ACR317，一种新型CDH17-ADC，在临床前胃肠道癌模型中显示出强效疗效

Background:Cadherin-17 (CDH17) is a well-validated target with high expression in gastrointestinal (GI) cancers, including colorectal (CRC) and gastric cancer, while its expression in normal tissues is restricted to the basolateral membrane of intestinal epithelial cells. This unique expression pattern makes CDH17 an attractive therapeutic target for antibody-drug conjugates (ADCs). The development of effective ADCs for GI malignancies, particularly for CRC, remains a significant challenge. The landscape is largely dominated by DS-8201, with many other candidates failing due to efficacy or safety concerns. Here, we present the preclinical profile of ACR317, a novel CDH17-targeting ADC developed using Adcoris' proprietary platform, designed to address this unmet need. Methods: IBR217 antibody, was isolated from a naïve fully human phage display library based on its high specificity and affinity for human CDH17. The binding affinity of IBR217 was determined by bio-layer interferometry (BLI), tumor cell binding activity was evaluated by flow cytometry, and internalization efficiency was assessed using a Fab-ZAP cytotoxicity assay. ACR317 was generated by site-specifically conjugating IBR217 to a novel topoisomerase I inhibitor payload using Adcoris' proprietary MuSC™ conjugation platform, achieving a drug-to-antibody ratio (DAR) of 8. In vivo antitumor activity was evaluated in multiple CDH17-positive and negative gastric and colorectal cancer cell-derived xenograft (CDX) models, with an IBR217- Dxd ADC included as a benchmark. Results: IBR217 exhibited high affinity for human CDH17, with a binding affinity (KD) of 2.47 nM, and demonstrated excellent specificity by showing no binding to other cadherins. It also displayed potent binding to CDH17-positive tumor cells, with a half-maximal effective concentration (EC50) of 0.30 nM, and was subsequently efficiently internalized by these cells. ACR317 was successfully generated with a drug-to-antibody ratio (DAR) of 8. The resulting ADC ACR317 demonstrated significant tumor growth inhibition in preclinical CDX models, showcasing superior efficacy compared to the IBR217-Dxd benchmark in two CDH17-positive gastric cancer and four CRC CDX models. As expected, it showed minimal activity in a CDH17-negative gastric model, confirming its target-dependent mechanism. In these studies, ACR317 was well tolerated, with no significant body weight loss or other observable toxicities noted. Pharmacokinetics and safety studies in cynomolgus monkeys are ongoing. Conclusions: ACR317 is a novel, highly specific CDH17-targeting ADC. The compelling preclinical efficacy observed suggest its therapeutic potential and form a solid foundation for subsequent clinical investigation in CDH17-positive gastrointestinal cancers.