Angiogenesis-modulating compositions and uses

• US 20050054568A1
• Filed: 08/29/2003
• Published: 03/10/2005
• Est. Priority Date: 06/16/2000
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Sanicola-Nadel, Michele, Rubin, Lee L., Ling, Leona E., Kotkow, Karen
• Granted Patent: US 7,498,304 B2
• Time in Patent Office: Days
• US Class Current: 514/8.100
• 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 of promoting angiogenesis in a subject animal comprising administering to the subject an angiogenic amount of a hedgehog polypeptide or agonist thereof.

2. The method of claim 1, wherein the step of administering comprises contacting the hedgehog polypeptide or agonist with a mesenchymal cell of the subject.

3. The method of claim 1, comprising administering to the subject a polypeptide including a hedgehog amino acid sequence, which hedgehog sequence directs the binding of the polypeptide to a patched receptor polypeptide and/or induces alkaline phosphatase activity in C3H10T1/2 cells.

4. The method of claim 1, comprising administering to the subject a polypeptide including a hedgehog amino acid sequence having at least 60% amino acid identity with SEQ ID No. 10-18 or 20.

5. The method of claim 1, comprising administering to the subject a polypeptide including a hedgehog amino acid sequence encoded by a coding sequence which hybridizes under stringent conditions to any of SEQ ID No. 1-9 or 19.

6. The method of claim 1, comprising administering to the subject a polypeptide including a hedgehog amino acid sequence represented by SEQ ID No. 26.

7. The method of any of claims 3-6, wherein the hedgehog sequence includes at least 50 resdiues of an extracellular domain of a hedgehog protein.

8. The method of any of claims 3-6, wherein the polypeptide is derivatized with one or more chemical moieties.

9. The method of claim 8, wherein the chemical moiety is a polyalkylene glycol polymer.

10. The method of claim 8, wherein the chemical moiety is a hydrophobic moiety.

11. The method of claim 10, wherein the hydrophobic moiety is a lipid.

12. The method of claim 8, wherein the chemical moiety is one or more phosphate groups.

13. The method of claim 8, wherein the chemical moiety is one or more acetyl groups.

14. The method of claim 8, wherein the chemical moiety is one or more sugar or carbohydrate groups.

15. The method of claim 8, wherein the chemical moieties are any combination of phosphate, acetyl, sugar, carbohydrate, or hydrophobic moieties.

16. The method of claim 4, wherein the method further comprises administering an agent that enhances agonistic properties of the hedgehog therapeutic.

17. The method of claim 16, wherein the agent is an angiogenic factor selected from the group consisting of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), angiopoietin 1, angiopoietin 2, monocyte chemotactic protein-1 (MCP-1).

25. The method of claim 1, wherein the hedgehog agonist is a small organic molecule.

26. The method of claim 25, wherein the hedgehog agonist has a molecular weight less than 2500 amu.

27. The method of claim 25, wherein the hedgehog agonist is represented by general formula (XII):

28. The method of any of claims 3-6, comprising administering a nucleic acid sequence encoding the polypeptide.

18. A method of inhibiting angiogenesis in a subject animal comprising administering to the subject an antiangiogenic amount of a hedgehog antagonist.

19. The method of claim 18, comprising administering a polypeptide including one or more antigen binding domains which bind to and inhibit hedgehog signalling.

20. The method of claim 18, comprising administering a polypeptide including one or more antigen binding domains which bind to patched and inhibit hedgehog signalling.

21. The method of claim 18, comprising administering a polypeptide including one or more antigen binding domains which bind to smoothened and inhibit hedgehog signalling.

22. The method of claim 19, 20 or 21, wherein the antigen binding domain is part of a an antibody structure selected from the group consisting of a humanized antibody homology, a human antibody homolog, a chimeric antibody homolog and fragments thereof.

23. The method of claim 18, comprising administering a functional antagonist of a hedgehog therapeutic.

24. The method of claim 18, or 20, wherein the subject has a condition selected from the group consisting of a malignant tumor, retinopathy, macular degeneration, a nonmalignant tumor, rheumatoid arthritis, osteoarthritis, neovascular glaucoma, keloids, Crohn'"'"'s disease, ulcerative colitis, and psoriasis.

