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 human subject suffering from TMA associated with hematopoietic stem cell transplant. 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.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A method of treating a human subject suffering from persistent TMA associated with hematopoietic stem cell transplant (HSCT-TMA) comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory antibody, or antigen-binding fragment thereof, effective to inhibit MASP-2-dependent complement activation. 
     
     
         2 . The method of  claim 1 , wherein the MASP-2 inhibitory antibody is a monoclonal antibody, or fragment thereof that specifically binds to human MASP-2. 
     
     
         3 . The method of  claim 1 , 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. 
     
     
         4 . The method of  claim 1 , wherein the MASP-2 inhibitory antibody does not substantially inhibit the classical pathway. 
     
     
         5 . The method of  claim 1 , wherein the MASP-2 inhibitory antibody inhibits C3b deposition in 90% human serum with an IC 50  of 30 nM or less. 
     
     
         6 . The method of  claim 1 , wherein the MASP-2 inhibitory antibody is delivered to the subject systemically. 
     
     
         7 . The method of  claim 1 , wherein the method further comprises identifying a human subject having persistent TMA associated with hematopoietic stem cell transplant prior to the step of administering to the subject a composition comprising an amount of a MASP-2 inhibitory antibody, or antigen-binding fragment thereof, effective to inhibit MASP-2-dependent complement activation. 
     
     
         8 . The method of  claim 1 , wherein the subject has previously undergone, or is currently undergoing, treatment with a humanized anti-C5 antibody or antigen-binding fragment thereof. 
     
     
         9 . The method of  claim 1 , wherein the MASP-2 inhibitory antibody or antigen-binding fragment thereof is administered in an amount effective to improve at least one or more of the following clinical parameters associated with persistent TMA associated with hematopoietic stem cell transplant: (i) an increase in platelet count (e.g., at least double, at least triple, at least quadruple the platelet count prior to treatment)); (ii) an increase in haptoglobin; (iii) a decrease in lactate dehydrogenase (LDH); and/or (iv) a decrease in creatinine. 
     
     
         10 . The method of  claim 1 , wherein the MASP-2 inhibitory antibody or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 of the amino acid sequence set forth as SEQ ID NO:67 and a light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 of the amino acid sequence set forth as SEQ ID NO:70.