Heteromultimers with reduced or silenced effector function

A heteromultimer comprising an IgG Fc construct having a first and a second Fc polypeptide, wherein:

• a. said first Fc polypeptide comprises the amino acid modifications E269Q/D270N and the second Fc polypeptide comprises the amino acid modifications E269K/D270R;
• or
• b. said first Fc polypeptide comprises the amino acid modifications L235K/A327K and the second Fc polypeptide does not comprise an amino acid modification at the hinge region;
• wherein the numbering of amino acids is according to the EU index as in Kabat, and wherein the IgG Fc construct displays reduced binding to the FcγRIa, FcγRIIa, FcγRIIb and FcγRIIIa receptors as compared to a corresponding parent IgG Fc construct.

A method of reducing the effector function of an IgG Fc construct comprising a first and a second Fc polypeptide, the method comprising:

• modifying the lower hinge region of the first and the second Fc polypeptide, wherein;
• the modified lower hinge region of said first Fc polypeptide comprises at least one amino acid modification,
• the modified lower hinge region of said second Fc polypeptide comprises at least one amino acid modification which is different from at least one amino acid modification of said first Fc polypeptide, and
• the IgG Fc construct displays reduced binding to the FcγRIa, FcγRIIa, FcγRIIb and FcγRIIIa receptors or to C1q protein as compared to a corresponding parent IgG Fc construct.