RU2006142852A - OPTIMIZED FC OPTIONS - Google Patents

Claims (21)

1. An Fc variant of a parent Fc polypeptide, wherein said Fc variant exhibits altered binding to an Fc ligand compared to said parent Fc polypeptide, wherein said variant includes a substitution or series of substitutions from the group consisting of: S239D / E272Y / I332E , S239D / E272S / I332E, S239D / E272K / I332E, S239D / E272I / I332E, S239D / E272Y / A330L / I332E, S239D / E272S / A330L / I332E, S239D / E272K / A330L / 27303/33230 / A330L2273K / A330L230 / A330L230 S239D / K274E / I332E; S239D / Y278T / I332E; S239D / K326T / I332E; S239D / K326E / I332E; S239D / K274E / A330L / I332E; S239D / S267E / I332E; S239D / S267E / A330L / I332E; Y278W; E283R / V302I / Y278W / E283R; Y278W / V302I; Y278W / E283R / V302I; / K246H, S239D / I332E / R255Y, S239D / I332E / S267E, S239D / I332E / E272R, S239D / I332E / E272H, I332E / G281D, S239D / I332E / E283H, S239D / I332E / E283L, I332E / V284E, S239D / I332E / V284E7, S329E, S329E, S329E S267E / P331D; S267E / V282G; G281D / V282G; V282G / P331D; G281E; G281N; G281Q; V284D; S298A / K326T / I332E; I332E / H268E; I332E / H268D; S239D / H268E; S239D / H268D; S239D / I332E / H268E; V284E, S239D / G236A, S239D / G236S, S239D / V264I, S239D / S298A, S239D / K326E, S239D / A330L, S239D / A330Y, S239D / A330I, I332E / K326E, I3326 / A3323 / G3E I332D / V264I; I332D / H268D; I332D / H268E; I332D / S298A; I332D / K326E; I332D / A330L; I332D / A330Y; I332D / A330I; I332D / G236A I332E, S239D / K326D / I332E, S239D / K334T / I332E, S239D / K246Н / Т260Н / I332Е, S239D / K246H / H268D / I332E, S239D / K246Н / Н268Е / I332E26826D26926826 S324G / I332E, S239D / H26 8D / K326T / I332E, S239D / H268E / K326T / I332E, S239D / H268D / A330L / I332E, S239D / H268E / A330L / I332E, S239D / H268D / A330Y / I332E, S239D / S2993303 / 293E29829 S267E / I332E, S239D / S298A / H268D / I332E, S239D / S298A / H268E / I332E, S239D / S298A / S324G / I332E, S239D / S298A / S324I / I332E, S239D / S299A3 / 293A29 / 293A29 / 291A I332E, S239D / S298A / A330Y / I332E and S239D / K326T / A330L / I332E, where the numbering is carried out in accordance with the EU index. 2. The Fc variant according to claim 1, where the series of substitutions is selected from the group consisting of I332E / A330I, I332E / G236A, I332E / G236S, I332D / V264I, I332D / H268D, I332D / H268E, I332D / S298A, I332D / K326 , I332D / A330L, I332D / A330Y, I332D / A330I, I332D / G236A, I332D / G236S, S239D / S324G / I332E, S239D / S324I / I332E, S239D / K326D / I332E, S239D260 / 2332HD3243D3243D3233D3D / I332E, S239D / K246H / H268D / I332E, S239D / K246H / H268E / I332E, S239D / H268D / S324G / I332E, S239D / H268E / S324G / I332E, S239D / H268D8 K3 S239D / H268D / A330L / I332E; S239D / H268E / A330L / I332E; S239D / H268D / A330Y / I332E; / S298A / H268E / I332E, S239D / S298A / S324G / I332E, S239D / S298A / S324I / I332E, S239D / S298A / A327D / I332E, S239D / S298A / A330L / I332E and S238293A293A293A293A / A330L / I332E. 3. The Fc variant of