Human igg1 fc region variants and uses thereof
AssigneeGenmab B.V.
InventorsPaul PARREN, Frank BEURSKENS, Rob N. DE JONG, Sandra VERPLOEGEN, Aran Frank LABRIJN, Janine SCHUURMAN
Life of this patent
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Abstract
Described herein are polypeptides and related antibodies comprising a variant Fc domain. The variant Fc domain provide for stabilized Fc: Fc interactions when the poly-peptide(s), antibody or antibodies are bound to its target, antigen or antigens on the surface of a cell, thus providing for improved complement-dependent cytotoxicity (CDC).
Claims27
A method of increasing complement-dependent cytotoxicity (CDC) and/or antibody dependent cell-mediated cytotoxicity (ADCC) of a parent polypeptide comprising an Fc domain of an immunoglobulin and a binding region, the method comprising introducing a mutation to the parent polypeptide in one or more amino acid residue(s) selected from the group corresponding to E430X, E345X, and S440W in the Fc region of a human IgG1 heavy chain, wherein X is any amino acid.
3-5. (canceled)
A method of increasing complement-dependent cytotoxicity (CDC) of a parent antibody, wherein the parent antibody is a bispecific antibody comprising a first polypeptide comprising a first CH2-CH3 region of an immunoglobulin and a first antigen-binding region, and a second polypeptide comprising a second CH2-CH3 region of an immunoglobulin and a second antigen-binding region, wherein the first and second antigen-binding regions bind different epitopes on the same antigen or on different antigens, and wherein the method comprises introducing a mutation to the first and/or second CH2-CH3 region in one or more amino acid residue(s) selected from the group corresponding to E430X, E345X, S440Y and S440W in the Fc region of a human IgG1 heavy chain, wherein X is any amino acid;
- and
- wherein the first CH2-CH3 region comprises a further amino acid mutation at a position selected from those corresponding to K409, T366, L368, K370, D399, F405, and Y407 in the Fc region of a human IgG1 heavy chain;
- and wherein the second CH2-CH3 region comprises a further amino acid mutation at a position selected from those corresponding to F405, T366, L368, K370, D399, Y407, and K409 in the Fc region of a human IgG1 heavy chain, and wherein the further amino acid mutation in the first CH2-CH3 region is different from the further amino acid mutation in the second CH2-CH3 region.
14-24. (canceled)
26-32. (canceled)
A variant of:
- (A) a parent polypeptide comprising an Fc domain of an immunoglobulin and a binding region, wherein the variant comprises one or more mutation(s) selected from the group corresponding to E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, and S440W in the Fc region of a human IgG1 heavy chain and provided that the variant does not contain any further mutations in the Fc domain which alter the binding of the variant to neonatal Fc receptor (FcRn),
- (B) a parent polypeptide comprising an Fc domain of an immunoglobulin and a binding region, wherein the variant comprises a first mutation selected from the group corresponding to E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, and S440W in the Fc region of a human IgG1 heavy chain;
- and a second mutation selected from the group corresponding to
- (i) an amino acid residue corresponding to K439 and S440 in the Fc region of a human IgG1 heavy chain, with the proviso that the mutation in S440 is not S440Y or S440W, and if the first mutation is S440Y or S440W the second mutation is in the amino acid residue corresponding to K439 in the Fc region of a human IgG1 heavy chain,
- (ii) an amino acid residue corresponding to K447D/E or corresponding to K447K/R/H and 448P in the Fc region of a human IgG1 heavy chain:
- or
- (iii) an amino acid residue corresponding to K447D/E or corresponding to K447K/R/H and 448K/R/H and 449P in the Fc region of a human IgG1 heavy chain;
- (C) a parent antibody which is a bispecific antibody comprising a first polypeptide comprising a first CH2-CH3 region of an immunoglobulin and a first antigen-binding region, and a second polypeptide comprising a second CH2-CH3 region of an immunoglobulin and a second antigen-binding region, wherein the first and second antigen-binding regions bind different epitopes on the same or on different antigens, and wherein the first and/or second CH2-CH3 regions comprise one or more mutation(s) selected from the group corresponding to E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, and S440W in the Fc region of a human IgG1 heavy chain, and wherein
- the first polypeptide comprises a further mutation in an amino acid residue selected from those corresponding to K409, T366, L368, K370, D399, F405, and Y407 in the Fc region of a human IgG1 heavy chain;
- and
- the second polypeptide comprises a further mutation in an amino acid residue selected from those corresponding to F405, T366, L368, K370, D399, Y407 and K409 in the Fc region of a human IgG1 heavy chain, and wherein the further mutation in the first polypeptide is different from the further mutation in the second polypeptide.
34-50. (canceled)
55-70. (canceled)
(canceled)
(canceled)
Dependencies are inferred from the claim text.