TROP2 Antibody-Drug Conjugate: Unique Epitope Engagement Drives Differentiated Efficacy

Abstract Background Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in various cancers and is associated with poor prognosis. While TROP2-targeted antibody-drug conjugates (ADCs), such as sacituzumab govitecan, sacituzumab tirumotecan, and datopotamab deruxtecan achieved clinical success, the mechanisms underlying resistance to these therapies remain incompletely understood. Consequently, the full therapeutic potential of TROP2 ADC has yet to be comprehended. Methods We developed R7059-DXD, a novel TROP2-targeted ADC featuring an antibody that binds an epitope distinct from sacituzumab and datopotamab. The structural basis of epitope recognition was elucidated using cryo-electron microscopy (cryo-EM), complemented by binding affinity analyses across multiple surface-expressed TROP2 variants. Functional activity was systematically evaluated through in vitro ADCC assays, in vitro ADC-mediated killing assays, and in vivo efficacy studies in tumor models, including resistant lines. Results The R7059 antibody exhibited high binding affinity across multiple TROP2 variants, addressing a key resistance mechanism. The cryo-EM structure analysis revealed that the R7059 epitope lies in the N-terminal domain of TROP2 and is distinct from the sacituzumab and datopotamab epitopes. Functionally, R7059 demonstrated potent anti-tumor activity through both ADCC-dependent and independent mechanisms, suggesting additional signaling effects. The R7059-ADC demonstrated robust efficacy in multiple preclinical tumor models, including those resistant to approved TROP2 ADCs. Conclusions R7059-DXD is a differentiated, epitope-distinct TROP2-targeted ADC with the potential to overcome resistance to existing therapies. These findings support its further clinical development as a novel treatment for TROP2-expressing malignancies, including in patients previously treated with sacituzumab- or datopotamab-based regimens.