CA2399832A1 - Enhancing the circulating half-life of antibody-based fusion proteins - Google Patents

Enhancing the circulating half-life of antibody-based fusion proteins Download PDF

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Publication number
CA2399832A1
CA2399832A1 CA002399832A CA2399832A CA2399832A1 CA 2399832 A1 CA2399832 A1 CA 2399832A1 CA 002399832 A CA002399832 A CA 002399832A CA 2399832 A CA2399832 A CA 2399832A CA 2399832 A1 CA2399832 A1 CA 2399832A1
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fusion protein
antibody
protein
mutation
polypeptide
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CA2399832C (en
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Stephen D. Gillies
Christa Burger
Kin Ming Lo
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Abstract

Disclosed are compositions and methods for enhancing the circulating half-life of antibody-based fusion proteins. Disclosed methods and compositions rely on altering the amino acid sequence of the junction region between the antibody moiety and the fused protein moiety in an antibody-based fusion protein. An antibody-based fusion protein with an altered amino acid sequence in the junction region has a greater circulating half-life when administered to a mammal. Disclosed methods and compositions are particularly useful for reducing tumor size and metastasis in a mammal.

Claims (47)

1. An antibody-based fusion protein comprising an immunoglobulin (Ig) chain linked to a non-Ig protein via a junction point, wherein said antibody-based fusion protein comprises an amino acid alteration within 10 amino acids from said junction point, in said Ig chain or said non-Ig protein, and wherein said antibody-based fusion protein has a longer circulating half life in vivo than a corresponding antibody-based fusion protein without said amino acid alteration.
2. The fusion protein of claim 1 wherein the amino acid alteration increases the hydrophobicity of said antibody-based fusion protein.
3. The fusion protein of claim 1 or 2 wherein said Ig chain is N-terminal to said non-Ig protein.
4. The fusion protein of claim 1, 2 or 3 wherein said alteration changes the C-terminal amino acid of the Ig chain.
5. The fusion protein of claim 1, wherein said non-Ig protein is a secreted protein.
6. The fusion protein of claim 5, wherein said non-Ig protein is a mature form of said secreted protein.
7. The fusion protein of claim 1, wherein the Ig chain comprises part of an Ig heavy chain.
8. The antibody-based fusion protein of claim 7 wherein said Ig chain comprises at least the CH2 domain of an IgG2 or an IgG4 constant region.
9. The antibody-based fusion protein of claim 7, wherein said Ig chain comprises at least a portion of an IgG1 constant region having a mutation or a deletion at one or more amino acids selected from the group consisting of Leu234, Leu235, Gly236, Gly237, Asn297, and Pro378.
10. The antibody-based fusion protein of claim 7, wherein said Ig chain comprises at least a portion of an IgG3 constant region having a mutation or a deletion at one or more amino acids selected from the group consisting of Leu281, Leu282, Gly283, Gly284, Asn344, and Pro378.
11. The antibody-based fusion protein of claim 7, wherein said Ig chain has binding affinity for an immunoglobulin protection receptor.
12. The antibody-based fusion protein of claim 7, wherein said Ig chain has substantially reduced binding affinity for a Fc receptor selected from the group consisting of Fc.gamma.RI, Fc.gamma.RII and Fc.gamma.RIII.
13. The antibody-based fusion protein of claim 7, wherein said non-Ig protein is selected from the group consisting of a cytokine, a ligand-binding protein, and a protein toxin.
14. The antibody-based fusion protein of claim 13, wherein said cytokine is selected from the group consisting of a tumor necrosis factor, an interleukin, and a lymphokine.
15. The antibody-based fusion protein of claim 14, wherein said tumor necrosis factor is tumor necrosis factor alpha.
16. The antibody-based fusion protein of claim 14, wherein said interleukin is interleukin-2.
17. The antibody-based fusion protein of claim 14, wherein said lymphokine is a lymphotoxin or a colony stimulating factor.
18. The antibody-based fusion protein of claim 11, wherein said colony stimulating factor is a granulocyte-macrophage colony stimulating factor.
19. The antibody-based fusion protein of claim 13, wherein said ligand-binding protein is selected from the group consisting of CD4, CTLA-4, TNF receptor, and an interleukin receptor.
20. A method for increasing the circulating half life of an antibody-based fusion protein having an Ig chain linked to a non-Ig protein via a junction point, the method comprising the step of substituting, deleting, inserting, or otherwise altering an amino acid at or near said junction point.
21. The method of claim 20, wherein said fusion protein comprises a portion of a heavy chain.
22. The method of claim 21, wherein said fusion protein comprises at least the CH2 domain of an IgG2 or an IgG4 constant region.
