CYTOTOXICITY-INDUCING THERAPEUTIC AGENT Russian patent published in 2024 - IPC C07K16/46 C07K16/30 C07K16/28 C12N15/09 A61K39/395 A61P35/00 

FIELD: biotechnology.

SUBSTANCE: described is a bispecific antibody having cellular cytotoxicity, which includes: a first light chain comprising a first VL domain and a first CL domain; a second light chain comprising a second VL domain and a second CL domain. First heavy chain contains the first variable region of the heavy chain and the first constant region of the heavy chain. First constant region of the heavy chain is a non-wild type constant region containing one of the sequences SEQ ID NO: 23, 24, 25 and 26 with one or more amino acid substitutions. Second heavy chain comprises a second variable region of the heavy chain and a second constant region of the heavy chain. Second constant region of the heavy chain is a non-wild type constant region of the heavy chain containing one of the sequences SEQ ID NO: 23, 24, 25 and 26 with one or more amino acid substitutions. Amino acid sequence of the second constant region of the heavy chain has the same isotype as the first constant region of the heavy chain. First light chain and the first heavy chain are bound to form a first antigen-binding domain which binds to CD3. Second light chain and the second heavy chain are bound to form a second antigen-binding domain which does not bind to CD3 and which binds to a cancer antigen which is not CD3. First constant region of the heavy chain binds to a second constant region of the heavy chain, where, when measured by surface plasmon resonance, the ability of the associated first and second constant regions of the heavy chain to bind to this human receptor Fcγ reduced compared to the ability of a human wild-type IgG antibody of the same isotype as the bispecific antibody, to bind to the human Fcγ receptor as a result of at least one of one or more amino acid substitutions within the first and second constant regions of the heavy chain. At least one substitution in the first and second constant regions of the heavy chain is a change in the amino acid sequence compared with the amino acid sequence of the heavy chain constant regions of the wild-type human IgG antibody and wherein at least one of the amino acids which leads to a reduced ability to bind to the human receptor Fcγ, is in a position selected from the following positions according to EU numbering in each of the first and second constant regions of the heavy chain: 220, 226, 229, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 264, 265, 266, 267, 269, 270, 295, 296, 297, 298, 299, 300, 325, 327, 328, 329, 330, 331 and 332. Also disclosed is a pharmaceutical composition containing said antibody and having anti-cancer activity.

EFFECT: antibody according to the invention retains strong anti-cancer activity and has improved safety characteristics inherent in BiTE, has a long half-life in blood and induces cytotoxicity in relation to various cells.

48 cl, 26 dwg, 3 tbl, 11 ex