FC RECEPTOR BINDING PROTEINS
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 - 110 . (canceled)
111 . An isolated antibody comprising a heavy chain (HC) immunoglobulin variable domain sequence and a light chain (LC) immunoglobulin variable domain sequence, wherein the antibody binds to human FcRn; and wherein:
the HC comprises:
a HC CDR1 comprising an amino acid sequence at least 80% identical to EYAMG (SEQ ID NO:144) or VYAMG (SEQ ID NO:156),
a HC CDR2 comprising an amino acid sequence at least 80% identical to SIGSSGGQTKYADSVKG (SEQ ID NO:145), or SIGSSGGPTKYADSVKG (SEQ ID NO:157), and
a HC CDR3 comprising an amino acid sequence at least 80% identical to 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 an amino acid sequence at least 90% identical to TGTGSDVGSYNLVS (SEQ ID NO:141),
a LC CDR2 comprising an amino acid sequence at least 85% identical to GDSQRPS (SEQ ID NO:142), and
a LC CDR3 comprising an amino acid sequence at least 90% identical to CSYAGSGIYV (SEQ ID NO:143).
112 . The isolated antibody of claim 111 , wherein the antibody comprises:
(i) a HC comprising a HC CDR1 that is at least 80% identical to EYAMG (SEQ ID NO:144), a HC CDR2 that is at least 90% identical to SIGSSGGQTKYADSVKG (SEQ ID NO:145), and a HC CDR3 that is at least 85% identical to LSTGELY(SEQ ID NO:146);
(ii) a HC comprising a HC CDR1 that is at least 80% identical to VYAMG (SEQ ID NO:156), a HC CDR2 that is at least 90% identical to SIGSSGGPTKYADSVKG (SEQ ID NO:157), and a HC CDR3 that is at least 85% identical to LSIRELV (SEQ ID NO:158);
(iii) a HC comprising a HC CDR1 that is at least that is at least 80% identical to VYAMG (SEQ ID NO:156), a HC CDR2 that is at least 90% identical to SIGSSGGPTKYADSVKG (SEQ ID NO:157), and a HC CDR3 that is at least 85% identical to LSIVDSY (SEQ ID NO:164);
(iv) a HC comprising a HC CDR1 that is at least 80% identical to EYAMG (SEQ ID NO:144), a HC CDR2 that is at least 90% identical to SIGSSGGQTKYADSVKG (SEQ ID NO:145), and a HC CDR3 that is at least 85% identical to LSLGDSY (SEQ ID NO:170); or
(v) a HC comprising a HC CDR1 that is at least 80% identical to EYAMG (SEQ ID NO:144), a HC CDR2 that is at least 90% identical to SIGSSGGQTKYADSVKG (SEQ ID NO:145), and a HC CDR3 that is at least 85% identical to LAIGDSY (SEQ ID NO:176).
113 . The antibody of claim 111 , wherein the antibody binds to the same FcRn epitope as M0171-A03, M0171-A01, M0159-A07, M0161-B04, M0090-F11 or DX2500.
114 . The antibody of claim 111 , wherein the antibody is a full length antibody.
115 . The antibody of claim 111 , wherein the antibody is an antigen-binding fragment of a full length antibody.
116 . A pharmaceutical composition comprising the antibody of claim 111 , and a pharmaceutically acceptable carrier.
117 . A method of detecting an FcRn in a sample, the method comprising:
contacting the sample with an antibody of claim 111 ; and
detecting an interaction between the antibody and the FcRn if present.
118 . A method of modulating an FcRn activity, the method comprising:
contacting an FcRn with an effective amount of an antibody of claim 111 , thereby modulating the activity of the FcRn.
119 . The method of claim 118 , wherein the FcRn is in a human subject.
120 . A method of treating an autoimmune disorder and/or modulating a symptom of the autoimmune disorder, the method comprising: administering to a subject in need thereof an effective amount of an antibody of claim 111 .
121 . The method of claim 118 , wherein the autoimmune disorder is a disorder selected from the group consisting of: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Myasthenia Gravis (MG), Graves Disease, Idiopathic Thrombocytopenia Purpura (ITP), Guillain-Barre Syndrome, autoimmune myocarditis, Membrane Glomerulonephritis, diabetes mellitus, Type I or Type II diabetes, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, gastritis, Celiac Disease, Vitiligo, Hepatitis, primary biliary cirrhosis, inflammatory bowel disease, spondyloarthropathies, experimental autoimmune encephalomyelitis, immune neutropenia, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines, T-lymphocytes typically found in tuberculosis, sarcoidosis, and polymyositis, polyarteritis, cutaneous vasculitis, pemphigus, pemphigold, Goodpasture's syndrome, Kawasaki's disease, systemic sclerosis, anti-phospholipid syndrome, and Sjogren's syndrome.
122 . A method of modulating the half life/levels of circulating IgG in a subject, the method comprising:
identifying a subject in need of modulated circulating IgG half life/levels; and
administering an antibody of claim 111 to the subject in an amount effective to modulate the half life/levels of circulating IgG in the subject.
123 . The method of claim 122 , wherein the antibody is administered in an amount effective to reduce the binding of IgG to FcRn in the subject.
124 . A method of reducing the concentration of undesired antibodies in an individual, the method comprising administrating to an individual in need thereof a therapeutically effective dose of an antibody of claim 111 .
125 . The method of claim 124 , wherein the undesired antibody is natalizumab.