CA2312188A1 - Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation - Google Patents

Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation Download PDF

Info

Publication number
CA2312188A1
CA2312188A1 CA002312188A CA2312188A CA2312188A1 CA 2312188 A1 CA2312188 A1 CA 2312188A1 CA 002312188 A CA002312188 A CA 002312188A CA 2312188 A CA2312188 A CA 2312188A CA 2312188 A1 CA2312188 A1 CA 2312188A1
Authority
CA
Canada
Prior art keywords
subunit
cytokine
chain
linked
fusion protein
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002312188A
Other languages
French (fr)
Other versions
CA2312188C (en
Inventor
Stephen D. Gillies
Kin-Ming Lo
Yan Lan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Lexigen Pharmaceuticals Corp.
Stephen D. Gillies
Kin-Ming Lo
Yan Lan
Emd Lexigen Research Center Corp.
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lexigen Pharmaceuticals Corp., Stephen D. Gillies, Kin-Ming Lo, Yan Lan, Emd Lexigen Research Center Corp., Merck Patent Gmbh filed Critical Lexigen Pharmaceuticals Corp.
Priority to CA2693296A priority Critical patent/CA2693296C/en
Publication of CA2312188A1 publication Critical patent/CA2312188A1/en
Application granted granted Critical
Publication of CA2312188C publication Critical patent/CA2312188C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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]
    • C07K14/5434—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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]
    • 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
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Disclosed are methods for producing fusion proteins with the heterodimeric cytokine, interleukin-12. In order to insure that the proper ration of fused and non-fused subunits are obtained in the fusion protein, a specific stepwise approach to genetic engineering is used. This consists of first expressing the non-fused p40 IL-12 subunit in a production cell line, followed by or simultaneously expressing in the same cell, a second recombinant fusion protein consisting of the fused polypeptide linked by a peptide bond to the p35 subunit of IL-12. Molecules containing the p35 fusion protein cannot be secreted from the transfected mammalian cell without first complexing in a one to ratio with the p40 subunit, thus ensuring the production of active heterodimeric fusion proteins.

Claims (24)

1. A heterodimeric fusion protein comprising a first and a second chimeric chain, said first chimeric chain comprising a portion of an Ig heavy chain linked by a peptide bond to a first subunit of a heterodimeric cytokine, said second chimeric chain comprising a portion of an Ig heavy chain linked by a peptide bond to a second subunit of said heterodimeric cytokine, said first and a second chain being linked by a disulfide bond.
2. A fusion protein comprising a first chimeric Ig chain comprising a portion of an Ig heavy chain linked by a peptide bond to a first subunit of a heterodimeric cytokine, said first subunit of said cytokine being linked to a second subunit of said cytokine.
3. The fusion protein of claim 2 further comprising a second chimeric Ig chain comprising a portion of an Ig heavy chain linked by a peptide bond to a first subunit of a heterodimeric cytokine, said first subunit of said cytokine being linked to a second subunit of said cytokine, said first and second chains being linked by a disulfide bond.
4. A trimeric fusion protein comprising a first and a second chimeric chain linked by a disulfide bond, said first chimeric chain comprising a portion of an Ig heavy chain linked by a peptide bond to a first subunit of a heterodimeric cytokine, said second chimeric chain comprising a portion of an Ig heavy chain linked by a peptide bond to a second subunit of said cytokine, said second subunit being linked by a disulfide bond to another said first subunit of said cytokine.
5. A fusion protein .comprising a chimeric Ig chain comprising a portion of an Ig light chain linked by a peptide bond to a first subunit of a heterodimeric cytokine, said first subunit of said cytokine being linked to a second subunit of said cytokine.
6. The fusion protein of claim 1, 2, 3, 4 or 5 wherein said fusion protein displays cytokine biological activity.
7. The fusion protein of claim 1, 2, 3, 4 or 5 wherein said fusion protein displays antigen-binding specificity.
8. The fusion protein of claim 1, 2, 3, 4 or 5 wherein said fusion protein has a longer circulating half life than an unlinked heterodimeric cytokine.
9. The fusion protein of claim 1, 2, 3 or 4 wherein said portion of an Ig heavy chain farther comprises a CH1 domain.
10. The fusion protein of claim 9 wherein said portion of an Ig heavy chain further comprises a CH2 domain.
11. The fusion protein of claim 10 wherein said portion of an Ig heavy chain further comprises a CH3 domain.
12. The fusion protein of claim 1, 2, 3 or 4 wherein said portion of an Ig heavy chain further comprises a CH2 and a CH3 domain.
13. The fusion protein of claim 1, 2, 3, 4 or 5 wherein said heterodimeric cytokine is IL-12.
14. A heterodimeric fusion protein comprising a first and a second chimeric chain, said first chimeric chain comprising an antigen linked to a first subunit of a heterodimeric cytokine, said second chimeric chain comprising an antigen linked to a second subunit of said heterodimeric cytokine, said first and a second chain being linked by a disulfide bond.
15. A fusion protein comprising a first chimeric Ig chain comprising an antigen linked to a first subunit of a heterodimeric cytokine, said first subunit of said cytokine being linked to a second subunit of said cytokine.
16. The fusion protein of claim 15 further comprising a second chimeric Ig chain comprising an antigen linked to a first subunit of a heterodimeric cytokine, said first subunit of said cytokine being linked to a second subunit of said cytokine, said first and second chains being linked by a disulfide bond.
17. A trimeric fusion protein comprising a first and a second chimeric chain linked by a disulfide bond, said first chimeric chain comprising an antigen linked to a first subunit of a heterodimeric cytokine, said second chimeric chain comprising an antigen linked to a second subunit of said cytokine, said second subunit being linked by a disulfide bond to another said fusion subunit of said cytokine.
18. A method of selectively targeting a heterodimeric cytokine, comprising the step of linking at least one subunit of said heterodimeric cytokine by a peptide bond to a portion of an Ig heavy chain, thereby to form a fusion protein displaying binding specificity for a predetermined antigen and cytokine biological activity.
19. A method of selectively targeting a heterodimeric cytokine, comprising the steps of (a) linking a first subunit of said heterodimeric cytokine by a peptide bond to a portion of a first Ig heavy chain, thereby forming a first chimeric chain;
(b) linking a second subunit of said heterodimeric cytokine by a peptide bond to a portion of a second Ig heavy chain, thereby forming a second chimeric chain;
and (c) linking said first and said second chimeric chain by a disulfide bond, thereby forming a heterodimeric fusion protein, said fusion protein displaying binding specificity for a predetermined antigen and cytokine biological activity.
20. A method of selectively targeting a heterodimeric cytokine, comprising the steps of:
(a) linking a first subunit of said heterodimeric cytokine by a peptide bond to a polypeptide, thereby forming a first chimeric chain, said first subunit of sand cytokine being linked to a second subunit of said cytokine by a disulfide bond;
(b) linking a lust subunit of said heterodimeric cytokine by a peptide bond to a polypeptide, thereby forming a second chimeric chain, said first subunit of said cytokine being linked to a second subunit of said cytokine by a disulfide bond; and (c) linking said first and said second chimeric chain by a disulfide bond, thereby forming a heterodimeric fusion protein, said fusion protein displaying binding specificity for a predetermined antigen and cytokine biological activity.
21. A method of increasing the circulating half-life of a heterodimeric cytokine, comprising the step of linking at least one subunit of said heterodimeric cytokine to a polypeptide, thereby forming a fusion protein having a longer circulating half-life than an unlinked heterodimeric cytokine.
22. The method of claim 21 wherein said polypeptide is selected from the group consisting of a portion of an Ig heavy chain, a portion of an Ig light chain, an antigen, and serum albumin.
23. A method of increasing the circulating half-life a heterodimeric cytokine, comprising the steps of:
(a) linking a first subunit of said heterodimeric cytokine by a peptide bond to a polypeptide, thereby forming a first chimeric chain, said first subunit of said cytokine being linked to a second subunit of said cytokine by a disulfide bond;
(b) linking a first subunit of said heterodimeric cytokine by a peptide bond to a polypeptide, thereby forming a second chimeric chain, said first subunit of said cytokine being linked to a second subunit of said cytokine by a disulfide bond; and (c) linking said first and said second chimeric chain by a disulfide bond, thereby forming a heterodimeric fusion protein, said fusion protein having a longer circulating half life than unlinked first and second heterodimeric cytokines.
24. The method of claim 23 wherein said first and second polypeptides are selected from the group consisting of a portion of an Ig heavy chain, a portion of an Ig light chain, an antigen, and serum albumin.
CA2312188A 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation Expired - Lifetime CA2312188C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2693296A CA2693296C (en) 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US98699797A 1997-12-08 1997-12-08
US08/986,997 1997-12-08
PCT/US1998/025978 WO1999029732A2 (en) 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CA2693296A Division CA2693296C (en) 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation

Publications (2)

Publication Number Publication Date
CA2312188A1 true CA2312188A1 (en) 1999-06-17
CA2312188C CA2312188C (en) 2010-06-29

Family

ID=25532973

Family Applications (2)

Application Number Title Priority Date Filing Date
CA2693296A Expired - Lifetime CA2693296C (en) 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation
CA2312188A Expired - Lifetime CA2312188C (en) 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA2693296A Expired - Lifetime CA2693296C (en) 1997-12-08 1998-12-08 Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation

Country Status (11)

Country Link
US (4) US6838260B2 (en)
EP (2) EP1489100B1 (en)
JP (2) JP4336452B2 (en)
AT (1) ATE267215T1 (en)
AU (1) AU763719B2 (en)
CA (2) CA2693296C (en)
DE (1) DE69824039T2 (en)
DK (1) DK1037927T3 (en)
ES (2) ES2221717T3 (en)
PT (1) PT1037927E (en)
WO (1) WO1999029732A2 (en)

Families Citing this family (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2686899B1 (en) * 1992-01-31 1995-09-01 Rhone Poulenc Rorer Sa NOVEL BIOLOGICALLY ACTIVE POLYPEPTIDES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
ATE267215T1 (en) * 1997-12-08 2004-06-15 Lexigen Pharm Corp HETERODIMARY FUSION PROTEINS FOR USE FOR TARGETED IMMUNTHERAPY AND GENERAL IMMUNE EXCITATION
US20030105294A1 (en) * 1998-02-25 2003-06-05 Stephen Gillies Enhancing the circulating half life of antibody-based fusion proteins
PL343462A1 (en) * 1998-04-15 2001-08-13 Lexigen Pharm Corp Enhancement of antibody-cytokine fusion protein mediated immune responses by co-administration with angiogenesis inhibitor
EP1187852B1 (en) * 1999-05-19 2007-08-08 EMD Lexigen Research Center Corp. EXPRESSION AND EXPORT OF INTERFERON-ALPHA PROTEINS AS Fc FUSION PROTEINS
US7067110B1 (en) 1999-07-21 2006-06-27 Emd Lexigen Research Center Corp. Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens
SK782002A3 (en) 1999-07-21 2003-08-05 Lexigen Pharm Corp FC fusion proteins for enhancing the immunogenicity of protein and peptide antigens
WO2001010912A1 (en) * 1999-08-09 2001-02-15 Lexigen Pharmaceuticals Corp. Multiple cytokine-antibody complexes
EP1731531B1 (en) 1999-08-09 2012-05-30 Merck Patent GmbH Multiple cytokine-antibody complexes
US20050202538A1 (en) * 1999-11-12 2005-09-15 Merck Patent Gmbh Fc-erythropoietin fusion protein with improved pharmacokinetics
CA2399832C (en) 2000-02-11 2011-09-20 Stephen D. Gillies Enhancing the circulating half-life of antibody-based fusion proteins
EP1274720A4 (en) * 2000-04-12 2004-08-18 Human Genome Sciences Inc Albumin fusion proteins
ES2288967T3 (en) * 2000-06-29 2008-02-01 Merck Patent Gmbh REINFORCEMENT OF IMMUNE ANSWERS MEDIATED BY THE ANTIBODY-CYTOKIN FUSION PROTEIN THROUGH THE TREATMENT COMBINED BY AGENTS THAT IMPROVE THE INCORPORATION OF IMMUNOCITOQUINE.
US6911204B2 (en) 2000-08-11 2005-06-28 Favrille, Inc. Method and composition for altering a B cell mediated pathology
CA2440221C (en) 2001-03-07 2013-02-05 Merck Patent Gesellschaft Mit Beschraenkter Haftung Expression technology for proteins containing a hybrid isotype antibody moiety
WO2002079415A2 (en) 2001-03-30 2002-10-10 Lexigen Pharmaceuticals Corp. Reducing the immunogenicity of fusion proteins
US7507413B2 (en) * 2001-04-12 2009-03-24 Human Genome Sciences, Inc. Albumin fusion proteins
US20050054051A1 (en) * 2001-04-12 2005-03-10 Human Genome Sciences, Inc. Albumin fusion proteins
BR0209177A (en) 2001-05-03 2004-10-05 Merck Patent Gmbh Recombinant tumor specific antibody and use
AU2002333241B2 (en) * 2001-07-18 2008-09-18 Merck Patent Gmbh Glycoprotein VI fusion proteins
ES2381025T3 (en) 2001-12-04 2012-05-22 Merck Patent Gmbh Immunocytokines with modulated selectivity
EP1463752A4 (en) 2001-12-21 2005-07-13 Human Genome Sciences Inc Albumin fusion proteins
EP2277888A3 (en) 2001-12-21 2011-04-27 Human Genome Sciences, Inc. Fusion proteins of albumin and erythropoietin
EP1418184A1 (en) * 2002-11-08 2004-05-12 Cell Center Cologne GmbH Recombinant fusion protein consisting of the p40 and p35 subunits of IL-12 and a ScFv and use thereof
ES2346205T3 (en) 2002-12-17 2010-10-13 Merck Patent Gmbh HUMANIZED ANTIBODY (H14.18) OF ANTIBODY 14.18 OF MOUSE THAT LINKS TO GD2 AND ITS FUSION WITH IL-2.
EP2829283B1 (en) * 2003-04-30 2017-06-07 Universität Zürich Methods for treating cancer using an immunotoxin
US20050069521A1 (en) * 2003-08-28 2005-03-31 Emd Lexigen Research Center Corp. Enhancing the circulating half-life of interleukin-2 proteins
WO2005063820A2 (en) 2003-12-30 2005-07-14 Merck Patent Gmbh Il-7 fusion proteins
KR20060124656A (en) * 2003-12-31 2006-12-05 메르크 파텐트 게엠베하 Fc-erythropoietin fusion protein with improved pharmacokinetics
