STABLE HETERODIMERIC ANTIBODY DESIGN WITH MUTATIONS IN THE Fc DOMAIN

An isolated heteromultimer comprising a heterodimer Fc region, wherein the heterodimer Fc region comprises a first Fc polypeptide and a second Fc polypeptide and a variant CH3 domain comprising amino acid modifications to promote heterodimer formation, wherein:

• (i) the first Fc polypeptide comprises amino acid modifications at positions F405 and Y407, wherein the amino acid modification at position F405 is F405A, F405S, F405T or F405V, and the amino acid modification at position Y407 is Y407A, Y407I, Y407L or Y407V, and
• (ii) the second Fc polypeptide comprises amino acid modifications at positions T366 and T394, wherein the amino acid modification at position T366 is T366I, T366L, T366M or T366V, and the amino acid modification at position T394 is T394W,
• wherein the heterodimer Fc region further comprises a variant CH2 domain comprising asymmetric amino acid modifications to promote selective binding of a Fcgamma receptor,
• wherein the heterodimer Fc region is based on an IgG Fc region,
• and wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat.