EpiTAC 双特异性降解剂 ADC 的双重模式将 c-MET 降解与细胞毒性载荷递送相结合，以克服当前 c-MET 靶向疗法的局限性

Extracellular targeted protein degradation (eTPD) is a new therapeutic modality designed to eliminate pathogenic extracellular and transmembrane proteins by leveraging proteosome and endosomal-lysosomal protein degradation pathways. EpiTACs are bispecific antibody-based eTPD therapeutics in which one arm binds to a pathogenic target protein and the other arm binds to a tissue-enriched degrading receptor to drive selective and potent protein removal. For the oncogenic receptor tyrosine kinase cMET, existing therapies such as tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) face limitations due to acquired resistance or off-target toxicities and dependence on high target expression in the case of ADCs. We developed EpiTACs and EpiTAC-ADCs to cMET to overcome these challenges using a novel mutation-independent mechanism of action to degrade oncogenic cMET and deliver a cytotoxic payload to drive deep, durable and broad responses across cMET tumors. We screened a panel of cancer-focused degrading receptors in cMET exon 14 skipping mutant and wild type amplified tumor cell-based assays and identified potent cMET-degrading EpiTACs that drove internalization and degradation independent of form in multiple tumor cell-based assays. Degradation of mutant cMET in vitro translated to strong tumor growth suppression in vivo, but not all tumor cell models responded to degradation alone. We developed EpiTAC-ADCs to solve for tumors that express cMET but do not rely exclusively on its oncogenic signaling. EpiTAC-ADCs demonstrated robust anti-tumor activity in vitro and in vivo xenograft tumor models, including cMET responsive and non-responsive models. Combining protein degradation with cytotoxic payload delivery induced strong anti-tumor activity against models with low cMET, where standard ADCs are ineffective. The dual mechanism of EpiTAC-ADCs also demonstrates robust activity at lower drug-antibody ratio (DAR), independent of cMET expression levels or oncogenic signaling dependence. EpiTAC-ADCs represent a novel class of eTPD therapeutics that can effectively degrade oncogenic receptors including cMET independent of mutation and form, while delivering a potent cytotoxic payload. This approach has the potential to address oncogenic driver and resistance mechanisms broadly across cMET-driven tumors. In addition to targeting cMET-high tumors, EpiTAC-ADCs have the potential to target low and medium cMET tumors in patients whose needs are not addressed by standard of care therapeutics including ADCs.