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.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . 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. 
     
     
         2 . The method of  claim 1 , 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. 
     
     
         3 . The method of  claim 1 , wherein the subject is infected with an enterogenic  E. coli  for which the use of antibiotics is contra-indicated. 
     
     
         4 . The method of  claim 1 , wherein the subject is infected with  shigella  or  salmonella.    
     
     
         5 . The method of  claim 3 , 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. 
     
     
         6 . The method of  claim 4 , 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. 
     
     
         7 . The method of  claim 1 , wherein the MASP-2 inhibitory agent is administered to the subject during a first time period via an intravenous catheter or other catheter delivery method. 
     
     
         8 . The method of  claim 7 , 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. 
     
     
         9 . The method of  claim 8 , 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. 
     
     
         10 . The method of  claim 5 , 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. 
     
     
         11 . The method of  claim 6 , 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. 
     
     
         12 . The method of  claim 10 , 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. 
     
     
         13 . The method of  claim 11 , 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. 
     
     
         14 . The method of  claim 1 , wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof. 
     
     
         15 . The method of  claim 14 , 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. 
     
     
         16 . The method of  claim 15 , wherein the monoclonal antibody or antigen-binding fragment thereof is an antibody having reduced effector function. 
     
     
         17 . The method of  claim 15 , wherein the monoclonal antibody or antigen-binding fragment thereof is a chimeric antibody. 
     
     
         18 . The method of  claim 15 , wherein the monoclonal antibody or antigen-binding fragment thereof is a humanized antibody. 
     
     
         19 . The method of  claim 15 , wherein the monoclonal antibody or antigen-binding fragment thereof is a human antibody. 
     
     
         20 . 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. 
     
     
         21 . The method of  claim 20 , further comprising treating the patient with plasmapheresis. 
     
     
         22 . The method of  claim 20 , wherein the composition comprising the MASP-2 inhibitory agent is administered in the absence of plasmapheresis. 
     
     
         23 . The method of  claim 20 , 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. 
     
     
         24 . The method of  claim 23 , 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. 
     
     
         25 . The method of  claim 20 , wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody, or fragment thereof. 
     
     
         26 . The method of  claim 25 , 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. 
     
     
         27 . The method of  claim 26 , wherein the monoclonal antibody or antigen-binding fragment thereof is an antibody having reduced effector function. 
     
     
         28 . The method of  claim 26 , wherein the monoclonal antibody or antigen-binding fragment thereof is a chimeric antibody. 
     
     
         29 . The method of  claim 26 , wherein the monoclonal antibody or antigen-binding fragment thereof is a humanized antibody. 
     
     
         30 . The method of  claim 26 , wherein the monoclonal antibody or antigen-binding fragment thereof is a human antibody.