Death domain containing receptors

• US 20030170203A1
• Filed: 07/05/2002
• Published: 09/11/2003
• 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 7,357,927 B2
• Time in Patent Office: Days
• US Class Current: 424/85.1
• 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. The invention further relates to screening methods for identifying agonists and antagonists of DR3 and DR3-V1 activity.

Claims

1. A method for treating graft versus host disease, cancer, an immunodeficiency, or an autoimmune disorder comprising administering to an individual therapeutically effective amounts of:

(a) a first therapeutic agent comprising an antibody which binds to a polypeptide consisting of amino acids 1 to 428 of SEQ ID NO;

2 or amino acids 1 to 417 of SEQ ID NO;

4; 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.

2. The method of claim 1, wherein said first therapeutic agent comprises an antibody which binds to a polypeptide consisting of amino acids 36 to 212 of SEQ ID NO:

2.

3. The method of claim 1, wherein said antibody is a monoclonal antibody.

4. The method of claim 1, wherein said antibody is a polyclonal antibody.

5. The method of claim 1, wherein said antibody is a chimeric antibody.

6. The method of claim 1, wherein said antibody is a humanized antibody.

7. The method of claim 1, wherein said antibody is a single-chain Fv antibody.

8. The method of claim 1, wherein said antibody is an Fab antibody fragment.

9. The method of claim 1, wherein said first and second therapeutic agents are administered to the individual at the same time.

10. The method of claim 1, wherein said first and second therapeutic agents are administered to the individual at different times.

11. The method of claim 1, 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

.

12. The method of claim 1, 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.

13. The method of claim 1, 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

.

14. A composition comprising:

(a) a first therapeutic agent comprising an antibody which binds to a polypeptide consisting of amino acids 1 to 428 of SEQ ID NO;

2 or amino acids 1 to 417 of SEQ ID NO;

4; 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.

15. A method for the treatment of graft versus host disease, cancer, an immunodeficiency, or an autoimmune disorder comprising administering to an individual a therapeutically effective amount of the composition of claim 14.

16. The composition of claim 14 which further comprises a pharmaceutically acceptable carrier or excipient.

17. An isolated polypeptide comprising an amino acid sequence at least 90% identical to amino acids 36 to 212 of SEQ ID NO:

2;

wherein said polypeptide is covalently attached to polyethylene glycol, said polyethylene glycol having an average molecule weight selected from the group consisting of 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000, 15,000, and 20,000.

18. The isolated polypeptide of claim 17, comprising an amino acid sequence at least 95% identical to amino acids 36 to 212 of SEQ ID NO:

2.

19. The isolated polypeptide of claim 18, wherein said amino acid sequence comprises amino acids 36 to 212 of SEQ ID NO:

2.

20. The isolated polypeptide of claim 17, wherein said polypeptide has an average degree of substitution with polyethylene glycol which falls within a range selected from the group consisting of 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, and 10-12.

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

22. The isolated polypeptide of claim 17, which comprises a heterologous polypeptide.

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

24. An isolated polynucleotide comprising a nucleic acid encoding an amino acid sequence at least 90% identical to amino acids 30 to 215 of SEQ ID NO:

2.

25. The isolated polynucleotide of claim 24, comprising a nucleic acid encoding an amino acid sequence at least 95% identical to amino acids 30 to 215 of SEQ ID NO:

2.

26. The isolated polynucleotide of claim 24, comprising a nucleic acid encoding an amino acid sequence at least 90% identical to amino acids 30 to 428 of SEQ ID NO:

2.

27. The isolated polynucleotide of claim 26, comprising a nucleic acid encoding an amino acid sequence at least 95% identical to amino acids 30 to 428 of SEQ ID NO:

2.

28. The isolated polynucleotide of claim 27, comprising a nucleic acid encoding amino acids 30 to 428 of SEQ ID NO:

2.

29. The isolated polynucleotide of claim 26, comprising a nucleic acid encoding an amino acid sequence at least 90% identical to amino acids 1 to 428 of SEQ ID NO:

2.

30. The isolated polynucleotide of claim 29, comprising a nucleic acid encoding an amino acid sequence at least 95% identical to amino acids 1 to 428 of SEQ ID NO:

2.

31. The isolated polynucleotide of claim 30, comprising a nucleic acid encoding amino acids 1 to 428 of SEQ ID NO:

2.

32. The isolated polynucleotide of claim 24, further comprising a heterologous polynucleotide.

33. The isolated polynucleotide of claim 32, wherein said heterologous polynucleotide encodes a heterologous polypeptide.

34. A method of producing a vector which comprises inserting the isolated polynucleotide of claim 24 into a vector.

35. A vector comprising the isolated polynucleotide of claim 24.

36. The vector of claim 35, wherein said isolated polynucleotide is operably associated with a heterologous regulatory polynucleotide.

37. A host cell comprising the isolated polynucleotide of claim 24.

38. The host cell of claim 37, wherein said isolated polynucleotide is operably associated with a heterologous regulatory polynucleotide.

39. A method of producing a polypeptide which comprises culturing the host cell of claim 38 under conditions such that said polypeptide is expressed, and recovering said polypeptide.