WO2005066348A2 (en) * 2004-01-05 2005-07-21 Emd Lexigen Research Center Corp. Interleukin-12 targeted to oncofoetal fibronectin
CA2553883C (en) 2004-01-22 2013-04-02 Merck Patent Gesellschaft Mit Beschraenkter Haftung Anti-cancer antibodies with reduced complement fixation
US7670595B2 (en) 2004-06-28 2010-03-02 Merck Patent Gmbh Fc-interferon-beta fusion proteins
DE602005020837D1 (en) * 2004-12-09 2010-06-02 Merck Patent Gmbh IL-7 VARIANTS WITH REDUCED IMMUNOGENITY
KR101281208B1 (en) * 2005-05-11 2013-07-26 필로겐 에스.피.에이. Fusion protein of antibody l19 against fibronectin ed-b and interleukin 12
US20070104689A1 (en) * 2005-09-27 2007-05-10 Merck Patent Gmbh Compositions and methods for treating tumors presenting survivin antigens
PT2270050E (en) 2005-12-30 2013-09-12 Merck Patent Gmbh Anti-cd19 antibodies with reduced immunogenicity
CA2635618C (en) * 2005-12-30 2015-10-06 Merck Patent Gesellschaft Mit Beschraekter Haftung Interleukin-12p40 variants with improved stability
ATE555383T1 (en) 2006-06-22 2012-05-15 Novo Nordisk As SOLUBLE HETERODIMERIC RECEPTORS AND THEIR USE
AU2010238858A1 (en) 2009-04-22 2011-12-08 Merck Patent Gmbh Antibody fusion proteins with modified FcRn binding sites
CA2769619C (en) * 2009-08-17 2019-04-30 Roche Glycart Ag Targeted immunoconjugates
US20110165122A1 (en) * 2009-11-10 2011-07-07 The Regents Of The University Of California Method for targeted and sustained antiviral therapy
BR112013019083A2 (en) 2011-02-10 2017-04-04 Roche Glycart Ag combination of (a) an immunoconjugate, pharmaceutical composition, use of (a) an immunoconjugate, method of treating a disease in an individual, method of stimulating cellular function in an individual, and kit for treating a disease.
US11492383B2 (en) 2011-06-24 2022-11-08 Stephen D. Gillies Light chain immunoglobulin fusion proteins and methods of use thereof
CA2850575C (en) * 2011-10-11 2020-12-15 Universitat Zurich Prorektorat Mnw Combination medicament comprising il-12 and an agent for blockade of t-cell inhibitory molecules for tumour therapy
US11951157B2 (en) 2011-10-11 2024-04-09 Universitat Zurich Methods of treating malignant tumour with IL-12 and anti-PD-1 antibody
KR20160058954A (en) 2013-10-02 2016-05-25 비벤티아 바이오 인코포레이티드 Anti-epcam antibodies and methods of use
GB201403775D0 (en) 2014-03-04 2014-04-16 Kymab Ltd Antibodies, uses & methods
CN105543279A (en) * 2014-10-30 2016-05-04 常州卡斯比生物科技有限公司 Preparation method and agent of IL-12/Fc fusion protein with functions of radiation ray injury prevention and treatment and tumor treatment
CN107580501A (en) 2015-03-12 2018-01-12 维文蒂亚生物公司 For targetting the administration strategy of EPCAM positive carcinomas of urinary bladder
JP6824183B2 (en) 2015-03-12 2021-02-03 セセン バイオ，インコーポレイテッド How to treat EPCAM-positive bladder cancer
US9567399B1 (en) 2016-06-20 2017-02-14 Kymab Limited Antibodies and immunocytokines
WO2018030806A1 (en) * 2016-08-10 2018-02-15 아주대학교산학협력단 Cytokine fused to immunoglobulin fc heterodimer and pharmaceutical composition comprising same
SG11201901071TA (en) 2016-08-10 2019-03-28 Univ Ajou Ind Academic Coop Found Cytokine fused to immunoglobulin fc heterodimer and pharmaceutical composition comprising same
US11779604B2 (en) 2016-11-03 2023-10-10 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses and methods
CN111094330A (en) 2017-07-03 2020-05-01 转矩医疗股份有限公司 Polynucleotides encoding immunostimulatory fusion molecules and uses thereof
US20200317787A1 (en) * 2017-12-26 2020-10-08 Nanjingjinsirui Science & Technology Biology Corp. Fusion protein dimer using antibody fc region as backbone and use thereof
CN110396133B (en) * 2018-04-25 2021-07-23 免疫靶向有限公司 Fusion protein type prodrug with interleukin 12 as active component
JP7439372B2 (en) 2018-06-21 2024-02-28 シャタック ラボ，インコーポレイテッド Heterodimeric proteins and their uses
JP2022502088A (en) 2018-09-27 2022-01-11 エクシリオ デベロップメント， インコーポレイテッド Masked cytokine polypeptide
WO2020072821A2 (en) 2018-10-03 2020-04-09 Xencor, Inc. Il-12 heterodimeric fc-fusion proteins
MX2021004711A (en) 2018-10-23 2021-07-02 Dragonfly Therapeutics Inc Heterodimeric fc-fused proteins.
KR102524247B1 (en) * 2018-12-21 2023-04-21 가톨릭대학교 산학협력단 p40-EBI3 COMPLEX AND USES THEREOF
AU2020291012A1 (en) 2019-06-12 2021-12-16 AskGene Pharma, Inc. Novel IL-15 prodrugs and methods of use thereof
US20220356221A1 (en) * 2019-09-28 2022-11-10 AskGene Pharma, Inc. Cytokine prodrugs and dual-prodrugs
WO2021067863A2 (en) 2019-10-03 2021-04-08 Xencor, Inc. Targeted il-12 heterodimeric fc-fusion proteins
CA3172641A1 (en) * 2020-04-01 2021-10-07 Xilio Development, Inc. Masked il-12 cytokines and their cleavage products

