Fc receptor binding proteins
View Patent ↗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. A method of modulating the half-life/levels of circulating IgG in a subject in need thereof, the method comprising:
administering to the subject in need thereof an effective amount of an antibody that binds human FcRn, wherein the antibody comprises 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 an amino acid sequence EYAMG (SEQ ID NO: 144) or VYAMG (SEQ ID NO:156),
a HC CDR2 comprising an amino acid sequence SIGSSGGQTKYADSVKG (SEQ ID NO: 145) or SIGSSGGPTKYADSVKG (SEQ ID NO:157), and
a HC CDR3 comprising an 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 an amino acid sequence TGTGSDVGSYNLVS (SEQ ID NO:141),
a LC CDR2 comprising an amino acid sequence GDSQRPS (SEQ ID NO: 142), and
a LC CDR3 comprising an amino acid sequence CSYAGSGIYV (SEQ ID NO: 143).
2. The method of claim 1 , wherein the antibody is administered in an amount effective to reduce the binding of IgG to FcRn in the subject.
3. The method of claim 1 , wherein the antibody is administered in an amount effective to reduce the half-life/levels of circulating IgG in the subject.
4. The method of claim 1 , wherein the HC comprises:
(i) a HC CDR1 of EYAMG (SEQ ID NO:144), a HC CDR2 of SIGSSGGQTKYADSVKG (SEQ ID NO:145), and a HC CDR3 of LSTGELY (SEQ ID NO:146);
(ii) a HC CDR1 of VYAMG (SEQ ID NO:156), a HC CDR2 of SIGSSGGPTKYADSVKG (SEQ ID NO:157), and a HC CDR3 of LSIRELV (SEQ ID NO:158);
(iii) a HC CDR1 of VYAMG (SEQ ID NO:156), a HC CDR2 of SIGSSGGPTKYADSVKG (SEQ ID NO:157), and a HC CDR3 of LSIVDSY (SEQ ID NO:164);
(iv) a HC CDR1 of EYAMG (SEQ ID NO:144), a HC CDR2 of SIGSSGGQTKYADSVKG (SEQ ID NO:145), and a HC CDR3 of LSLGDSY (SEQ ID NO:170); or
(v) a HC CDR1 of EYAMG (SEQ ID NO:144), a HC CDR2 of SIGSSGGQTKYADSVKG (SEQ ID NO:145), and a HC CDR3 of 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).
5. The method of claim 1 , wherein the amount of the antibody is effective in reducing the concentration of undesired antibodies in the subject.
6. The method of claim 5 , wherein the undesired antibody is administered to the subject.
7. The method of claim 6 , wherein the undesired antibody is natalizumab.
8. The method of claim 1 , wherein the amount of the antibody is effective in modulating an FcRn activity in the subject.
9. The method of claim 8 , wherein the activity of the FcRn is binding of the FcRn to an endogenous Ig.
10. The method of claim 8 , wherein the activity of the FcRn is binding of the FcRn to a therapeutic antibody.
11. The method of claim 1 , wherein the subject has or is suspected of having an autoimmune disorder.
12. The method of claim 11 , wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Myasthenia Gravis (MG), Graves Disease, Idiopathic Thrombocytopenia Purpura (ITP), Guillain-Barre Syndrome, autoimmune myocarditis, Membrane Glomerulonephritis, Type I diabetes, multiple sclerosis, Raynaud's syndrome, autoimmune thyroiditis, gastritis, Celiac Disease, Vitiligo, Hepatitis, primary biliary cirrhosis, inflammatory bowel disease, spondyloarthropathies, experimental autoimmune encephalomyelitis, immune neutropenia, sarcoidosis, polymyositis, polyarteritis, cutaneous vasculitis, pemphigus, pemphigoid, Goodpasture's syndrome, Kawasaki's disease, systemic sclerosis, anti-phospholipid syndrome, or Sjogren's syndrome.