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Optimized proteins that target the epidermal growth factor receptor

  • US 20050142133A1
  • Filed: 12/03/2004
  • Published: 06/30/2005
  • Est. Priority Date: 12/03/2003
  • Status: Abandoned Application
First Claim
Patent Images

1. An anti-human EGFR antibody that comprises a variant human immunoglobulin G constant region comprising a sequence having the formula:


  • Vx(222)-Vx(223)-Vx(224)-Vx(225)-Fx(226)-Vx(227)-Vx(228)-Fx(229)-Vx(230)-Fx(231)-Vx(232)-Vx(233)-Vx(234)-Vx(235)-Vx(236)-Vx(237)-Vx(238)-Vx(239)-Vx(240)-Vx(241)-Fx(242)-Vx(243)-Vx(244)-Vx(245)-Vx(246)-Vx(247)-Fx(248-254)-Vx(255)-Fx(256-257)-Vx(258)-Fx(259)-Vx(260)-Fx(261)-Vx(262)-Vx(263)-Vx(264)-Vx(265)-Vx(266)-Vx(267)-Vx(268)-Vx(269)-Vx(270)-Vx(271)-Vx(272)-Vx(273)-Vx(274)-Vx(274)-Vx(275)-Vx(276)-Fx(277)-Vx(278)-Fx(279)-Vx(280)-Vx(281)-Vx(282)-Vx(283)-Vx(284)-Vx(285)-Vx(286)-Fx(287)-Vx(288)-Fx(289)-Vx(290)-Vx(291)-Vx(292)-Vx293)-Vx(294)-Vx(295)-Vx(296)-Vx(297)-Vx(298)-Vx(299)-Vx(300)-Vx(301)-Vx(302)-Vx(303)-Vx(304)-Vx(305)-Fx(306-312)-Vx(313)-Fx(314-316)-Vx(317)-Vx(318)-Fx(319)-Vx(320)-Fx(321)-Vx(322)-Vx(323)-Vx(324)-Vx(325)-Vx(326)-Fx(327)-Vx(328)-Vx(329)-Fx(330)-Vx(331)-Vx(332)-Vx(333)-Vx(334)-Vx(335)-Vx(336)-Vx(337)-Fx(338-447) wherein Vx(222) is an amino acid selected from the group consisting of K, E and Y;

    Vx(223) is an amino acid selected from the group consisting of T, E and K;

    Vx(224) is an amino acid selected from the group consisting of H, E and Y;

    Vx(225) is an amino acid selected from the group consisting of T, E, K and W;

    Fx(226) is the human wild-type IgG1 sequence at position 226;

    Vx(227) is an amino acid selected from the group consisting of P, E, G, K and Y;

    Vx(228) is an amino acid selected from the group consisting of P, E, G, K and Y;

    Fx(229) is the human wild-type IgG1 sequence at position 229;

    Vx(230) is an amino acid selected from the group consisting of P, A, E, G and Y;

    Fx(231) is the human wild-type IgG1 sequence at position 231;

    Vx(232) is an amino acid selected from the group consisting of P, E, G, K and Y;

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

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

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

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

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

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

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

    Vx(240) is an amino acid selected from the group consisting of V, A, I, M and T;

    Vx(241) is an amino acid selected from the group consisting of F, D, E, L, R, W and Y;

    Fx(242) is the human wild-type IgG1 sequence at position 242;

    Vx(243) is an amino acid selected from the group consisting of F, E, L, Q, R, W and Y;

    Vx(244) is an amino acid selected from the group consisting of P and H;

    Vx(245) is an amino acid selected from the group consisting of P and A;

    Vx(246) is an amino acid selected from the group consisting of K, D, E, H and Y;

    Vx(247) is an amino acid selected from the group consisting of P, G and V;

    Fx(248-254) is the human wild-type IgG1 sequence at positions 248-254;

    Vx(255) is an amino acid selected from the group consisting of R, E and Y;

    Fx(256-257) is the human wild-type IgG1 sequence at positions 256-257;

    Vx(258) is an amino acid selected from the group consisting of E, H, S and Y;

    Fx(259) is the human wild-type IgG1 sequence at position 259;

    Vx(260) is an amino acid selected from the group consisting of T, D, E, H and Y;

    Fx(261) is the human wild-type IgG1 sequence at position 261;

