Modulation of angiogenesis by a-beta peptide fragments

• US 20080031954A1
• Filed: 11/13/2006
• Published: 02/07/2008
• Est. Priority Date: 11/10/2005
• Status: Active Grant

• Current Assignee: Alzheimer's Institute Of America
• Original Assignee: Alzheimer's Institute Of America
• Inventors: Paris, Daniel, Mullan, Michael
• Granted Patent: US 8,067,372 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein

Abstract

Provided are Aβ peptide fragments that are useful in inhibiting angiogenesis. Also provided are methods for the treatment of pathological or unwanted angiogenesis and conditions and diseases associated therewith by administering an effective amount of an Aβ fragment. In a particular embodiment, the peptide fragment includes the sequence HHQKLVFF.

Claims

1. An anti-angiogenic Aβ

peptide fragment, wherein the fragment is between 8 and 39 amino acids in length, and variants and homologs thereof.

2. The anti-angiogenic Aβ

peptide fragment of claim 1, wherein the fragment is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39 amino acids in length.

3. The anti-angiogenic Aβ

peptide fragment of claim 1, wherein the fragment is Aβ

_1-28, Aβ

_10-35, Aβ

_12-28 or Aβ

_13-20.

4. The anti-angiogenic Aβ

peptide fragment of claim 3, wherein the fragment is β

_12-28.

5. The anti-angiogenic Aβ

peptide fragment of claim 1, wherein the fragment is Aβ

_13-20.

6. The anti-angiogenic Aβ

peptide fragment of claim 5, wherein the Aβ

_12-28 fragment comprises the amino acid sequence HHQKLVFF or a variant or homolog thereof.

7. The anti-angiogenic Aβ

peptide fragment of claim 5, wherein the Aβ

_13-20 peptide fragment is the amino acid sequence HHQKLVFF or a variant or homolog thereof.

8. The anti-angiogenic Aβ

peptide fragment of claim 1, wherein the variant or homolog exhibits from about 80.0% to about 99.9% amino acid identity to the native Aβ

peptide fragment.

9. The anti-angiogenic Aβ

peptide fragment of claim 1, wherein the variant contains at least one amino acid substitution.

10. The anti-angiogenic Aβ

peptide fragment of claim 9, wherein the amino acid substitution is a non-natural amino acid or an amino acid analog.

11. The anti-angiogenic Aβ

peptide fragment of claim of claim 1, further comprising a linker.

12. The anti-angiogenic Aβ

peptide fragment of claim 1, wherein the fragment is joined to a second peptide or protein.

13. A pharmaceutical composition comprising the anti-angiogenic Aβ

peptide fragment of claim 1 and one or more pharmaceutically acceptable carriers, diluents, or excipients

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a controlled release formulation.

15. The pharmaceutical composition of claim 14, wherein the controlled release formulation is a polymer matrix.

16. A method of treating a disease or disorder mediated by pathological angiogenesis comprising administering to a subject in need thereof an effective amount of a biologically active Aβ

peptide fragment, or a variant or homolog thereof, wherein the fragment is between 8 and 39 amino acids in length.

17. The method of claim 16, wherein the fragment is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39 amino acids in length.

18. The method of claim 16, wherein the fragment is Aβ

_1-28.

19. The method of claim 16, wherein the fragment is Aβ

_10-35.

20. The method of claim 16, wherein the fragment is Aβ

_12-28.

21. The method of claim 16, wherein the fragment is Aβ

_13-20.

22. The method of claim 16, wherein the fragment is the amino acid sequence HHQKLVFF or a variant or homolog thereof.

23. The method of claim 16, wherein the disease or disorder is cancer.

24. The method of claim 16, wherein the disease or disorder is a proliferative disorder.

25. The method of claim 16, wherein the disease or disorder is an inflammatory disorder.

26. The method of claim 16, wherein the subject is a mammal.

27. The method of claim 16, wherein the subject is a human.

28. The method of claim 16, wherein the biologically active Aβ

peptide fragment is administered by a route selected from the group consisting of oral, parenteral, intravenous, intraarterially, pulmonary, mucosal, topical, transdermal, subcutaneous, intramuscular, rectal, intracranial, intracerebroventricular, intracerebral, intravaginal, intrauterine, intrathecal or intraperitoneal administration.

29. The method of claim 16, wherein the biologically active Aβ

peptide fragment is administered to the subject with a carrier.

30. The method of claim 16, wherein the Aβ

peptide fragment is administered to the subject in a controlled release formulation.

31. The method of claim 16, wherein the controlled release formulation comprises a polymer matrix.

32. The method of claim 16, further comprising administering one more additional therapeutic agents in combination or alternation with the biologically active Aβ

peptide fragment.

33. The method of claim 32, wherein the additional therapeutic agent is a chemotherapeutic agent.

34. The method according to claim 16, wherein the Aβ

peptide fragment is administered to the patient as a fusion peptide.

50. The method of claim 29, further comprising (c) separately contacting a second biological sample capable of undergoing angiogenesis with a biologically active amount of an Aβ

peptide fragment and an angiogenic agent;

(d) determining the extent of angiogenesis that occurs in the second biological sample; and

(e) comparing the extent of angiogenesis that occurs in the first biological sample with that which occurs in the second biological sample.

35. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a biologically active Aβ

peptide fragment, or a variant or homolog thereof, wherein the fragment is between 8 and 39 amino acids in length.

36. The method of claim 35, wherein the fragment is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39 amino acids in length.

37. The method of claim 35, wherein the fragment is selected from the group consisting of Aβ

_1-28, Aβ

_10-35, Aβ

_12-28 and Aβ

_13-20.

38. The method of claim 37, wherein the fragment is Aβ

_13-20.

39. The method of claim 38, wherein the Aβ

_13-20 peptide fragment is the amino acid sequence HHQKLVFF or a variant or homolog thereof.

40. The method of claim 35, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, uterine cancer, colon cancer and non-Hodgkins'"'"' lymphoma.

41. The method of claim 35, wherein the subject is a mammal.

42. The method of claim 35, wherein the subject is a human.

43. The method of claim 35, further comprising administering one or more additional therapeutic agents.

44. The method of claim 43, wherein the additional therapeutic agent is a chemotherapeutic agent.

45. The method of claim 44, wherein the chemotherapeutic agent is selected from the group consisting of alkylating agents, nitrosoureas, antimetabolites, topoisomerase inhibitors, mitotic inhibitors, corticosteriod inhibitors.

49. A method for identifying compounds that interfere with Aβ

-induced angiogenesis inhibition, comprising (a) contacting a first biological sample capable of undergoing angiogenesis with a test compound, a biologically active amount of an Aβ

peptide fragment, and an angiogenic agent; and

(b) determining the extent of angiogenesis that occurs in the first biological sample.