Local Complement Inhibition for Treatment of Complement-Mediated Disorders

• US 20100166862A1
• Filed: 02/05/2008
• Published: 07/01/2010
• Est. Priority Date: 02/05/2007
• Status: Active Grant

• Current Assignee: Apellis Pharmaceuticals, Inc.
• Original Assignee: Potentia Pharmaceuticals, Inc.
• Inventors: Francois, Cedric, Deschatelets, Pascal, Olson, Paul
• Granted Patent: US 8,580,735 B2
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/435 from animals; from humans
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

The present invention features the local administration of complement inhibitors for treatment of complement-mediated disorders. In certain embodiments the invention features inhibiting activation of one or more locally produced complement proteins. The invention provides sustained release formulations and devices comprising a complement inhibitor and methods of use thereof.

Claims

1. A method of treating a complement-mediated disorder comprising the step of:

administering a complement inhibitor directly to an extravascular location that is a site of local complement activation in said disorder.

2. The method of claim 1, wherein said complement inhibitor is administered in an amount sufficient to inhibit complement activity attributable to at least one complement activation pathway at said location by at least 25%.

3. The method of claim 1, wherein said complement inhibitor is administered in an amount sufficient to reduce complement activity attributable to at least one complement pathway at said location to a level no more than twice the average level found at said location in the absence of said disorder.

5. The method of claim 1, wherein the disorder is mediated at least in part by a locally produced soluble complement protein, wherein the complement inhibitor is administered in an amount sufficient to reduce complement activity attributable to said locally produced complement protein to a level no more than twice the average level found at said extravascular location in the absence of said disorder.

6. The method of claim 1, wherein said complement inhibitor inhibits an enzymatic activity of a soluble complement protein.

7. The method of claim 1, wherein said complement inhibitor inhibits cleavage of a complement component selected from the group consisting of:

C3, C5, and factor B.

8. The method of claim 1, wherein said complement inhibitor binds to a complement component selected from the group consisting of:

C3, C5, factor B, and factor D.

9. The method of claim 1, wherein said complement inhibitor is a peptide, small molecule, or aptamer.

10. The method of claim 1, wherein said complement inhibitor is an antibody.

11. The method of claim 1, wherein said complement inhibitor is a compstatin analog.

13. The method of claim 1, wherein said extravascular location is within a joint.

14. The method of claim 1, wherein said extravascular location is within the spinal canal.

15. The method of claim 1, wherein said extravascular location is on or in the skin.

16. The method of claim 1, wherein said extravascular location is within the respiratory tract.

17. The method of claim 1, wherein said disorder is selected from the group consisting of:

arthritis, asthma, infection, multiple sclerosis, spinal cord or other nerve injury, chronic pain, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, chronic obstructive pulmonary disease, stroke, brain injury, allergic dermatitis, psoriasis, age-related macular degeneration, uveitis, diabetic retinopathy, glaucoma, and pemphigus.

19. The method of claim 1, wherein said effective amount has essentially no effect on systemic complement activation when administered at said extravascular location.

20. The method of claim 1, wherein said complement inhibitor is released from a sustained release formulation or device that releases the complement inhibitor over time.

21. The method of claim 20, wherein said sustained release formulation comprises a plurality of microparticles or nanoparticles.

22. The method of claim 20, wherein said sustained release formulation comprises a gel.

23. The method of claim 20, wherein said sustained release formulation comprises a gel that forms in the body following administration of a liquid that contains the complement inhibitor.

24. The method of claim 20, wherein said sustained release formulation is a solid article of manufacture.

25. The method of claim 20, wherein said sustained release formulation comprises a biodegradable polymeric matrix.

30. The method of claim 1, further comprising the step of administering a second agent effective against said disorder.

32. The method of claim 1, further comprising the step of:

determining whether complement activity is aberrantly high in an extravascular location in the subject'"'"'s body.

128. The method of claim 1, wherein said complement inhibitor is administered in an amount that reduces systemic complement activation by less than 20%.

4. (canceled)

12. (canceled)

18. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

31. (canceled)

33. (canceled)

34. (canceled)

35. A composition comprising a complement inhibitor, wherein said composition comprises a gel, cream, lotion, or ointment suitable for application to the skin.

