Optimized Fc Variants

1 . A method of enhancing macrophage activation comprising administering to a patient an anti-CD20 antibody comprising an Fc variant of the human Fc polypeptide comprising SEQ ID NO:1, wherein said Fc variant portion comprises at least one substitution at a position corresponding to the position of SEQ ID NO:1 selected from the group consisting of positions 234, 235, 239, 240, 241, 243, 244, 245, 247, 262, 263, 264, 265, 266, 267, 269, 296, 297, 298, 299, 313, 325, 326, 327, 328, 329, 330, 332, 333, and 334, wherein said Fc variant enhances macrophage activation as compared to the unsubstituted Fc variant.

2 . The method of enhancing macrophage activation according to claim 1 , wherein said Fc variant has the formula:

Vb(234)-Vb(235)-Fx(236-238)-Vb(239)-Vb(240)-Vb(241)-Fx(242)-Vb(243)-Vb(244)-Vb(245)-Fx(246)-Vb(247)-Fx(248-261)-Vb(262)-Vb(263)-Vb(264)-Vb(265)-Vb(266)-Vb(267)-Fx(268)-Fx(269-295)-Vb(296)-Vb(297)-Vb(298)-Vb(299)-Fx(300-312)-Vb(313)-Fx(314-324)-Vb(325)-Fx(326)-Vb(327)-Vb(328)-Vb(329)-Vb(330)-Fx(331)-Vb(332);

wherein:

Vb(234) is selected from the group consisting of L, D, E, N, Q, T, H, Y, I, V, F;

Vb(235) is selected from the group consisting of L, D, S, N, Q, T, H, Y, I, V, F;

Fx(236-238) is (G-G-P);

Vb(239) is selected from the group consisting of S, D, E, N, Q, F, T, H, Y;

Vb(240) is selected from the group consisting of V, I, A, T, M;

Vb(241) is selected from the group consisting of F, W, L, Y, E, R;

Fx(242) is L;

Vb(243) is selected from the group consisting of F, W, L Y, R, Q;

Vb(244) is selected from the group consisting of P, H;

Vb(245) is selected from the group consisting of P, A;

Fx(246) is K;

Vb(247) is selected from the group consisting of P, G, V; Fx(248-261) is the sequence -(K-D-T-L-M-I-S-R-T-P-E-V-T-C)-;

Vb(262) is selected from the group consisting of V, I, A, T, E;

Vb(263) is selected from the group consisting of V, A, I, M, T;

Vb(264) is selected from the group consisting of V, L, I, W, T, R, F, M, Y, E;

Vb(265) is selected from the group consisting of D, N, Q, Y, F, V, I, L, H, T;

Vb(266) is selected from the group consisting of V, A, I, M, T;

Vb(267) is selected from the group consisting of S, Q, L;

Fx (268) is H;

Vb(269) is selected from the group consisting of E, H, Y, F, R;

Fx (270-295) is the sequence (-D-P-E-V-K-F-N-W-Y-V-D-G-V-E-V-H-N-A-K-T-K-P-R-E-E-Q-);

Vb(296) is selected from the group consisting of Y, E, Q, D, N, S, T, L, I, H;

Vb(297) is selected from the group consisting of N, S, D, E;

Vb(298) is selected from the group consisting of S and H;

Vb(299) is selected from the group consisting of T, I, L, A, S, V, H, F, E;

Fx(300-312) is the sequence (-Y-R-V-V-S-V-L-T-V-L-H-Q-D-);

Vb(313) is selected from the group consisting of W, F;

Fx(314-324) is (L-N-G-K-E-Y-K-C-K-V-S-);

Vb(325) is selected from the group consisting of N, Q, L, I, D, E, A, T, V, H;

Fx(326) is K;

Vb(327) is selected from the group consisting of A, N, L;

Vb(328) is selected from the group consisting of L, M, D, E, N, Q, F, I, V, T, H, A;

Vb(329) is selected from the group consisting of P, F;

Vb(330) is selected from the group consisting of A, L, Y, V, I, F, R, H; and

Fx(331) is P; and

Vb(332) is selected from the group consisting of I, D, E, N, Q, T, H, Y, and A.

3 . The method according to claim 1 , wherein said Fc variant has enhanced FcgRIIIa and FcgRI binding.

4 . The method according to claim 1 , wherein administering said antibody causes increased macrophage phagocytosis.

5 . A method of treating a tumor comprising administering to a patient the anti-CD20 antibody of claim 1 .

6 . The method of claim 1 , wherein said Fc variant comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 240, 244, 245, 247, 262, 263, 266, 299, 313, 325, 328, and 332.

7 . The method of claim 6 , wherein said Fc variant comprises a substitution at position 332.

8 . The method according to claim 1 , wherein said Fc variant is selected from the group consisting of 264L, 264I, 241W, 241L, 243W, 243L, 241L/243L/262I/264I, 241W/243W, 241W/243W/262A/264A, 241 L/262I, 243L/264I, 243L/262I/264W, 241Y/243Y/262T/264T, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241E/243Y/262T/264R, 328M, 328E, 328F, 332E, 328M/332E, 244H, 245A, 247V, 313F, 244H/245A/247V, 247G, 264I/332E, 241E/243R/262E/264R/332E, 241E/243Q/262T/264E/332E, 241R/243Q/262T/264R/332E, 241E/243Y/262T/264R/332E, 298A/332E, 239E1332E, 239Q/332E, 239E, 265G, 265N, 239E/265G, 239E/265N, 239E/265Q, 296E, 296Q, 299I, 327N, 267Q/327S, 267L/3275, 327L, 329F, 330L, 330Y, 332D, 297S, 297D, 297S/332E, 297D/332E, 297E/332E, 265Y/297D/332E, 265Y/297D/299L/332E, 265F/297E/332E, 3281/332E, 328Q/332E, 332N, 332Q, 264T, 264F, 240I, 263I, 266I, 299A, 299S, 299V, 325Q, 325L, 325I, 239D, 239N, 239F, 239D/332D, 239D/332E, 239D/332N, 239D/332Q, 239E/332D, 239E/332N, 239E/332Q, 239N/332D, 239N/332E, 239N/332N, 239N1332Q, 239Q/332D, 239Q/332N, 239Q/332Q, 296D, 296N, 241Y/243Y/262T/264T/297D/332E, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235D, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 239T, 239H, 239Y, 240A, 240T, 240M, 263A, 263T, 263M, 264M, 264Y, 266A, 266T, 266M, 269H, 269Y, 269F, 269R, 296S, 296T, 296L, 296I, 298H, 299H, 330V, 330I, 330F, 330R, 330H, 325D, 325E, 325A, 325T, 325V, 325H, 328D/332E, 328E/332E, 328N/332E, 328Q/332E, 328V/332E, 328T/332E, 328H/332E, 3281/332E, 328A, 332T, 332H, 332Y, 332A, 239E/264I/332E, 239Q/264I/332E, 239E/264I/330Y/332E, 239E/264I/298A/330Y/332E, 239D/297D/332E, 239E/297D/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, 264E/297D/332E, 296D/297D/332E, 296E/297D/332E, 296N/297D/332E, 296Q/297D/332E, 296H/297D/332E, 296T/297D/332E, 297D/299V/332E, 297D/2991/332E, 297D/299L/332E, 297D/299F/332E, 297D/299H/332E, 297D/299E/332E, 297D/330Y/332E, 297D/298A/330Y1332E, 239D/330Y/332E, 239N/330Y/332E, 239D/330L/332E, 239N/330L/332E, 264I/298A/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.

9 . The method according to claim 3 , wherein said FcgRIIIa is a V158 or F158 allotype of FcgRIIIa.