Methods for Treating Conditions Associated with MASP-2 Dependent Complement Activation

• US 20120258095A1
• Filed: 04/06/2012
• Published: 10/11/2012
• Est. Priority Date: 04/08/2011
• Status: Active Grant

• Current Assignee: Omeros Corporation, University of Leicester
• Original Assignee: Omeros Corporation, University of Leicester
• Inventors: Dudler, Thomas, Schwaeble, Hans-Wilhelm, Demopulos, Gregory A.
• Granted Patent: US 8,951,522 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• 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 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• 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: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

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 suffering from paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to the subject a composition comprising 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 is an anti-MASP-2 antibody or fragment thereof.

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

6.

4. The method of claim 1, wherein the composition increases the survival of red blood cells in the subject.

5. The method of claim 1, wherein the subject exhibits one or more symptoms selected from the group consisting of (i) below normal levels of hemoglobin, (ii) below normal levels of platelets;

(iii) above normal levels of reticulocytes, and (iv) above normal levels of bilirubin.

6. The method of claim 1, wherein the subject has previously undergone, or is currently undergoing, treatment with a terminal complement inhibitor that inhibits cleavage of complement protein C5.

7. The method of claim 1, wherein the method further comprises administering to the subject a terminal complement inhibitor that inhibits cleavage of complement protein C5.

8. The method of claim 7, wherein the terminal complement inhibitor is a humanized anti-C5 antibody or antigen-binding fragment thereof.

9. The method of claim 8, wherein the terminal complement inhibitor is eculizumab.

10. The method of claim 2, wherein the antibody or fragment thereof is selected from the group consisting of a recombinant antibody, an antibody having reduced effector function, a chimeric antibody, a humanized antibody and a human antibody.

11. The method of claim 1, wherein the composition is administered subcutaneously, intra-muscularly, intra-arterially, intravenously, or as an inhalant.

12. The method of claim 11, wherein the composition is administered subcutaneously.

13. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from or at risk for developing non-Factor H-dependent atypical hemolytic uremic syndrome (aHUS), comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

14. The method of claim 13, wherein prior to administration of the composition the subject is determined to exhibit one or more symptoms selected from the group consisting of (i) anemia, (ii) thrombocytopenia (iii) renal insufficiency and (iv) rising creatinine, and the composition is administered in an effective amount and for a sufficient time period to improve said one or more symptoms.

15. The method of claim 13, wherein the subject is suffering from aHUS associated with factor I, factor B, or membrane cofactor CD46.

16. The method of claim 13, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

17. The method of claim 13, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

18. A method for reducing the likelihood that a subject at risk for developing atypical hemolytic uremic syndrome (aHUS) will suffer clinical symptoms associated with aHUS comprising:

(a) determining the presence of a genetic marker in the subject known to be associated with aHUS;

(b) periodically monitoring the subject to determine the presence or absence of at least one symptom selected from the group consisting of anemia, thrombocytopenia, renal insufficiency and rising creatinine; and

(c) administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation upon the determination of the presence of at least one of anemia, thrombocytopenia, renal insufficiency or rising creatinine, wherein the composition is administered in an effective amount and for a sufficient time period to improve said one or more symptoms.

19. The method of claim 18, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

20. The method of claim 19, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ NO:

6.

21. The method of claim 18, wherein step (a) comprises performing a genetic screening test on a sample obtained from the subject and identifying the presence of at least one genetic marker associated with aHUS in a gene selected from the group consisting of complement factor H(CFH), factor I (CFI), factor B (CFB), membrane cofactor CD46, C3, complement factor H-related protein (CFHR1), anticoagulant protein thrombodulin (THBD), complement factor H-related protein 3 (CFHR3) and complement factor II-related protein 4 (CFHR4).

22. The method of claim 18, wherein the method further comprises monitoring the subject for the occurrence of an event known to be associated with 2.5 triggering aHUS clinical symptoms and administering to the subject the composition comprising the MASP-2 inhibitory agent prior to, during, or after the occurrence of the triggering event.

23. The method of claim 22, wherein the event associated with triggering aHUS clinical symptoms is selected from the group consisting of drug exposure, infection, malignancy, injury, organ or tissue transplant and pregnancy.

24. The method of claim 23, wherein the infection is a bacterial infection.

25. The method of claim 18, wherein the composition is administered subcutaneously.

26. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from, or at risk for developing, atypical hemolytic uremic syndrome (aHUS) secondary to an infection, comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 complement activation.

27. The method of claim 26, wherein the subject is suffering from, or at risk for developing non-enteric aHUS associated with an S. pneumonia infection.

28. The method of claim 26, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

29. The method of claim 28, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

30. A method of treating a subject suffering from atypical hemolytic uremic syndrome (aHUS) comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation, wherein the administration of the MASP-2 inhibitory agent is administered via an intravenous catheter or other catheter delivery method.

31. The method of claim 30, further comprising treating the patient with plasmapheresis.

32. The method of claim 30, wherein the composition comprising the MASP-2 inhibitory agent is administered in the absence of plasmapheresis.

33. The method of claim 32, wherein the composition comprising the MASP-2 inhibitory agent is administered via a catheter for a first time period, further comprising administering the composition comprising the MASP-2 inhibitory agent for a second time period, wherein the composition is administered subcutaneously during the second time period.

34. The method of claim 33, further comprising periodically determining the level of at least one complement factor, wherein the determination of a reduced level of the at least one complement factor in comparison to a standard value or a healthy subject is indicative of the need for continued treatment with the composition.

