Fc receptor binding proteins

Abstract

This disclosure provides, inter alia, proteins that bind to FcRn, e.g., immunoglobulins that inhibit FcRn with high affinity and selectivity. The FcRn-binding proteins can be used to treat a variety of disorders including autoimmune disorders.

1 - 23 . (canceled) 
     
     
         24 . An isolated antibody, or a fragment thereof, which binds to human FcRn, wherein the antibody is generated against the heavy chain of human FcRn or a fragment thereof, wherein the antibody functions as a non-competitive inhibitor of IgG binding to human FcRn, and wherein the antibody does not bind β2-microglobulin. 
     
     
         25 - 110 . (canceled) 
     
     
         111 . The isolated antibody of  claim 24 , comprising a heavy chain (HC) immunoglobulin variable domain sequence and a light chain (LC) immunoglobulin variable domain sequence; and wherein
 the HC comprises:
 a HC CDR1 comprising the amino acid sequence EYAMG (SEQ ID NO:144) or VYAMG (SEQ ID NO:156), 
 a HC CDR2 comprising the amino acid sequence SIGSSGGQTKYADSVKG (SEQ ID NO:145) or SIGSSGGPTKYADSVKG (SEQ ID NO:157), and 
 a HC CDR3 comprising the amino acid sequence LSTGELY (SEQ ID NO:146), LSIRELV (SEQ ID NO:158), LSIVDSY (SEQ ID NO:164), LSLGDSY (SEQ ID NO:170), or, LAIGDSY (SEQ ID NO:176); and 
   the LC comprises:
 a LC CDR1 comprising the amino acid sequence TGTGSDVGSYNLVS (SEQ ID NO:141), 
 a LC CDR2 comprising the amino acid sequence GDSQRPS (SEQ ID NO:142), and 
 a LC CDR3 comprising the amino acid sequence CSYAGSGIYV (SEQ ID NO:143). 
   
     
     
         112 . The isolated antibody of  claim 111 , wherein the HC comprises:
 a HC CDR1 comprising the amino acid sequence EYAMG (SEQ ID NO:144),   a HC CDR2 comprising the amino acid sequence SIGSSGGQTKYADSVKG (SEQ ID NO:145), and   a HC CDR3 comprising the amino acid sequence LAIGDSY (SEQ ID NO:176).   
     
     
         113 . The isolated antibody of  claim 111 , wherein the HC comprises,
 a HC CDR1 comprising the amino acid sequence VYAMG (SEQ ID NO:156),   a HC CDR2 comprising the amino acid sequence SIGSSGGPTKYADSVKG (SEQ ID NO:157), and   a HC CDR3 comprising the amino acid sequence LSIVDSY (SEQ ID NO:164).   
     
     
         114 . The isolated antibody of  claim 111 , wherein the HC comprises,
 a HC CDR1 comprising the amino acid sequence EYAMG (SEQ ID NO:144),   a HC CDR2 comprising the amino acid sequence SIGSSGGQTKYADSVKG (SEQ ID NO:145), and   a HC CDR3 comprising the amino acid sequence LSTGELY (SEQ ID NO:146).   
     
     
         115 . The isolated antibody of  claim 24 , wherein the antibody binds human FcRn at about pH range 5-7.4 with a dissociation constant (K D ) of less than 100 nM. 
     
     
         116 . The antibody of any one of  claim 24 , wherein the antibody inhibits the binding of IgG-Fc with an IC 50  of less than about 800 nM, less than about 600 nM, less than about 300 nM, less than about 100 nM, less than about 50, nM, less than about 25 nM, less than about 10 nM, or less than about 5 nM at about pH 6. 
     
     
         117 . A method for suppressing the level of an IgG antibody in an individual comprising:
 providing an antibody or a fragment thereof of  claim 24  which binds to human FcRn, is generated against the heavy chain of human FcRn or a fragment thereof, is a non-competitive inhibitor of IgG binding to human FcRn and does not bind β2-microglobulin; and   administering the antibody or the fragment thereof to an individual in an amount sufficient to suppress the level of an IgG antibody in an individual.   
     
     
         118 . The method of  claim 117 , wherein the IgG antibody is a therapeutic IgG antibody. 
     
     
         119 . The method of  claim 118 , wherein the therapeutic IgG antibody is natalizumab. 
     
     
         120 . The method of  claim 117 , wherein the IgG antibody is non-self Human Leukocyte Antigen. 
     
     
         121 . The method of  claim 117 , wherein the method further comprises a plasma exchange step.