claim 1, wherein said variant further includes a substitution selected from the group consisting of: 227E, 227G, 227K, 227Y, 228E, 228G, 228K, 228Y, 230A, 230E, 230G, 230Y, 231E, 231G, 231K, 231P, 231Y, 232E, 232G, 232K, 232Y, 233A, 233F, 233H, 233I, 233K, 233L, 233M, 233N, 233Q, 233R, 233S, 233T, 233V, 233W, 233Y, 234D, 234E, 234F, 234G, 234H, 234I, 234K, 234M, 234N, 234P, 234Q, 234R, 234S, 234T, 234W, 234Y, 235D, 235F, 235G, 235H, 235I, 235K, 235M, 235N, 235Q, 235R, 235R, 235T, 235V, 235W, 235Y, 236D, 236E, 236F, 236H, 236I, 236K, 236L, 236M, 236N, 236P, 236Q, 236R, 236S, 236T, 236V, 236W, 236Y, 237D, 237E, 237F, 237F, 237I, 237K, 237L, 237M, 237N, 237P, 237Q, 237R, 237S, 237T, 237V, 237W, 237Y, 238D, 238E, 238F, 238G, 238H, 238I, 238K, 238L, 238M, 238N, 238Q, 238Q, 238S, 238T, 238V, 238W, 238Y, 239D, 239E, 239F, 239G, 239H, 239I, 239K, 239L, 239M, 239N, 239P, 239Q, 239R, 2 39T, 239V, 239W, 239Y, 240M, 240T, 241D, 241E, 241R, 241S, 241W, 241Y, 243E, 243H, 243Q, 243R, 243W, 243Y, 245A, 246D, 246H, 246Y, 247G, 247V, 249H, 249Q, 249Y, 255E, 255Y, 258H, 258S, 258Y, 260D, 260E, 260H, 260Y, 262A, 262E, 262F, 262I, 262T, 263A, 263I, 263M, 263T, 264D, 264E, 264F, 264G, 264H, 264I, 264K, 264L, 264M, 264N, 264P, 264Q, 264R, 264S, 264T, 264W, 264Y, 265F, 265G, 265H, 265I, 265K, 265L, 265M, 265P, 265Q, 265R, 265S, 265T, 265T, 265W, 265Y, 266A, 266I, 266M, 266T, 267D, 267E, 267F, 267H, 267I, 267K, 267L, 267M, 267N, 267P, 267Q, 267R, 267V, 267W, 267Y, 268F, 268G, 268I, 268I, 268I, 268I 268P, 268T, 268V, 268W, 269F, 269G, 269H, 269I, 269L, 269M, 269N, 269P, 269R, 269S, 269T, 269V, 269W, 269Y, 270F, 270G, 270H, 270I, 270L, 270M, 270P, 270Q, 270R, 270S, 270T, 270W, 270Y, 271A, 271D, 271E, 271F, 271G, 271H, 271I, 271K, 271L, 271M, 271N, 271Q, 271R, 271S, 271T, 271V, 271W, 271Y, 272F, 272G, 272H, 272I, 272K, 272L, 272M, 272P, 272R, 272S, 272T, 272V, 272W, 272Y, 274D, 274E, 274F, 274G, 274H, 274I, 274L, 274M, 274P, 274R, 274T, 274V, 274W, 274Y, 275W, 276D, 276E, 276F, 276G, 276H, 276I, 276L, 276M, 276P, 276R, 276S, 276T, 276V, 276V, 278D, 278E, 278G, 278H, 278I, 278K, 278L, 278M, 278N, 278P, 278Q, 278R, 278S, 278T, 278V, 278W, 280G, 280P, 280W, 281E, 281K, 281N, 281P, 281Y, 282G, 282P, 282Y, 283G, 283H, 283K, 283L, 283P, 283R, 283Y, 284L, 284N, 284Q, 284T, 284Y, 285K, 285Q, 285W, 285Y, 286G, 286P, 286Y, 288Y, 290H, 290L, 290L, 290 291D, 291E, 291G, 291H, 291I, 291Q, 291T, 292D, 292E, 292T, 292Y, 293F, 293G, 293H, 293I, 293L, 293M, 293N, 293P, 293R, 293S, 293T, 293W, 293y, 293y, 294y 294G, 294H, 294I, 294K, 294L, 294M, 294P, 294R, 294S, 294T, 294V, 294W, 294Y, 295D, 295F, 295G, 295H, 295I, 295M, 295N, 295P, 295R, 295S, 295T, 295V, 295W, 295Y, 296A, 296D, 296E, 296G, 296I, 296K, 296L, 296M, 296N, 296Q, 296S, 296T, 296V, 297E, 297F, 297G, 297M, 297L, 297L 297P, 297R, 297S, 297T, 297V, 297W, 297Y, 298E, 298F, 298H, 298I, 298K, 298M, 298Q, 298R, 298W , 298Y, 299A, 299D, 299E, 299F, 299G, 299H, 299I, 299K, 299L, 299M, 299N, 299P, 299Q, 299R, 299S, 299V, 299W, 299Y, 300A, 300D, 300E, 300G, 300H, 300K , 300M, 300N, 300P, 300Q, 