Methods for treating conditions associated with MASP-2 dependent complement activation

• US 20070172483A1
• Filed: 12/22/2006
• Published: 07/26/2007
• Est. Priority Date: 06/10/2004
• Status: Active Grant

• Current Assignee: Omeros Corporation, University of Leicester
• Original Assignee: Omeros Corporation, University of Leicester
• Inventors: Schwaeble, Hans-Wilhelm, Fujita, Teizo, Tedford, Clark, Parent, James, Stover, Cordula
• Granted Patent: US 7,919,094 B2
• Time in Patent Office: Days
• US Class Current: 424/146.100
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 2267/0375 Animal model for cardiovascular diseases
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/40 : against enzymes
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12N 9/6408 : Serine endopeptidases (3.4.21)
• CPC Class Codes: C12N 9/6424 : Serine endopeptidases (3.4.21)
• CPC Class Codes: C12Y 304/21104 : Mannan-binding lectin-associated serine protease-2 (3.4.21.104)

Abstract

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (C1q-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

Claims

1. A method of inhibiting MASP-2-dependent complement activation in a subject in need thereof, comprising administering to the subject an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

2. The method of claim 1, wherein the MASP-2 inhibitory agent specifically binds to a polypeptide comprising SEQ ID NO:

6.

3. The method of claim 1, wherein the MASP-2 inhibitory agent specifically binds to a polypeptide comprising SEQ ID NO:

6 with an affinity of at least 10 times greater than it binds to a different antigen in the complement system.

4. The method of claim 2, wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:

6.

5. The method of claim 1, wherein the MASP-2 inhibitory agent is an antibody or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

6. The method of claim 5, wherein the antibody or fragment thereof is monoclonal.

7. The method of claim. 5, wherein the antibody or fragment thereof is polyclonal.

8. The method of claim 5, wherein the antibody or fragment thereof is a recombinant antibody.

9. The method of claim 5, wherein the antibody has reduced effector function.

10. The method of claim 5, wherein the antibody is a chimeric, humanized or human antibody.

11. The method of claim 5, wherein the antibody is produced in a MASP-2 deficient transgenic animal.

12. The method of claim 1, wherein the MASP-2 inhibitory agent is a peptide derived from a polypeptide selected from the group consisting of human MASP-2, human MBL that inhibits MASP-2, human H-ficolin that inhibits MASP-2, human M-ficolin that inhibits MASP-2, human L-ficolin that inhibits MASP-2 and human C4 that inhibits MASP-2.

13. The method of claim 1, wherein the MASP-2 inhibitory agent is a non-peptide agent that specifically binds to a polypeptide comprising SEQ ID NO:

6.

14. The method of claim 13, wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:

6.

15. A method of inhibiting MASP-2-dependent complement activation in a subject in need thereof, comprising administering to the subject an amount of a MASP-2 inhibitory agent effective to selectively inhibit MASP-2-dependent complement activation without substantially inhibiting C1q-dependent complement activation.

16. The method of claim 15, wherein the MASP-2 inhibitory agent specifically binds to a polypeptide comprising SEQ ID NO:

6.

17. The method of claim 16, wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:

6.

18. The method of claim 15, wherein the MASP-2 inhibitory agent is an antibody or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

19. The method of claim 18, wherein the antibody or fragment thereof is monoclonal.

20. The method of claim 18, wherein the antibody is a chimeric, humanized or human antibody.

21. The method of claim 18, wherein the antibody is produced in a MASP-2 deficient transgenic animal.

22. The method of claim 15, wherein the MASP-2 inhibitory agent is a peptide derived from a polypeptide selected from the group consisting of human MASP-2, human MBL that inhibits MASP-2, human H-ficolin that inhibits MASP-2, human L-ficolin that inhibits MASP-2 and human C4 that inhibits MASP-2.

23. The method of claim 15, wherein the MASP-2 inhibitory agent is a non-peptide agent that specifically binds to a polypeptide comprising SEQ ID NO:

6.

24. A composition for inhibiting MASP-2-dependent complement activation comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

25. A method of manufacturing a medicament for use in inhibiting the effects of MASP-2-dependent complement activation in living subjects in need thereof, comprising combining a therapeutically effective amount of a MASP-2 inhibitory agent in a pharmaceutical carrier.

26. A method of treating a subject suffering from a MASP-2-dependent complement mediated vascular condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

27. The method of claim 26, wherein the vascular condition is selected from the group consisting of a cardiovascular condition, a cerebrovascular condition, a peripheral (e.g., musculoskeletal) vascular condition, a renovascular condition, a mesenteric/enteric vascular condition, revascularization to transplants and/or replants, vasculitis, Henoch-Schonlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu'"'"'s disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki'"'"'s disease (arteritis), venous gas embolus (VGE), and restenosis following stent placement, rotational atherectomy and percutaneous transluminal coronary angioplasty (PTCA).

28. A method of treating a subject suffering from a MASP-2-dependent complement mediated condition associated with an ischemia-reperfusion injury comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

29. The method of claim 28, wherein the ischemia-reperfusion injury is associated with aortic aneurysm repair, cardiopulmonary bypass, vascular reanastomosis in connection with organ transplants and/or extremity/digit replantation, stroke, myocardial infarction, and hemodynamic resuscitation following shock and/or surgical procedures.

