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 . (canceled) 
     
     
         2 . The method according to  claim 12 , 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 region. 
     
     
         3 . The method according to  claim 12 , wherein said at least one further amino acid substitution is selected from S228P, E233P, L234A, L235A, L235E, N297A, N297D, and P331S. 
     
     
         4 . The method according to  claim 3 , 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 method according to  claim 12 , wherein the affinity to at least one further human receptor is reduced compared to the polypeptide comprising a wild-type human IgG Fc region, wherein the further human receptor is selected from FcγI, FcγIIA, and C1q. 
     
     
         6 . The method according to  claim 12 , wherein the polypeptide comprises a human IgG1 or IgG4 Fc region. 
     
     
         7 . The method according to  claim 12 , wherein the polypeptide is an antibody or an Fc fusion protein. 
     
     
         8 . The method according to  claim 12 , 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 method according to  claim 12 , 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 method according to  claim 12 , wherein the polypeptide is an anti-CD9 antibody comprising a heavy chain variable region comprising SEQ ID NO:9 and a variable light chain region comprising SEQ ID NO:8. 
     
     
         12 . A method of treating a disease comprising administering 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, FcγRIIA, and FcγRI compared to the polypeptide comprising the wildtype IgG Fc region, and wherein the antibody-dependent cell-mediated cytotoxicity (ADCC) induced by said polypeptide is 0-20% of the ADCC induced by the polypeptide comprising a wild-type human IgG Fc region,
 wherein it is favorable for treating the disease that an effector function of the polypeptide is strongly reduced compared to the effector function induced by the polypeptide comprising a wild-type human IgG Fc region. 
 
     
     
         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 the polypeptide comprising a wildtype human Fc polypeptide, comprising administering to an individual an effective amount of 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, FcγRIIA, and FcγRI compared to the polypeptide comprising the wildtype IgG Fc region, and wherein the antibody-dependent cell-mediated cytotoxicity (ADCC) induced by said polypeptide is 0-20% of the ADCC induced by the polypeptide comprising a wild-type human IgG Fc region. 
     
     
         15 . A method for down-modulating ADCC comprising a polypeptide comprising an Fc variant of a wild-type human IgG Fc region, said polypeptide having Pro329 of the human IgG Fc region substituted with glycine, wherein the residues are numbered according to the EU index of Kabat, wherein said polypeptide exhibits a reduced affinity to the human FcγRIIIA and FcγRIIA, wherein ADCC is down-modulated to at least 20% of the ADCC induced by the polypeptide comprising the wildtype human IgG Fc region. 
     
     
         16 . The method according to any one of  claim 15 ,  22 , or  23  wherein the Fc variant 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. 
     
     
         17 . The method of  claim 16 , wherein thrombocyte aggregation induced by the polypeptide is reduced compared to the thrombocyte aggregation induced by the polypeptide comprising a wildtype human Fc region, wherein the polypeptide is a platelet activating antibody. 
     
     
         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. 
     
     
         20 . The method according to  claim 11 , wherein the polypeptide is formulated as a pharmaceutical formulation. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 15  further comprising down-modulating antibody-dependent cellular phagocytosis (ADCP). 
     
     
         23 . A method for down-modulating ADCP comprising a polypeptide comprising an Fc variant of a wild-type human IgG Fc region, said polypeptide having Pro329 of the human IgG Fc region substituted with glycine, wherein the residues are numbered according to the EU index of Kabat, wherein said polypeptide exhibits a reduced affinity to the human FcγRIIIA and FcγRIIA.