Angiogenesis-modulating compositions and uses

• US 7,498,304 B2
• Filed: 08/29/2003
• Issued: 03/03/2009
• Est. Priority Date: 06/16/2000
• Status: Expired due to Fees

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee L., Kotkow, Karen
• Primary Examiner(s): Fetterolf; Brandon J
• Application Number:
  US10/652,686
• Publication Number:
  US 20050054568A1
• Time in Patent Office: 2,013 Days
• Field of Search: 424/130.1, 424/138.1, 424/155.1, 424/156.1
• US Class Current: 514/1.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• 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 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/195 Chemokines, e.g. RANTES
• CPC Class Codes: C07K 14/43581 from Drosophila
• CPC Class Codes: C07K 14/461 from fish
• CPC Class Codes: C07K 14/465 from birds
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

Hedgehog agonists and antagonists can be used to regulate angiogenesis, and to prevent angiogenesis driven pathologies. Furthermore, hedgehog agonists and antagonists have utility in modulating tissue repair and in the treatment of many forms of cancer.

Claims

1. A method for treating an endometrial or liver tumor in a patient in need thereof, comprising assaying whether said tumor expresses at least one of a Sonic hedgehog gene or a gli-1 gene and administering to said patient an amount of a hedgehog antagonist sufficient to decrease at least one of the growth, proliferation or survival of the tumor, wherein the tumor expresses at least one of a Sonic hedgehog gene or a gli-1 gene, and wherein the hedgehog antagonist is a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling.

2. The method of claim 1, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

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

5. The method of claim 4, wherein said monoclonal antibody is selected from 5E1 or an antigen-binding fragment thereof.

19. The method of claim 1, wherein said tumor is an endometrial tumor.

20. The method of claim 1, wherein said tumor is a liver tumor.

34. The method of claim 1, wherein the hedgehog antibody is a humanized antibody.

41. The method of claim 1, wherein the hedgehog antibody is a human antibody.

3. A method of inhibiting at least one of growth, proliferation or survival of an endometrial or liver cancer or tumor cell, comprising

(a) assaying whether said cell expresses a Sonic hedgehog gene, and

(b) contacting said cell which expresses said Sonic hedgehog gene with an effective amount of a hedgehog antagonist;

wherein contacting said cell with said hedgehog antagonist decreases at least one of cell growth, proliferation or survival, and wherein the hedgehog antagonist is a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling.

21. The method of claim 3, wherein said cell is an endometrial cancer or tumor cell.

22. The method of claim 3, wherein said cell is a liver cancer or tumor cell.

35. The method of claim 3, wherein the hedgehog antibody is a humanized antibody.

42. The method of claim 3, wherein the hedgehog antibody is a human antibody.

6. A method of inhibiting at least one of cell growth, proliferation or survival of an endometrial or liver cancer or tumor cell in a patient in need thereof, comprising

(a) assaying whether the cell expresses a Sonic hedgehog gene, and

(b) administering to said patient an effective amount of a hedgehog antibody, which hedgehog antibody binds to Sonic hedgehog protein and specifically antagonizes hedgehog signaling in both the tumor cell and in an adjacent non-tumor stromal cell;

wherein administering said hedgehog antibody decreases at least one of cell growth, proliferation or survival.

7. The method of claim 6, wherein said hedgehog antibody which specifically antagonizes hedgehog signaling is a monoclonal antibody.

8. The method of claim 7, wherein said monoclonal antibody is 51 or an antigen-binding fragment thereof.

9. The method of claim 6, wherein said hedgehog antibody which antagonizes hedgehog signaling is formulated in a pharmaceutically acceptable carrier.

10. The method of claim 9, wherein said hedgehog antibody is administered as part of a cancer treatment regimen.

23. The method of claim 6, wherein said cell is an endometrial cancer or tumor cell.

24. The method of claim 6, wherein said cell is a liver cancer or tumor cell.

36. The method of claim 6, wherein the hedgehog antibody is a humanized antibody.

43. The method of claim 6, wherein the hedgehog antibody is a human antibody.

11. A method of inhibiting at least one of cell growth, proliferation or survival of an endometrial or liver cancer or tumor cell, comprising

(a) assaying whether said cell expresses a Sonic hedgehog gene, and

(b) contacting said cell which expresses said Sonic hedgehog gene with an effective amount of a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling, which hedgehog antibody is 5E1, a humanized antibody thereof, or an antigen-binding fragment thereof;

wherein contacting said cell with said hedgehog antibody decreases at least one of cell growth, proliferation or survival.

12. The method of claim 11, wherein said hedgehog antibody which antagonizes hedgehog signaling is formulated in a pharmaceutically acceptable carrier.

13. The method of claim 11, wherein said hedgehog antibody is administered as part of a cancer treatment regimen.

25. The method of claim 11, wherein said cell is an endometrial cancer or tumor cell.

26. The method of claim 11, wherein said cell is a liver cancer or tumor cell.

37. The method of claim 11, wherein the hedgehog antibody is a humanized antibody.

44. The method of claim 11, wherein the hedgehog antibody is a human antibody.

14. A method for treating a liver tumor in a patient in need thereof comprising administering to said patient an amount of a hedgehog antagonist effective to decrease at least one of the growth, proliferation or survival of said tumor, wherein the hedgehog antagonist is a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling, and wherein the liver tumor expresses Sonic hedgehog.