300R, 300S, 300T, 300V, 300W, 301D, 301E, 301Y, 302I, 303D, 303E, 303Y, 304H, 304L, 304N, 304T, 305E, 305T, 305Y, 313F, 317E , 317Q, 318H, 318L, 318Q, 318R, 318Y, 320D, 320F, 320G, 320H, 320I, 320L, 320N, 320P, 320S, 320T, 320V, 320W, 320Y, 322D, 322F, 322G, 322H, 322I, 322P , 322S, 322T, 322V, 322W, 322Y, 324D, 324F, 324G, 324H, 324I, 324L, 324M, 324P, 324R, 324T, 324V, 324W, 324Y, 325A, 325D, 325E, 325F, 325G, 325H, 325I , 325K, 325L, 325M, 325P, 325Q, 325R, 325S, 325T, 325V, 325W, 325Y, 326L, 326P, 326T, 327D, 327E, 327F, 327H, 327I, 327K, 327L, 327M, 327P, 327R, 327V , 327W, 327Y, 328A, 328D, 328E, 328F, 328G, 328H, 328K, 328M, 328N, 328P, 328Q, 328R, 328S, 328T, 328V, 328W, 328Y, 329D, 329E, 329F, 329G, 329H, 329I , 329K, 329L, 329M, 329N, 329Q, 329R, 329S, 329T, 329V, 329W, 329Y, 330E, 330F, 330H, 330I, 330L, 33 0M, 330N, 330P, 330W, 330Y, 331D, 331F, 331H, 331I, 331L, 331M, 331Q, 331R, 331T, 331V, 331W, 331Y, 332A, 332F, 332H, 332L, 332M, 332N, 332P, 332Q, 332S, 332T, 332V, 332W, 332Y, 333F, 333H, 333I, 333L, 333M, 333P, 333T, 333Y, 334F, 334P, 334T, 335D, 335F, 335G, 335H, 335I, 335L, 335M, 335P, 335R, 335S, 335V, 335W, 335Y, 336E, 336K, 336Y, 337H and 337N. 4. The Fc variant according to claim 1, where the specified Fc variant further includes at least one substitution selected from the group consisting of: 234A, 234V, 235A, 235E, 236A, 264A, 265N, 267T, 296H, 297Q, 298A, 298N, 298T, 326E, 327S, 330S, 333A, 334A and 334L. 5. The Fc variant according to claim 1, wherein said Fc variant further comprises at least one substitution selected from the group consisting of: 221Y, 222E, 225K, 233D, 233G, 235P, 240A, 240I, 241L, 243L, 244H, 246E, 268L, 269K, 272D, 273I, 274N, 275L, 276Y, 280L, 281D, 290N, 293V, 295E, 301H, 323I, 326I, 327NT, 328I, 330G, 330T, 330V, 334I, 335N and 337E. 6. The Fc variant according to claim 1, wherein said Fc variant further includes at least one substitution selected from the group consisting of 280K, 298D, 330R, 332D, 332E, 332K and 332R. 7. The Fc variant according to claim 1, wherein said Fc variant further comprises at least one substitution selected from the group consisting of 281Q, 282K, 284D, 284E, 285D, 286E, 288D, 290D and 304D. 8. The Fc variant of claim 1, wherein said Fc variant further comprises at least one substitution selected from the group consisting of 268D, 268E, 268K, 268Q, 268R, 282E, 285E, and 288E. 9. The Fc variant of claim 1, wherein said series of substitutions is selected from the group consisting of 298A / 326E, 298A / 334L and 298A / 326E / 334L. 10. The Fc variant according to claim 1, where the specified Fc variant further includes at least one substitution selected from the group consisting of 234A, 235E, 236A, 264A and 297Q. 11. The Fc variant of claim 2, wherein said variant further includes a substitution selected from the group consisting of 227E, 227G, 227K, 227Y, 228E, 228G, 228K, 228Y, 230A, 230E, 230G, 230Y, 231E, 231G, 231K, 231P, 231Y, 232E, 232G, 232K, 232Y, 233A, 233F, 233H, 233I, 233K, 233L, 233M, 233N, 233Q, 233R, 233S, 