Abstract LB215: A first-in-class anti-TROP2/EGFR bispecific antibody-drug conjugate, DM001, exhibits potent anti-tumor efficacy

作者：Zhuolin Li, Chengzhang Shang, Xuewa Guan, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-lb215 · 被引用次数：5 · 研究领域：HER2/EGFR in Cancer Research、Monoclonal and Polyclonal Antibodies Research、Radiopharmaceutical Chemistry and Applications

Abstract EGFR is a well-established target for the treatment of many cancers. However, limitations encountered with current therapies, such as drug resistance and low cytotoxicity, indicate a need for alternative treatments. In particular, antibody-drug conjugates (ADCs) are a promising new therapeutic strategy, due to their potent killing effects and high target specificity. However, the toxicity of the payload can often cause safety concerns with ADCs, so their efficacy and safety must be carefully evaluated. With these challenges in mind, we hypothesized that development of a bispecific ADC (BsADC) targeting EGFR and a second tumor-associated antigen could help to improve the tumor selectivity of the ADC, thereby limiting the occurrence of on-target off-tumor effects. TROP2 and EGFR are co-expressed in multiple types of solid tumors, including head and neck, esophageal, lung, and pancreatic cancers, indicating that this target combination could provide therapeutic benefit for a wide range of tumors. Herein, we developed a novel bispecific ADC, DM001, targeting TROP2 and EGFR, conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, internalization of DM001 bsAb into a TROP2+EGFR+ cell line is comparable with that of its parental monoclonal anti-TROP2 or anti-EGFR antibodies. Tumor killing of double positive cell lines is also comparable between DM001 and its parental ADCs. Compared with single positive cells, DM001 can selectively bind and ...