35. The method of claim 30, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

36. The method of claim 35, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

37. A method for decreasing the likelihood of developing impaired renal function in a subject at risk for developing hemolytic uremic syndrome (HUS) comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

38. The method of claim 37, wherein the subject at risk for developing HUS exhibits at least one or more of the symptoms selected from the group consisting of diarrhea, a hematocrit level of less than 30% with smear evidence of intravascular erythrocyte destruction, thrombocytopenia and rising creatinine levels.

39. The method of claim 37, wherein the subject is infected with an enterogenic E. coli for which the use of antibiotics is contra-indicated.

40. The method of claim 37, wherein the subject is infected with shigella or salmonella.

41. The method of claim 39, wherein the composition comprising the MASP-2 inhibitory agent is administered to the subject during a first time period in the absence of an antibiotic.

42. The method of claim 40, wherein the composition comprising the MASP-2 inhibitory agent is administered to the subject during a first time period in the presence of an antibiotic.

43. The method of any one of claim 37, 41 or 42, wherein the MASP-2 inhibitory agent is administered to the subject during the first time period via an intravenous catheter or other catheter delivery method.

44. The method of claim 41, claim 42 or claim 43, further comprising administering the composition comprising the MASP-2 inhibitory agent for a second time period, wherein the composition is administered subcutaneously during the second time period.

45. The method of claim 44, further comprising periodically determining the level of at least one complement factor, wherein the determination of a reduced level of the at least one complement factor in comparison to a standard value or a healthy subject is indicative of the need for continued treatment with the composition.

46. The method of claim 37, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

47. The method of claim 46, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof, that specifically binds to a portion of SEQ ID NO:

6.

48. A method of treating a subject suffering from hemolytic uremic syndrome (HUS) comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation, wherein the administration of the MASP-2 inhibitory agent is administered to the subject via an intravenous catheter or other catheter delivery method.

49. The method of claim 48, further comprising treating the patient with plasmapheresis.

50. The method of claim 48, wherein the composition comprising the MASP-2 inhibitory agent is administered in the absence of plasmapheresis.

51. The method of claim 48, wherein the composition comprising the MASP-2 inhibitory agent is administered via a catheter for a first time period, further comprising administering the composition comprising the MASP-2 inhibitory agent for a second time period, wherein the composition is administered subcutaneously during the second time period.

52. The method of claim 51, further comprising periodically determining the level of at least one complement factor, wherein the determination of a reduced level of the at least one complement factor in comparison to a standard value or a healthy subject is indicative of the need for continued treatment with the composition.

53. The method of claim 48, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

54. The method of claim 53, wherein the MASP-2 inhibitory agent is an anti MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ NO:

6.

65. The method of claim 54, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

55. A method of treating a subject suffering from thrombotic thrombocytopenic purpura (TTP), or exhibiting symptoms consistent with a diagnosis of TTP, comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation, wherein the administration of the MASP-2 inhibitory agent is administered to the subject via an intravenous catheter or other catheter delivery method.

56. The method of claim 55, wherein the subject exhibits at least one or more symptoms selected from the group consisting of central nervous system involvement, thrombocytopenia, severe cardiac involvement, severe pulmonary involvement, gastro-intestinal infarction and gangrene.

57. The method of claim 55, wherein the subject tests positive for the presence of an inhibitor of ADAMTS13, and the method further comprises administering an immunosuppressant to the subject.

58. The method of claim 55, wherein the composition comprising the MASP-2 inhibitory agent is administered for a first time period in the absence of plasmapheresis.

59. The method of claim 55, wherein the subject tests positive for the presence of an inhibitor of ADAMTS-13, and the method further comprises administering ADAMTS-13.

60. The method of claim 55, further comprising treating the patient with plasmapheresis.

61. The method of claim 55, wherein the composition comprising the MAST-2 inhibitory agent is administered in the presence of plasmapheresis.

62. The method of claim 55, wherein the composition comprising the MASP-2 inhibitory agent is administered via a catheter for a first time period, further comprising administering the composition comprising the MASP-2 inhibitory agent for a second time period, wherein the composition is administered subcutaneously during the second time period.

63. The method of claim 62, further comprising periodically determining the level of at least one complement factor, wherein the determination of a reduced level of the at least one complement factor in comparison to a standard value or a healthy subject is indicative of the need for continued treatment with the composition.

64. The method of claim 55, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

66. A method of treating a subject suffering from refractory thrombotic thrombocytopenic purpura (TTP) comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

67. The method of claim 66, wherein the composition is administered subcutaneously.

68. The method of claim 66, further comprising periodically determining the level of at least one complement factor, wherein the determination of a reduced level of the at least one complement factor in comparison to a standard value or a healthy subject is indicative of the need for continued treatment with the composition.

69. The method of claim 66, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

70. The method of claim 69, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

71. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from cryoglobulinemia, comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

72. The method of claim 71, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

73. The method of claim 72, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof.

74. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from cold agglultinin disease, comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

75. The method of claim 74, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

76. The method of claim 75, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof.

77. A method of inhibiting MASP-2 dependent complement activation in a subject suffering from glaucoma, comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

78. The method of claim 77, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

79. The method of claim 78, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof.

80. A method of inhibiting MASP-2 dependent complement activation in a subject at risk for developing, or is suffering from acute radiation syndrome comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.

81. The method of claim 80, wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof.

82. The method of claim 81, wherein the MASP-2 inhibitory agent is an anti-MASP-2 monoclonal antibody, or fragment thereof.

83. The method of claim 81, wherein the MASP-2 inhibitory agent is administered prophylactically to the subject prior to radiation exposure.

84. The method of claim 81, wherein the MASP-2 inhibitory agent is administered to the subject within 24 hours to 48 hours after radiation exposure.

85. The method of claim 81, wherein the MASP-2 inhibitory agent is administered to the subject after radiation exposure.