Death Domain Containing Receptors

• US 20080171016A1
• Filed: 03/11/2008
• Published: 07/17/2008
• Est. Priority Date: 03/12/1996
• Status: Active Grant

• Current Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Original Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Inventors: Gentz, Reiner L., Yu, Guo-Liang, Ni, Jian, Dillon, Patrick J.
• Granted Patent: US 7,708,996 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/4747 Apoptosis related proteins
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70578 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C12N 2799/026 where the vector is derived from a baculovirus

Abstract

The present invention relates to novel Death Domain Containing Receptor (DR3 and DR3-V1) proteins that are members of the tumor necrosis factor (TNF) receptor family. In particular, isolated nucleic acid molecules are provided encoding the human DR3 and DR3-V1 proteins. DR3 and DR3-V1 polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. Also provided are antibodies and fragments thereof that bind to polypeptides of the invention. The invention further relates to screening methods for identifying agonists and antagonists of DR3 and DR3-V1 activity.

Claims

1. An isolated antibody which binds to a polypeptide selected from the group consisting of:

(a) amino acids 1 to 428 of SEQ ID NO;

2; and

(b) amino acids 1 to 417 of SEQ ID NO;

4.

2. The isolated antibody of claim 1, wherein said antibody enhances apoptosis.

3. The isolated antibody of claim 1, wherein said antibody inhibits apoptosis.

4. The isolated antibody of claim 1, wherein said antibody is selected from the group consisting of:

(a) a monoclonal antibody;

(b) a polyclonal antibody;

(c) a chimeric antibody;

(d) a humanized antibody;

(e) a single-chain Fv antibody; and

(f) an Fab antibody fragment.

5. A method for treating a disease or condition selected from the group consisting of:

(a) cancer;

(b) inflammation;

(c) an autoimmune disease; and

(d) graft v. host disease,

wherein said method comprises administering to an individual a therapeutically effective amount of the antibody of claim 1.

6. The method of claim 5 further comprising administering an additional therapeutic agent selected from the group consisting of:

(a) a tumor necrosis factor blocking agent;

(b) an immunosuppressive agent;

(c) an antibiotic;

(d) an anti-inflammatory agent;

(e) a chemotherapeutic agent; and

(f) a cytokine.

7. The method of claim 6, wherein said tumor necrosis factor blocking agent comprises an antibody which binds to a protein selected from the group consisting of:

(a) TNF-α

;

(b) TNF-β

; and

(c) TNF-γ

-β

.

8. The method of claim 6, wherein said immunosuppressive agent is selected from the group consisting of:

(a) cyclosporine;

(b) cyclophosphamide;

(c) methylprednisone;

(d) prednisone;

(e) azathioprine;

(f) FK-506; and

(g) 15-deoxyspergualin.

9. The method of claim 6, wherein said cytokine is selected from the group consisting of:

(a) IL-2;

(b) IL-3;

(c) IL-4;

(d) IL-5;

(e) IL-6;

(f) IL-7;

(g) IL-10;

(h) IL-12;

(i) IL-13;

(j) IL-15; and

(k) IFN-γ

.

10. The method of claim 6, wherein said antibody and said additional therapeutic agent are administered to the individual at different times.

11. A composition comprising:

(a) a first therapeutic agent comprising the antibody of claim 1; and

(b) a second therapeutic agent selected from the group consisting of;

(i) a tumor necrosis factor blocking agent;

(ii) an immunosuppressive agent;

(iii) an antibiotic;

(iv) an anti-inflammatory agent;

(v) a chemotherapeutic agent; and

(vi) a cytokine.

12. The composition of claim 11 which further comprises a pharmaceutically acceptable carrier or excipient.

13. An isolated polypeptide comprising an amino acid sequence at least 95% identical to:

(a) amino acids 36 to 212 of SEQ ID NO;

2;

(b) amino acids 30 to 217 of SEQ ID NO;

2;

(c) amino acids 30 to 428 of SEQ ID NO;

2; and

(d) amino acids 1 to 428 of SEQ ID NO;

2.

14. The isolated polypeptide of claim 13, which is produced by a recombinant host cell.

15. The isolated polypeptide of claim 13, which further comprises a heterologous amino acid sequence.

16. A composition comprising the isolated polypeptide of claim 13 and a pharmaceutically acceptable carrier.

17. An isolated polypeptide comprising an amino acid sequence at least 95% identical to:

(a) amino acids 1 to 417 of SEQ ID NO;

4;

(b) amino acids 25 to 417 of SEQ ID NO;

4; and

(c) amino acids 25 to 201 of SEQ ID NO;

4.

18. The isolated polypeptide of claim 17, which is produced by a recombinant host cell.

19. The isolated polypeptide of claim 17, which further comprises a heterologous amino acid sequence.

20. A composition comprising the isolated polypeptide of claim 17 and a pharmaceutically acceptable carrier.