15. The method of claim 14, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

16. The method of claim 14, wherein said hedgehog antibody comprises a monoclonal antibody.

17. The method of claim 16, wherein said monoclonal antibody comprises 5E1 or an antigen-binding fragment thereof.

18. The method of claim 14, wherein said hedgehog antagonist is formulated in a pharmaceutically acceptable carrier.

38. The method of claim 14, wherein the hedgehog antibody is a humanized antibody.

45. The method of claim 14, wherein the hedgehog antibody is a human antibody.

68. The method of claim 14, wherein the liver tumor expresses a Sonic hedgehog gene.

69. The method of claim 14, wherein the liver tumor expresses a Sonic hedgehog protein.

27. A method for treating an endometrial or liver tumor in a patient, comprising assaying whether said tumor expresses a Sonic hedgehog protein, and administering to said patient an amount of a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling sufficient to decrease at least one of the growth, proliferation or survival of the tumor, wherein the tumor expresses a Sonic hedgehog protein.

28. The method of claim 27, wherein said hedgehog antibody is administered as part of a cancer treatment regimen.

30. The method of claim 27, wherein said tumor is an endometrial tumor.

31. The method of claim 27, wherein said tumor is a liver tumor.

39. The method of claim 27, wherein the hedgehog antibody is a humanized antibody.

46. The method of claim 27, wherein the hedgehog antibody is a human antibody.

29. A method of inhibiting at least one of growth, proliferation or survival of an endometrial or liver cancer or tumor cell, comprising

(a) assaying whether said cell expresses a Sonic hedgehog protein, and

(b) contacting said cell which expresses said Sonic hedgehog protein with an effective amount of a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling;

wherein contacting said cell with said hedgehog antibody decreases at least one of cell growth, proliferation or survival.

32. The method of claim 29, wherein said cancer or tumor cell is an endometrial cancer or tumor cell.

33. The method of claim 29, wherein said cancer or tumor cell is a liver cancer or tumor cell.

40. The method of claim 29, wherein the hedgehog antibody is a humanized antibody.

47. The method of claim 29, wherein the hedgehog antibody is a human antibody.

48. A method for treating an endometrial or liver tumor in a patient in need thereof, comprising assaying whether said tumor expresses at least one of a Sonic hedgehog gene or a gli-1 gene and administering to said patient an amount of a hedgehog antagonist sufficient to decrease at least one of the growth, proliferation or survival of the tumor, wherein the tumor expresses at least one of a Sonic hedgehog gene or a gli-1 gene, and wherein the hedgehog antagonist is a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling and is selected from 5E1 or an antigen-binding fragment thereof.

50. The method of claim 48, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

53. The method of claim 48, wherein the hedgehog antibody is a humanized antibody.

54. The method of claim 48, wherein the hedgehog antibody is a human antibody.

62. The method of claim 48, wherein the method is a method for treating an endometrial tumor.

63. The method of claim 48, wherein the method is a method for treating a liver turn or.

49. A method of inhibiting at least one of growth, proliferation or survival of an endometrial or liver cancer or tumor cell, comprising

(a) assaying whether said cell expresses a Sonic hedgehog gene, and

(b) contacting said cell which expresses said Sonic hedgehog gene with an effective amount of a hedgehog antagonist;

wherein contacting said cell with said hedgehog antagonist decreases at least one of cell growth, proliferation or survival, and wherein the hedgehog antagonist is a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling and is selected from 5E 1 or an antigen-binding fragment thereof.

55. The method of claim 49, wherein the hedgehog antibody is a humanized antibody.

56. The method of claim 49, wherein the hedgehog antibody is a human antibody.

64. The method of claim 49, wherein the method is a method for treating an endometrial cancer or tumor cell.

65. The method of claim 49, wherein the method is a method for treating a liver cancer or tumor cell.

51. A method for treating a liver tumor in a patient in need thereof, comprising administering to said patient an amount of a hedgehog antagonist effective to decrease at least one of the growth, proliferation or survival of said tumor, wherein the liver tumor expresses Sonic hedgehog and the hedgehog antagonist is a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling and is selected from 5E1 or an antigen-binding fragment thereof.

52. The method of claim 51, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

57. The method of claim 51, wherein the hedgehog antibody is a humanized antibody.

58. The method of claim 51, wherein the hedgehog antibody is a human antibody.

59. A method for treating an endometrial or liver tumor in a patient, comprising assaying whether said tumor expresses a Sonic hedgehog protein, and administering to said patient an amount of a hedgehog antibody that binds to Sonic hedgehog protein and inhibits hedgehog signaling sufficient to decrease at least one of the growth, proliferation or survival of the tumor, which hedgehog antibody is selected from 5E1 or an antigen-binding fragment thereof, wherein the tumor expresses a Sonic hedgehog protein.

60. The method of claim 59, wherein the hedgehog antibody is a humanized antibody.

61. The method of claim 59, wherein the hedgehog antibody is a human antibody.

66. The method of claim 59, wherein the method is a method for treating an endometrial tumor in a patient.

67. The method of claim 59, wherein the method is a method for treating a liver tumor in a patient.