Family Cites Families (151)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4196265A (en) 1977-06-15 1980-04-01 The Wistar Institute Method of producing antibodies
US4469797A (en) 1982-09-23 1984-09-04 Miles Laboratories, Inc. Digoxigenin immunogens, antibodies, labeled conjugates, and related derivatives
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
NZ210501A (en) * 1983-12-13 1991-08-27 Kirin Amgen Inc Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence
US4703008A (en) * 1983-12-13 1987-10-27 Kiren-Amgen, Inc. DNA sequences encoding erythropoietin
KR850004274A (en) * 1983-12-13 1985-07-11 원본미기재 Method for preparing erythropoietin
US5082658A (en) 1984-01-16 1992-01-21 Genentech, Inc. Gamma interferon-interleukin-2 synergism
EP0158198A1 (en) 1984-03-29 1985-10-16 Takeda Chemical Industries, Ltd. DNA and use thereof
US5807715A (en) 1984-08-27 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin
US4690915A (en) 1985-08-08 1987-09-01 The United States Of America As Represented By The Department Of Health And Human Services Adoptive immunotherapy as a treatment modality in humans
US5679543A (en) * 1985-08-29 1997-10-21 Genencor International, Inc. DNA sequences, vectors and fusion polypeptides to increase secretion of desired polypeptides from filamentous fungi
US5643565A (en) 1985-09-20 1997-07-01 Chiron Corporation Human IL-2 as a vaccine adjuvant
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
US4935233A (en) 1985-12-02 1990-06-19 G. D. Searle And Company Covalently linked polypeptide cell modulators
DE3712985A1 (en) 1987-04-16 1988-11-03 Hoechst Ag BIFUNCTIONAL PROTEINS
US5359035A (en) 1985-12-21 1994-10-25 Hoechst Aktiengesellschaft Bifunctional proteins including interleukin-2 (IL-2) and granuloctyte macrophage colony stimulating factor (GM-CSF)
EP0237019A3 (en) 1986-03-14 1988-03-09 Toray Industries, Inc. Interferon conjugate and production thereof using recombinant gene
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
DK173067B1 (en) * 1986-06-27 1999-12-13 Univ Washington Human erythropoietin gene, method of expression thereof in transfected cell lines, the transfected cell lines
US4894227A (en) 1986-08-01 1990-01-16 Cetus Corporation Composition of immunotoxins with interleukin-2
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5508031A (en) 1986-11-21 1996-04-16 Cetus Oncology Corporation Method for treating biological damage using a free-radial scavenger and interleukin-2
US5019368A (en) 1989-02-23 1991-05-28 Cancer Biologics, Inc. Detection of necrotic malignant tissue and associated therapy
EP0307434B2 (en) * 1987-03-18 1998-07-29 Scotgen Biopharmaceuticals, Inc. Altered antibodies
US5091513A (en) 1987-05-21 1992-02-25 Creative Biomolecules, Inc. Biosynthetic antibody binding sites
US5258498A (en) 1987-05-21 1993-11-02 Creative Biomolecules, Inc. Polypeptide linkers for production of biosynthetic proteins
DE3856559T2 (en) 1987-05-21 2004-04-29 Micromet Ag Multifunctional proteins with predetermined objectives
ATE122238T1 (en) 1987-06-10 1995-05-15 Dana Farber Cancer Inst Inc BIFUNCTIONAL ANTIBODY CONSTRUCTIONS AND METHOD FOR SELECTIVE KILLING OF CELLS.
US5064646A (en) 1988-08-02 1991-11-12 The University Of Maryland Novel infectious bursal disease virus
ES2054753T3 (en) 1987-09-02 1994-08-16 Ciba Geigy Ag CONJUGATES OF CYTOKINES WITH IMMUNOGLOBULINS.
EP0308936B1 (en) 1987-09-23 1994-07-06 Bristol-Myers Squibb Company Antibody heteroconjugates for the killing of HIV-infected cells
NZ226414A (en) 1987-10-02 1992-07-28 Genentech Inc Cd4 peptide adhesion variants and their preparation and use
AU2635088A (en) 1987-12-04 1989-06-08 Du Pont Merck Pharmaceutical Company, The Immobilized interleukin 2 and interleukin 2 containing a carboxyl-terminal extension
WO1989006692A1 (en) 1988-01-12 1989-07-27 Genentech, Inc. Method of treating tumor cells by inhibiting growth factor receptor function
CA1341588C (en) 1988-01-26 2009-01-06 Michel Revel Human ifn-beta2/i1-6, its purification and use
US5120525A (en) 1988-03-29 1992-06-09 Immunomedics, Inc. Radiolabeled antibody cytotoxic therapy of cancer
US4975369A (en) 1988-04-21 1990-12-04 Eli Lilly And Company Recombinant and chimeric KS1/4 antibodies directed against a human adenocarcinoma antigen
IT1217724B (en) 1988-05-26 1990-03-30 Ist Naz Ric Sul Cancro SPECIFIC MONOCLONAL ANTIBODY FOR A SEQUENCE OF FIBRONETIN EXPRESSED IN TRANSFORMED HYBRID CELLS ACCORDING TO SUCH ANTIBODY AND USE OF THE MONOCLONAL ANTIBODY FOR THE DIAGNOSIS OF TUMORS
IE62463B1 (en) 1988-07-07 1995-02-08 Res Dev Foundation Immunoconjugates for cancer diagnosis and therapy
US5601819A (en) 1988-08-11 1997-02-11 The General Hospital Corporation Bispecific antibodies for selective immune regulation and for selective immune cell binding
US5457038A (en) * 1988-11-10 1995-10-10 Genetics Institute, Inc. Natural killer stimulatory factor
US5242824A (en) 1988-12-22 1993-09-07 Oncogen Monoclonal antibody to human carcinomas
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US5225538A (en) 1989-02-23 1993-07-06 Genentech, Inc. Lymphocyte homing receptor/immunoglobulin fusion proteins
US5166322A (en) 1989-04-21 1992-11-24 Genetics Institute Cysteine added variants of interleukin-3 and chemical modifications thereof
US6750329B1 (en) * 1989-05-05 2004-06-15 Research Development Foundation Antibody delivery system for biological response modifiers
ZA902949B (en) 1989-05-05 1992-02-26 Res Dev Foundation A novel antibody delivery system for biological response modifiers
US6291158B1 (en) 1989-05-16 2001-09-18 Scripps Research Institute Method for tapping the immunological repertoire
US5399346A (en) 1989-06-14 1995-03-21 The United States Of America As Represented By The Department Of Health And Human Services Gene therapy
ATE123065T1 (en) 1989-07-07 1995-06-15 Takeda Chemical Industries Ltd PROTEINS AND THEIR PRODUCTION.
US5073627A (en) 1989-08-22 1991-12-17 Immunex Corporation Fusion proteins comprising GM-CSF and IL-3
US5856298A (en) * 1989-10-13 1999-01-05 Amgen Inc. Erythropoietin isoforms
ATE163675T1 (en) 1989-12-22 1998-03-15 Hoffmann La Roche CYTOTOXIC LYMPHOCYTE MATURATION FACTOR
US5314995A (en) 1990-01-22 1994-05-24 Oncogen Therapeutic interleukin-2-antibody based fusion proteins
US5349053A (en) 1990-06-01 1994-09-20 Protein Design Labs, Inc. Chimeric ligand/immunoglobulin molecules and their uses
US7253264B1 (en) * 1990-06-28 2007-08-07 Sanofi-Arentideutschland GmbH Immunoglobulin fusion proteins, their production and use
US5650150A (en) 1990-11-09 1997-07-22 Gillies; Stephen D. Recombinant antibody cytokine fusion proteins
ATE218889T1 (en) * 1990-11-09 2002-06-15 Stephen D Gillies CYTOKINE IMMUNOCONJUGATES
US5709859A (en) 1991-01-24 1998-01-20 Bristol-Myers Squibb Company Mixed specificity fusion proteins
US6072039A (en) 1991-04-19 2000-06-06 Rohm And Haas Company Hybrid polypeptide comparing a biotinylated avidin binding polypeptide fused to a polypeptide of interest
DE69233482T2 (en) 1991-05-17 2006-01-12 Merck & Co., Inc. Method for reducing the immunogenicity of antibody variable domains
US5199942A (en) 1991-06-07 1993-04-06 Immunex Corporation Method for improving autologous transplantation
ATE173763T1 (en) 1991-08-30 1998-12-15 Hutchinson Fred Cancer Res HYBRID CYTOKINE
US20020037558A1 (en) * 1991-10-23 2002-03-28 Kin-Ming Lo E.coli produced immunoglobulin constructs
US6627615B1 (en) * 1991-12-17 2003-09-30 The Regents Of The University Of California Methods and compositions for in vivo gene therapy
ATE260971T1 (en) 1992-04-01 2004-03-15 Univ Rockefeller METHOD FOR THE IN VITRO CULTIVATION OF DENDRITIC PRECURSOR CELLS AND THEIR USE FOR IMMUNOGENIC PRODUCTION
DK0615451T3 (en) 1992-05-26 2006-04-24 Immunex Corp Hitherto unknown cytokine that binds to CD30
CA2134773A1 (en) 1992-06-04 1993-12-09 Robert J. Debs Methods and compositions for in vivo gene therapy
US5614184A (en) 1992-07-28 1997-03-25 New England Deaconess Hospital Recombinant human erythropoietin mutants and therapeutic methods employing them
CA2142007C (en) 1992-08-11 2007-10-30 Robert Glen Urban Immunomodulatory peptides
DE4228839A1 (en) * 1992-08-29 1994-03-03 Behringwerke Ag Methods for the detection and determination of mediators
DE69232604T2 (en) 1992-11-04 2002-11-07 City Of Hope Duarte ANTIBODY CONSTRUCTS
EP1757694A3 (en) 1992-11-05 2008-02-27 Sloan Kettering Institute For Cancer Research Prostate-specific membrane antigen
US5738849A (en) 1992-11-24 1998-04-14 G. D. Searle & Co. Interleukin-3 (IL-3) variant fusion proteins, their recombinant production, and therapeutic compositions comprising them
US5543297A (en) 1992-12-22 1996-08-06 Merck Frosst Canada, Inc. Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2 activity
US6096331A (en) * 1993-02-22 2000-08-01 Vivorx Pharmaceuticals, Inc. Methods and compositions useful for administration of chemotherapeutic agents
US5759551A (en) 1993-04-27 1998-06-02 United Biomedical, Inc. Immunogenic LHRH peptide constructs and synthetic universal immune stimulators for vaccines
JPH08509614A (en) * 1993-04-29 1996-10-15 アボツト・ラボラトリーズ Erythropoietin analog compositions and methods
US5554512A (en) 1993-05-24 1996-09-10 Immunex Corporation Ligands for flt3 receptors
CA2125763C (en) 1993-07-02 2007-08-28 Maurice Kent Gately P40 homodimer of interleukin-12
GB9316989D0 (en) * 1993-08-16 1993-09-29 Lynxvale Ltd Binding molecules
CN1057534C (en) 1993-08-17 2000-10-18 柯瑞英-艾格公司 Erythropoietin analogs
US5837682A (en) 1996-03-08 1998-11-17 The Children's Medical Center Corporation Angiostatin fragments and method of use
US5639725A (en) 1994-04-26 1997-06-17 Children's Hospital Medical Center Corp. Angiostatin protein
AU692865B2 (en) 1994-04-26 1998-06-18 Children's Medical Center Corporation Angiostatin and method of use for inhibition of angiogenesis
CU22615A1 (en) 1994-06-30 2000-02-10 Centro Inmunologia Molecular PROCEDURE FOR OBTAINING LESS IMMUNOGENIC MONOCLONAL ANTIBODIES. MONOCLONAL ANTIBODIES OBTAINED
US6429199B1 (en) * 1994-07-15 2002-08-06 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules for activating dendritic cells
US5888773A (en) 1994-08-17 1999-03-30 The United States Of America As Represented By The Department Of Health And Human Services Method of producing single-chain Fv molecules
US6309853B1 (en) 1994-08-17 2001-10-30 The Rockfeller University Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof
US5541087A (en) 1994-09-14 1996-07-30 Fuji Immunopharmaceuticals Corporation Expression and export technology of proteins as immunofusins
PT706799E (en) 1994-09-16 2002-05-31 Merck Patent Gmbh IMUNOCONJUGADOS II
DE69534265T2 (en) * 1994-12-12 2006-05-04 Beth Israel Deaconess Medical Center, Inc., Boston CHIMERIC CYTOKINS AND ITS USE
US6485726B1 (en) * 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6086875A (en) 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
US5691309A (en) 1995-01-31 1997-11-25 Eli Lilly And Company Anti-obesity proteins
US5552524A (en) 1995-01-31 1996-09-03 Eli Lilly And Company Anti-obesity proteins
US5891680A (en) * 1995-02-08 1999-04-06 Whitehead Institute For Biomedical Research Bioactive fusion proteins comprising the p35 and p40 subunits of IL-12
ES2225874T3 (en) 1995-03-10 2005-03-16 Genentech, Inc. RECEIVER ACTIVATION THROUGH GAS.
US5719266A (en) 1995-03-17 1998-02-17 Eli Lilly And Company Anti-obesity proteins
WO1997002004A2 (en) 1995-06-30 1997-01-23 Eli Lilly And Company Methods for treating diabetes
US6406689B1 (en) 1995-10-03 2002-06-18 Frank W. Falkenberg Compositions and methods for treatment of tumors and metastatic diseases
US5854205A (en) 1995-10-23 1998-12-29 The Children's Medical Center Corporation Therapeutic antiangiogenic compositions and methods
WO1997020062A1 (en) * 1995-12-01 1997-06-05 University Of Massachusetts Il-12 p40 subunit fusion polypeptides and uses thereof
US6620413B1 (en) * 1995-12-27 2003-09-16 Genentech, Inc. OB protein-polymer chimeras
US5723125A (en) 1995-12-28 1998-03-03 Tanox Biosystems, Inc. Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide
US6080409A (en) 1995-12-28 2000-06-27 Dendreon Corporation Immunostimulatory method
US6750334B1 (en) * 1996-02-02 2004-06-15 Repligen Corporation CTLA4-immunoglobulin fusion proteins having modified effector functions and uses therefor
AU2527397A (en) * 1996-03-13 1997-10-01 Protein Design Labs, Inc. Fas ligand fusion proteins and their uses
CN1136197C (en) 1996-05-30 2004-01-28 霍夫曼-拉罗奇有限公司 Novel pyridajinone derivatives
US5922685A (en) 1996-06-05 1999-07-13 Powderject Vaccines, Inc. IL-12 gene therapy of tumors
ATE218143T1 (en) 1996-09-03 2002-06-15 Gsf Forschungszentrum Umwelt USE OF BI- AND TRISPECIFIC ANTIBODIES TO INDUCE TUMOR IMMUNITY
US5994104A (en) * 1996-11-08 1999-11-30 Royal Free Hospital School Of Medicine Interleukin-12 fusion protein
US6100387A (en) 1997-02-28 2000-08-08 Genetics Institute, Inc. Chimeric polypeptides containing chemokine domains
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
EP0973550B1 (en) 1997-04-11 2002-10-09 G.D. SEARLE & CO. Antagonistic anti-avb3 integrin antibodies
ATE267215T1 (en) 1997-12-08 2004-06-15 Lexigen Pharm Corp HETERODIMARY FUSION PROTEINS FOR USE FOR TARGETED IMMUNTHERAPY AND GENERAL IMMUNE EXCITATION
US20030105294A1 (en) * 1998-02-25 2003-06-05 Stephen Gillies Enhancing the circulating half life of antibody-based fusion proteins
PL343462A1 (en) * 1998-04-15 2001-08-13 Lexigen Pharm Corp Enhancement of antibody-cytokine fusion protein mediated immune responses by co-administration with angiogenesis inhibitor