36. The composition of claim 35, wherein said complement inhibitor is a compstatin analog.

37. An inhalable composition comprising a complement inhibitor.

38. The composition of claim 37, wherein said complement inhibitor is a compstatin analog.

39. The composition of claim 37, which is a dry powder suitable for delivering the complement inhibitor to the lung.

40. (canceled)

41. (canceled)

42. A method of treating inflammatory arthritis comprising administering a complement inhibitor directly to a joint or bursa, wherein said complement inhibitor is administered in an amount effective to substantially inhibit activation of a locally produced soluble complement component.

43. The method of claim 42, wherein said amount is not sufficient to significantly inhibit systemic complement activation when administered directly to said joint.

44. The method of claim 42, wherein said inflammatory arthritis is rheumatoid arthritis, psoriatic arthritis, Reiter'"'"'s syndrome, juvenile arthritis, or gout.

45. The method of claim 42, wherein said complement inhibitor is a compstatin analog.

46. (canceled)

47. (canceled)

48. A method of treating an inflammatory condition of the respiratory system comprising administering a complement inhibitor directly to the respiratory tract, wherein said complement inhibitor is a peptide or antibody that binds to a locally produced soluble complement protein.

49. The method of claim 48, wherein said inflammatory condition of the respiratory system is selected from the group consisting of:

asthma, COPD, allergic rhinitis, and infection-associated inflammation.

50. The method of claim 48, wherein said complement inhibitor is a compstatin analog.

53. The method of claim 48, wherein said complement inhibitor is administered as a component of an inhalable dry powder.

54. The method of claim 48, wherein said complement inhibitor is administered as a component of an inhalable liquid aerosol.

51. (canceled)

52. (canceled)

55. (canceled)

56. A method of treating a complement-mediated disorder of the nervous system comprising administering a complement inhibitor to a region of the nervous system by a route selected from the group consisting of:

intrathecal, intranasal, and by local injection into a nerve sheath.

57. The method of claim 56, wherein said complement inhibitor is a peptide or antibody that binds to a locally produced soluble complement protein.

58. The method of claim 56, wherein said complement inhibitor is a compstatin analog.

60. The method of claim 56, wherein said complement-mediated disorder is selected from the group consisting of:

spinal cord injury, multiple sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s Disease, stroke, and chronic pain.

61. The method of claim 56, wherein said complement inhibitor is a compstatin analog.

59. (canceled)

62. (canceled)

63. (canceled)

64. A method of treating a skin condition comprising administering a complement inhibitor directly to the skin, wherein said complement inhibitor is administered in an amount effective to inhibit activation of a locally produced soluble complement component or in an amount effective to inhibit local activation of complement and is not sufficient to significantly inhibit systemic complement activation when administered directly to the skin.

65. The method of claim 64, wherein said complement inhibitor is a compstatin analog.

67. The method of claim 64, wherein said skin condition is selected from the group consisting of:

psoriasis, pemphigus, scleroderma, and lupus.

68. The method of claim 64, wherein said complement inhibitor is administered as a component of a cream, paste, ointment, gel, or lotion.

66. (canceled)

69. (canceled)

70. (canceled)

71. (canceled)

72. (canceled)

73. (canceled)

74. (canceled)

75. A method of treating a complement-mediated disorder comprising administering a sustained release formulation comprising an effective amount of a compstatin analog to an extravascular location where complement activation occurs, wherein said location is not the eye.

76. The method of claim 75, wherein said composition does not significantly inhibit systemic complement activation when administered at said location.

77. The method of claim 75, wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′

aa-Gln-Asp-Xaa-Gly (SEQ ID NO;

     3), where X′

aa and Xaa are selected from Trp, analogs of Trp.

78. The method of claim 75, wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′

aa-Gln-Asp-Xaa-Gly-X″

aa (SEQ ID NO;

     4), where X′

aa and Xaa are each independently selected from Trp and analogs of Trp and X″

aa is selected from His, Ala, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp.

79-127. -127. (canceled)