Abstract 5819: An anti-TROP2-CPT113 ADC, exhibits potent targeted antitumor activity and favorable pharmacokinetic properties

Abstract Trophoblast cell surface antigen 2 (TROP2) is highly expressed in a number of epithelial cancer types and is considered to be a poor prognostic marker. We have developed an anti-TROP2 antibody-drug conjugate, DXC1002, that contains a potent inhibitor of DNA topoisomerase I payload (CPT113) attached to the antibody mainly in the Fab region via a unique hydrophilic CrossConju™ linker. The anti-tumor activities of DXC1002 were studied in various human cancer cell lines and xenograft mouse models and pharmacokinetic profile of DXC1002 were evaluated in cynomolgus monkeys and rats. DXC1002 demonstrated potent anti-tumor activity in TROP2 tumor cells of various expression levels in vitro, and at low dose of 1 mg/kg for one injection, in both high and moderate Trop2 expression xenograft models. In plasma stability studies, wherein DXC1002 was incubated in the plasma of five different species for 168 hours (7 days) at 37 oC, over 90% ADC was intact, exhibiting good stability of the CrossConju™ linker. Pharmacokinetic studies of DXC1002 in monkeys (TROP2 cross-species) and rats (non-TROP2 cross-species) showed half-lives of about 61. 27 and 236. 77 hours, respectively. Systemic clearance in monkey and rat was 0. 41-0. 67 and 0. 279-0. 309 mL/h/kg, respectively. The longer half-lives and slower clearance observed in rats the results offered a more direct assessment of the linker stability as target-mediated clearance played no role in rats. In summary, with the conjugation of a DNA topoisomerase I inhibitor payload to Trop2 antibody via the CrossConju™ linker, DXC1002 demonstrates remarkable anti-tumor properties and pharmacokinetic profile, with a potential to be further validated in clinical applications. Citation Format: Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Yongxiang Chen, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Juan Wang, Miaomiao Chen, Qingliang Yang, Robert Y. Zhao. An anti-TROP2-CPT113 ADC, exhibits potent targeted antitumor activity and favorable pharmacokinetic properties abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5819.