The Preclinical Characterization Of Tst001, A Novel Humanized Anti-Claudin18.2 Mab With Enhanced Binding Affinity And Anti-Tumor Activity

Claudin-18 isoform 2 (CLDN18.2) is a member of the human claudin family of tetraspan membrane proteins that are crucial structural and functional components of tight junctions. Unlike other family members, CLDN18.2 expression is strictly limited to differentiated epithelial cells of gastric mucosa. Interestingly CLDN18.2 was ectopically expressed at a significant level in multiple tumor types including gastric, esophageal, pancreatic and lung cancers, which makes it as an attractive anti-cancer target. TST001 is a novel humanized IgG1 monoclonal antibody, which specifically binds to cells expressing human CLDN18.2 with high affinity but not to the closely related Claudin 18.1. TST001 can compete with IMAB362, the clinical stage anti-CLDN18.2 mAb, for its binding to CLDN18.2 yet engages distinct epitope for binding. By reducing fucosylation during cell culture process, TST001 has further enhanced binding affinity to FcγRIIIa, which translates into more potent ADCC activity. Indeed, TST001 showed sub-nanomolar ADCC activity against gastric cancer cells expressing medium to low CLDN18.2 in the presence of human PBMC and NK cells, which is significantly more potent than IMAB362. TST001 also showed more potent CDC and ADCP activities against CLDN18.2 expressing cells than IMAB362. In both Sprague Dawley Rat and Cynomolgus Monkey, the systemic exposure of TST001 increased proportionally in a dose-dependent manner. In gastric cancer cell line and patient derived xenograft tumor models, TST001 showed more potent anti-tumor activity as compared with IMAB362. Furthermore, the combination of TST001 with chemo agents resulted in synergistic anti-tumor effect in these tumor models. In addition, we have also generated and characterized an antibody that is suitable for IHC based detection and is selective to CLDN18.2 over CLDN18.1. Altogether, these preclinical findings warrant further clinical evaluation of TST001 in patients with CLDN18.2 positive tumors. Citation Format: Fei Teng, Yi Gu, Hui Chai, Huanhuan Guo, Hongjun Li, Xiwen Wu, Xinlai Yao, Fei Xu, Lei Shi, Zhenzhi Yan, Xiaoli Zi, Zheng Dai, Timethy Liao, Lisa Zheng, Francis Fan, Zhen Li, Jerry Yang, Xueming Qian. The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5183.