Abstract 3136: EOS-215, a first-in-class TREM2 antagonist, designed to reprogram the tumor microenvironment and overcome resistance

Abstract TREM2 (triggering receptor expressed on myeloid cells 2) is a central regulator of macrophage functions involved in tissue damage and resolution of inflammation in multiple pathologies. TREM2 macrophages have recently emerged to play a critical role in oncology, shaping a tolerogenic tumor microenvironment, favoring resistance to multiple therapeutic approaches (including anti-PD-1) and promoting metastasis, across solid tumor indications. EOS-215 a first-in-class human TREM2 antagonist, has been specifically designed to reprogram TREM2+ macrophages and block their pleiotropic pro-tumoral functions. This antibody demonstrates a sub-nanomolar affinity to human, cynomolgus and mouse TREM2. In Silico modeling has predicted that EOS-215 could compete with multiple TREM2 ligands such as phosphatidylserine (PS) and low density lipoprotein (LDL), and thereby prevent the TREM2 multimerization required for downstream signaling. Those predictions were confirmed in in vitro competition and signaling assays. Importantly EOS-215 was specifically selected among a panel of antibodies to potently inhibit efferocytosis, a key mechanism driving macrophage pro-tumoral functions, LAM (lipid associated macrophage) formation and involved in the metastatic niche formation. In vitro, EOS-215 profoundly impacted the transcriptomic program of various models of In monocyte derived macrophages. Hallmark gene set enrichment analysis (GSEA) revealed a significant enrichment in genes related to metabolism and regulation of the immune response, supporting the ability of EOS-215 to reprogram macrophages. This was further confirmed by increased secretion of pro-inflammatory markers from macrophages in response to EOS-215. In vivo efficacy of EOS-215 was first tested in the orthotopic 4T1 triple negative breast cancer model. This model shows limited response to anti-PD-1 and spontaneously leads to the development of lung metastasis. In this model, EOS215 decreased metastasis burden in monotherapy and this effect is reinforced when combined with anti-PD-1 treatment. In another anti-PD-1 resistant model, CT26, EOS-215 combined with anti-PD-1 significantly delayed tumor growth. In conclusion, EOS-215 is a potent TREM2 antagonist with a sub-nM potency proven preclinically to block pro-tumoral function in macrophages, consequently leading to in vivo efficacy. EOS-215 is now ready to enter clinical trials in 2025. Citation Format: Thibaut Janss, Romain Pirson, Virginie Rabolli, Iain Welsby, Clotilde Hoyos, Quentin Dubray, Laura Saerens, Jean-Philippe Deglasse, David Carbonez, Lennart Raman, Francesco Strozzi, Julie Chesne, Joao Matos Marchante, Reece Marillier, Yvonne McGrath, Catherine Hoofd. EOS-215, a first-in-class TREM2 antagonist, designed to reprogram the tumor microenvironment and overcome resistance [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 3136.