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Background CT-202 is a fully humanized pH-dependent Nectin-4 x CD3 bispecific T cell engager (TCE) that is designed to overcome cytokine release syndrome (CRS) and known on-target Nectin-4 healthy tissue toxicities. Nectin-4 has been identified as a target antigen for urothelial, colorectal, lung, breast, and other cancers because of its high expression on tumor cells and limited expression on normal tissues. The binding domains for Nectin-4 and CD3 have been designed to bind their respective targets specifically and reversibly under the low pH conditions found in the tumor microenvironment (TME), and to have reduced binding outside of the TME. The pH-dependent binding to both the Nectin-4 and CD3 arms are required to engage T cell killing of the tumor, thus enabling the combined selectivity of each pH-dependent binding arm in the bispecific antibody.Methods In vitro studies have shown that our pH-dependent bispecific TCE, CT-202, binds to the target proteins, human Nectin-4 and human CD3, with high specificity and affinity under the characteristic acidic conditions of the TME (~pH 6.5), while its binding is highly reduced under normal cells’ alkaline physiological conditions (pH 7.4). In vivo studies with CT-202 indicate that the therapeutic index was improved more than 30-fold relative to non-pH dependent variants, supporting the potential differentiation of pH-dependent bispecific antibodies versus more traditional bispecific antibodies.Results Our results suggest CT-202 is a promising new immune-activating therapeutic modality for the treatment of Nectin-4-positive cancers that reduces the risk of on-target, off-tumor T cell activation through pH-dependent binding to both the Nectin-4 and CD3 arms.Conclusions The safety and tolerability features highlight the developability of CT-202 in solid tumors that express Nectin-4. An IND application is expected in the middle of 2026.Ethics Approval All animal studies will be conducted in facilities that comply with all appropriate GLP, OECD, USDA, AALAC and fully approved by the institution’s IACUC committees.