TRANSCENTA HOLDING - A Global Fully Integrated Biotherapeutics Company
Transcenta, Biologics, Antibody, Claudin 18.2
22 Jun, 2020
Fei Teng1, Yi Gu1, Hui Chai1, Huanhuan Guo1, Hongjun Li1, Xiwen Wu1, Xinlai Yao1, Fei Xu1, Lei Shi1, Zhenzhi Yan1, Xiaoli Zi1, Zheng Dai2, Timethy Liao2, Lisa Zheng1, Francis Fan2, Zhen Li1, Jerry Yang2, Xueming Qian1.
1Mabspace Biosciences (Suzhou) Co., Limited, Suzhou, China;
2HJB (Hangzhou) Co, Limited, Hangzhou, China
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.
◆TST001 displayed specific, high affinity binding to CLDN18.2.
◆ With reduced fucosylation, TST001 has an enhanced affinity to FcgRIIIa and ADCC activity.
◆ In gastric cancer cell xenograft model, TST001 resulted in tumor regression in a dose-dependent manner.
◆ TST001 combined with chemotherapeutic agent, such as Paclitaxel, resulted in greater tumor inhibition than single agent in a
CLDN18.2 positive PDX model.
◆ TST001 has a linear PK profile and is well tolerated in Cynomolgus monkeys.
◆ Antibody 14G11 displayed high specificity and sensitivity to CLDN18.2 in fixed tumor sample and is suitable for IHC detection.
◆ Conclusions: These studies demonstrated that TST001 is capable of potently inducing tumor killing both in vitro and in vivo
and warrant further clinical evaluation of TST001 in patients with CLDN18.2 expressing tumors.