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 an attractive anti-cancer target. TST001 is a novel humanized lgG1 monoclonal antibody, which specifically binds to cells expressing human CLDN18.2 with high affinity but not to the closely related Claudin 18.1. TST001 binds to CLDN18.2 via a distinct epitope. By reducing fucosylation during cell culture process, TST001 has further enhanced binding affinity to FcyRllla, and has 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 analog. TST001 also showed more potent CDC and ADCP activities against CLDN18.2 expressing cells than IMAB362 analog. 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 analog. Furthermore, the combination with chemotherapeutic agents resulted in enhanced anti-tumor activity of TST001 in these tumor models. In addition, we have also generated and characterized an antibody that is selective to CLDN18.2 over CLDN18.1 and is suitable for IHC based detection. Altogether, these preclinical findings warrant further clinical evaluation of TST001 in patients with CLDN18.2 expressing tumors.