Abstract 6391: OMTX705: A dual-mechanism ADC targeting FAP-positive CAFs, to overcome chemo and immunotherapy resistance in solid tumors

Abstract ADCs targeting the tumor stroma offer a promising strategy to address tumor heterogeneity. Traditional tumor-targeting ADCs face limitations, as intratumor and interpatient variability in target protein expression can result in incomplete targeting. In contrast, the tumor stroma is more genetically stable and consistent across patients. CAFs, the predominant stromal cell type within the tumor microenvironment, play a critical role in cancer progression and immune evasion in multiple cancers. OMTX705, a clinical-stage ADC, targets FAP-positive CAFs in the tumor microenvironment. OMTX705 presents an optimized and highly stable linker and it is quickly internalized and transported to late endosomal compartments in FAP-expressing cells. Its novel cytolysin-based payload demonstrates strong cell killing activity upon specific ADC internalization in FAP positive cells. Indeed, enhanced cytotoxicity was observed when compared to MMAE, particularly in cells with high PgP expression, offering a potential solution for tumor drug resistance. OMTX705 has demonstrated preclinical robust efficacy, achieving 100% tumor growth inhibition and even regression, in PDX murine models for pancreatic, gastric, ovarian, triple negative breast and lung cancers, with or without humanized immune systems, and showing no significant toxicity. Higher anti-tumoral effect was evidenced over both classical chemotherapy and modern immunotherapy drugs, as a single agent or in combination therapies with Gemcitabine/Abraxane or immune checkpoint inhibitors. OMTX705 even displays superiority compared to other FAP-targeted ADCs bearing different payloads such as deruxtecan in pancreas cancer models. Moreover, it exhibits high plasma stability and excellent safety profile, with no adverse effects observed in non-human primates at doses up to 100 mg/kg. OMTX705 operates through a dual mechanism of action. First, upon ADC internalization, the bystander effect of the payload released from FAP-positive CAFs leads to efficient killing of neighboring tumor cells. This effect has been validated through different experimental techniques in vitro and in preclinical tumor samples. The second mechanism involves immune cell infiltration within the tumor microenvironment, further strengthening its therapeutic potential. This dual effect, combined with a favorable safety profile, positions OMTX705 as a promising candidate among cancer therapeutics, targeting the stroma in solid tumors and enhancing antitumor immune responses. Citation Format: Patricia González, Isabel Egaña, Cristina Ferrer, Roland Kontermann, Oliver Seifert, Klaus Pfizenmaier, Wolfgang Richter, Laureano Simon, Myriam Fabre. OMTX705: A dual-mechanism ADC targeting FAP-positive CAFs, to overcome chemo and immunotherapy resistance in solid 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 6391.