Abstract LB215: A first-in-class anti-TROP2/EGFR bispecific antibody-drug conjugate, DM001, exhibits potent anti-tumor efficacy
Authors: Li Zhuolin , Shang Chengzhang , Guan Xuewa , An Gao , Guo Yuming , Zhang Ellen , Lin Qingcong , Yang Yi 
Published: April 2023

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 better kill double positive cells. Mechanistically, DM001 delays progression of the cell cycle and increases the frequency of apoptosis in vitro in an antigen-dependent manner. Pharmacokinetic analyses in mice with humanized FcRn (B-hFcRn) demonstrated a similar half-life of DM001 to isotype controls. Importantly, DM001 demonstrated strong anti-tumor activity in several cell line-derived and patient-derived xenografts, including lung and pancreatic tumors. Notably, the efficacy of DM001 was superior to benchmark ADCs in A431 and Panc.02.03 xenografts. Interestingly, the efficacy of DM001 was superior to its parental ADCs in BP0508 lung cancer and BP0209 pancreatic cancer PDX models, but not obvious in Panc.02.03 CDX models, indicating that DM001 may effectively target heterogeneous tumors, which better mimic the tumor microenvironment in patients. In summary, DM001 is a novel bispecific ADC with promising therapeutic potential that can be further exploited to treat TROP2 and EGFR co-expressing tumors.

Citation Format: Zhuolin Li, Chengzhang Shang, Xuewa Guan, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class anti-TROP2/EGFR bispecific antibody-drug conjugate, DM001, exhibits potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB215.