Background
Metastatic urothelial carcinoma (mUC) carries a poor prognosis, with a 5-year survival rate of 10-15%. Although antibody-drug conjugates (ADCs) targeting Nectin-4 (enfortumab vedotin) or TROP2 (sacituzumab govetecan) have validated these antigens as therapeutic nodes in UC, heterogeneous tumor expression, resistance, and single-target toxicities limit their long-term efficacy. To circumvent these limitations, we developed BCG039, a novel bispecific ADC (bsADC) co-targeting Nectin-4 and TROP2, designed to enhance tumor-specific internalization, overcome antigen heterogeneity, and improve the therapeutic index.
Methods
Fully human monoclonal antibodies against Nectin-4 and TROP2 were generated using RenLite® transgenic mice. Parental arms were screened and selected based on internalization kinetics to construct a 1+1 format bispecific antibody. The resulting antibody was conjugated to either vcMMAE or a proprietary, highly hydrophilic, enzyme-cleavable linker-payload (BLD1102, featuring a novel topoisomerase I inhibitor), both at a drug-to-antibody ratio (DAR) of 4. In vitro internalization was evaluated across multiple cancer cell lines. In vivo anti-tumor efficacy was assessed in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor models alongside clinical benchmark ADCs
Results
The selected Nectin-4 and TROP2 arms demonstrated significantly enhanced internalization when formatted as a 1+1 bispecific antibody compared to their respective monovalent parental counterparts, indicating a cooperative dual-targeting interaction. Consistently, the vcMMAE-conjugated bsADC exhibited superior in vivo anti-tumor activity to the parental monovalent ADCs in CDX and PDX models. Furthermore, BCG039 (the BLD1102-conjugated bsADC) demonstrated robust tumor growth inhibition that outperformed the anti-Nectin-4 benchmark and matched or exceeded certain anti-TROP2 benchmark ADCs. Finally, the parental bispecific antibody displayed favorable biophysical properties and developability, successfully supporting its transition into current CMC development.
Conclusions
BCG039 is a novel Nectin-4xTROP2 bsADC that delivers superior preclinical anti-tumor efficacy relative to single-targeting parental and benchmark ADCs. The cooperative dual-antigen binding and internalization kinetics not only maximize therapeutic potency in heterogeneous tumors but also offer a promising strategy to mitigate the on-target, off-tumor toxicities frequently associated with monospecific ADCs in mUC.
