METHODS FOR TREATING DISSEMINATED INTRAVASCULAR COAGULATION BY INHIBITING MASP-2 DEPENDENT COMPLEMENT ACTIVATION

• US 20110091450A1
• Filed: 10/15/2010
• Published: 04/21/2011
• Est. Priority Date: 10/16/2009
• Status: Active Grant

• Current Assignee: Omeros Corporation, University of Leicester
• Original Assignee: Omeros Corporation, University of Leicester
• Inventors: Dudler, Thomas, Parent, James B., Schwaeble, Hans-Wilhelm, Tedford, Clark E., Demopulos, Gregory A.
• Granted Patent: US 8,652,477 B2
• Time in Patent Office: Days
• US Class Current: 424/132.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 25/00 Drugs for disorders of the nervous system
• 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 37/00 Drugs for immunological or allergic disorders
• 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 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• 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 2317/76 : 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: 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. In one embodiment, the invention provides methods of treating a subject suffering from a complement mediated coagulation disorder, such as disseminated intravascular coagulation. 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, or at risk for developing, a coagulation disorder, 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 patient is suffering from, or at risk for developing disseminated intravascular coagulation.

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

6.

4. 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.

5. The method of claim 3, wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:

6.

6. 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.

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

8. The method of claim 6, wherein the antibody or fragment thereof is polyclonal.

9. The method of claim 6, wherein the antibody or fragment thereof is a recombinant antibody.

10. The method of claim 6, wherein the antibody has reduced effector function.

11. The method of claim 6, wherein the antibody is a chimeric, humanized or human antibody.

12. The method of claim 6, wherein the antibody is produced in a MASP-2 deficient transgenic animal.

13. 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.

14. 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.

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

6.

16. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from, or at risk for developing, a coagulation disorder, 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.

17. The method of claim 16, wherein the patient is suffering from or at risk for developing disseminated intravascular coagulation.

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

6.

19. The method of claim 18, wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:

6.

20. The method of claim 16, wherein the MASP-2 inhibitory agent is an antibody or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

21. The method of claim 20, wherein the antibody or fragment thereof is monoclonal.

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

23. The method of claim 20, wherein the antibody is produced in a MASP-2 deficient transgenic animal.

24. The method of claim 16, 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.

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

6.

26. A method of manufacturing a medicament for use in inhibiting the effects of MASP-2-dependent complement activation in living subjects suffering from a complement mediated coagulation disorder, comprising combining a therapeutically effective amount of a MASP-2 inhibitory agent in a pharmaceutical carrier.

28. The method of claim 26, wherein the composition is administered systemically to the subject.

29. The method of claim 26, wherein the subject is suffering from a disease or condition selected from the group consisting of sepsis, trauma, malignancy, transplant rejection, transfusion reaction, obstetric complication, vascular aneurysm, hepatic failure, heat stroke, burn, radiation exposure and severe toxic reaction.

30. The method of claim 26, wherein the subject is suffering from a neurological trauma.

31. The method of claim 26, wherein the subject is suffering from a bacterial infection.

32. The method of claim 30, wherein the bacterial infection is a N. meningitidis infection.

33. The method of claim 26, wherein the MASP-2 inhibitory agent specifically binds to a polypeptide comprising SEQ ID NO:

6.

34. The method of claim 26, 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.

35. The method of claim 32, wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:

6.

36. The method of claim 26, wherein the MASP-2 inhibitory agent is an antibody or fragment thereof that specifically binds to a portion of SEQ ID NO:

6.

27. A method of treating, preventing, or reducing the severity of disseminated intravascular coagulation in a subject in need thereof, comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation.