IP Library › Patent Application 11841843
Patent Application
App. No. 11/841,843

Fc Variants with Increased Affinity for FcyRIIc

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Patent No.
US None
App. No.
11/841,843
Abstract

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

Claims (118)

1 . A protein comprising an Fc variant of a human Fc polypeptide (SEQ ID NO:1), wherein said variant exhibits altered binding to an Fc ligand as compared to human Fc polypeptide, wherein said variant has the formula comprising:

Vb(221)-Vb(222)-Vb(223)-Vb(224)-Vb(225)-Fx(226)-Vb(227)-Vb(228)-Fx(229)-Vb(230)-Vb(231)-Vb(232)-Vb(233)-Vb(234)-Vb(235)-Vb(236)-Vb(237)-Vb(238)-Vb(239)-Vb(240)-Vb(241)-Fx(242)-Vb(243)-Vb(244)-Vb(245)-Vb(246)-Vb(247)-Fx(248)-Vb(249)-Fx(250-254)-Vb(255)-Fx(256-257)-Vb(258)-Fx(259)-Vb(260)-Fx(261)-Vb(262)-Vb(263)-Vb(264)-Vb(265)-Vb(266)-Vb(267)-Vb(268)-Vb(269)-Vb(270)-Vb(271)-Vb(272)-Vb(273)-Vb(274)-Vb(275)-Vb(276)-Fx(277)-Vb(278)-Fx(279)-Vb(280)-Vb(281)-Vb(282)-Vb(283)-Vb(284)-Vb(285)-Vb(286)-Fx(287)-Vb(288)-Fx(289)-Vb(290)-Vb(291)-Vb(292)-Vb(293)-Vb(294)-Vb(295)-Vb(296)-Vb(297)-Vb(298)-Vb(299)-Vb(300)-Vb(301)-Vb(302)-Vb(303)-Vb(304)-Vb(305)-Fx(306-312)-Vb(313)-Fx(314-316)-Vb(317)-Vb(318)-Fx(319)-Vb(320)-Fx(321)-Vb(322)-Vb(323)-Vb(324)-Vb(325)-Vb(326)-Vb(327)-Vb(328)-Vb(329)-Vb(330)-Vb(331)-Vb(332)-Vb(333)-Vb(334)-Vb(335)-Vb(336)-Vb(337);

wherein Vb(221) is selected from the group consisting of D, K and Y;

Vb(222) is selected from the group consisting of K, E and Y;

Vb(223) is selected from the group consisting of T, E and K;

Vb(224) is selected from the group consisting of H, E and Y;

Vb(225) is selected from the group consisting of T, E, K and W;

Fx(226) is C;

Vb(227) is selected from the group consisting of P, E, G, K, Y

Vb(228) is selected from the group consisting of P, E, G, K, Y

Fx(229) is C;

Vb(230) is selected from the group consisting of P, A, E, G AND Y;

Vb(231) is selected from the group consisting of A, E, G, K, P AND Y;

Vb(232) is selected from the group consisting of P, E, G, K AND Y;

Vb(233) is selected from the group consisting of A, D, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, Y;

Vb(234) is selected from the group consisting of L, A, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W, Y

Vb(235) is selected from the group consisting of L, A, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W, Y;

Vb(236) is selected from the group consisting of G, A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y;

Vb(237) is selected from the group consisting of G, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y;

Vb(238) is selected from the group consisting of P, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, Y;

Vb(239) is selected from the group consisting of S, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W, Y

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

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

Fx(242) is L;

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

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

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

Vb(246) is selected from the group consisting of K, D, E, H, Y;

Vb(247) is selected from the group consisting of P, G, V

Fx(248) is K;

Vb(249) is selected from the group consisting of D, H, Q, Y;

Fx(250-254) is the sequence -(T-L-M-I-S)-

Vb(255) is selected from the group consisting of R, E, Y;

Fx(256-257) is the sequence -(T-P)-;

Vb(258) is selected from the group consisting of E, H, S, Y;

Fx(259) is V;

Vb(260) is selected from the group consisting of T, D, E, H, Y;

Fx(261) is C;

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

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

Vb(264) is selected from the group consisting of V, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, W and Y;

Vb(265) is selected from the group consisting of D, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y;

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

Vb(267) is selected from the group consisting of S, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, Y;

Vb(268) is selected from the group consisting of H, D, E, F, G, I, K, L, M, N, P, Q, R, T, V, W, Y;

Vb(269) is selected from the group consisting of E, F, G, H, I, K, L, M, N, P, R, S, T, V, W, Y;

Vb(270) is selected from the group consisting of D, F, G, H, I, L, M, P, Q, R, S, T, W, Y;

Vb(271) is selected from the group consisting of A, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, Y;