233T, 233V, 233W, 233Y, 234D, 234E, 234F, 234G, 234H, 234I, 234K, 234M, 234N, 234P, 234Q, 234R, 234S, 234T, 234W, 234Y, 235D, 235F, 235G, 235H, 235I, 235K, 235M, 235N, 235Q, 235R, 235R, 235T, 235V, 235W, 235Y, 236D, 236E, 236F, 236H, 236I, 236K, 236L, 236M, 236N, 236P, 236Q, 236R, 236S, 236T, 236V, 236W, 236Y, 237D, 237E, 237F, 237I, 237K, 237L, 237M, 237N, 237P, 237Q, 237R, 237S, 237T, 237V, 237W, 237Y, 238D, 238E, 238F, 238G, 238H, 238I, 238K, 238L, 238M, 238N, 238Q, 238Q, 238S, 238T, 238V, 238W, 238Y, 239D, 239E, 239F, 239G, 239H, 239I, 239K, 239L, 239M, 239N, 239P, 239Q, 239R, 239T , 239V, 239W, 239Y, 240M, 240T, 241D, 241E, 241R, 241S, 241W, 241Y, 243E, 243H, 243Q, 243R, 243W, 243Y, 245A, 246D, 246H, 246Y, 247G, 247V, 249H, 249 , 249Y, 255E, 255Y, 258H, 258S, 258Y, 260D, 260E, 260H, 260Y, 262A, 262E, 262F, 262I, 262T, 263A, 263I, 263M, 263T, 264D, 264E, 264F, 264G, 264H, 264I , 264K, 264L, 264M, 264N, 264P, 264Q, 264R, 264S, 264T, 264W, 264Y, 265F, 265G, 265H, 265I, 265K, 265L, 265M, 265P, 265Q, 265R, 265S, 265T, 265V, 265V, , 265Y, 266A, 266I, 266M, 266T, 267D, 267E, 267F, 267H, 267I, 267K, 267L, 267M, 267N, 267P, 267Q, 267R, 267V, 267W, 267Y, 268F, 268G, 268I, 268M, 268M. , 268T, 268V, 268W, 269F, 269G, 269H, 269I, 269L, 269M, 269N, 269P, 269R, 269S, 269T, 269V, 269W, 269Y, 270F, 270G, 270H, 270I, 270L, 270M, 270P, 270Q , 270R, 270S, 270T, 270W, 270Y, 271A, 271D, 271E, 271F, 271G, 271H, 271I, 271K, 271L, 271M, 271N, 271Q, 271R, 271S, 271T, 271V, 271W, 271Y, 272F, 272G , 272H, 272I, 272K, 272L, 272M, 272P, 272R, 272S, 272T, 272V, 272W, 272Y, 274D, 274E, 274F, 274 G, 274H, 274I, 274L, 274M, 274P, 274R, 274T, 274V, 274W, 274Y, 275W, 276D, 276E, 276F, 276G, 276H, 276I, 276L, 276M, 276P, 276R, 276S, 276T, 276V 276W, 278D, 278E, 278G, 278H, 278I, 278K, 278L, 278M, 278N, 278P, 278Q, 278R, 278S, 278T, 278V, 278W, 280G, 280P, 280W, 281E, 281K, 281N, 281P, 281Y, 282G, 282P, 282Y, 283G, 283H, 283K, 283L, 283P, 283R, 283Y, 284L, 284N, 284Q, 284T, 284Y, 285K, 285Q, 285W, 285Y, 286G, 286P, 286Y, 288Y, 290H, 290, 290 290W, 291D, 291E, 291G, 291H, 291I, 291Q, 291T, 292D, 292E, 292T, 292Y, 293F, 293G, 293H, 293I, 293L, 293M, 293N, 293P, 293R, 293S, 293T, 293W, 293W 294F, 294G, 294H, 294I, 294K, 294L, 294M, 294P, 294R, 294S, 294T, 294V, 294W, 294Y, 295D, 295F, 295G, 295H, 295I, 295M, 295N, 295P, 295R, 295S, 295 295V, 295W, 295Y, 296A, 296D, 296E, 296G, 296I, 296K, 296L, 296M, 296N, 296Q, 296R, 296S, 296T, 296V, 297D, 297E, 297F, 297G, 297L, 297K 297M, 297P, 297R, 297S, 297T, 297V, 297W, 297Y, 298E, 298F, 298H, 298I, 298K, 298M, 298Q, 298R, 298W, 2 98Y, 299A, 299D, 299E, 299F, 299G, 299H, 299I, 299K, 299L, 299M, 299N, 299P, 299Q, 299R, 299S, 299V, 299W, 299Y, 300A, 300D, 300E, 300G, 300H, 300K, 300M, 300N, 300P, 300Q, 300R, 300S, 300T, 300V, 300W, 301D, 301E, 301Y, 302I, 303D, 303E, 303Y, 304H, 304L, 304N, 304T, 305E, 305T, 305Y, 313F, 317E, 317Q, 318H, 318L, 318Q, 318R, 318Y, 320D, 320F, 320G, 320H, 320I, 320L, 320N, 320P, 320S, 320T, 320V, 320W, 320Y, 322D, 322F, 322G, 322H, 322I, 322P, 322S, 322T, 322V, 322W, 