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 PDFInfo
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- 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
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- subunit
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Animal Behavior & Ethology (AREA)
- Cell Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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.
(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.
(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.
(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.
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 |
---|---|---|---|
CA2312188A Expired - Lifetime CA2312188C (en) | 1997-12-08 | 1998-12-08 | Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation |
CA2693296A Expired - Lifetime CA2693296C (en) | 1997-12-08 | 1998-12-08 | Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation |
Family Applications After (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) | CA2312188C (en) |
DE (1) | DE69824039T2 (en) |
DK (1) | DK1037927T3 (en) |
ES (2) | ES2590912T3 (en) |
PT (1) | PT1037927E (en) |
WO (1) | WO1999029732A2 (en) |
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1998
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- 1998-12-08 PT PT98961978T patent/PT1037927E/en unknown
- 1998-12-08 ES ES04011760.8T patent/ES2590912T3/en not_active Expired - Lifetime
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EP1489100B1 (en) | 2016-06-15 |
EP1489100A3 (en) | 2012-06-06 |
WO1999029732A2 (en) | 1999-06-17 |
US20020193570A1 (en) | 2002-12-19 |
EP1037927A2 (en) | 2000-09-27 |
JP4336452B2 (en) | 2009-09-30 |
ES2590912T3 (en) | 2016-11-24 |
JP2001525423A (en) | 2001-12-11 |
CA2693296A1 (en) | 1999-06-17 |
DE69824039T2 (en) | 2005-08-18 |
US7879319B2 (en) | 2011-02-01 |
JP2009149640A (en) | 2009-07-09 |
US7226998B2 (en) | 2007-06-05 |
AU763719B2 (en) | 2003-07-31 |
DE69824039D1 (en) | 2004-06-24 |
AU1716099A (en) | 1999-06-28 |
US6838260B2 (en) | 2005-01-04 |
DK1037927T3 (en) | 2004-09-06 |
ES2221717T3 (en) | 2005-01-01 |
EP1489100A2 (en) | 2004-12-22 |
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Effective date: 20181210 |