FIELD: pharmaceutics.
SUBSTANCE: present invention relates to a pharmaceutical composition for preventing or treating a malignant tumour, containing, as active ingredients, a dimeric fusion protein containing a CD80 fragment and an IL-2 variant, and an anticancer agent; wherein the fused protein has the following structural formula (I): N'-X-[linker (1)]n-Fc-domain-[linker (2)]m-Y-C' (I), where N' is the N-end of the fused protein, C' is the C-end of the fused protein, X is a CD80 fragment, wherein the CD80 fragment is an extracellular domain of the CD80 protein, Y is a variant of the IL-2 protein containing substitutions R38A and F42A in the amino acid sequence SEQ ID NO: 10, linker (1) is a peptide linker consisting of the amino acid sequence SEQ ID NO: 3, linker (2) is a peptide linker consisting of the amino acid sequence SEQ ID NO: 5, and n and m are equal to 1, and wherein the anticancer agent is any selected from the group consisting of: VEGFR inhibitor, EGFR inhibitor, PARP inhibitor, DNA methyltransferase inhibitor, TGF-β receptor inhibitor, CDK4/6 inhibitor, STING agonist, alkylating agent, microtubule inhibitor, antimetabolite, topoisomerase inhibitor and combinations thereof.
EFFECT: present invention provides the development of the most effective structure of the fused protein, which stimulates the proliferation of CD80+ T- and NK-cells without increasing the number of Treg-cells, as well as an optimum distance allowing two active domains in the fused protein to work synergistically without steric interference in binding to each target, wherein the obtained structure interacts effectively with all CTLA-4 on regulatory T cells; IL2Rβ on NK cells; and IL2Rβ on effector T cells, thus showing an unexpected synergistic anticancer effect in animal models compared to single or combined treatment with each protein as a separate molecule.
11 cl, 29 tbl, 133 dwg, 49 ex
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Authors
Dates
2025-05-06—Published
2021-03-18—Filed