Fc mutants with improved functional activity
The present invention relates to a variant of a parent polypeptide comprising an Fc fragment, wherein the variant exhibits an increased affinity for at least one of the Fc (FcR) fragment receptors selected from among FcγRIIIa (CD16a), FcγRIIa (CD32a), and FcγRIIb (CD32b) receptors, relative to that of the parent polypeptide, characterized in that it comprises at least one mutation chosen from among K290G, Y296W, V240H, V240I, V240M, V240N, V240S, F241H, F241Y, L242A, L242F, L242G, L242H, L242I, L242K, L242P, L242S, L242T, L242V, F243L, F243S, E258G, E258I, E258R, E258M, E258Q, E258Y, V259C, V259I, V259L, T260A, T260H, T260I, T260M, T260N, T260R, T260S, T260W, V262A, V262S, V263T, V264L, V264S, V264T, V266L, V266M, S267A, S267Q, S267V, K290D, K290E, K290H, K290L, K290N, K290Q, K290R, K290S, K290Y, P291G, P291Q, P291R, R292I, R292L, E293A, E293D, E293G, E293M, E293Q, E293S, E293T, E294A, E294G, E294P, E294Q, E294R, E294T, E294V, Q295I, Q295M, Y296H, S298A, S298R, Y300I, Y300V, Y300W, R301A, R301M, R301P, R301S, V302A, V302F, V302L, V302M, V302R, V302S, V303S, V303Y, S304T, V305A, V305F, V305I, V305L, V305R and V305S of the Fc fragment, wherein the numbering is that of the EU index or equivalent in Kabat.
1. A variant of a parent polypeptide comprising a human IgG1 Fc fragment, wherein the variant has an increased affinity for at least one of the Fc (FcR) fragment receptors selected from among FcγRIIIa (CD16a), FcγRIIa (CD32a) and FcγRIIb (CD32b) receptors, relative to that of the parent polypeptide, wherein the variant comprises at least the mutation Y296W, of the Fc fragment; and
(i) a mutation chosen from 334N, 378V and 397M; and
ii) at least three mutations chosen from 334N, 352S, 378V and 397M, with the condition that mutations (i) and (ii) do not occur on the same amino acids,
wherein the numbering is that of the EU index or equivalent in Kabat.
2. Variant according to claim 1 , having an increased affinity for the FcγRIIIa (CD16a) receptor.
3. Variant according to claim 1 , characterized in that it is selected from an isolated Fc fragment, a sequence derived from an isolated Fc fragment, an antibody and a fusion protein comprising an Fc fragment.
4. Variant of a parent polypeptide according to claim 1 , characterized in that it is an antibody.
5. Variant according to claim 1 , directed against an antigen selected from a tumor antigen, a viral antigen, a bacterial antigen, a fungal antigen, a toxin, a membrane or circulating cytokine and a membrane receptor.
6. Pharmaceutical composition comprising (1) a variant according to claim 1 , and (2) at least one pharmaceutically acceptable excipient.