Abstract 5587: VTS208: A first-in-class CD3/CLDN18.2/CDH17 Tri-specific T cell engager (TCE) for the treatment of gastrointestinal (GI) cancer

Abstract Zolbetuximab (Astellas’ anti-CLDN18.2 mAb, approved) has validated CLDN18.2 as a promising tumor-associated antigen (TAA) for gastrointestinal (GI) cancer therapy. CLDN18.2-targeting T cell engagers (TCEs), including IBI389 (phase I) and ASP2138 (phase I), demonstrate anti-tumor activity in patients with low CLDN18.2 expression, indicating that the TCE modality is effective even with minimal TAA expression. However, short duration of response and drug resistance persist because tumor heterogeneity drives therapeutic limitations. Notably, CDH17 (Cadherin 17) has emerged as a novel biologic target, frequently overexpressed in GI cancers. CLDN18.2 and CDH17 exhibit highly complementary expression patterns (co-expressed or individually expressed) across multiple cancers with limited normal tissue expression, positioning them as ideal dual targets for trispecific TCE design that may address tumor heterogeneity and overcome antigen-loss resistance in single-target therapies. We present VTS208, a first-in-class trispecific antibody featuring a proprietary CD3 arm that targets both CLDN18.2 and CDH17. It achieves potent on-target cytotoxicity with reduced concomitant T cell activation, thereby widening the therapeutic window. Its bi-paratopic CDH17-targeting design enhances binding avidity and efficacy against low-expression tumors. In human PBMC-reconstituted CDX models with variable CLDN18.2/CDH17 expression across gastric cancer (GC), pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), VTS208 demonstrated robust anti-tumor activity even at low doses. Preliminary cynomolgus monkey toxicity studies confirmed favorable tolerability under step-up dosing. Current development includes CMC process optimization and dose-range-finding (DRF) toxicity studies. With mini-pool fermentation titers of 4-6 g/L supporting targeted drug substance concentrations for subcutaneous administration, the IND application is scheduled for filing in H2 2026. In summary, VTS208’s unique trispecific design and differentiated features demonstrate promising efficacy and safety, positioning it as a compelling first-in-class TCE candidate for clinical development. Citation Format: Wei (Vivian) Wang, Xuekun Zhang, Man Xu, Yingchun Wang, Mei Yuan, Yanwei Wang, Liping Chen, Yanling Gong, Jing Li. VTS208: A first-in-class CD3/CLDN18.2/CDH17 Tri-specific T cell engager (TCE) for the treatment of gastrointestinal (GI) cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5587.