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

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.

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 . (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. 
     
     
         30 - 58 . (canceled) 
     
     
         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.