Vb(272) is selected from the group consisting of E, D, F, G, H, I, K, L, M, P, R, S, T, V, W, Y;

Vb(273) is selected from the group consisting of V, I;

Vb(274) is selected from the group consisting of K, D, E, F, G, H, L, M, N, P, R, T, V, W, Y;

Vb(275) is selected from the group consisting of F, L, W;

Vb(276) is selected from the group consisting of N, D, E, F, G, H, I, L, M, P, R, S, T, V, W, Y;

Fx(277) is W;

Vb(278) is selected from the group consisting of Y, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V, W;

Fx(279) is V;

Vb(280) is selected from the group consisting of D, G, K, L, P, W;

Vb(281) is selected from the group consisting of G, D, E, K, N, P, Q, Y;

Vb(282) is selected from the group consisting of V, E, G, K, P, Y;

Vb(283) is selected from the group consisting of E, G, H, K, L, P, R, Y;

Vb(284) is selected from the group consisting of V, D, E, L, N, Q, T, Y;

Vb(285) is selected from the group consisting of H, D, E, K, Q, W, Y;

Vb(286) is selected from the group consisting of N, E, G, P, Y;

Fx(287) is selected from the group consisting of A;

Vb(288) is selected from the group consisting of K, D, E, Y;

Fx(289) is T;

Vb(290) is selected from the group consisting of K, D, H, L, N, W;

Vb(291) is selected from the group consisting of P, D, E, G, H, I, Q, T;

Vb(292) is selected from the group consisting of R, D, E, T, Y;

Vb(293) is selected from the group consisting of E, F, G, H, I, L, M, N, P, R, S, T, V, W, Y;

Vb(294) is selected from the group consisting of E, F, G, H, I, K, L, M, P, R, S, T, V, W, Y;

Vb(295) is selected from the group consisting of Q, D, E, F, G, H, I, M, N, P, R, S, T, V, W, Y;

Vb(296) is selected from the group consisting of Y, A, D, E, G, H, I, K, L, M, N, Q, R, S, T, V;

Vb(297) is selected from the group consisting of N, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, Y;

Vb(298) is selected from the group consisting of S, D, E, F, H, I, K, M, N, Q, R, T, W, Y;

Vb(299) is selected from the group consisting of T, A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, V, W, Y;

Vb(300) is selected from the group consisting of Y, A, D, E, G, H, K, M, N, P, Q, R, S, T, V, W;

Vb(301) is selected from the group consisting of R, D, E, H, Y;

Vb(302) is selected from the group consisting of V, I;

Vb(303) is selected from the group consisting of V, D, E, Y;

Vb(304) is selected from the group consisting of S, D, H, L, N, T;

Vb(305) is selected from the group consisting of V, E, T, Y;

Fx(306-312) is -(L-T-V-L-H-Q-D)-;

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

Fx(314-316) is -(L-N-G)-;

Vb(317) is selected from the group consisting of K, E, Q;

Vb(318) is selected from the group consisting of E, H, L, Q, R, Y;

Fx(319) is Y;

Vb(320) is selected from the group consisting of K, D, F, G, H, I, L, N, P, S, T, V, W, Y;

Fx(321) is C;

Vb(322) is selected from the group consisting of K, D, F, G, H, I, P, S, T, V, W, Y;

Vb(323) is selected from the group consisting of V, I;

Vb(324) is selected from the group consisting of S, D, F, G, H, I, L, M, P, R, T, V, W, Y;

Vb(325) is selected from the group consisting of N, A, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, Y;

Vb(326) is selected from the group consisting of K, I, L, P, T;

Vb(327) is selected from the group consisting of A, D, E, F, H, I, K, L, M, N, P, R, S, T, V, W, Y;

Vb(328) is selected from the group consisting of L, A, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W, Y;

Vb(329) is selected from the group consisting of P, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, Y;

Vb(330) is selected from the group consisting of A, E, F, G, H, I, L, M, N, P, R, S, T, V, W, Y;

Vb(331) is selected from the group consisting of P, D, F, H, I, L, M, Q, R, T, V, W, Y;

Vb(332) is selected from the group consisting of I, A, D, E, F, H, K, L, M, N, P, Q, R, S, T, V, W, Y;

Vb(333) is selected from the group consisting of E, F, H, I, L, M, N, P, T, Y;

Vb(334) is selected from the group consisting of K, F, I, L, P, T;

Vb(335) is selected from the group consisting of T, D, F, G, H, I, L, M, N, P, R, S, V, W, Y;

Vb(336) is selected from the group consisting of I, E, K, Y;

Vb(337) is selected from the group consisting of S, E, H, N; and

and wherein said variant comprises from one to four amino acid substitutions as compared to SEQ ID NO:1.

