Abstract 1571: Discovery of c-MET degrading bispecific antibodies (EpiTACs) for NSCLC and other c-MET driven tumors

Abstract Extracellular targeted protein degradation (eTPD) has emerged as a promising new drug modality focused on the elimination of pathogenic extracellular and transmembrane proteins. In contrast to intracellular degraders, which require the ubiquitin-proteosome system, extracellular degraders can also harness endosomal-lysosomal protein degradation pathways. EpiTACs are a novel class of bispecific antibody-based eTPD therapeutic, in which one arm binds a target of interest, and the other arm binds a degrading receptor. EpiTACs leverage a novel atlas of disease- and tissue-enriched degrading receptors comprised of transmembrane ubiquitin ligases, cytokine/chemokine receptors, and internalizing receptors, resulting in selective protein degradation. EpiTACs are agnostic of oncogenic mutation status and can deeply antagonize oncogenic signaling through removal of the target and its associated scaffolding function. They also have advantageous pharmacological and drug-like manufacturing properties compared to other degradation technologies. We developed EpiTACs against oncogenic receptor tyrosine kinase family members including cellular mesenchymal-epithelial transition (c-MET) and epidermal growth factor receptor (EGFR). Genomic alterations of c-MET are oncogenic in a variety of cancers, including non-small cell lung cancer (NSCLC), where small molecule inhibitors have been clinically approved for exon 14 skipping mutations. Aberrations in c-MET have also been reported in gastric, colorectal, renal, pancreatic, skin and brain cancers. However, therapeutic benefit to patients has been limited by the broad array of primary and acquired c-MET mutations. Biologics against this target have demonstrated insufficient activity, likely related to antibody-mediated receptor dimerization, and associated pro-oncogenic signaling. A bioinformatics-informed set of cancer-focused degrading receptors was screened in tumor cell-based assays to identify degraders for c-MET. Top hits were enriched in NSCLC and other overexpressed/amplified tumors. c-MET degraders were overlapping and unique compared to previously reported screens conducted against EGFR. They drove internalization and degradation of c-MET in multiple tumor cell-based assays, including those carrying exon 14 skipping mutations and amplifications. Degradation of c-MET robustly inhibited tumor cells in vitro, and strongly suppressed patient-derived xenograft tumor models in vivo. These newly discovered degraders are being paired with novel c-MET binders that lack dimerization-induced signaling capacity, to create safer and more efficacious c-MET degrading therapeutics. In conclusion, eTPD represents a promising new drug modality, and EpiTACs have expanded the toolbox of extracellular targeted protein degraders to address challenging drug targets with a new approach. Citation Format: Jonathan Sitrin, Hai Tran, Lisa Marshall, Kenneth Ng, May Dayao, Jacob Cohen, Kimberly Hoi, Josef Gramespacher, Zhong Huang, Andy Goodrich, Kevin Carlin, Noah Solomon, Shruti Yadav, Aleysha Chen, Katarina Pance, Rami Hannoush, Maia Vinogradova, Isaac J. Rondon, Shyra J. Gardai. Discovery of c-MET degrading bispecific antibodies (EpiTACs) for NSCLC and other c-MET driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1571.