Homodimeric bispecific antibodies against her2 and cd3 and uses thereof

Abstract

A tetravalent, homodimeric bispecific antibody molecule simultaneously targeting immune effector cell antigen CD3 and human epidermal growth factor receptor 2 (Her2), the bispecific antibody molecule is sequentially from N-terminus to C-terminus It comprises a first single-chain Fv that can specifically bind to Her2, a second single-chain Fv that can specifically bind to CD3, and an Fc fragment, the first and second single-chain Fv are connected by a linking peptide, and the second single-chain Fv is directly connected to the Fc fragment. Linked or linked via a linking peptide; the Fc fragment does not have effector functions such as CDC, ADCC and ADCP. Bispecific antibodies can significantly inhibit or kill tumor cells, but also have controlled toxic side effects that may be caused by overactivation of effector cells. The maximum safe initial dose of the preclinical toxicology evaluation test is much higher than other doses of the same target, and no systemic immunotoxicity occurs, suggesting that the drug safety window of bispecific antibodies is wide; in addition, this bispecific antibody It is a homodimer type, there is no heavy chain and light chain mismatch problem, the purification steps are simple and efficient, the expression amount is high, and its physicochemical 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...

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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

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