Fc Variants Having Decreased Affinity for FcyRllla

Abstract

The present invention relates to Fc variants having decreased affinity for FcγRIIIa, 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 at least one position selected from the group consisting of: 227, 228, 230, 231, 232, 237, 241, 244, 247, 264, 266, 271, 281, 282, 291, 299, 300, 304, 317, 325, 328, 332, and 336, wherein numbering is according to the EU index and wherein said Fc variant has decreased binding affinity to FcγRIIIa relative to said parent polypeptide.  
     
     
         2 . The polypeptide of  claim 1  wherein the Fc variant comprises at least one substitution at at least one position selected from the group consisting of: 227, 228, 231, 232, 244, 247, 282, 291, and 336.  
     
     
         3 . The polypeptide of  claim 1  wherein said Fc variant comprises at least one substitution selected from the group consisting of: 227Y, 228Y, 228G, 230Y, 230G, 231K, 231P, 232K, 232Y, 232G, 237D, 237E, 237K, 237R, 237S, 237T, 237H, 237V, 237L, 237I, 237F, 237M, 237Y, 241W, 241D, 241E, 244H, 247V, 247G, 264D, 264E, 264N, 264Q, 264K, 264S, 264H, 264W, 264G, 266T, 271E, 271N, 271Q, 271K, 271R, 271S, 271T, 271H, 271V, 271L, 271F, 271M, 271Y, 271W, 281K, 281Y, 282E, 282K, 282G, 291D, 291E, 291Q, 291T, 291I, 291G, 299I, 299A, 299V, 299H, 299D, 299E, 299N, 299Q, 299K, 299L, 299F, 299M, 299Y, 299W, 299P, 299G, 300E, 300N, 300K, 300R, 300A, 300V, 300P, 300G, 304D, 304H, 317E, 325L, 325I, 325D, 325E, 325A, 325V, 325S, 325F, 325Y, 325W, 325P, 325G, 328E, 328F, 328N, 328H, 328D, 328Q, 328K, 328R, 328S, 328T, 328Y, 328W, 328G, 332Q, 332K, 332R, 336E, 336K, and 336Y.  
     
     
         4 . The polypeptide of  claim 1  wherein the Fc variant comprises at least one combination of substitutions selected from the group consisting of: 230A/233D, 235D/239D/297D/332E, 239N/332N, 239N/332Q, 239Q/332N, 239Q/332Q, 239D/297D/332E, 239E/297D/332E, 239D/278T/332E, 239D/265V/297D/332E, 239D/265I/297D/332E, 239D/265L/297D/332E, 239D/265F/297D/332E, 239D/265Y/297D/332E, 239D/265H/297D/332E, 239D/265T/297D/332E, 239D/297D/330Y/332E, 239D/297D/326E/332E, 239D/241S/243H/262T/264T/297D/330Y/332E, 241W/243W, 241L/262I, 241L/243L/262I/264I, 241W/243W/262A/264A, 241Y/243Y/262T/264T, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241E/243Y/262T/264R, 241E/243R/262E/264R/332E, 241E/243Y/262T/264R/332E, 241Y/243Y/262T/264T/297D/332E, 243L/262I/264W, 244H/245A/247V, 264E/297D/332E, 265Y/297D/332E, 296E/297D/332E, 296N/297D/332E, 296Q/297D/332E, 296H/297D/332E, 296T/297D/332E, 297S/332E, 297D/332E, 297E/332E, 297D/299V/332E, 297D/299I/332E, 297D/299L/332E, 297D/299F/332E, 297D/299H/332E, 297D/299E/332E, 297D/330Y/332E, 297D/298A/330Y/332E, 328E/332E, and 328Q/332E.  
     
     
         5 . The polypeptide of  claim 1  wherein said parent polypeptide is an antibody.  
     
     
         6 . The polypeptide of  claim 1  wherein said parent polypeptide is an Fc fusion protein.  
     
     
         7 . The polypeptide of  claim 1  wherein said polypeptide further comprises an engineered glycoform.  
     
     
         8 . The polypeptide of  claim 7  wherein said engineered glycoform comprises an altered level of fucosylation or bisecting oligosaccharides as compared to said parent polypeptide.  
     
     
         9 . A pharmaceutical composition comprising the polypeptide of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         10 . A method of treating a mammal in need of said treatment comprising administering the polypeptide of  claim 1 .  
     
     
         11 . The polypeptide of  claim 1  wherein said polypeptide is a full length antibody.  
     
     
         12 . The polypeptide of  claim 1  wherein said polypeptide is a human antibody.  
     
     
         13 . The polypeptide of  claim 1  wherein said polypeptide is an antibody fragment.