METHODS FOR TREATING CONDITIONS ASSOCIATED WITH MASP-2 DEPENDENT COMPLEMENT ACTIVATION

• US 20100074899A1
• Filed: 09/16/2009
• Published: 03/25/2010
• Est. Priority Date: 06/10/2004
• Status: Abandoned Application

• Current Assignee: Omeros Corporation, University of Leicester
• Original Assignee: Omeros Corporation, University of Leicester
• Inventors: Parent, James B., Schwaeble, Hans-Wilhelm, Tedford, Clark E., Fujita, Teizo, Stover, Cordula Margaret
• Application Number:
  US12/561,202
• Publication Number:
  US 20100074899A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 suffering from or at risk of a condition associated with an ischemia-reperfusion injury, 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. The method of claim 1, wherein the MASP-2 inhibitory agent is effective to selectively inhibit MASP-2-dependent complement activation without substantially inhibiting C1q-dependent complement activation.

16-27. -27. (canceled)

28. A method of treating a subject suffering from or at risk of 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, gastrointestinal ischemia-reperfusion and hemodynamic resuscitation following shock and/or surgical procedures.

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

6.

60. The method of claim 59, wherein the antibody has reduced effector function.

61. The method of claim 59, wherein the antibody is effective to selectively inhibit MASP-2-dependent complement activation without substantially inhibiting C1q-dependent complement activation.

30-58. -58. (canceled)