HETEROMULTIMERS WITH REDUCED OR SILENCED EFFECTOR FUNCTION Russian patent published in 2018 - IPC C07K16/46 C07K16/32 

FIELD: biotechnology.

SUBSTANCE: according to an embodiment, present invention provides a heteromultimer construct comprising an IgG Fc construct having a first and a second Fc polypeptide, each Fc polypeptide comprising a modified lower hinge region, wherein the modified lower hinge region of said first Fc polypeptide comprises an amino acid modification in position L234 and/or position L235, wherein the amino acid modification increases the total charge of the modified lower hinge region of the first Fc polypeptide under pH conditions close to physiological, the modified hinge region of the second Fc polypeptide contains an amino acid modification that is different from the amino acid modification of the first Fc polypeptide, and the IgG Fc construct demonstrates reduced binding to receptors FcγRIa, FcγRIIa, FcγRIIb and FcγRIIIa compared with the corresponding parent IgG Fc construct, and wherein the amino acid numbering corresponds to the EU index according to Kabat. Also described is a heteromultimer with a reduced or silenced effector function comprising an IgG Fc construct, which contains a first and a second Fc polypeptide, characterised in that the first Fc polypeptide comprises E269Q/D270N amino acid modifications, and the second Fc polypeptide comprises E269K/D270R amino acid modifications; or the first Fc polypeptide comprises L235K/A327K amino acid modifications, and the second Fc polypeptide does not contain an amino acid modification in the hinge region; wherein the numbering of the amino acid residues corresponds to the EU index according to Kabat, and wherein the IgG Fc construct exhibits reduced binding to receptors FcγRIa, FcγRIIa, FcγRIIb and FcγRIHa compared to the corresponding parent IgG Fc construct. Disclosed is a polynucleotide encoding the first and second Fc polypeptides of said heteromultimers. Also disclosed is a host cell for producing a heteromultimer with a reduced or silenced effector function, comprising said polynucleotide and a corresponding method for producing a heteromultimer. Disclosed is use of said heteromultimers in the manufacture of a pharmaceutical composition for the treatment of a disease or disorder in a patient. Disclosed is a method for reducing the effector function of an IgG Fc construct comprising a first and a second Fc polypeptide, comprising a modification of the lower hinge region of the first and second Fc polypeptide, wherein the modified lower hinge region of said first Fc polypeptide comprises an amino acid modification in position L234 and/or position L235, wherein the amino acid modification increases the total charge of the modified lower hinge region of the first Fc polypeptide under pH conditions close to physiological, the modified lower hinge region of the second Fc polypeptide comprises an amino acid modification that is different from the amino acid modification of the first Fc polypeptide, and the IgG Fc construct demonstrates reduced binding to receptors FcγRIa, FcγRIIa, FcγRIIb and FcγRIIIa compared with the corresponding parent IgG Fc construct, and wherein the amino acid numbering corresponds to the EU index according to Kabat.

EFFECT: heteromultimer constructs with reduced or silenced effector function are described.

37 cl, 8 dwg, 14 tbl, 12 ex