The CDH3 protein is a member of the cell adhesion molecule family and functions as a calcium-dependent glycoprotein that facilitates cell-cell adhesion. It is frequently overexpressed in several malignant solid tumors, including pancreatic, head and neck, esophageal, breast, gastric, lung, and colorectal cancers. Consequently, CDH3 represents a promising target for antibody-drug conjugates (ADCs), with significant potential for therapeutic applications across various solid tumors.

Utilizing the fully human RenLite CDH3 knockout mouse platform, we screened the Ab.20 antibody, which specifically targets CDH3 without cross-reacting with other members of the CDH3 family. Ab.20 effectively binds to various tumor cell lines and demonstrates robust internalization activity, exhibiting high affinity for both human and cynomolgus CDH3 antigens. Moreover, Ab.20 shows promising developability under stress conditions. In proof-of-concept studies, the Ab.20-vcMMAE conjugate demonstrated superior efficacy compared to the benchmark Ab-vcMMAE in patient-derived xenograft (PDX) models. Subsequently, Ab.20 was conjugated with BLD1102, a novel topoisomerase I inhibitor payload, leading to the development of BCG014, which exhibited potent efficacy across multiple PDX models. Ongoing studies are evaluating the efficacy, pharmacokinetics, and toxicity of BCG014. These findings suggest that BCG014 has the potential to be a novel therapeutic alternative for tumors expressing CDH3.