Fc Variants Having Decreased Affinity for FcyRlla

Abstract

The present invention relates to Fc variants having decreased affinity for FcγRIIa, methods for their generation, Fc polypeptides comprising optimized Fc variants, and methods for using optimized Fc variants.

1 . A polypeptide comprising an Fc variant comprising at least one amino acid substitution in the Fc region of a parent polypeptide, wherein said Fc variant comprises at least one substitution at a position selected from the group consisting of: 227, 230, 231, 232, 240, 241, 244, 245, 247, 262, 266, 268, 271, 275, 278, 282, 283, 284, 285, 286, 291, 299, 300, 302, 304, 305, 317, 318, 325, 328, 332, 336, and 337, wherein numbering is according to the EU Index, and wherein said Fc variant decreases binding affinity to FcγRIIa as compared to said parent polypeptide.  
     
     
         2 . A polypeptide according to  claim 1 , wherein said Fc variant comprises at least one substitution at a position selected from the group consisting of: 227, 231, 244, 247, 282, 283, 286, 291, 305, 318, 336, and 337, wherein numbering is according to the EU Index, and wherein said Fc variant increases binding affinity to FcγRIIa as compared to said parent polypeptide.  
     
     
         3 . A polypeptide according to  claim 1 , wherein said Fc variant comprises at least one substitution selected from the group consisting of 227Y, 230G, 230Y, 231 K, 232E, 232G, 232K, 240T, 241W, 244H, 245A, 247G, 247V, 262E, 266T, 268G, 268I, 268L, 268M, 268P, 268T, 268W, 271D, 271E, 271F, 271H, 271K, 271L, 271M, 271N, 271Q, 271R, 271S, 271T, 271V, 271W, 271Y, 275W, 278E, 278K, 278M, 278N, 278R, 282K, 283G, 283P, 283R, 284N, 284T, 285W, 286E, 286Y, 291G, 291T, 299A, 299D, 299E, 299G, 299H, 299I, 299K, 299L, 299M, 299N, 299P, 299Q, 299R, 299V, 299W, 299Y, 300A, 300D, 300G, 300K, 300N, 300P, 300R, 302I, 304D, 304H, 304N, 305E, 305T, 305Y, 317E, 318H, 318L, 318Q, 318R, 318Y, 325D, 325E, 325F, 325G, 325I, 325L, 325M, 325S, 325T, 325V, 325W, 325Y, 328D, 328E, 328F, 328G, 328I, 328K, 328M, 328P, 328Q, 328R, 328T, 328V, 328Y, 332K, 332R, 336E, 336K, 336Y, and 337H.  
     
     
         4 . A polypeptide according to  claim 1 , wherein said Fc variant comprises multiple substitutions selected from the group consisting of: 230A/233D, 230A/233D/332E, 239N/332N, 239E/332Q, 239N/332Q, 239Q/332D, 239Q/332Q, 239Q/332N, 239Q/264I/332E, 239D/265T/297D/332E, 239D/272Y/330L/332E, 239E/264I/298A/330Y/332E, 241L/262I, 241W/243W, 241L/243L/262I/264I, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241W/243W/262A/264A, 241E/243Y/262T/264R, 241Y/243Y/262T/264T, 241Y/243Y/262T/264T/297D/332E, 243L/262I/264W, 244H/245A/247V, 264I/332E, 264E/297D/332E, 264I/330L/332E, 265Y/297D/332E, 265F/297E/332E, 297D/332E, 297E/332E, 297S/332E, 328E/332E, 328H/332E, 328M/332E, 328N/332E, and 328V/332E.  
     
     
         5 . A polypeptide according to  claim 1 , wherein said parent polypeptide is an antibody.  
     
     
         6 . A polypeptide according to  claim 1 , wherein said parent polypeptide is an Fc fusion protein.  
     
     
         7 . A polypeptide according to  claim 1 , wherein said polypeptide further comprises an engineered glycoform.  
     
     
         8 . A polypeptide according to  claim 7  wherein said engineered glycoform comprises an altered level of fucosylation or bisecting oligosaccharides as compared to the parent polypeptide.  
     
     
         9 . A pharmaceutical composition comprising a polypeptide according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         10 . A method of treating a mammal in need of said treatment, comprising administering a polypeptide of  claim 1 .  
     
     
         11 . A polypeptide according to  claim 1  wherein said polypeptide is a full length antibody.  
     
     
         12 . A polypeptide according to  claim 1  wherein said polypeptide is a human antibody.  
     
     
         13 . A polypeptide according to  claim 1  wherein said polypeptide is an antibody fragment.