23. The method of claim 20, 21, or 22, wherein said fusion protein comprises a heavy chain moiety having a mutation that affects interaction with an Fc protection receptor.
24. The fusion protein of claim 1 comprising a linker between said Ig chain and said non-Ig protein.
25. The fusion protein of claim 4, 5, 6, or 7, wherein said alteration is a substitution of one or more amino acids.
26. An antibody-based fusion protein comprising a) a first polypeptide comprising an Ig chain, and, b) a second polypeptide comprising a non-Ig protein, wherein said first polypeptide is joined to said second polypeptide to produce a junction region having at least one mutation, and wherein said fusion protein has a longer circulating half life than a fusion protein having a junction region without said mutation.
27. The fusion protein of claim 26, wherein said mutation is in the C-terminal portion of said first polypeptide.
28. The fusion protein of claim 26, wherein said mutation is in the N-terminal portion of said second polypeptide.
29. The fusion protein of claim 26 comprising a first mutation in the C-terminal portion of said first polypeptide and a second mutation in the N-terminal portion of said second polypeptide.
30. The fusion protein of claim 27 or 29 wherein said C-terminal portion comprises between 1 and 100 C-terminal amino acids of said first polypeptide.
31. The fusion protein of claim 30 wherein said C-terminal portion comprises between 1 and C-terminal amino acids of said first polypeptide.
32. The fusion protein of claim 28 or 29 wherein said N-terminal portion comprises between 1 and 100 N-terminal amino acids of said second polypeptide.
33. The fusion protein of claim 32 wherein said N-terminal portion comprises between l and 10 N-terminal amino acids of said second polypeptide.
34. The fusion protein of claim 26 wherein said Ig is IgG1.
35. The fusion protein of claim 26 wherein said mutation is selected from the group consisting of point mutations, deletions, insertions, and rearrangements.
36. The fusion protein of claim 34 wherein the C-terminal residue of said first polypeptide is mutated to be an amino acid with a non-ionizable side chain.
37. The fusion protein of claim 36 wherein said C-terminal residue is a non-lysine amino acid.
38. The fusion protein of claim 26 wherein said junction region consists of the C-terminal region of said first polypeptide and the N-terminal region of said second polypeptide, and wherein said mutation is present in one of said C-terminal and N-terminal regions.
39. The fusion protein of claim 26 wherein said junction region comprises a spacer or linker peptide.
40. The fusion protein of claim 39 wherein said mutation consists of the presence of a spacer or linker peptide between said first and said second polypeptides.
41. The fusion protein of claim 26 wherein said mutation is in a region that does not interact with FcR or FcRp.
42. A method for identifying a mutation that increases the circulating half life of an antibody-based fusion protein having an Ig moiety and a non-Ig moiety comprising the steps of a) introducing a mutation in the region spanning the junction between the Ig moiety and the non-Ig moiety;
b) comparing the serum half lives of the antibody-based fusion protein with and without a mutation; and, c) selecting a mutation that increases the serum half life of the antibody-based fusion protein.
43. An antibody-based fusion protein comprising a mutation identified according to the method of claim 42.
44. A method for treating a disease comprising the step of administering to a patient an antibody-based fusion protein of claim 26.
45. The fusion protein of claim 1, 26, or 36, having a hydrophobic or non-polar amino acid introduced via addition or substitution at or near said junction.
46. The fusion protein of claim 45, wherein said amino acid is selected from the group consisting of Leu, Ala, Trp, and Gly.
47. The fusion protein of claim 48, wherein said amino acid is Ala.
CA2399832A 2000-02-11 2001-02-09 Enhancing the circulating half-life of antibody-based fusion proteins Expired - Lifetime CA2399832C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US18176800P 2000-02-11 2000-02-11
US60/181,768 2000-02-11
PCT/US2001/004455 WO2001058957A2 (en) 2000-02-11 2001-02-09 Enhancing the circulating half-life of antibody-based fusion proteins

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CA2399832A1 true CA2399832A1 (en) 2001-08-16
CA2399832C CA2399832C (en) 2011-09-20

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EP (1) EP1252192B1 (en)
JP (2) JP5179689B2 (en)
CN (1) CN1406249B (en)
AT (1) ATE336514T1 (en)
AU (1) AU4314801A (en)
CA (1) CA2399832C (en)
CY (1) CY1105725T1 (en)
DE (1) DE60122286T2 (en)
DK (1) DK1252192T3 (en)
ES (1) ES2269366T3 (en)
HU (1) HUP0204475A2 (en)
MX (1) MXPA02007733A (en)
NO (1) NO20023774D0 (en)
PT (1) PT1252192E (en)
WO (1) WO2001058957A2 (en)

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