322Y, 324D, 324F, 324G, 324H, 324I, 324L, 324M, 324P, 324R, 324T, 324V, 324W, 324Y, 325A, 325D, 325E, 325F, 325G, 325H, 325I, 325K, 325L, 325M, 325P, 325Q, 325R, 325S, 325T, 325V, 325W, 325Y, 326L, 326P, 326T, 327D, 327E, 327F, 327H, 327I, 327K, 327L, 327M, 327P, 327R, 327V, 327W, 327Y, 328A, 328D, 328E, 328F, 328G, 328H, 328K, 328M, 328N, 328P, 328Q, 328R, 328S, 328T, 328V, 328W, 328Y, 329D, 329E, 329F, 329G, 329H, 329I, 329K, 329L, 329M, 329N, 329Q, 329R, 329S, 329T, 329V, 329W, 329Y, 330E, 330F, 330H, 330I, 330L, 330M, 330N, 330P, 330W, 330Y, 331D, 331F, 331H, 331I, 331L, 331M, 331Q, 331R, 331T, 331V, 331W, 331Y, 332A, 332F, 332H, 332L, 332M, 332N, 332P, 332Q, 332S, 332T, 332V, 332W, 332Y, 333F, 333H, 333I, 333L, 333M, 333P, 333T, 333Y, 334F, 334P, 334T, 335D, 335F, 335G, 335H, 335I, 335L, 335M, 335P, 335R, 335S, 335V, 335W, 335Y, 336E, 336K, 336Y, 337H and 337N. 12. The Fc variant according to claim 2, where the specified Fc variant further includes at least one substitution selected from the group consisting of: 234A, 234V, 235A, 235E, 236A, 264A, 265N, 267T, 296H, 297Q, 298A, 298N, 298T, 326E, 327S, 330S, 333A, 334A and 334L. 13. The Fc variant according to claim 2, wherein said Fc variant further includes at least one substitution selected from the group consisting of: 221Y, 222E, 225K, 233D, 233G, 235P, 240A, 240I, 241L, 243L, 244H, 246E, 268L, 269K, 272D, 2731, 274N, 275L, 276Y, 280L, 281D, 290N, 293V, 295E, 301H, 323I, 326I, 327NT, 328I, 330G, 330T, 330V, 334I, 335N and 337E. 14. The Fc variant according to claim 2, wherein said Fc variant further includes at least one substitution selected from the group consisting of 280K, 298D, 330R, 332D, 332E, 332K and 332R. 15. The Fc variant according to claim 2, wherein said Fc variant further comprises at least one substitution selected from the group consisting of 281Q, 282K, 284D, 284E, 285D, 286E, 288D, 290D and 304D. 16. The Fc variant according to claim 2, wherein said Fc variant further comprises at least one substitution selected from the group consisting of 268D, 268E, 268K, 268Q, 268R, 282E, 285E and 288E. 17. The Fc variant of claim 2, wherein said series of substitutions is selected from the group consisting of 298A / 326E, 298A / 334L and 298A / 326E / 334L. 18. The Fc variant according to claim 2, wherein said Fc variant further comprises at least one substitution selected from the group consisting of 234A, 235E, 236A, 264A and 297Q. 19. The Fc variant according to any one of claims 1 to 18, wherein said Fc variant selectively enhances binding to human FcγRIIa compared to one or more other human FcγR. 20. The Fc variant according to any one of claims 1 to 18, wherein said Fc variant selectively enhances binding to human FcγRII compared to human FcγRI or human FcγRIIIa. 21. Variant antibody of the parent antibody, wherein said variant antibody comprises an Fc variant according to any one of claims 1 to 18, wherein said variant antibody targets CD20 and mediates more significant in vivo depletion of B cells compared to said parent antibody.