2 . The protein of claim 1 , wherein said substitution is selected from the group consisting of: G236S, G236A, S239D, S239E, S239N, S239Q, S239T, K246H, T260H, K246Y, D249Y, R255Y, E258Y, V264I, S267E, H268D, H268E, E272Y, E272I, E272H, K274E, G281D, E283L, E283H, S304T, S324G, S324I, K326T, A327D, A330Y, A330L, A330I, I332D, I332E, I332N, I332Q, E333Y, K334T, and K334F, wherein numbering is according to the EU index.

3 . The protein of claim 2 , wherein said Fc variant is selected from the group consisting of: S239D/I332E, S239D/G236A, S239D/G236S, S239D/V264I, S239D/H268D, S239D/H268E, S239D/S298A, S239D/K326E, S239D/A330L, S239D/A330Y, S239D/A330I, I332E/V264I, I332E/H268D, I332E/H268E, I332E/S298A, I332E/K326E, I332E/A330L, I332E/A330Y, I332E/A330I, I332E/G236A, I332E/G236S, I332D/V264I, I332D/H268D, I332D/H268E, I332D/S298A, I332D/K326E, I332D/A330L, I332D/A330Y, I332D/A330I, I332D/G236A, I332D/G236S, S239D/K246H/I332E, S239D/V264I/I332E, S239D/S267E/I332E, S239D/H268D/I332E, S239D/H268E/I332E, S239D/S298A/I332E, S239D/S324G/I332E, S239D/S324I/I332E, S239D/K326T/I332E, S239D/K326E/I332E, S239D/K326D/I332E, S239D/A327D/I332E, S239D/A330L/I332E, S239D/A330Y/I332E, S239D/A330I/I332E, S239D/K334T/I332E, S239D/K246H/T260H/I332E, S239D/K246H/H268D/I332E, S239D/K246H/H268E/I332E, S239D/H268D/S324G/I332E, S239D/H268E/S324G/I332E, S239D/H268D/K326T/I332E, S239D/H268E/K326T/I332E, S239D/H268D/A330L/1332 E, S239D/H268E/A330L/I332E, S239D/H268D/A330Y/I332 E, S239D/H268E/A330Y/I332E, S239D/S298A/S267E/I332E, S239D/S298A/H268D/I332E, S239D/S298A/H268E/I332E, S239D/S298A/S324G/I332E, S239D/S298A/S324I/I332E, S239D/S298A/K326T/I332E, S239D/S298A/K326E/I332E, S239D/S298A/A327D/I332E, S239D/S298A/A330L/I332E, S239D/S298A/A330Y/I332E, S239D/K326T/A330Y/I332E, S239D/K326E/A330Y/I332E, S239D/K326T/A330L/I332E, and S239D/K326E/A330L/I332E, wherein numbering is according to the EU index.

4 . The protein of claim 2 , additionally comprising a substitution selected from the group consisting of S298A, K326E, K326D, K326A, E333A, and K334A, wherein numbering is according to the EU index.

5 . A protein comprising an Fc variant of a human Fc polypeptide (SEQ ID NO:1), said Fc variant comprising at least one amino acid modification in the Fc region of said parent Fc polypeptide, wherein said variant protein selectively enhances binding to one or more Fc ligands relative to one or more other Fc ligands, and wherein said Fc variant comprises a substitution at a position selected from the group consisting of: 234, 235, 236, 267, 268, 292, 293, 295, 300, 324, 327, 328, 330, and 335, wherein numbering is according to the EU index.

6 . A protein according to claim 5 , wherein said Fc variant enhances binding to one or more FcγRII's relative to an FcγRIII.

7 . A protein according to claim 6 , wherein said Fc variant comprises the substitution G236S or G236A.

8 . A protein according to claim 5 , wherein said Fc variant enhances binding to FcγRIIa or FcγRIIc relative to FcγRIIb.

9 . A protein according to claim 8 , wherein said Fc variant comprises the substitution G236S or G236A.

10 . A protein comprising an Fc variant of a parent Fc polypeptide, said Fc variant comprising at least one amino acid modification in the Fc region of said parent Fc polypeptide, wherein said variant protein reduces binding to one or more Fc ligands, and wherein said Fc variant comprises a substitution at a position selected from the group consisting of: 232, 234, 235, 236, 237, 239, 264, 265, 267, 269, 270, 299, 325, 328, 329, and 330, wherein numbering is according to the EU index.

11 . A protein according to claim 10 , wherein said Fc variant comprises a substitution at position 299 or 328, wherein numbering is according to the EU index.

12 . A protein comprising SEQ ID NO:5, wherein said variant exhibits altered binding to an Fc ligand as compared to human Fc polypeptide.