EP1071469A2 (en) 1998-04-17 2001-01-31 Lexigen Pharmaceuticals Corp. Enhancement of antibody-cytokine fusion protein mediated immune responses by co-administration with prostaglandin inhibitor
WO1999054484A1 (en) * 1998-04-20 1999-10-28 The Regents Of The University Of California Modified immunoglobulin molecules and methods for use thereof
WO1999058662A1 (en) 1998-05-14 1999-11-18 Merck Patent Gmbh Fused protein
US6620382B1 (en) * 1998-05-22 2003-09-16 Biopheresis Technologies, Llc. Method and compositions for treatment of cancers
US20020142374A1 (en) * 1998-08-17 2002-10-03 Michael Gallo Generation of modified molecules with increased serum half-lives
CA2339331C (en) 1998-08-25 2011-03-01 Lexigen Pharmaceuticals Corporation Expression and export of angiogenesis inhibitors as immunofusins
US6646113B1 (en) 1998-09-17 2003-11-11 The Trustees Of The University Of Pennsylvania Nucleic acid molecule encoding human survival of motor neuron-interacting protein 1 (SIP1) deletion mutants
US6335176B1 (en) * 1998-10-16 2002-01-01 Pharmacopeia, Inc. Incorporation of phosphorylation sites
KR20020007287A (en) 1999-01-07 2002-01-26 추후보정 EXPRESSION AND EXPORT OF ANTI-OBESITY PROTEINS AS Fc FUSION PROTEINS
KR100922809B1 (en) 1999-05-06 2009-10-21 웨이크 포리스트 유니버시티 Compositions And Methods For Identifying Antigens Which Elicit An Immune Response
US6348192B1 (en) 1999-05-11 2002-02-19 Bayer Corporation Interleukin-2 mutein expressed from mammalian cells
EP1187852B1 (en) * 1999-05-19 2007-08-08 EMD Lexigen Research Center Corp. EXPRESSION AND EXPORT OF INTERFERON-ALPHA PROTEINS AS Fc FUSION PROTEINS
JO2291B1 (en) * 1999-07-02 2005-09-12 اف . هوفمان لاروش ايه جي Erythopintin derivatives
CZ299516B6 (en) * 1999-07-02 2008-08-20 F. Hoffmann-La Roche Ag Erythropoietin glycoprotein conjugate, process for its preparation and use and pharmaceutical composition containing thereof
WO2001010912A1 (en) * 1999-08-09 2001-02-15 Lexigen Pharmaceuticals Corp. Multiple cytokine-antibody complexes
CA2399832C (en) * 2000-02-11 2011-09-20 Stephen D. Gillies Enhancing the circulating half-life of antibody-based fusion proteins
PT1257297E (en) * 2000-02-24 2006-12-29 Philogen Spa Compositions and methods for treatemnt of angiogenesis in pathological lesions
US6586398B1 (en) * 2000-04-07 2003-07-01 Amgen, Inc. Chemically modified novel erythropoietin stimulating protein compositions and methods
MXPA02011016A (en) * 2000-05-12 2004-03-16 Neose Technologies Inc In vitro.
ES2288967T3 (en) * 2000-06-29 2008-02-01 Merck Patent Gmbh REINFORCEMENT OF IMMUNE ANSWERS MEDIATED BY THE ANTIBODY-CYTOKIN FUSION PROTEIN THROUGH THE TREATMENT COMBINED BY AGENTS THAT IMPROVE THE INCORPORATION OF IMMUNOCITOQUINE.
JP2004525621A (en) 2001-01-18 2004-08-26 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Bifunctional fusion protein having glucocerebrosidase activity
WO2002069232A2 (en) * 2001-02-19 2002-09-06 Merck Patent Gmbh Method for identification of t-cell epitopes and use for preparing molecules with reeduced immunogenicity
JP2004532620A (en) * 2001-02-19 2004-10-28 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Artificial proteins with reduced immunogenicity
CA2440221C (en) * 2001-03-07 2013-02-05 Merck Patent Gesellschaft Mit Beschraenkter Haftung Expression technology for proteins containing a hybrid isotype antibody moiety
WO2002079415A2 (en) * 2001-03-30 2002-10-10 Lexigen Pharmaceuticals Corp. Reducing the immunogenicity of fusion proteins
BR0209177A (en) * 2001-05-03 2004-10-05 Merck Patent Gmbh Recombinant tumor specific antibody and use
ES2381025T3 (en) * 2001-12-04 2012-05-22 Merck Patent Gmbh Immunocytokines with modulated selectivity
JP3712985B2 (en) 2002-02-22 2005-11-02 アンリツ株式会社 Method for detecting carrier leak adjustment point of quadrature modulator, carrier leak adjustment method, and quadrature modulation apparatus
ES2346205T3 (en) * 2002-12-17 2010-10-13 Merck Patent Gmbh HUMANIZED ANTIBODY (H14.18) OF ANTIBODY 14.18 OF MOUSE THAT LINKS TO GD2 AND ITS FUSION WITH IL-2.
DE10310387B3 (en) 2003-03-07 2004-07-22 Heraeus Electro-Nite International N.V. Measurement sensor determining oxygen activity and other elements in molten metal or slag, includes solid electrolyte tube coated with calcium zirconate and a fluoride
US20050069521A1 (en) * 2003-08-28 2005-03-31 Emd Lexigen Research Center Corp. Enhancing the circulating half-life of interleukin-2 proteins

