A novel 2+2 IgG-like bispecific antibody-drug conjugate with dual payloads for targeted therapy of heterogeneous gastrointestinal cancers

Gastrointestinal (GI) cancers, including colorectal, gastric, and pancreatic cancers, remain a leading cause of cancer-related mortality globally due to their high incidence, aggressive progression, and profound intratumoral heterogeneity. This heterogeneity often leads to treatment resistance and limits the efficacy of monotherapies. Cadherin-17 (CDH17) and Guanylate Cyclase C (GUCY2C) are two promising tumor-associated antigens (TAAs) that are broadly and specifically overexpressed in various GI cancers, making them ideal targets for dual-specific therapy. Bispecific antibodies (bsAbs) offer a strategic advantage by co-targeting two distinct antigens, potentially enhancing tumor selectivity, overcoming heterogeneity, and improving therapeutic outcomes. Here, we report the development of a novel 2+2 IgG-like bispecific antibody-drug conjugate (ADC) targeting both CDH17 and GUCY2C, engineered to address the unmet needs in GI cancer treatment. The bispecific antibody was constructed as a 2+2 IgG-like molecule. The CDH17-binding arm was derived from a humanized single-domain antibody (VHH) isolated from an immunized alpaca library, selected for high affinity and specificity. The GUCY2C-binding arm was a fully human IgG1 kappa antibody identified through biopanning of a human phage display library. The resulting bsAb was site-specifically conjugated to a proprietary dual-payload linker-drug system from Hangzhou DAC, consisting of a potent antimetabolite drug and a topoisomerase I inhibitor. The bsAb exhibited high-affinity binding to both CDH17 and GUCY2C (KD values in the low nanomolar range) and demonstrated dual-specific binding to cells expressing either or both antigens. This ADC agent also demonstrated potent cytotoxicity against both single and dual antigen-expressing tumor cells. The promising preclinical efficacy profile of this ADC support its potential as a targeted therapy for patients with advanced GI cancers, offering a new strategy to overcome treatment resistance and improve clinical outcomes.