Death domain containing receptor 5

• US 20050233958A1
• Filed: 11/03/2004
• Published: 10/20/2005
• Est. Priority Date: 03/17/1997
• Status: Abandoned Application

• 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, Rosen, Craig A.
• Application Number:
  US10/979,831
• Publication Number:
  US 20050233958A1
• Time in Patent Office: Days
• US Class Current: 514/18.900
• 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: 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 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The present invention relates to novel Death Domain Containing Receptor-5 (DR5) proteins which are members of the tumor necrosis factor (TNF) receptor family, and have now been shown to bind TRAIL. In particular, isolated nucleic acid molecules are provided encoding the human DR5 proteins. DR5 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 antagonists and antagonists of DR5 activity. The invention also relates to the treatment of diseases associated with reduced or increased levels of apoptosis using antibodies specific for DR5, which may be agonists and/or antagonists of DR5 activity.

Claims

1. An isolated polypeptide selected from the group consisting of:

(a) the polypeptide of SEQ ID NO;

2; and

(b) a fragment of the polypeptide of (a).

2. The polypeptide of claim 1, wherein said fragment binds TRAIL.

3. The polypeptide of claim 1, wherein said fragment inhibits apoptosis.

4. The polypeptide of claim 1, wherein said fragment induces apoptosis.

5. The polypeptide of claim 1, wherein said polypeptide comprises amino acids n¹ to 360 of SEQ ID NO:

2, wherein n¹ represents an integer from −

50 to 355.

6. The polypeptide of claim 2, wherein said polypeptide comprises amino acids n¹ to 360 of SEQ ID NO:

2, wherein n¹ represents an integer from −

50 to 355.

7. The polypeptide of claim 3, wherein said polypeptide comprises amino acids n¹ to 360 of SEQ ID NO:

2, wherein n¹ represents an integer from −

50 to 355.

8. The polypeptide of claim 4, wherein said polypeptide comprises amino acids n¹ to 360 of SEQ ID NO:

2, wherein n¹ represents an integer from −

50 to 355.

9. The polypeptide of claim 1, wherein said fragment is soluble.

10. The polypeptide of claim 2, wherein said fragment is soluble.

11. The polypeptide of claim 3, wherein said fragment is soluble.

28. A composition comprising the polypeptide of claim 1, and a pharmaceutically acceptable carrier.

29. A composition comprising the polypeptide of claim 2, and a pharmaceutically acceptable carrier.

30. A composition comprising the polypeptide of claim 3, and a pharmaceutically acceptable carrier.

31. A composition comprising the polypeptide of claim 4, and a pharmaceutically acceptable carrier.

32. A composition comprising the polypeptide of claim 9, and a pharmaceutically acceptable carrier.

33. A composition comprising the polypeptide of claim 10, and a pharmaceutically acceptable carrier.

34. A composition comprising the polypeptide of claim 11, and a pharmaceutically acceptable carrier.

39. The polypeptide of claim 1, wherein said fragment comprises the cysteine-rich domains of SEQ ID NO:

2.

40. The polypeptide of claim 39, wherein said fragment comprises amino acids 33 to 128 of SEQ ID NO:

2.

41. The polypeptide of claim 39, wherein said polypeptide binds TRAIL.

42. The polypeptide of claim 39, wherein said polypeptide inhibits apoptosis.

43. The polypeptide of claim 39, wherein said polypeptide induces apoptosis.

53. A multimer comprising at least two polypeptides of claim 39.

54. A multimer comprising at least two polypeptides of claim 40.

55. A multimer comprising at least two polypeptides of claim 41.

56. A multimer comprising at least two polypeptides of claim 42.

57. A multimer comprising at least two polypeptides of claim 43.

67. The multimer of claim 55, wherein the multimer is a dimer or trimer.

68. The multimer of claim 56, wherein the multimer is a dimer or trimer.

69. The multimer of claim 57, wherein the multimer is a dimer or trimer.

72. A composition comprising the polypeptide of claim 41, and a pharmaceutically acceptable carrier.

73. A composition comprising the polypeptide of claim 42, and a pharmaceutically acceptable carrier.

74. A composition comprising the polypeptide of claim 43, and a pharmaceutically acceptable carrier.

80. A composition comprising the multimer of claim 55, and a pharmaceutically acceptable carrier.

81. A composition comprising the multimer of claim 56, and a pharmaceutically acceptable carrier.

82. A composition comprising the multimer of claim 57, and a pharmaceutically acceptable carrier.

84. An isolated polynucleotide encoding the polypeptide of claim 1.

85. An isolated antibody that specifically binds the polypeptide of claim 1.

12. An isolated polypeptide comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO:

2.

