Recent advances in bispecific antibody-drug conjugates for breast cancer therapy.

PURPOSE: Bispecific antibody-drug conjugates (BsADCs) represent a promising strategy to overcome limitations of conventional ADCs in breast cancer, such as tumor heterogeneity and inefficient internalization. This review summarizes recent advances and the therapeutic potential of BsADCs.

METHODS

We conducted a literature review, focusing on BsADC candidates selected for clinical relevance (e.g., ZW49, BL-B01D1), mechanistic innovation (e.g., biparatopic targeting, engaging fast-internalizing receptors), and potential in challenging subtypes like triple-negative breast cancer (TNBC).

RESULTS

BsADCs enhance drug delivery through dual targeting. Biparatopic HER2-targeting agents (e.g., ZW49, JSKN003) induce receptor clustering and robust internalization. BsADCs co-engaging rapidly internalizing receptors (e.g., HER2×CD63) hijack efficient endocytic pathways, showing activity even in low HER2-expression models. Furthermore, BsADCs targeting compensatory pathways, such as EGFR×HER3 (BL-B01D1) and TROP2×HER3 (JSKN016), have demonstrated breakthrough efficacy in TNBC. Optimization of linker technology and drug-to-antibody ratio (DAR) has improved stability and the therapeutic window, enabling the progression of several BsADCs into Phase III trials.

CONCLUSION

BsADCs are a transformative therapeutic modality for breast cancer. Their ability to enhance tumor selectivity, overcome heterogeneity, and target resistant pathways positions them as key players in the future oncology landscape, with ongoing trials poised to define their clinical role.