Abstract 4765: Suppression of triple-negative breast cancer metastasis by a new glyco-humanized polyclonal antibody

Abstract Context: Triple-negative breast cancer (TNBC) is an aggressive subtype accounting for 15-20% of breast cancer cases, characterized by poor prognosis, high recurrence rates, and limited treatment options. The lack of hormone receptors associated with a high level of molecular heterogeneity of TNBC hinders the development of effective therapies. Chemotherapy remains the standard of care but is often compromised by resistance and toxicity, emphasizing the urgent need for innovative treatments. Here, we assess the efficacy of XON7, a first-in-class glyco-humanized polyclonal antibody (GH-pAb), in preclinical models of TNBC. Methods: The anti-tumor efficacy of XON7 was assessed in TNBC cell lines for its capacity to induce complement-dependent cytotoxicity (CDC) and apoptosis, compared to paclitaxel and the ADC Sacituzumab Govitecan. Apoptotic mechanisms were explored by evaluating caspase 8/9 activation, reactive oxygen species (ROS) levels, and mitochondrial membrane potential. In vitro 3D cultures, XON7's ability to inhibit tumor growth, spheroid formation, and metastasis was tested. In vivo antitumor efficacy was evaluated in orthotopic and metastatic models in SRG rats inoculated with MDA-MB-231-Luc cells, using bioluminescence imaging. Results: XON7 demonstrated potent and selective cytotoxicity across human TNBC cell lines (80-100% cytotoxicity), sparing healthy PBMCs. Apoptotic induction involved both intrinsic and extrinsic pathways, evidenced by caspase 8/9 activation, ROS generation, and mitochondrial membrane potential loss. In 3D cultures, XON7 reduced spheroid size by 50% after two treatments (300 µg/ml) and significantly decreased cancer cell viability (28% remaining). Pre-treatment with XON7 prevented spheroid formation, outperforming paclitaxel and sacituzumab govitecan. XON7 also inhibited metastasis in transwell invasion assays. In vivo, bi-weekly XON7 treatments reduced tumor growth by 50% and eliminated lung metastases in an orthotopic rat model. In a metastatic model, tri-weekly XON7 treatments reduced total metastases (lung, liver, etc.) by 90%. Conclusion: XON7 is a multi-target antibody currently under clinical evaluation, it represents a promising candidate for advancing treatment paradigms in TNBC. Citation Format: Carine Ciron, Ophélie Dauphouy, Pierre-Joseph Royer, Pierre Morice, Odile Duvaux, Firas Bassissi. Suppression of triple-negative breast cancer metastasis by a new glyco-humanized polyclonal antibody [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 4765.