Dual modality of EpiTAC bispecific degrader ADCs combines c-MET degradation with cytotoxic payload delivery to overcome limitations of current c-MET-targeted therapies
Presenter: Lisa Marshall, BS;MS Session: Antibody-Drug Conjugates and Linker Engineering 2 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Lisa Marshall , Jonathan Sitrin , Kenneth Ng , Shruti Yadav , May Dayao , Hai Tran , Josef Gramespacher , Jacob Cohen , Kimberly Hoi , Zhong Huang , Noah Solomon , John Coan , Andy Goodrich , Adison McLaggan , Sarah Yan , Brian Hillier , Danica Manalo-Hebert , Lichao Zhang , Maia Vinogradova , Isaac J. Rondon , Shyra J. Gardai EpiBiologics, San Mateo, CA
Abstract
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.
Disclosure
L. Marshall, EpiBiologics Employment, Stock Option. J. Sitrin, EpiBiologics Employment, Stock Option. K. Ng, EpiBiologics Employment, Stock Option. S. Yadav, EpiBiologics Employment, Stock Option. M. Dayao, EpiBiologics Employment, Stock Option. H. Tran, EpiBiologics Employment, Stock Option. J. Gramespacher, EpiBiologics Employment, Stock Option. J. Cohen, EpiBiologics Employment, Stock Option. K. Hoi, EpiBiologics Employment, Stock Option. Z. Huang, EpiBiologics Employment, Stock Option. N. Solomon, EpiBiologics Employment, Stock Option. J. Coan, EpiBiologics Employment, Stock Option. A. Goodrich, EpiBiologics Employment, Stock Option. A. McLaggan, EpiBiologics Employment, Stock Option. S. Yan, EpiBiologics Employment, Stock Option. B. Hillier, EpiBiologics Employment, Stock Option. D. Manalo-Hebert, EpiBiologics Employment, Stock Option. L. Zhang, EpiBiologics Employment, Stock Option. M. Vinogradova, EpiBiologics Employment, Stock Option. I. J. Rondon, EpiBiologics Employment, Stock Option. S. J. Gardai, EpiBiologics Employment, Stock Option.
Cited in
Control: 2493 · Presentation Id: 5397 · Meeting 21436