Abstract 1666: Targeting the extra-cellular matrix in the tumor microenvironment with a novel antibody-drug conjugate

Abstract Background: Tumors with high stromal content are associated with poor prognosis, in part due to these tumors’ resistance to standard of care therapies and increased aggressiveness. A common, highly deregulated program of extensive ECM remodeling exists in most solid tumors. Therefore, targeting the tumor ECM with an antibody drug conjugate (ADC) offers a promising strategy to improve tumor selectivity and treatment efficacy. Methods: Proteomic analysis of decellularized tumor tissues processed to preserve ECM-bound proteins, and pan-cancer transcriptomic profiling of CAF-associated ECM genes was used to identify and validate target selection. Antibodies were developed against a novel, tumor microenvironment (TME)-specific antigen expressed in multiple solid tumors, including PDAC and CRC. High-affinity antibodies were conjugated to exatecan via a cleavable linker and efficacy was evaluated in an in vitro transwell-based tumor cell cytotoxicity assay. Results: Integrative analysis transcriptomic and proteomic analysis revealed numerous ECM proteins that are selectively expressed by CAFs and biochemically stable within the tumor matrix. Among these, we identified a target, EGTX004, that was consistently upregulated across multiple solid tumor types, and not expressed in adjacent non-tumor tissue or healthy control tissue samples. The increased and tumor-specific expression of EGTX004 was confirmed by IHC using proprietary antibodies against the target. EGTX004 expression is elevated early in tumorigenesis and increases as tumors progress to become more invasive.The antibodies against EGTX004 demonstrated positive target engagement in biochemical, cell-based stromal deposition with sub- to low nanomolar affinities (0.5 - 2 nM). EGTX004 ADCs were also demonstrated to have tumor killing activity in vitro. EGTX004 expression has also been found to be increased in a number of CDX and PDX models. The induction EGTX004 in these models appears to be driven by the mouse fibroblast response to the human tumor cell insult, and EGTX004 expression progresses as the tumors grow larger. Conclusions: Integrating transcriptomic and proteomic analyses of CAF-derived ECM proteins enables discovery of novel, broadly applicable ADC targets. Our findings provide compelling evidence that targeting the TME with a rationally designed ADC can yield robust anti-tumor responses. Citation Format: Matthew J. Edwards, Kovilen Sawmynaden, Aurelie Michelet, Edward Long, Rachel Evans, Dhruv Chauhan, Cecilia Pennica, Nafia Guljar, Cherie Akpotor, Luca Frenguelli, Gareth Muirhead, Sam Cooper, Athiva Shankar, TuVinh Luong, Emma Huang, Giuseppe Mazza, Chris Stevenson, . Targeting the extra-cellular matrix in the tumor microenvironment with a novel antibody-drug conjugate abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1666.