    Vx(262) is an amino acid selected from the group consisting of V, A, E, F, I and T;

    Vx(263) is an amino acid selected from the group consisting of V, A, I, M and T;

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

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

    Vx(266) is an amino acid selected from the group consisting of V, A, I, M and T;

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

    Vx(268) is an amino acid selected from the group consisting of H, D, E, F, G, I, K, L, M, P, Q, R, T, V and W;

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

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

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

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

    Vx(273) is an amino acid selected from the group consisting of V and I;

    Vx(274) is an amino acid selected from the group consisting of K, D, E, F, G, H, I, L, M, N, P, R, S, T, V, W and Y;

    Vx(275) is an amino acid selected from the group consisting of F, L and W;

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

    Fx(277) is the human wild-type IgG1 sequence at position 277;

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

    Fx(279) is the human wild-type IgG1 sequence at position 279;

    Vx(280) is an amino acid selected from the group consisting of D, G, K, L, P and W;

    Vx(281) is an amino acid selected from the group consisting of G, D, K, P and Y;

    Vx(282) is an amino acid selected from the group consisting of V, E, G, K, P and Y;

    Vx(283) is an amino acid selected from the group consisting of E, G, H, K, L, P, R and Y;

    Vx(284) is an amino acid selected from the group consisting of V, E, L, N, T and Y;

    Vx(285) is an amino acid selected from the group consisting of H, D, E, K, Q, W and Y;

    Vx(286) is an amino acid selected from the group consisting of N, E, G, P and Y;

    Fx(287) is the human wild-type IgG1 sequence at position 287;

    Vx(288) is an amino acid selected from the group consisting of K, D, E and Y;

    Fx(289) is the human wild-type IgG1 sequence at position289;

    Vx(290) is an amino acid selected from the group consisting of K, D, H, L, N and W;

    Vx(291) is an amino acid selected from the group consisting of P, D, E, G, H, I, Q and T;

    Vx(292) is an amino acid selected from the group consisting of R, D, E, T and Y;

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

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

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

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

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

    Vx(298) is an amino acid selected from the group consisting of S, D, E, F, I, K, M, Q, R, W and Y;

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

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

    Vx(301) is an amino acid selected from the group consisting of R, D, E, H and Y;

    Vx(302) is an amino acid selected from the group consisting of V and I;

    Vx(303) is an amino acid selected from the group consisting of V, D, E and Y;

    Vx(304) is an amino acid selected from the group consisting of S, D, H, L, N and T;

    Vx(305) is an amino acid selected from the group consisting of V, E, T and Y;

    Fx(306-312) is the human wild-type IgG1 sequence at positions 306-312;

    Vx(313) is an amino acid selected from the group consisting of W and F;

    Fx(314-316) is the human wild-type IgG1 sequence at positions 314-316;

    Vx(317) is an amino acid selected from the group consisting of K E and Q;

    Vx(318) is an amino acid selected from the group consisting of E, H, L, Q, R and Y;

    Fx(319) is the human wild-type IgG1 sequence at position 319;

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

    Fx(321) is the human wild-type IgG1 sequence at position 321;

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

    Vx(323) is an amino acid selected from the group consisting of V and I;

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

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

    Vx(326) is an amino acid selected from the group consisting of K, I, L, P and T;

    Fx(327) is the human wild-type IgG1 sequence at position 327 Vx(328) is an amino acid selected from the group consisting of L, A, D, E, F, G, H. I, K, M, N, P, Q, R, S, T, V, W and Y;

    Vx(329) is an amino acid selected from the group consisting of P, D, E, F, G, H. 1, K, L, M, N, Q, R, S, T, V, W and Y;

    Fx(330) is the human wild-type IgG1 sequence at position330;

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

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

    Vx(333) is an amino acid selected from the group consisting of E, F, H, I, L, M, P, T and Y;

    Vx(334) is an amino acid selected from the group consisting of K, F, I, P and T;

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

    Vx(336) is an amino acid selected from the group consisting of I, E, K and Y;

    Vx(337) is an amino acid selected from the group consisting of S, E, H and N;

    Fx(338-447) is the human wild-type IgG1 sequence at positions 338-447;

    wherein at least one amino acid is substituted as compared to the wild-type sequence (SEQ ID NO;

    X), and wherein said antibody has an altered property, said property selected from the group consisting of altered Fcγ

    R binding and altered effector function.

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