Abstract Introduction: Nectin-4 has emerged as a clinically validated antigen for the treatment of urothelial, colorectal, lung, breast, and other solid malignancies. However, Nectin-4’s physiological expression in epidermal keratinocytes restricts the utility of potent immunotherapeutic strategies such as bispecific T cell engagers (TCEs) and chimeric antigen receptor T cells (CAR-Ts), due to on-target, off-tumor toxicity. CT-202 is a fully humanized, dual pH-dependent Nectin-4 x CD3 bispecific TCE engineered to widen the therapeutic window by selectively targeting Nectin-4 and CD3 within the acidic tumor microenvironment (TME). Methods: CT-202 was characterized for pH-dependent binding to both Nectin-4 and CD3, employing in vitro affinity assays across pH gradients mimicking physiological (pH 7.4) and tumoral (pH ∼6.5) conditions. In vivo pharmacology and safety assessments were performed in non-human primates comparing CT-202 and non-pH-dependent bispecific controls. In vitro functional assays, including cytotoxicity and cytokine release, were used to determine dose-response relationships to inform initial human dosing strategies. Results: CT-202 demonstrated high affinity and specificity for Nectin-4 and CD3 exclusively at the lower pH characteristic of the TME; at neutral pH, binding was markedly attenuated. This conditional dual engagement was essential for effective T cell-mediated cytotoxicity against tumor targets in vitro. In non-human primate toxicology studies, CT-202 exhibited a 30-fold improvement in the Highest Not Severely Toxic Dosage (HNSTD) relative to traditional bispecifics lacking pH modulation, delineating a superior safety profile. Integrated analysis of in vitro potency and in vivo toxicology data supported a rational selection of starting dose for forthcoming clinical investigation. Conclusion: CT-202 represents a novel dual pH-selective bispecific TCE targeting Nectin-4 x CD3, designed to optimize tumor selectivity and minimize off-tumor toxicity. Preclinical data validate the differentiated pharmacological and safety attributes of this modality, justifying its advancement to first-in-human Phase 1 trials. This approach highlights the potential of dual pH-dependent bispecific antibodies as a next-generation platform for the selective immunotherapy of Nectin-4-expressing solid tumors. Citation Format: Stanley Roberts, Kelly Byrnes-Blake, Heather Ansorge, Eric Butz, Daniel Olson. Targeting solid tumors with pH-dependent dual-specific TCEs: First-in-human development of CT-202 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 5392.
Roberts et al. (2026) studied this question.