Abstract 3807: Engineering and preclinical development of a differentiated EGFR/PDL1 bispecific ADC for the targeted therapy of solid tumors

Abstract Both EGFR and PDL1 are well-established therapeutic targets for a broad range of malignancies. Nevertheless, their therapeutic efficacy remain limited, as many patients are either refractory to or develop resistance during the course of treatment. EGFR and PDL1 are frequently co-expressed in multiple tumors, where they play key roles in promoting tumor progression and immune evasion. Notably, PDL1 expression is modulated by EGFR signaling, and the significant crosstalk between EGFR and PDL1 signaling has been reported. In this study, we developed a bispecific antibody (bsAb) targeting both EGFR and PDL1. The bsAb demonstrated enhanced binding avidity towards PDL1+/EGFR+ cancer cells, with higher efficiency of internalization, and more potent EGFR-directed blockade of PD1/PDL1 interaction. Several bsAb ADCs were generated by conjugating with various cytotoxic payloads. In vitro data demonstrated that the lead bsADC induced potent antitumor activity and strong bystander killing activity. Importantly, no Immunotoxicity was observed on PDL1+ human antigen-presenting cells. In vivo efficacy studies demonstrated that the lead bsADC achieved superior antitumor activity compared with MRG003 analog (an anti-EGFR ADC) and the clinical-stage PDL1V analog (an anti-PDL1 ADC) in multiple CDX models. Citation Format: Liang Zhu, Chen Chuan, Mei Tian, Dandan Liu, Jiyuan Tian, Lisha Dong, Yongxin Shang, Rongmei Yan, Kezhen Ye, Liang Tian, Jian Peng, Zhenping Zhu. Engineering and preclinical development of a differentiated EGFR/PDL1 bispecific ADC for the targeted therapy of solid tumors 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 3807.