Novel ADC and γδ T Cell Engager Targeting CDH17 for the Therapy of Gastrointestinal Cancers

Abstract Background Cadherin-17 (CDH17) is a cell-adhesion molecule physiologically expressed along the intestinal epithelial tight junctions. Aberrant overexpression of CDH17 in gastrointestinal (GI) cancers promotes tumor growth, metastasis, and poor patient prognosis. Due to its restricted expression in normal tissues and strong association with malignancy, CDH17 represents an emerging therapeutic target for GI tract cancers. Methods A high-affinity anti-CDH17 monoclonal antibody (TAVO307) was generated and conjugated with auristatin-derived cytotoxic payloads to obtain CDH17-directed antibody–drug conjugates (ADCs). In parallel, a VHH antibody capable of activating γδ T cell receptors from both Vδ1 and Vδ2 subsets was identified and combined with the anti-CDH17 antibody to generate CDH17-targeted T cell engager (TCE) to recruit γδ T cells, which are abundant in the intestinal mucosa and play a critical role in tumor immunosurveillance. An attenuated interleukin-15 (IL-15) fused with the IL-15 receptor α sushi domain was further incorporated on TCE to enhance γδ T cell expansion and activation. Results CDH17-based ADCs exhibited potent and selective cytotoxicity in multiple GI cancer cell lines and significant tumor regression in xenograft models. The CDH17 γδ TCE induced tumor antigen-dependent γδ T cell degranulation and redirected both Vδ1 and Vδ2 T cells to effectively kill CDH17-expressing cancer cells. IL-15 fusion further augmented γδ T cell expansion and activation. Conclusions Both CDH17-targeted ADCs and γδ TCEs demonstrated promising potency and efficacy to control GI cancers. They could offer complementary therapeutic options that could be used in combination therapy.