Death domain containing receptor 5

• US 20080248046A1
• Filed: 01/18/2008
• Published: 10/09/2008
• 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: Yu, Guo-Liang, Ni, Jian, Rosen, Craig A., Gentz, Reiner L.
• Application Number:
  US12/010,106
• Publication Number:
  US 20080248046A1
• Time in Patent Office: Days
• US Class Current: 424/139.1
• 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: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 2317/74 Inducing cell proliferation
• 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. A method for inducing apoptosis of a DR5-expressing cell, comprising contacting said cell with an agonist antibody or fragment thereof that specifically binds to a polypeptide consisting of amino acids 1 to 133 of SEQ ID NO:

2 in combination with a second agent selected from the group consisting of;

(a) an alkylating agent;

(b) an antimetabolite;

(c) a farnesyl transferase inhibitor;

(d) a mitotic spindle inhibitor;

(e) a topoisomerase inhibitor;

(f) a tyrosine kinase inhibitor;

(g) a proteasome inhibitor;

(h) an antibiotic;

(i) an IAP inhibitor;

(j) a histone deacetylase inhibitor;

(k) a HSP90 inhibitor;

(l) thalidomide;

(m) a thalidomide analog;

(n) a monoclonal antibody;

(o) radiation therapy;

(p) a PPAR-gamma antagonist;

(q) a AKT/mTOR signaling pathway inhibitor; and

(r) a BCL-2 inhibitor.

2. The method of claim 1, wherein said alkylating agent is a nitrogen mustard.

3. The method of claim 1, wherein said alkylating agent is carboplatin.

4. The method of claim 1, wherein said alkylating agent is cisplatin.

5. The method of claim 1, wherein said alkylating agent is oxaliplatin.

6. The method of claim 1, wherein said antimetabolite is methotrexate.

7. The method of claim 1, wherein said antimetabolite is fluorouracil+leucovorin.

8. The method of claim 1, wherein said antimetabolite is cytosine arabinoside.

9. The method of claim 1, wherein said antimetabolite is pemetrexed.

10. The method of claim 1, wherein said antimetabolite is gemcitabine.

11. The method of claim 1, wherein said antimetabolite is capecitabine.

12. The method of claim 1, wherein said mitotic spindle inhibitor is docetaxel.

13. The method of claim 1, wherein said mitotic spindle inhibitor is paclitaxel.

14. The method of claim 1, wherein said mitotic spindle inhibitor is vincristine.

15. The method of claim 1, wherein said mitotic spindle inhibitor is vinblastine.

16. The method of claim 1, wherein said topoisomerase inhibitor is 9-aminocamptothecin.

17. The method of claim 1, wherein said topoisomerase inhibitor is topotecan.

18. The method of claim 1, wherein said topoisomerase inhibitor is irinotecan.

19. The method of claim 1, wherein said topoisomerase inhibitor is etoposide.

20. The method of claim 1, wherein said tyrosine kinase inhibitor is imatinib mesylate.

21. The method of claim 1, wherein said tyrosine kinase inhibitor is BAY 43-9006.

22. The method of claim 1, wherein said proteasome inhibitor is PS-341.

23. The method of claim 1, wherein said proteasome inhibitor is NPI-0052.

24. The method of claim 1, wherein said antibiotic is bleomycin.

25. The method of claim 1, wherein said antibiotic is daunorubicin.

26. The method of claim 1, wherein said antibiotic is doxorubicin.

27. The method of claim 1, wherein said antibiotic is dactinomycin.

28. The method of claim 1, wherein said IAP inhibitor is an XIAP inhibitor.

29. The method of claim 1, wherein said monoclonal antibody is bevacizumab.

30. The method of claim 1, wherein said monoclonal antibody is rituximab.

31. The method of claim 1, wherein said thalidomide analog is revlimid.

32. A method for treating cancer of a DR5-expressing cell, comprising contacting said cell with an agonist antibody or fragment thereof that specifically binds to a polypeptide consisting of amino acids 1 to 133 of SEQ ID NO:

2 in combination with a second agent selected from the group consisting of;

(a) an alkylating agent;

(b) an antimetabolite;

(c) a farnesyl transferase inhibitor;

(d) a mitotic spindle inhibitor;

(e) a topoisomerase inhibitor;

(f) a tyrosine kinase inhibitor;

(g) a proteasome inhibitor;

(h) an antibiotic;

(i) an IAP inhibitor;

(j) a histone deacetylase inhibitor;

(k) a HSP90 inhibitor;

(l) thalidomide;

(m) a thalidomide analog;

(n) a monoclonal antibody;

(o) radiation therapy;

(p) a PPAR-gamma antagonist;

(q) a AKT/mTOR signaling pathway inhibitor; and

(r) a BCL-2 inhibitor.

33. The method of claim 32, wherein said alkylating agent is a nitrogen mustard.

34. The method of claim 32, wherein said alkylating agent is carboplatin.

35. The method of claim 32, wherein said alkylating agent is cisplatin.

36. The method of claim 32, wherein said alkylating agent is oxaliplatin.

37. The method of claim 32, wherein said antimetabolite is methotrexate.

38. The method of claim 32, wherein said antimetabolite is fluorouracil+leucovorin.

39. The method of claim 32, wherein said antimetabolite is cytosine arabinoside.

40. The method of claim 32, wherein said antimetabolite is pemetrexed.

41. The method of claim 32, wherein said antimetabolite is gemcitabine.

42. The method of claim 32, wherein said antimetabolite is capecitabine.

43. The method of claim 32, wherein said mitotic spindle inhibitor is docetaxel.

44. The method of claim 32, wherein said mitotic spindle inhibitor is paclitaxel.

45. The method of claim 32, wherein said mitotic spindle inhibitor is vincristine.

46. The method of claim 32, wherein said mitotic spindle inhibitor is vinblastine.

47. The method of claim 32, wherein said topoisomerase inhibitor is 9-aminocamptothecin.

48. The method of claim 32, wherein said topoisomerase inhibitor is topotecan.

49. The method of claim 32, wherein said topoisomerase inhibitor is irinotecan.

50. The method of claim 32, wherein said topoisomerase inhibitor is etoposide.

51. The method of claim 32, wherein said tyrosine kinase inhibitor is imatinib mesylate.

52. The method of claim 32, wherein said tyrosine kinase inhibitor is BAY 43-9006.

53. The method of claim 32, wherein said proteasome inhibitor is PS-341.

54. The method of claim 32, wherein said proteasome inhibitor is NPI-0052.

55. The method of claim 32, wherein said antibiotic is bleomycin.

56. The method of claim 32, wherein said antibiotic is daunorubicin.

57. The method of claim 32, wherein said antibiotic is doxorubicin.

58. The method of claim 32, wherein said antibiotic is dactinomycin.

59. The method of claim 32, wherein said IAP inhibitor is an XIAP inhibitor.

60. The method of claim 32, wherein said monoclonal antibody is bevacizumab.

61. The method of claim 32, wherein said monoclonal antibody is rituximab.

62. The method of claim 32, wherein said thalidomide analog is revlimid.

63. A method of treating cancer, comprising administering to a patient a therapeutically effective amount of an agonist antibody or fragment thereof that specifically binds to a polypeptide consisting of amino acids 1 to 133 of SEQ ID NO:

2, wherein said cancer is selected from the group consisting of;

(a) multiple myeloma;

(b) bile duct carcinoma;

(c) hepatoma; and

(d) lung cancer.

64. The method of claim 63, wherein said cancer is multiple myeloma.

65. The method of claim 63, wherein said cancer is bile duct carcinoma.

66. The method of claim 63, wherein said cancer is a hepatoma.

67. The method of claim 63, wherein said cancer is lung cancer.

68. A method of treating hepatitis C, comprising administering to a patient a therapeutically effective amount of an agonist antibody or fragment thereof that specifically binds to a polypeptide consisting of amino acids 1 to 133 of SEQ ID NO:

2.