一种靶向CDH17并具有4-1BB共刺激的下一代三特异性T细胞衔接器,用于治疗胃肠道癌症

Background : Cadherin-17 (CDH17), a membranous cell adhesion protein, is highly expressed in gastrointestinal (GI) cancers, particularly in colorectal cancer. In normal intestine tissue, CDH17 is restricted to the lateral side of the epithelial cells and remains largely inaccessible to antibody, making it a promising therapeutic target for GI malignancies. Our platform has demonstrated that incorporating 4-1BB costimulation can effectively convert immunologically "cold" tumors into "hot". This transformation is achieved by enhancing the infiltration of peripheral T cells into the tumor and systemically remodeling the tumor microenvironment. Moreover, this strategy elicits a durable T cell memory response and significantly prolongs survival. Given that GI cancer is a classic "cold" tumor, we have developed a novel tri-specific T cell engager (TCE) that targets CDH17 on cancer cells and engages CD3 and 4-1BB on T cells. This TCE is engineered to redirect and enhance T cell responses against CDH17-expressing tumor cells. With a manageable safety profile, this approach holds strong potential to improve clinical outcomes for patients with GI cancers. Methods: The in vitro activities of the CDH17-CD3-4-1BB tri-specific TCE were evaluated in both CDH17-positive and -negative tumor cell lines. These assessments included T cell-mediated cytotoxicity, T cell activation, cytokine release and T cell proliferation. In vivo anti-tumor activity was investigated in two models: a humanized syngeneic mice model bearing B16F10-hCDH17 tumors and NCG-MHC-dKO mice with human PBMC bearing Lovo tumors. Cytokine release assay (CRA) was conducted to evaluate potential cytokine storm risk. Additionally, the toxicological profile was assessed in a pilot toxicity study in cynomolgus monkeys. Results: CDH17-CD3-4-1BB tri-specific TCE demonstrated CDH17-dependent activation of CD3 and 4-1BB. It effectively induced tumor lysis in multiple CDH17+ tumor cell lines and significantly enhanced T cell activation, cytokine production and T cell proliferation in the presence of CDH17-expressing target cells. In humanized syngeneic tumor mouse model and human PBMC xenograft tumor mouse model, this molecule demonstrated robust tumor growth inhibition and prolonged survival rate. Furthermore, an in vitro CRA indicated lower IL-6 release compared to a clinical benchmark, indicating a more manageable risk of cytokine release syndrome (CRS). In the pilot tox study, no adverse effects were observed in clinical signs and histopathology. Conclusion: CDH17-CD3-4-1BB tri-specific TCE represents a novel CDH17-targeted T cell engager with potent and durable anti-tumor activity. Collectively, these results underscore its potential as a novel therapeutic agent against GI cancers and support its advancement into clinical development.