Targeting solid tumors with pH-dependent dual-specific TCEs: First-in-human development of CT-202
Presenter: Daniel Olson, MD Session: Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Stanley Roberts 1 , Kelly Byrnes-Blake 2 , Heather Ansorge 3 , Eric Butz 4 , Daniel Olson 5 1 SAR Safety Assessment, Northbrook, IL, 2 Northwest PK Solutions, LLC, Cordova, AK, 3 Context Therapeutics Inc, Philadelpha, PA, 4 Context Therapeutics Inc, Philadelphia, PA, 5 University of Chicago, Chicago, IL
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.
Disclosure
S. Roberts, None.. K. Byrnes-Blake, None.. H. Ansorge, None.. E. Butz, None. D. Olson, Bristol Myers Squibb Other, Consultant. Iovance Biotherapeutics Other, Consultant. Deciphera Other, Consultant. Springworks Therapeutics Other, Consultant. Novartis Other, Consultant. Astellas Other, Institutional Support. Immunocore Other, Institutional Support. Bayer Other, Institutional Support.
Cited in
Control: 4035 · Presentation Id: 9663 · Meeting 21436