Development and characterization of CR101-ADC, a fully-human anti-claudin18.2 monoclonal antibody-drug conjugate.

Claudin18.2 (CLDN18.2) is a stomach-specific tight junction protein aberrantly exposed in multiple cancers, particularly gastric and pancreatic malignancies, making it an attractive therapeutic target. Here, we developed CR101-ADC, a novel antibody-drug conjugate (ADC) constructed from a fully human anti-CLDN18.2 monoclonal antibody conjugated to the microtubule inhibitor MMAE via a cleavable linker. The CR101 antibody exhibits high affinity and specificity for claudin18.2, demonstrating superior tumor cell-killing efficiency compared to IMAB362. Additionally, CR101 shows cross-species reactivity in humans, mice, and monkeys, simplifying preclinical pharmacology and efficacy studies. In vitro pharmacodynamic studies confirmed that CR101-ADC effectively induces targeted cytotoxicity, while multiple tumor models demonstrated its potent anti-tumor activity and favorable safety profile with minimal toxicity. Transcriptomic analysis revealed that CR101-ADC primarily affects cytoskeletal, inflammatory, and stress pathways and represents a promising candidate for the treatment of gastrointestinal malignancies. Collectively, these findings demonstrate that CR101-ADC combines high specificity, potent intracellular drug delivery, and favorable safety, representing a promising next-generation therapeutic candidate for CLDN18.2-positive gastrointestinal cancers.