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

• Published in: Chemical science (Cambridge) 2024-07, Vol.15 (29), p.11272-11278
• Main Authors: Shao, Chihao, Tang, Bo, Chu, Jacky C. H, Lau, Kwai Man, Wong, Wai-Ting, Che, Chi-Ming, Tai, William C. S, Wong, Wing-Tak, Wong, Clarence T. T
• Format: Article
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d4sc00851k

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. A novel peptidic bispecific antibody (pBsAb) is developed by integrating EGFR-binding cyclic peptide with an anti-SIRP-α antibody, promotes cancer cells recognition, suppresses "don't eat me" signal, and enhances phagocytosis and tumour infiltration.