Abstract 6554: A bispecific TROP2/PDL1 antibody-drug conjugate demonstrates enhanced antitumor activity and favorable safety profile

Abstract Purpose: This study aimed to develop and characterize a bispecific antibody-drug conjugate (ADC) targeting both TROP2 and PDL1, to address the limitations of current single-target therapies in advanced cancers. Methods: We engineered a humanized bispecific antibody (bsAb) against TROP2 and PDL1 (α TROP2/PDL1), and subsequently produced the bispecific ADC using an optimized hydrophilic linker and TOP1 inhibitor payload. Comprehensive in vitro characterization encompassed binding affinity, internalization efficiency, and PDL1 degradation assays. In vivo efficacy was assessed across multiple xenograft models, while safety assessment was conducted in transgenic mice and non-human primates. Results: α TROP2/PDL1 demonstrated potent bispecific activity, featuring efficient cellular binding and rapid internalization. The bsAb induced significant PDL1 internalization and degradation, and showed marked tumor growth inhibition in MC-38-huTrop2/PDL1 model. The bsAb TOP1i conjugated ADC (α TROP2/PDL1-TOP1i) exhibited enhanced potency, characterized by robust cytotoxicity against multiple Trop2/PDL1-expressing cell lines, potent bystander killing effects, and tumor regression in multiple CDX models. Notably, the ADC showed excellent stability and tolerability in cynomolgus monkeys, with no significant adverse effects observed in safety studies. Conclusion: α TROP2/PDL1-TOP1i represents a promising therapeutic strategy for treatment-resistant cancers, effectively combining PD1/PDL1 immune checkpoint blockade with TROP2-targeted cytotoxic payload delivery while maintaining a favorable safety profile, supporting its advancement to clinical development. Citation Format: Chuan Chen, Yue Wu, Chenpeng Su, Dandan Liu, Jiyuan Tian, Yujuan Li, Yongxin Shang, Xiaoqian Chen, Rongmei Yan, Liang Tian, Jian Peng, Zhenping Zhu. A bispecific TROP2/PDL1 antibody-drug conjugate demonstrates enhanced antitumor activity and favorable safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6554.