Novel T cell engager targeting CD3 and CDH17 for the treatment of solid tumors

Background: Despite the success of T-cell engagers (TCEs) in hematologic cancers, their translation to solid tumors has been limited by key obstacles such as the immunosuppressive tumor microenvironment, inefficient T-cell trafficking, and antigen heterogeneity. The pursuit of suitable target antigens is therefore critical. Cadherin-17 (CDH17), which is highly expressed in many gastrointestinal malignancies but shows limited normal tissue expression, offers a compelling opportunity for next-generation TCE therapy. Methods: A novel, bispecific T-cell engager (TCE) was engineered for concurrent binding to CD3 and cadherin-17 (CDH17). Its cytotoxic potency was quantified against a panel of CDH17-positive human cancer cell lines in co-culture assays with healthy donor peripheral blood mononuclear cells (PBMCs). T-cell activation (CD69+/CD25+ upregulation) and cytokine secretion were profiled by flow cytometry and immunoassay, respectively. In vivo antitumor efficacy was evaluated in immunodeficient mice bearing CDH17-positive gastric cancer cell-derived xenografts (CDX). Results: The CDH17xCD3 T cell engager exhibited high-affinity binding to CDH17, coupled with a modulated affinity for CD3. In vitro , the molecule induced potent and specific lysis of CDH17-positive tumor cells in a dose-dependent manner, while sparing CDH17-negative controls. This targeted cytotoxicity was accompanied by a reduced cytokine release profile compared to a conventional CD3-engaging benchmark, In vivo , our TCE treatment led to enhanced tumor growth inhibition and marked regression in CDH17-high CDX models, with no significant systemic toxicity observed at efficacious doses. Conclusion: The novel CDH17xCD3 bispecific T-cell engager exhibits potent and targeted anti-tumor activity, supporting its translational potential as an immunotherapeutic agent for CDH17-positive solid tumors. The favorable efficacy and safety profile observed warrants further clinical investigation.