Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer.

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?=?1.52， 2.03， and 0.86?nM) and KATO-III/hCLDN18.2 (IC?=?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.