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 suffering from, or at risk for developing a thrombotic microangiopathy (TMA). 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.

1 . A method of inhibiting MASP-2-dependent complement activation in a subject suffering from, or at risk for developing a thrombotic microangiopathy (TMA), wherein the TMA is at least one of (i) a TMA secondary to cancer; (ii) a TMA secondary to chemotherapy, or (iii) a TMA secondary to transplantation, 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 is suffering from, or is at risk for developing, a TMA secondary to cancer, and wherein the MASP-2 inhibitory agent is administered systemically to the subject in an amount effective to reduce the risk of developing TMA, or reduce the severity of TMA. 
     
     
         3 . The method of  claim 1 , wherein the subject is suffering from, or is at risk for developing, a TMA secondary to chemotherapy, and wherein the MASP-2 inhibitory agent is administered systemically to the subject prior to, during, or after chemotherapy, in an amount effective to reduce the risk of developing TMA, or reduce the severity of TMA. 
     
     
         4 . The method of  claim 1 , wherein the subject is suffering from, or is at risk for developing, a TMA secondary to transplantation, and wherein the MASP-2 inhibitory agent is administered systemically to the subject prior to, during, or after the transplant procedure, in an amount effective to reduce the risk of developing TMA, or reduce the severity of TMA. 
     
     
         5 . The method of  claim 1 , wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody or fragment thereof. 
     
     
         6 . The method of  claim 1 , 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. 
     
     
         7 . The method of  claim 1 , wherein the subject has previously undergone, or is currently undergoing, treatment with a terminal complement inhibitor that inhibits cleavage of complement protein C5. 
     
     
         8 . The method of  claim 1 , wherein the method further comprises administering to the subject a terminal complement inhibitor that inhibits cleavage of complement protein C5. 
     
     
         9 . The method of  claim 8 , wherein the terminal complement inhibitor is a humanized anti-C5 antibody or antigen-binding fragment thereof. 
     
     
         10 . The method of  claim 8 , wherein the terminal complement inhibitor is eculizumab. 
     
     
         11 . The method of  claim 8 , 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. 
     
     
         12 . The method of  claim 1 , wherein the composition is administered subcutaneously, intra-muscularly, intra-arterially, intravenously, or as an inhalant. 
     
     
         13 . The method of  claim 1 , wherein the transplant is an allogeneic hematopoietic stem cell transplant. 
     
     
         14 .- 41 . (canceled) 
     
     
         42 . A method of inhibiting thrombus formation in a subject suffering from atypical hemolytic uremic syndrome (aHUS), comprising administering to the subject an amount of a MASP-2 inhibitory antibody, or antigen-binding fragment thereof, effective to inhibit MASP-2-dependent complement activation. 
     
     
         43 . The method of any of  claim 42 , wherein said MASP-2 inhibitory antibody is a monoclonal antibody, or antigen-binding fragment thereof that specifically binds to a portion of SEQ ID NO:6. 
     
     
         44 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody binds human MASP-2 with a K D  of 10 nM or less. 
     
     
         45 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody binds an epitope in the CCP1 domain of MASP-2. 
     
     
         46 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody inhibits C3b deposition in an in vitro assay in 1% human serum at an IC 50  of 10 nM or less. 
     
     
         47 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody inhibits C3b deposition in 90% human serum with an IC 50  of 30 nM or less. 
     
     
         48 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody is an antibody fragment selected from the group consisting of Fv, Fab, Fab′, F(ab) 2  and F(ab′) 2 . 
     
     
         49 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody is a single-chain molecule. 
     
     
         50 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody is selected from the group consisting of an IgG1 molecule, an IgG2 and an IgG4 molecule. 
     
     
         51 . The method of  claim 50 , wherein the IgG4 molecule comprises a S228P mutation. 
     
     
         52 . The method of  claim 42 , wherein said MASP-2 inhibitory antibody does not substantially inhibit the classical pathway. 
     
     
         53 . The method of  claim 42 , wherein the MASP-2 inhibitory antibody inhibits thrombus formation in serum from a subject suffering from aHUS by at least 40% as compared to untreated serum. 
     
     
         54 . The method of  claim 42 , wherein the MASP-2 inhibitory antibody inhibits thrombus formation in serum from a subject suffering from aHUS at a level of at least 20% greater than its inhibitory effect on C5b-9 deposition in the serum from the same subject. 
     
     
         55 . The method of  claim 42 , wherein the subject is in the acute phase of aHUS. 
     
     
         56 . The method of  claim 42 , wherein the subject is in the remission phase of aHUS. 
     
     
         57 . The method of  claim 43 , wherein the MASP-2 inhibitory monoclonal antibody, or antigen-binding fragment thereof, comprises:
 (a) a heavy-chain variable region comprising: i) a heavy chain CDR-H1 comprising the amino acid sequence from 31-35 of SEQ ID NO:67; and ii) a heavy-chain CDR-H2 comprising the amino acid sequence from 50-65 of SEQ ID NO:67; and iii) a heavy-chain CDR-H3 comprising the amino acid sequence from 95-102 of SEQ ID NO:67 and   (b) a light-chain variable region comprising: i) a light-chain CDR-L1 comprising the amino acid sequence from 24-34 of SEQ ID NO:70; and ii) a light-chain CDR-L2 comprising the amino acid sequence from 50-56 of SEQ ID NO:70; and iii) a light-chain CDR-L3 comprising the amino acid sequence from 89-97 of SEQ ID NO:70.   
     
     
         58 . The method of  claim 43 , wherein the MASP-2 inhibitory monoclonal antibody comprises a heavy-chain variable region set forth as SEQ ID NO:67 and a light-chain variable region set forth as SEQ ID NO:70. 
     
     
         59 . The method of  claim 43 , wherein the MASP-2 inhibitory antibody or antigen binding-fragment thereof specifically recognizes at least part of an epitope recognized by a reference antibody comprising a heavy chain variable region as set forth in SEQ ID NO:67 and a light-chain variable region as set forth in SEQ ID NO:70.