Antibody Fc Mutants with Ablated Effector Functions

Abstract

Antibody and other Fc-containing molecules with variations in the Fc region with reduced binding to Fc gamma receptors and resulting activity and can be used in the treatment of various diseases and disorders.

What is claimed: 
     
         1 . An Fc-containing molecule having decreased affinity for at least one Fcγ receptor as compared to a wildtype Fc, comprising an antibody Fc domain with a mutated IgG constant region, wherein amino acid residues 233, 234, 235, 237, and 238 defined by the EU numbering system, comprise a sequence selected from PAAAP (SEQ ID NO: 4), PAAAS (SEQ ID NO:5), and SAAAS (SEQ ID NO:6). 
     
     
         2 . The Fc-containing molecule of  claim 1 , wherein the Fc domain further comprises the mutations H268A or H268Q, V309L, A330S and P331S as defined by the EU numbering system. 
     
     
         3 . The Fc-containing molecule of  claim 1 , wherein the domain is capable of specifically binding FcRn. 
     
     
         4 . The Fc-containing molecule of  claim 1 , wherein the Fc domain sequence is at least 90% identity with the human IgG2 heavy chain CH2 domain. 
     
     
         5 . The Fc-containing molecule of  claim 1 , wherein the Fc-containing molecule is an antibody or Fc fusion protein. 
     
     
         6 . The Fc-containing molecule of  claim 1 , wherein residue 228 is mutated from S to P. 
     
     
         7 . A recombinant polypeptide based binding molecule comprising: (i) a binding domain capable of binding a target molecule, and (ii) an Fc domain having an amino acid sequence substantially homologous to all or part of a CH2 and CH3 constant domains of a human immunoglobulin heavy chain and wherein residues 233, 234, 235, 237, and 238 defined by the EU numbering system, comprise an amino acid sequence selected from PAAAP, PAAAS, and SAAAS; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target. 
     
     
         8 . The binding molecule of  claim 7 , wherein the Fc domain is capable of specifically binding FcRn. 
     
     
         9 . The binding molecule of  claim 8 , wherein the binding domain is selected from the binding site of an antibody; an enzyme; a hormone; a receptor; a cytokine; an immune cell surface antigen; a ligand and an adhesion molecule. 
     
     
         10 . The binding molecule of  claim 9 , wherein the molecule exhibits avidity. 
     
     
         11 . The binding molecule according to any of  claims 7 - 10 , wherein the binding domain specifically binds a target within a neurological tissue, an endocrine tissue, a vascular tissue, a cardiac tissue, a synovial tissue, a dermal tissue, or a mucosal tissue. 
     
     
         12 . A method for treating a disease characterized by the migration and concentration of macrophages, comprising administering to a subject or patient an Fc-containing protein preparation according to any of  claims 1 - 7 . 
     
     
         13 . A method of treating Graft-vs-host disease; host-vs-graft disease; organ transplant rejection; bone-marrow transplant rejection; autoimmunity, vasculitis, autoimmune haemolytic anaemia, autoimmune thrombocytopenia and arthritis; alloimmunity such as fetal/neonatal alloimmune thrombocytopenia; asthma and allergy; chronic or acute inflammatory diseases, Crohn's Disease or scleroderma; Alzheimer's Disease, or coronary artery occlusion comprising administering to a subject or patient an Fc-containing molecule according to any of  claims 1 - 7 . 
     
     
         14 . A method for treating a condition comprising administering to a subject or patient an Fc-containing molecule according to any of  claims 1 - 7 , wherein the binding molecule is administered to a patient, or optionally wherein the patient is an unborn infant, to the mother of the patient. 
     
     
         15 . An Fc-containing molecule having decreased affinity for Fcγ receptors as compared to a wildtype Fc, comprising an antibody Fc domain based on an IgG2 constant region, wherein amino acid residues 233, 234, 235, 237, and 238 defined by the EU numbering system, comprise a sequence selected from PAAAP, PAAAS, and SAAAS and further comprising mutations H268A or H268Q, V309L, A330S and P331S as defined by the EU numbering system. 
     
     
         16 . A method of altering binding of an IgG2 based Fc-containing molecule to Fcγ receptors as compared to a wildtype IgG2 based Fc, comprising altering the sequence of an Fc domain based on an IgG2 constant region at residues 233, 234, 235, 237, and 238 defined by the EU numbering system, to comprise a sequence selected from PAAAP, PAAAS, and SAAAS, and comprise mutations H268A or H268Q, V309L, A330S and P331S. 
     
     
         17 . Any invention described herein.