Antibody fc variants

Abstract

The invention relates to engineered polypeptides comprising Fc variants and their uses. More specifically, Fc variants are described exhibiting reduced effector function. These variants cause a benefit for a patient suffering from a disease which could be treated with an antibody for which it is desirable to reduce the effector function elicited by antibodies.

1 . A polypeptide comprising an Fc variant of a wild-type human IgG Fc region, said Fc variant comprising an amino acid substitution at position Pro329 and at least one further amino acid substitution, wherein the residues are numbered according to the EU index of Kabat, and wherein said polypeptide exhibits a reduced affinity to one or more of human FcγRIIIA and/or FcγRIIA and/or FcγRI compared to the polypeptide comprising the wildtype IgG Fc region, and wherein the ADCC induced by said polypeptide is reduced to at least 20% of the ADCC induced by the polypeptide comprising a wild-type human IgG Fc region. 
     
     
         2 . The polypeptide according to  claim 1 , wherein Pro329 of the wild-type human Fc region is substituted with glycine or arginine or an amino acid residue large enough to destroy the proline sandwich within the Fc/Fcγ receptor interface. 
     
     
         3 . The polypeptide according to  claim 1 , wherein said at least one further amino acid substitution is selected from S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S. 
     
     
         4 . The polypeptide according to  claim 1 , wherein said at least one further amino acid substitution is L234A and L235A of the human IgG1 Fc region or S228P and L235E of the human IgG4 Fc region. 
     
     
         5 . The polypeptide according to  claim 1 , wherein the affinity to at least one further human receptor of the group comprising the human receptors FcγI, FcγIIA, and C1q is reduced compared to the polypeptide comprising a wild-type human IgG Fc region. 
     
     
         6 . The polypeptide according to  claim 1 , wherein the polypeptide comprises a human IgG1 or IgG4 Fc region. 
     
     
         7 . The polypeptide according to  claim 1 , wherein the polypeptide is an antibody or an Fc fusion protein. 
     
     
         8 . The polypeptide according to  claim 1 , wherein thrombocyte aggregation induced by the polypeptide is reduced compared to the thrombocyte aggregation induced by a polypeptide comprising a wild-type human IgG Fc region. 
     
     
         9 . The polypeptide according to  claim 1 , wherein CDC induced by the polypeptide is strongly reduced compared to the CDC induced by a polypeptide comprising a wild-type human IgG Fc region. 
     
     
         10 . (canceled) 
     
     
         11 . The polypeptide according to  claim 1 , wherein the polypeptide is an anti-CD9 antibody, which is characterized in that the polypeptide comprising the wildtype Fc region comprises a heavy chain variable region SEQ ID NO:9 and a variable light chain region SEQ ID NO:8. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . A method of treating an individual having a disease, wherein it is favorable that the effector function of the polypeptide comprising an Fc variant of a wild-type human IgG Fc region is strongly reduced compared to the effector function induced by a polypeptide comprising a wildtype human Fc polypeptide, comprising administering to an individual an effective amount of the polypeptide according to  claim 1 . 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A method of treating an individual having a disease with a polypeptide, said polypeptide having Pro329 of the human IgG Fc region substituted with Gly, wherein the residues are numbered according to the EU index of Kabat, wherein said polypeptide is characterized by a strongly reduced binding to FcγRIIIA and FcγRIIA compared to the polypeptide comprising a wildtype human IgG Fc region, comprising administering to the individual an effective amount of said polypeptide. 
     
     
         19 . The method according to  claim 18 , wherein said polypeptide comprises at least two further amino acid substitution at L234A and L235A of the human IgG1 Fc region or S228P and L235E of the human IgG4 Fc region.