Also Published As

Publication number Publication date
US7576193B2 (en) 2009-08-18
US6838260B2 (en) 2005-01-04
US20080311655A1 (en) 2008-12-18
EP1489100A3 (en) 2012-06-06
WO1999029732A2 (en) 1999-06-17
ES2590912T3 (en) 2016-11-24
US7226998B2 (en) 2007-06-05
EP1489100B1 (en) 2016-06-15
CA2693296C (en) 2013-09-10
WO1999029732A3 (en) 1999-08-26
DE69824039D1 (en) 2004-06-24
ES2221717T3 (en) 2005-01-01
US20050137384A1 (en) 2005-06-23
AU1716099A (en) 1999-06-28
DE69824039T2 (en) 2005-08-18
US20100015089A1 (en) 2010-01-21
JP4336452B2 (en) 2009-09-30
CA2693296A1 (en) 1999-06-17
AU763719B2 (en) 2003-07-31
JP2001525423A (en) 2001-12-11
US7879319B2 (en) 2011-02-01
EP1037927A2 (en) 2000-09-27
JP2009149640A (en) 2009-07-09
PT1037927E (en) 2004-10-29
DK1037927T3 (en) 2004-09-06
US20020193570A1 (en) 2002-12-19
ATE267215T1 (en) 2004-06-15
CA2312188C (en) 2010-06-29
EP1489100A2 (en) 2004-12-22
EP1037927B1 (en) 2004-05-19

Similar Documents

Publication Publication Date Title
CA2312188A1 (en) Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation
Gillies et al. Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells.
Seckinger et al. Characterization of a tumor necrosis factor alpha (TNF-alpha) inhibitor: evidence of immunological cross-reactivity with the TNF receptor.
DK0673420T3 (en) Mammalian receptors for interleukin 10 (IL-10)
KR950700419A (en) MONOMERIC AND DIMERIC ANTIBODY-FRAGMENT FUSION PROTEINS
AU664801B2 (en) Humanised antibodies
ATE313633T1 (en) EXPRESSION VECTORS ENCODING BISPECIFIC PROTEINS AND METHOD FOR PRODUCING BIOLOGICALLY-ACTIVE BISPECIFIC FUSION PROTEINS IN MAMMAL CELLS
HUP0301102A2 (en) Mammalian interleukin-12 p40 and interleukin b30, combinations thereof, antibodies, uses in pharmaceutical compositions
UA41888C2 (en) Fusion protein containing murine or humanized monoclonal antibody mab425 or its fragment directed against tumor cell, method of production, pharmaceutical composition
WO2003087320A3 (en) Antagonists of il-21 and modulation of il-21-mediated t cell responses
ATE237641T1 (en) BLOOD-FORMING FUSION PROTEIN WITH IL-3 VARIANTS
DE69412614D1 (en) RECOMBINANT DISULFID-STABILIZED POLYPEPTIDES WITH BINDING SPECIFICITY
DE69024291T2 (en) Receptors for tumor necrosis factor alpha and beta
DE3855536D1 (en) RECEPTORS FOR GROWTH HORMONES
AU639226B2 (en) Recombinant protein receptor
DK0759942T3 (en) Interleukin-15 receptors
ES2149244T3 (en) PROCEDURES FOR PRODUCING PROTEIN C.

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20181210