Abstract 6072: Engineering and preclinical development of an anti-TROP2/PD-L1 bispecific antibody drug conjugate (ADC) for enhanced anti-tumor efficacy

Abstract Human trophoblast cell surface antigen 2 (TROP2) and programmed death ligand 1 (PD-L1) are often overexpressed in a variety of human cancers. Both anti-PD-L1 antibodies and TROP2-based antibody drug conjugates (ADCs) have shown significant clinical benefit, and a number of these agents, including atezolizumab and durvalumab (both anti-PD-L1 antibodies) and sacituzumab govitecan (an anti-TROP2-SN38 ADC), have been approved by the US FDA for certain cancer indications. The efficacy of these agents is, however, often limited by the unwanted on-target/off-tumor toxicities and the emergence of resistance of tumor cells. In this study, we engineered a humanized bispecific antibody (bsAb) simultaneously targeting both TROP2 and PD-L1 and produced several drug conjugates utilizing various linkers and cytotoxic payloads. The bsAb ADC binds efficiently to tumor cells that express either or co-express both TROP2 and PD-L1, trigger rapid ADC internalization, and induce potent tumor killing activity. Further, the bsAb ADC also effectively blocks PD1/PD-L1 interaction, and in parallel, induce PD-L1 internalization and down-regulation on tumor cell surface, resulting in significantly enhanced T cell activation for tumor cell killing. In multiple xenografted tumor models, the bsAb ADC demonstrated greater tumor inhibitory activity than their respective monospecific parent antibody ADCs. Taken together, our findings support further development of this bsAb ADC for the treatment of multiple TROP2- and/or PD-L1-expressing cancers, and of those patients who are refractory and/or resistant to TROP2 or PD-L1 single target-based therapies. Citation Format: Chuan Chen, Liang Tian, Chenpeng Su, Dandan Liu, Jiyuan Tian, Yujuan Li, Bing Yang, Yongxin Shan, Xiaoqian Chen, Jian Peng, Zhenping Zhu. Engineering and preclinical development of an anti-TROP2/PD-L1 bispecific antibody drug conjugate (ADC) for enhanced anti-tumor efficacy [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 6072.