Homodimeric bispecific antibody against her2 and cd3 and use thereof

Abstract

The present invention provides a tetravalent, homodimeric bispecific antibody molecule targeting immune effector cell antigen CD3 and human epidermal growth factor receptor 2 (Her2), the bispecific antibody molecule starts from the N-terminal To the C-terminus, the first single-chain Fv that can specifically bind to Her2, the second single-chain Fv that can specifically bind to CD3, and the Fc fragment are sequentially included. The first and second single-chain Fv are linked by a connecting peptide, and the second single-chain Fv Linked directly to the Fc fragment or via a connecting peptide; the Fc fragment does not have effector functions such as CDC, ADCC and ADCP. The bispecific antibody provided by the invention can significantly inhibit or kill tumor cells, and has controlled toxic side effects that may be caused by excessive activation of effector cells. The maximum safe initial dose of the preclinical toxicology evaluation test has been much higher than the dose of other same targets, and no systemic immunotoxicity has occurred, suggesting that the drug safety window of the bispecific antibody provided by the present invention is relatively wide; in addition, this The bispecific antibody is a homodimer type, there is no heavy chain and light chain mismatch problem, the purification step is simple and efficient, the expression level is high, and its physical, chemical and in vivo stability are significantly improved.

Description

[0001] Related applications [0002] This application claims the priority of Chinese patent application CN 201811294887.4 filed on November 1, 2018. The contents of the above-referenced priority applications are incorporated herein by reference in their entirety. technical field [0003] The present invention relates to the field of immunology, and more particularly to bispecific antibodies directed against human epidermal growth factor receptor 2 (Her2) and clustering determinant 3 (CD3), and the use of such antibodies, especially in the treatment of use in tumors. Background technique [0004] 1. Bispecific antibodies [0005] In 1985, the concept of using T cells to kill tumor cells has been proposed (Stearz UD et al., Nature, 314:628-631, 1985). It is generally believed that effective activation of T cells requires dual signals. The first signal comes from the binding of MHC-antigen complexes on antigen-presenting cells to the T cell receptor TCR-CD3, and the second ...

AI Technical Summary

Problems solved by technology

However, even if each antibody can correctly bind to its antigen alone, there is no guarantee that it can retain its original binding ability after forming a bispecific antibody, and due to steric hindrance, there is no guarantee that after forming a bispecific antibody, it can successfully bind to its antigen. synergy

Images