Guoyun Zhu , 1 , Davide Foletti 1 , 5 , Xiaohui Liu 1 , Sheng Ding 1 , 6 , Jody Melton Witt 1 , 7 , Adela Hasa-Moreno 1 , 8 , Mathias Rickert 1 , 9 , Charles Holz 1 , 7 , Laura Aschenbrenner 2 , 10 , Amy H. Yang 2 , Eugenia Kraynov 3 , Winston Evering 2 , Leslie Obert 4 , 11 , Chenyu Lee 1 , 12 , Tao Sai 1 , Tina Mistry 1 , Kevin C. Lindquist 1 , Thomas Van Blarcom 1 , 13 , Pavel Strop 1 , 14 , Javier Chaparro-Riggers 1 , Shu-Hui Liu 1 , 15
10 June 2019
Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.2 via naked antibody and CAR-T modalities. Herein we describe CLDN18.2-targeting via a CD3-bispecific and an antibody drug conjugate and the characterization of these potential therapeutic molecules in efficacy and preliminary toxicity studies. Anti-hCLDN18.2 ADC, CD3-bispecific and diabody, targeting a protein sequence conserved in rat, mouse and monkey, exhibited in vitro cytotoxicity in BxPC3/hCLDN18.2 (IC 50 = 1.52, 2.03, and 0.86 nM) and KATO-III/hCLDN18.2 (IC 50 = 1.60, 0.71, and 0.07 nM) respectively and inhibited tumor growth of pancreatic and gastric patient-derived xenograft tumors. In a rat exploratory toxicity study, the ADC was tolerated up to 10 mg/kg. In a preliminary assessment of tolerability, the anti-CLDN18.2 diabody (0.34 mg/kg) did not produce obvious signs of toxicity in the stomach of NSG mice 4 weeks after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer.