携带双载荷的MET/HER3抗体药物偶联物：一种消除肿瘤逃逸机制的双靶点策略

Clinical evidence supports combination approaches such as EGFR plus MET TKIs, which achieve responses in MET-amplified resistance settings and demonstrate the critical role of MET signaling in acquired resistance. Meanwhile, HER3-directed ADCs have shown meaningful activity in refractory tumors, underscoring the therapeutic relevance of HER3 in resistant and heterogeneous cancer populations. Together, these findings highlight the rationale for co-targeting cMET and HER3, as simultaneous inhibition of these complementary pathways provides a strong foundation for the development of a bispecific ADC (BsADC) to overcome resistance and enhance antitumor efficacy. Our MET/HER3 bispecific ADC was constructed using the proprietary glycan-based site specific platform to simultaneously engage c-MET and HER3. The ADC carries two complementary cytotoxins- a microtubule inhibitor, MMAE and a topoisomerase I inhibitor derivative, exatecan, conjugated through the stable linker for controlled intracellular release and maximize antitumor activity. Blue native PAGE (BN-PAGE) and proximity ligation assay (PLA) data confirmed that simultaneous MET and HER3 engagement promote receptor clustering, enhancing internalization and intracellular payload delivery. In preclinical models, the bispecific dual-payload ADC induced stronger tumor regression than monospecific or parental ADCs. Broad activity was observed in c-MET/HER3 dual-positive non-small cell lung cancer and colorectal cancer models. This glycan-based site specific MET/HER3 bispecific dual-payload ADC warrants further clinical investigation as a promising therapeutic option for refractory tumors co-expressing cMET and HER3.