30. The method of claim 18, wherein the hedgehog antagonist is a small organic molecule.

31. The method of claim 30, wherein the hedgehog antagonist has a molecular weight less than 2500 amu.

32. The method of claim 30, wherein the hedgehog antagonist is represented by one or more of formulas I-XI.

33. The method of claim 30, wherein the hedgehog antagonist is represented by general formula (I):

34. The method of claim 30, wherein the hedgehog antagonist is represented by general formula (VI):

29. The method of claim 29, wherein the nucleic acid sequences encoding the polypeptide are introduced via a viral vector, via lipofection, and/or as naked DNA.

35. A method for treating a tumor in a patient, comprising 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 hedgehog gene or a gli gene.

36. The method of claim 35, wherein hedgehog antagonist is administered as part of a cancer treatment regimen.

37. A method of inhibiting at least one of unwanted growth, proliferation or survival of a cell, comprising

(a) determining whether said cell expresses a hedgehog gene, and

(b) contacting said cell which expresses said 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.

38. The method of claim 37, wherein said hedgehog gene is Sonic hedgehog.

39. The method of claim 37, wherein said hedgehog antagonist is a hedgehog antibody.

40. The method of claim 39, wherein said hedgehog antibody is a monoclonal antibody.

41. The method of claim 40, wherein said monoclonal antibody is selected from 5E1 or a monoclonal antibody which binds the same epitope as 5E1.

42. The method of claim 37, wherein said unwanted cell growth, proliferation or survival of a cell is cancer.

43. A method of inhibiting at least one of unwanted cell growth, proliferation or survival of a cell, comprising

(a) determining whether cells express a hedgehog gene, and

(b) contacting cells which express said hedgehog gene wth an effective amount of a hedgehog antibody, which hedgehog antibody specifically antagonizes hedgehog signaling;

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

44. The method of claim 43, wherein said hedgehog antibody which specifically antagonizes hedgehog signaling is a monoclonal antibody.

45. The method of claim 44, wherein said monoclonal antibody is 5E1 or a monoclonal antibody which binds the same epitope as 5E1.

46. The method of claim 43, wherein said unwanted cell growth, proliferation or survival of a cell is cancer.

47. The method of claim 43, wherein said hedgehog antibody which antagonizes hedgehog signaling is formulated in a pharmaceutically acceptable carrier.

48. The method of claim 47, wherein said hedgehog antibody is administererd as part of a cancer treatment regimen.

49. A method of inhibiting at least one of unwanted cell growth, proliferation or survival of a cell, comprising

(a) determining whether said cell expresses a hedgehog gene, and

(b) contacting said cell which expresses said hedgehog gene wth an effective amount of a hedgehog antibody, which hedgehog antibody is 5E1 or an antibody which binds the same epitope as 5E1;

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

50. The method of claim 49, wherein said unwanted cell growth, proliferation or survival of a cell is cancer.

51. The method of claim 49, wherein said hedgehog antibody which antagonizes hedgehog signaling is formulated in a pharmaceutically acceptable carrier.

52. The method of claim 49, wherein said hedgehog antibody is administererd as part of a cancer treatment regimen.

53. A method for treating a tumor is a patient, 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.

54. The method of claim 53, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

55. The method of claim 53, wherein said hedgehog antagonist comprises a hedgehog antibody.

56. The method of claim 55, wherein said hedgehog antibody comprises a monoclonal antibody.

57. The method of claim 56, wherein said monoclonal antibody comprises 5E1 or an antibody which binds the same epitope as 5E1.

58. The method of claim 53, wherein said hedgehog antagonist is formulated in a pharmaceutically acceptable carrier.

59. Use of a hedgehog agonist in the manufacture of a medicament for promoting angiogenesis.

60. Use of a hedgehog antagonist in the manufacture of a medicament for inhibiting angiogenesis.

61. Use of a hedgehog antagonist in the manufacture of a medicament for inhibiting at least one of unwanted growth, proliferation or survival of a cell.

62. Use of a hedgehog antagonist in the manufacture of a medicament for the treatment of cancer.