Abstract 3419: EPS 226, a novel HER2 targeting IgE therapeutic, delivers immune dependent anti-tumor activity in preclinical models of breast cancer

HER2 is expressed at low levels in approximately 30-40% of cancers, including in breast cancer patients. Therapeutic IgE antibodies have been shown to deliver robust immune-dependent preclinical anti-tumor activity across a wide range of antigen levels. To explore the potential utility of a HER2-targeting IgE for the treatment of low HER2 breast cancer, EPS 226 was profiled in two in vivo models.EPS 226 was tested in the HER2-low, trastuzumab-resistant, human breast cancer model, JIMT1, in PBMC engrafted mice and the rat metastatic breast cancer model, MTLn3, in a fully immune competent rat. Briefly, female NXG mice were implanted with JIMT1 cells subcutaneously and engrafted with PBMC in the presence of FLT3 ligand once the tumors reached 50mm3. Female Fischer rats were implanted with MTLn3 subcutaneously and once tumors reached 50mm3, they were randomized into treatment groups. Animals were dosed twice weekly with EPS 226 or appropriate controls by intravenous administration. Tumor volumes were assessed, and the tumors were formalin fixed, or snap frozen, for further analysis at the end of study.EPS 226 induced an antigen specific tumor cell killing of JIMT1 and MTLn3 cells via antibody dependent cellular cytotoxicity (ADCC) in vitro, in the presence of human or rat PBMCs respectively. In the JIMT1 model, EPS 226 resulted in a dose dependent tumor growth inhibition. At 20mg/kg, EPS 226 resulted in a 62±10% tumor growth inhibition in the presence of PBMCs. No anti-tumor activity was observed in the absence of PBMCs demonstrating this efficacy was immune dependent. To fully explore the impact of EPS 226 on the immune system a rat syngeneic model, MTLn3, was established and shown to express low levels of HER2. Across multiple experiments EPS 226 resulted in an average of 50% tumor growth inhibition. In contrast, in this model, anti-PDL1 did not statistically significantly impact tumor growth. The efficacy of EPS 226 was associated with a 1.9-fold increase in tumor resident macrophages compared to the PBS control. Histology analysis also demonstrated that EPS 226 resulted in a 2.7-fold increase in T cells, comprising of predominantly CD8+ T cells. RNA Seq analysis of the bulk tumor showed a statistically significant increase (p adj <0.05) in the activated CD8 T cell signature, compared to PBS controls.These studies are the first to demonstrate immune dependent anti-tumor efficacy of a novel HER2-targeting IgE antibody in models that have low HER2 expression. Treatment with EPS 226 resulted in an upregulation of immune cells, including an increased level of activated T cells, within the tumor microenvironment. These findings suggest that a HER2 targeting IgE has the potential to deliver clinical efficacy, in the context of low HER2 expressing patients, via a unique mechanism of action. Citation Format: Elizabeth Hardaker, Lais C. Palhares, Melanie Grandits, Katie Stoker, Jitesh Chauhan, Tim Wilson, Sophia N. Karagiannis, Heather J. Bax, Kevin FitzGerald. EPS 226, a novel HER2 targeting IgE therapeutic, delivers immune dependent anti-tumor activity in preclinical models of breast cancer [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 3419.