Abstract 1588: The novel trispecific tumor-conditional TRAIL-R agonist M0674 induces tumor cell apoptosis and deepens therapeutic efficacy of systemic and targeted chemotherapies

Abstract Background: TRAIL death receptors are upregulated in a wide range of tumors, and their pharmacological activation induces apoptosis. Targeting TRAIL receptors (TRAIL-R) has emerged as a critical therapeutic strategy for cancer treatment. Despite some evidence for preclinical activity with past and present TRAIL-R agonists, only limited clinical efficacy has been reported so far, likely due to insufficient TRAIL-R clustering, decoy receptor binding, and hepatotoxicity. To address these limitations, M0674 has been designed as a trispecific antibody that simultaneously binds to tumor-associated (TA) MUC1, TRAIL-R1 and TRAIL-R2 but not to TRAIL decoy receptors. Methods: We conducted a detailed pharmacological characterization of M0674 compared to other TRAIL-R agonists through in vitro and in vivo studies. Apoptosis and viability assays were performed on cancer cells and human hepatocytes. The antitumor activity of M0674, both as a monotherapy and in combination with chemotherapy and an anti-CEACAM5 ADC with an exatecan payload (M9140), was evaluated using cell line-derived (CDX) and patient-derived (PDX) xenograft models. Results: Treatment with M0674 results in potent TA-MUC1-dependent induction of apoptosis and inhibition of viability in cancer cell lines, while human hepatocytes remain unaffected. M0674 demonstrates superior antitumor activity compared to other TRAIL-R agonists in both in vitro and in vivo studies. In vivo models show strong antitumor effects, including regressions, when M0674 is combined with systemic and targeted chemotherapies. MUC1-dependent single-agent activity and combination benefits with docetaxel are observed in three out of five nsqNSCLC PDX models that do not respond to docetaxel alone. Additionally, five out of six PDAC PDX models exhibit a strong combination benefit of M0674 with gemcitabine. Furthermore, the combination of M0674 with the anti-CEACAM5 ADC M9140 induces complete regression in a gastric CDX model. Conclusion: M0674 induces tumor-specific hyperclustering of TRAIL-R1 and R2 by binding to TA-MUC1, effectively triggering apoptosis in tumor cells without affecting healthy cells. The robust preclinical antitumor activity across various cancer types highlights the potential of M0674 as a safe and effective combination partner for systemic chemotherapies and ADCs. Citation Format: Christina Esdar, Doreen Musch, Carolin Sellmann, Ana Hecht, Achim Doerner, Enrico Guarnera, Julian Kreis. The novel trispecific tumor-conditional TRAIL-R agonist M0674 induces tumor cell apoptosis and deepens therapeutic efficacy of systemic and targeted chemotherapies [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 1588.