30. A method of treating and/or preventing atherosclerosis in a subject in need thereof, comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

31. A method of treating a subject suffering from a MASP-2-dependent complement mediated condition associated with an inflammatory gastrointestinal disorder comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

32. The method of claim 31, wherein the inflammatory gastrointestinal disorder is selected from the group consisting of pancreatitis, Crohn'"'"'s disease, ulcerative colitis, irritable bowel syndrome and diverticulitis.

33. A method of treating a subject suffering from a MASP-2-dependent complement mediated pulmonary condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

34. The method of claim 33, wherein the pulmonary condition is selected from the group consisting of acute respiratory distress syndrome, transfusion-related acute lung injury, ischemia/reperfusion acute lung injury, chronic obstructive pulmonary disease, asthma, Wegener'"'"'s granulomatosis, antiglomerular basement membrane disease (Goodpasture'"'"'s disease), meconium aspiration syndrome, bronchiolitis obliterans syndrome, idiopathic pulmonary fibrosis, acute lung injury secondary to burn, non-cardiogenic pulmonary edema, transfusion-related respiratory depression and emphysema.

35. A method of inhibiting MASP-2-dependent complement activation in a subject that has undergone, is undergoing, or will undergo an extracorporeal reperfusion procedure comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

36. The method of claim 35, wherein the extracorporeal reperfusion procedure is selected from the group consisting of hemodialysis, plasmapheresis, leukopheresis, extracorporeal membrane oxygenator (ECMO), heparin-induced extracorporeal membrane oxygenation LDL precipitation (HELP) and cardiopulmonary bypass (CPB).

37. A method of treating a subject suffering from a MASP-2-dependent complement mediated musculoskeletal condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

38. The method of claim 37, wherein the musculoskeletal condition is selected from the group consisting of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, neuropathic arthropathy, psoriatic arthritis, spondyloarthropathy, crystalline arthropathy, muscular dystrophy and systemic lupus erythematosus (SLE).

39. A method of treating a subject suffering from a MASP-2-dependent complement mediated renal condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

40. The method of claim 39, wherein the renal condition is selected from the group consisting of mesangioproliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute postinfectious glomerulonephritis (poststreptococcal glomerulonephritis), cryoglobulinemic glomerulonephritis, lupus nephritis, Henoch-Schonlein purpura nephritis and IgA nephropathy.

41. A method of treating a subject suffering from a MASP-2-dependent complement mediated skin condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

42. The method of claim 41, wherein the skin condition is selected from the group consisting of psoriasis, autoimmune bullous dermatoses, eosinophilic spongiosis, bullous pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, thermal burn injury and chemical burn injury.

43. A method of inhibiting MASP-2-dependent complement activation in a subject that has undergone, is undergoing, or will undergo an organ or tissue transplant procedure comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

44. The method of claim 43, wherein the transplant procedure is selected from the group consisting of organ allotransplantation, organ xenotransplantation organ and tissue graft.

45. A method of treating a subject suffering from a MASP-2-dependent complement mediated condition associated with a nervous system disorder or injury comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-dependent complement activation.

46. The method of claim 45, wherein the nervous system disorder or injury is selected from the group consisting of multiple sclerosis, myasthenia gravis, Huntington'"'"'s disease, amyotrophic lateral sclerosis, Guillain Barre syndrome, reperfusion following stroke, degenerative discs, cerebral trauma, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, Miller-Fisher syndrome, cerebral trauma and/or hemorrhage, demyellination and meningitis.

47. A method of treating a subject suffering from a MASP-2-dependent complement mediated condition associated with a blood disorder comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

48. The method of claim 47, wherein the blood disorder is selected from the group consisting of sepsis, severe sepsis, septic shock, acute respiratory distress syndrome resulting from sepsis, systemic inflammatory response syndrome, hemorrhagic shock, hemolytic anemia, autoimmune thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

49. A method of treating a subject suffering from a MASP-2-dependent complement mediated condition associated with a urogenital condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

50. The method of claim 49, wherein the urogenital condition is selected from the group consisting of painful bladder disease, sensory bladder disease, chronic abacterial cystitis, interstitial cystitis, infertility, placental dysfunction and miscarriage and pre-eclampsia.

51. A method of treating a subject suffering from a MASP-2-dependent complement mediated condition associated with nonobese diabetes (Type-1 diabetes or Insulin-dependent diabetes mellitus) and/or complications associated with Type-1 or Type-2 (adult onset) diabetes comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

52. The method of claim 51, wherein the complication associated with Type 1 or Type 2 diabetes is selected from the group consisting of angiopathy, neuropathy and retinopathy.

53. A method of inhibiting MASP-2-dependent complement activation in a subject that has undergone, is undergoing, or will undergo chemotherapeutic treatment and/or radiation therapy comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

54. A method of treating a subject suffering from a malignancy comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

55. A method of treating a subject suffering from an endocrine disorder comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

56. The method of claim 55, wherein the endocrine disorder is selected from the group consisting of Hashimoto'"'"'s thyroiditis, stress, anxiety, hormonal disorders involving regulated release of prolactin, growth or other insulin-like growth factor and adrenocorticotropin from the pituitary.

57. A method of treating a subject suffering from a complement mediated ophthalmologic condition comprising administering an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.

58. The method of claim 57, wherein the ophthalmologic condition is age-related macular degeneration.