13. The polypeptide of claim 12, wherein said polypeptide binds TRAIL.

14. The polypeptide of claim 12, wherein said polypeptide inhibits apoptosis.

15. The polypeptide of claim 12, wherein said polypeptide induces apoptosis.

16. The polypeptide of claim 12, wherein said polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:

2.

17. The polypeptide of claim 16, wherein said polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

2.

18. The polypeptide of claim 13, wherein said polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:

2.

19. The polypeptide of claim 18, wherein said polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

2.

20. The polypeptide of claim 14, wherein said polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:

2.

21. The polypeptide of claim 20, wherein said polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

2.

22. The polypeptide of claim 15, wherein said polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO:

2.

23. The polypeptide of claim 22, wherein said polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

2.

24. A dimer, trimer, or tetramer of the polypeptide of claim 12.

25. A dimer, trimer, or tetramer of the polypeptide of claim 13.

26. A dimer, trimer, or tetramer of the polypeptide of claim 14.

27. A dimer, trimer, or tetramer of the polypeptide of claim 15.

75. A composition comprising the dimer, trimer, or tetramer of claim 24, and a pharmaceutically acceptable carrier.

76. A composition comprising the dimer, trimer, or tetramer of claim 25, and a pharmaceutically acceptable carrier.

77. A composition comprising the dimer, trimer, or tetramer of claim 26, and a pharmaceutically acceptable carrier.

78. A composition comprising the dimer, trimer, or tetramer of claim 27, and a pharmaceutically acceptable carrier.

35. An isolated polypeptide encoded by a DNA comprising the nucleotide sequence of SEQ ID NO:

1.

36. An isolated polypeptide comprising amino acids n² to 133 of SEQ ID NO:

2, wherein n² represents an integer from −

51 to 128, and wherein said polypeptide binds TRAIL.

37. The polypeptide of claim 36, wherein said polypeptide comprises amino acids 1 to 133 of SEQ ID NO:

2.

38. The polypeptide of claim 36, wherein said polypeptide is soluble.

50. A multimer comprising at least two polypeptides of claim 36.

51. A multimer comprising at least two polypeptides of claim 37.

52. A multimer comprising at least two polypeptides of claim 38.

64. The multimer of claim 50, wherein the multimer is a dimer or trimer.

65. The multimer of claim 51, wherein the multimer is a dimer or trimer.

66. The multimer of claim 52, wherein the multimer is a dimer or trimer.

70. The multimer of claim 64, wherein the multimer is a dimer.

71. A composition comprising the polypeptide of claim 36, and a pharmaceutically acceptable carrier.

79. A composition comprising the multimer of claim 50, and a pharmaceutically acceptable carrier.

83. A composition comprising the multimer of claim 64, and a pharmaceutically acceptable carrier.

44. An isolated soluble polypeptide comprising an amino acid sequence at least 80% identical to the sequence of amino acids 1 to 133 of SEQ ID NO:

2.

45. The polypeptide of claim 44, wherein said polypeptide binds TRAIL.

46. The polypeptide of claim 44, wherein said polypeptide inhibits apoptosis.

47. The polypeptide of claim 44, wherein the polypeptide comprises an amino acid sequence at least 90% identical to the sequence of amino acids 1 to 133 of SEQ ID NO:

2.

48. The polypeptide of claim 45, wherein the polypeptide comprises an amino acid sequence at least 90% identical to the sequence of amino acids 1 to 133 of SEQ ID NO:

2.

49. The polypeptide of claim 46, wherein the polypeptide comprises an amino acid sequence at least 90% identical to the sequence of amino acids 1 to 133 of SEQ ID NO:

2.

58. A multimer comprising at least two polypeptides of claim 44.

59. A multimer comprising at least two polypeptides of claim 45.

60. A multimer comprising at least two polypeptides of claim 46.

61. A multimer comprising at least two polypeptides of claim 47.

62. A multimer comprising at least two polypeptides of claim 48.

63. A multimer comprising at least two polypeptides of claim 49.