Abstract 3499: Engineering and construction of anti-B7-H3 antibody-based T cell engagers (TCEs) and antibody-drug conjugates (ADCs) for cancer therapy

Abstract B7-H3 (CD276), an immunomodulatory protein of the B7 superfamily, is overexpressed in a wide range of solid tumors. Various antibody-based therapeutic modalities targeting B7-H3 have shown antitumor response in preclinical and clinical studies. Ifinatamab deruxtecan (I-DXd), a B7-H3-directed DXd antibody drug conjugate (ADC) has demonstrated promising efficacy in patients with pretreated ES-SCLC in phase II clinical study. Further, several bispecific T-cell engagers (TCE) targeting B7-H3 and CD3 have also entered early phase clinical trials. In this study, leveraging our streamlined AI-guided antibody engineering platform, we generated several biparatopic TCEs targeting B7-H3 and CD3 as well as a number of biparatopic anti-B7-H3 ADCs constructed with various linkers and cytotoxic payloads. Our biparatopic TCEs were designed to simultaneously target two distinct epitopes on B7-H3 and with monovalent binding to CD3 on T cells with moderate to low affinity, in an attempt to enhance T cell-mediated specific cytotoxicity while mitigating the risk of cytokine release syndrome (CRS). The lead biparatopic TCE molecule demonstrated a robust B7-H3-specific T cell-dependent cellular cytotoxicity towards multiple B7-H3-positive tumor cells with various B7-H3 expression levels. The biparatopic ADCs demonstrated high avidity-driven binding activity to B7-H3 positive cancer cells and were capable of mediating strong internalization activity with higher tumor cell killing efficiency compared to their counterpart ADCs targeting to a single binding epitope. Further in vitro assays and in vivo efficacy studies for the lead biparatopic TCE and ADC molecules in xenografted tumor animal models are being investigated. Taken together, our studies provide support for the further development of the biparatopic B7-H3-targeting ADCs and TCEs for the treatment of B7-H3-expressing solid cancers. Citation Format: Chuan Chen, Yue Wu, Liang Tian, Chenpeng Su, Xiaoou Xu, Xiaoqian Chen, Dandan Liu, Yang He, Jiyuan Tian, Jian Peng, Zhenping Zhu. Engineering and construction of anti-B7-H3 antibody-based T cell engagers (TCEs) and antibody-drug conjugates (ADCs) for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3499.