40. An isolated polynucleotide comprising a nucleic acid encoding an amino acid sequence at least 90% identical to the mature amino acid sequence encoded by the cDNA clone in ATCC Deposit No. 97456.

41. The isolated polynucleotide of claim 40, comprising a nucleic acid encoding an amino acid sequence at least 95% identical to the mature amino acid sequence encoded by the cDNA clone in ATCC Deposit No. 97456.

42. The isolated polynucleotide of claim 40, comprising a nucleic acid encoding an amino acid sequence at least 90% identical to the complete amino acid sequence encoded by the cDNA clone in ATCC Deposit No. 97456.

43. The isolated polynucleotide of claim 42, comprising a nucleic acid encoding an amino acid sequence at least 95% identical to the complete amino acid sequence encoded by the cDNA clone in ATCC Deposit No. 97456.

44. The isolated polynucleotide of claim 40, further comprising a heterologous polynucleotide.

45. The isolated polynucleotide of claim 44, wherein said heterologous polynucleotide encodes a heterologous polypeptide.

46. A method of producing a vector which comprises inserting the isolated polynucleotide of claim 40 into a vector.

47. A vector comprising the isolated polynucleotide of claim 40.

48. The vector of claim 47, wherein said isolated polynucleotide is operably associated with a heterologous regulatory polynucleotide.

49. A host cell comprising the isolated polynucleotide of claim 40.

50. The host cell of claim 49, wherein said isolated polynucleotide is operably associated with a heterologous regulatory polynucleotide.

51. A method of producing a polypeptide which comprises culturing the host cell of claim 50 under conditions such that said polypeptide is expressed, and recovering said polypeptide.

52. An isolated polypeptide comprising an amino acid sequence at least 90% identical to amino acids 30 to 215 of SEQ ID NO:

2.

53. The isolated polypeptide of claim 52, wherein said amino acid sequence is at least 95% identical to amino acids 30 to 215 of SEQ ID NO:

2.

54. The isolated polypeptide of claim 52, wherein said amino acid sequence is at least 90% identical to amino acids 30 to 428 of SEQ ID NO:

2.

55. The isolated polypeptide of claim 54, wherein said amino acid sequence is at least 95% identical to amino acids 30 to 428 of SEQ ID NO:

2.

56. The isolated polypeptide of claim 55, wherein said amino acid sequence comprises amino acids 30 to 428 of SEQ ID NO:

2.

57. The isolated polypeptide of claim 52, wherein said amino acid sequence is at least 90% identical to amino acids 1 to 428 of SEQ ID NO:

2.

58. The isolated polypeptide of claim 57, wherein said amino acid sequence is at least 95% identical to amino acids 1 to 428 of SEQ ID NO:

2.

59. The isolated polypeptide of claim 58, wherein said amino acid sequence comprises amino acids 1 to 428 of SEQ ID NO:

2.

60. The isolated polypeptide of claim 52, which is produced by a recombinant host cell.

61. The isolated polypeptide of claim 52, which comprises a heterologous polypeptide.

62. A composition comprising the isolated polypeptide of claim 52 and a pharmaceutically acceptable carrier.

63. An isolated polypeptide comprising an amino acid sequence at least 90% identical to the mature amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 97456.

64. The isolated polypeptide of claim 63, which comprises an amino acid sequence at least 95% identical to the mature amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 97456.

65. The isolated polypeptide of claim 63, which comprises an amino acid sequence at least 90% identical to the complete amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 97456.

66. The isolated polypeptide of claim 65, which comprises an amino acid sequence at least 95% identical to the complete amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. 97456.

67. The isolated polypeptide of claim 63, which is produced by a recombinant host cell.

68. The isolated polypeptide of claim 63, which comprises a heterologous polypeptide.

69. A composition comprising the isolated polypeptide of claim 63 and a pharmaceutically acceptable carrier.

70. An isolated antibody which binds to a polypeptide consisting of amino acids 1 to 428 of SEQ ID NO:

2.

71. The isolated antibody of claim 70, wherein said antibody is a monoclonal antibody.

72. The isolated antibody of claim 70, wherein said antibody is a polyclonal antibody.

73. The isolated antibody of claim 70, wherein said antibody is an Fab antibody fragment.

74. 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 70.

75. A composition comprising the antibody of claim 70 and a pharmaceutically acceptable carrier.

76. A method for treating an autoimmune disease or preventing graft rejection in an individual comprising administering to said individual a composition of claim 75.

77. An isolated antibody which binds to a polypeptide consisting of the complete amino acid sequence encoded by the CDNA clone contained in ATCC Deposit No. 97456.

78. The isolated antibody of claim 77, wherein said antibody is a monoclonal antibody.

79. The isolated antibody of claim 77, wherein said antibody is a polyclonal antibody.

80. The isolated antibody of claim 77, wherein said antibody is an Fab antibody fragment.

81. 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 77.

82. A composition comprising the antibody of claim 77 and a pharmaceutically acceptable carrier.

83. A method for treating an autoimmune disease or preventing graft rejection in an individual comprising administering to said individual a composition of claim 82.