HUMANIZED AFFINITY MATURED ANTI-FcRn ANTIBODIES

Abstract

Provided herein are recombinant antibodies and antigen-binding portions thereof useful for binding to FcRn and blocking binding of FcRn to IgG Fc. The FcRn-binding proteins can be used to treat a variety of disorders including autoimmune disorders.

We claim: 
     
         1 . A method of increasing the clearance of immune complexes from a subject, the method comprising administering to the subject in need thereof an effective amount of an antibody or antigen-binding fragment thereof which binds to FcRn, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region and wherein each of the heavy chain and the light chain variable regions comprises a CDR1, CDR2, and CDR3; and wherein:
 the sequence of CDR1 of the heavy chain is SEQ ID NO:2; and   the sequence of CDR2 of the heavy chain is SEQ ID NO:4; and   the sequence of CDR3 of the heavy chain is SEQ ID NO:55; and   the sequence of CDR1 of the light chain is SEQ ID NO:6; and   the sequence of CDR2 of the light chain is SEQ ID NO:8; and   the sequence of CDR3 of the light chain is SEQ ID NO: 10.   
     
     
         2 . The method of  claim 1 , wherein the subject has a vasculitis that is immune complex-mediated. 
     
     
         3 . The method of  claim 1 , wherein the sequence of the heavy chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:56, and wherein the sequence of the light chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:22. 
     
     
         4 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof has isotype IgG4. 
     
     
         5 . The method of  claim 4 , wherein the antibody or antigen-binding fragment thereof contains a S241P modification in the heavy chain. 
     
     
         6 . A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof which binds to FcRn, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region and wherein each of the heavy chain and the light chain variable regions comprises a CDR1, CDR2, and CDR3; and wherein:
 the sequence of CDR1 of the heavy chain is SEQ ID NO:2; and   the sequence of CDR2 of the heavy chain is SEQ ID NO:4; and   the sequence of CDR3 of the heavy chain is SEQ ID NO:55; and   the sequence of CDR1 of the light chain is SEQ ID NO:6; and   the sequence of CDR2 of the light chain is SEQ ID NO:8; and   the sequence of CDR3 of the light chain is SEQ ID NO: 10.   
     
     
         7 . The method of  claim 6 , wherein the autoimmune disease is selected from the group consisting of pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, rheumatoid arthritis, systemic lupus erythematosis, Crohn's disease, idiopathic thrombocytopenic purpura (ITP), heparin induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), myasthenia gravis (MG), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), multifocal motor neuropathy, neuromyelitis optica, autoimmune thrombocytopenia, immune neutropenia, antihemophilic FVIII inhibitor, antiphospholipid syndrome, Kawasaki Syndrome, ANCA-associated disease, polymyositis, dermatomyositis, bullous pemphigoid, multiple sclerosis (MS), Guillain-Barre Syndrome, chronic polyneuropathy, ulcerative colitis, diabetes mellitus, autoimmune thyroiditis, Graves' opthalmopathy, autoimmune urticaria, vasculitides, and Rasmussen's encephalitis. 
     
     
         8 . The method of  claim 7 , wherein the autoimmune disease is selected from the group consisting of pemphigus vulgaris, pemphigus foliaceus, autoimmune hemolytic anemia (AIHA), and myasthenia gravis (MG). 
     
     
         9 . The method of  claim 6 , wherein the sequence of the heavy chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:56, and wherein the sequence of the light chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:22. 
     
     
         10 . The method of  claim 6 , wherein the antibody or antigen-binding fragment thereof has isotype IgG4. 
     
     
         11 . The method of  claim 10 , wherein the antibody or antigen-binding fragment thereof contains a S241P modification in the heavy chain. 
     
     
         12 . A method of treating an IgG-mediated disease in a subject in need thereof, the method comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof which binds to FcRn, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region and wherein each of the heavy chain and the light chain variable regions comprises a CDR1, CDR2, and CDR3; and wherein:
 the sequence of CDR1 of the heavy chain is SEQ ID NO:2; and   the sequence of CDR2 of the heavy chain is SEQ ID NO:4; and   the sequence of CDR3 of the heavy chain is SEQ ID NO:55; and   the sequence of CDR1 of the light chain is SEQ ID NO:6; and   the sequence of CDR2 of the light chain is SEQ ID NO:8; and   the sequence of CDR3 of the light chain is SEQ ID NO: 10.   
     
     
         13 . The method of  claim 12 , wherein the sequence of the heavy chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:56, and wherein the sequence of the light chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:22. 
     
     
         14 . The method of  claim 12 , wherein the antibody or antigen-binding fragment thereof has isotype IgG4. 
     
     
         15 . The method of  claim 14 , wherein the antibody or antigen-binding fragment thereof contains a S241P modification in the heavy chain. 
     
     
         16 . A method of promoting degradation of an autoantibody in a subject, the method comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof which binds to FcRn, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region and wherein each of the heavy chain and the light chain variable regions comprises a CDR1, CDR2, and CDR3; and wherein:
 the sequence of CDR1 of the heavy chain is SEQ ID NO:2; and   the sequence of CDR2 of the heavy chain is SEQ ID NO:4; and   the sequence of CDR3 of the heavy chain is SEQ ID NO:55; and   the sequence of CDR1 of the light chain is SEQ ID NO:6; and   the sequence of CDR2 of the light chain is SEQ ID NO:8; and   the sequence of CDR3 of the light chain is SEQ ID NO: 10.   
     
     
         17 . The method of  claim 16 , wherein degradation of the autoantibody is promoted prior to the administration of a therapeutic antibody, and wherein the subject is in need of treatment with the therapeutic antibody. 
     
     
         18 . The method of  claim 16 , wherein the sequence of the heavy chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:56, and wherein the sequence of the light chain variable region of the antibody or antigen-binding fragment is SEQ ID NO:22. 
     
     
         19 . The method of  claim 16 , wherein the antibody or antigen-binding fragment thereof has isotype IgG4. 
     
     
         20 . The method of  claim 19 , wherein the antibody or antigen-binding fragment thereof contains a S241P modification in the heavy chain.