XON9-A Glyco-Humanized Polyclonal Antibody Effective Against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the main leading cause of cancer-related deaths. Treatments for advanced HCC include multikinase inhibitors (Sorafenib or Lenvatinib), with limited response rates and serious side effects, or immunotherapy applicable to a small fraction of patients. Thus, new strategies are needed to improve the management of HCC. We evaluate here the efficacy and safety of XON9, a first-in-class glyco-humanized polyclonal antibody (GH-pAb). Cytotoxic activity of XON9 against Hep3B, Huh7, HepG2 or primary hepatocytes was investigated. Apoptosis, caspase activity, production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were evaluated. Efficacy of XON9 was then assessed in vivo in NMRI nude mice, while pharmacokinetics and safety were evaluated in a non-human primate. XON9 showed a potent complement-dependent cytotoxicity (CDC) against Hep3B and Huh7 (EC50 < 10 µg/mL), and to a less extent against HepG2. XON9 induced apoptosis of HCC cells with activation of caspases 8 and 9, increase in ROS and drop in MMP. Overall, in vitro lytic activity of XON9 was superior to that of Sorafenib. In vivo, XON9 significantly reduced tumor progression and outperformed Sorafenib. No toxicity was observed after repeated injections of XON9 in a non-human primate. XON9 represents a promising and selective immunotherapy against refractory HCC.