Macrophage-engaging peptidic bispecific antibodies (pBsAbs) for immunotherapy via a facile bioconjugation strategy

作者：Chihao Shao, Bo Tang, Jacky C. H. Chu, Kwai Man Lau, Wai‐Ting Wong, Chi‐Ming Che, William Tai, Wing‐Tak Wong, Clarence T. T. Wong · 发表于：Chemical Science · 年份：2024 · DOI：10.1039/d4sc00851k · 被引用次数：10 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Peptidase Inhibition and Analysis、CAR-T cell therapy research

Bispecific antibodies are artificial molecules that fuse two different antigen-binding sites of monoclonal antibodies into one single entity. They have emerged as a promising next-generation anticancer treatment. Despite the fascinating applications of bispecific antibodies, the design and production of bispecific antibodies remain tedious and challenging, leading to a long R&D process and high production costs. We herein report an unprecedented strategy to cyclise and conjugate tumour-targeting peptides on the surface of a monoclonal antibody to form a novel type of bispecific antibody, namely the peptidic bispecific antibody (pBsAb). Such design combines the merits of highly specific monoclonal antibodies and serum-stable cyclic peptides that endows an additional tumour-targeting ability to the monoclonal antibody for binding with two different antigens. Our results show that the novel pBsAb, which comprises EGFR-binding cyclic peptides and an anti-SIRP-α monoclonal antibody, could serve as a macrophage-engaging bispecific antibody to initiate enhanced macrophage-cancer cell interaction and block the "don't eat me" signal between CD47-SIRP-α, as well as promoting antibody-dependent cellular phagocytosis and 3D cell spheroid infiltration. These findings give rise to a new type of bispecific antibody and a new platform for the rapid generation of new bispecific antibodies for research and potential therapeutic uses.