Abstract 4766: Characterization of XON9, an effective glyco-humanized polyclonal antibody against hepatocarcinoma

Context: Hepatocarcinoma is the second leading cause of cancer-related death, and its incidence is increasing. Multikinase inhibitors (Sorafenib or Lenvatinib) are the conventional first line treatment for unresectable HCC, with limited response rates and serious side effects. Although immune base therapies such as checkpoint inhibitors have recently showed promising results, they remain applicable to a small fraction of patients. Thus, new treatment and strategies are desperately needed to improve the management of hepatocarcinoma. We evaluate here the in vitro and in vivo efficacy and safety of XON9, first-in-class glyco-humanized polyclonal antibody (GH-pAb) against hepatocarcinoma. Material and methods: Cytotoxic activity of XON9 against HUH7, HepG2 and Hep3B cell lines was investigated and compared to the activity of standards of care Sorafenib and Lenvatinib. Primary hepatocytes were used as control. Mechanisms of apoptosis were further explored. Activity of caspases 8 and 9, level of reactive oxygen species (ROS) and mitochondrial membrane potential was investigated after treatment with XON9. The in vivo efficacy of XON9 was then assessed in NMRI nude engrafted with HUH7 cancer cells while pharmacokinetics and safety parameters were evaluated in a non-human primate after once weekly dosing at 50mg/kg over 2 weeks. Results: XON9 shows a potent complement dependent cytotoxicity (CDC) against HUH7, HepG2 and Hep3B cells (EC50<10µg/ml). By contrast, primary hepatocytes were relatively spared by XON9 (EC50>50µg/ml). Moreover, XON9 treatment induced apoptosis of the three cell lines tested with activation of caspases 8 and 9, increase of ROS levels and drop of mitochondrial membrane potential. Overall, in vitro lytic activity of XON9 towards HUH7, HepG2 and Hep3B was superior to that of Sorafenib and Lenvatinib, the current standards of care for hepatocarcinoma. In vivo, XON9 significantly reduced tumour progression in a mouse xenograft model (40% reduction at day 25). No toxicity was observed after repeated injections of 50mg/kg of XON9 in a non-human primate. Conclusion: Although recent immunotherapy advances have been made, hepatocarcinoma remains an incurable disease with a real need for innovative therapies. XON9 represents a promising and selective immunotherapy against refractory hepatocarcinoma. Citation Format: Pierre-Joseph Royer, Carine Ciron, Ophelie Dauphouy, George Graur, Odile Devaux, Firas Bassissi. Characterization of XON9, an effective glyco-humanized polyclonal antibody against hepatocarcinoma [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 4766.