the vaccine of claim 10 or 11, prior to exposure of said subject to an influenza virus.
18. The method of claim 14 or 17, wherein the method further comprises administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.
19. The method of claim 18, wherein said anti-viral drug is a neuraminidase inhibitor, a HA
inhibitor, a sialic acid inhibitor or an M2 ion channel.
20. The method of claim 19, wherein said M2 ion channel inhibitor is amantadine or rimantadine.
21. The method of claim 19, wherein said neuraminidase inhibitor is zanamivir or oseltamivir phosphate.
22. The method of claim 14 or 17, further comprising administering a second anti-Influenza A antibody.
23. The method of claim 22, wherein said antibody is administered prior to or after exposure to Influenza virus.
24. The method of claim 15, wherein the subject is at risk of contracting an influenza infection.
25. The method of claim 14 or 17, wherein said composition is administered at a dose sufficient to promote viral clearance or eliminate influenza infected cells.
26. A method for determining the presence of an Influenza virus infection in a subject, comprising the steps of:
(a) contacting a biological sample obtained from the subject with the antibody according to any one of claims 1, 7-9;
(b) detecting an amount of the antibody that binds to the biological sample;
and (c) comparing the amount of antibody that binds to the biological sample to a control value, and therefrom determining the presence of the Influenza virus in the subject.
27. The method of claim 26, wherein the control value is determined by contacting a control sample obtained from the subject with the antibody according to any one of claims 1, 7-9 and detecting an amount of the antibody that binds to the control sample.
28. A diagnostic kit comprising the composition of claim 1, 7, 8, or 9.
29. A prophylactic kit comprising the vaccine according to claim 10 or 11.
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