{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:46:16Z","timestamp":1788486376176,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T00:00:00Z","timestamp":1758326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 &lt; 10 \u00b5g\/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.<\/jats:p>","DOI":"10.3390\/ijms26189185","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T13:04:44Z","timestamp":1758546284000},"page":"9185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["XON9\u2014A Glyco-Humanized Polyclonal Antibody Effective Against Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5534-7982","authenticated-orcid":false,"given":"Pierre-Joseph","family":"Royer","sequence":"first","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8814-529X","authenticated-orcid":false,"given":"Carine","family":"Ciron","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwenaelle","family":"Evanno","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oph\u00e9lie","family":"Dauphouy","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Rousse","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Graur","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odile","family":"Duvaux","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firas","family":"Bassissi","sequence":"additional","affiliation":[{"name":"Xenothera, 44200 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yang, H., Liu, Y., Zhang, N., Tao, F., and Yin, G. (2024). Therapeutic Advances in Hepatocellular Carcinoma: An Update from the 2024 ASCO Annual Meeting. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1453412"},{"key":"ref_2","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/hep.31288","article-title":"Epidemiology of Hepatocellular Carcinoma","volume":"73","author":"McGlynn","year":"2021","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41571-023-00825-3","article-title":"Global Trends in Hepatocellular Carcinoma Epidemiology: Implications for Screening, Prevention and Therapy","volume":"20","author":"Singal","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global Burden of Primary Liver Cancer in 2020 and Predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1159\/000529824","article-title":"Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials","volume":"12","author":"Tan","year":"2023","journal-title":"Liver Cancer"},{"key":"ref_7","first-page":"EVIDoa2100070","article-title":"Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma","volume":"1","author":"Lau","year":"2022","journal-title":"NEJM Evid."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/S1470-2045(23)00469-2","article-title":"Lenvatinib plus Pembrolizumab versus Lenvatinib plus Placebo for Advanced Hepatocellular Carcinoma (LEAP-002): A Randomised, Double-Blind, Phase 3 Trial","volume":"24","author":"Llovet","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S1470-2045(22)00326-6","article-title":"Cabozantinib plus Atezolizumab versus Sorafenib for Advanced Hepatocellular Carcinoma (COSMIC-312): A Multicentre, Open-Label, Randomised, Phase 3 Trial","volume":"23","author":"Kelley","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Wei, S., Xu, M., Wu, X., Dou, W., Li, H., Zhang, Z., and Zhang, S. (2024). CAR-T Cell Therapy for Hepatocellular Carcinoma: Current Trends and Challenges. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1489649"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Aggeletopoulou, I., Kalafateli, M., and Triantos, C. (2024). Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052631"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour Heterogeneity and Resistance to Cancer Therapies","volume":"15","author":"Shaw","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1080\/19420862.2017.1325051","article-title":"Contribution of Physiologists to the Identification of the Humoral Component of Immunity in the 19th Century","volume":"9","author":"Lahaie","year":"2017","journal-title":"mAbs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4655","DOI":"10.1172\/JCI82267","article-title":"Rabbit Antithymocyte Globulin\u2014Induced Serum Sickness Disease and Human Kidney Graft Survival","volume":"125","author":"Salama","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_16","first-page":"e166231","article-title":"Polyclonal Antibodies, Inhibit Selectively Tumor Growth and Invasion and Synergize with Immune Checkpoint Inhibitors","volume":"9","author":"Ciron","year":"2023","journal-title":"JCI Insight"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Poulakou, G., Royer, P.J., Evgeniev, N., Evanno, G., Shneiker, F., Marcelin, A.G., Vanhove, B., Duvaux, O., Marot, S., and Calvez, V. (2024). Anti-SARS-CoV-2 Glyco-Humanized Polyclonal Antibody XAV-19: Phase II\/III Randomized Placebo-Controlled Trial Shows Acceleration to Recovery for Mild to Moderate Patients with COVID-19. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1330178"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"ofad525","DOI":"10.1093\/ofid\/ofad525","article-title":"Effect of Swine Glyco-Humanized Polyclonal Neutralizing Antibody on Survival and Respiratory Failure in Patients Hospitalized with Severe COVID-19: A Randomized, Placebo-Controlled Trial","volume":"10","author":"Gaborit","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e139","DOI":"10.1097\/TP.0000000000004967","article-title":"First-in-Human Study with LIS1, a Next-Generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation","volume":"108","author":"Viklicky","year":"2024","journal-title":"Transplantation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1177\/1087057106292763","article-title":"Rapid Generation of Single-Tumor Spheroids for High-Throughput Cell Function and Toxicity Analysis","volume":"11","author":"Ivascu","year":"2006","journal-title":"J. Biomol. Screen."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.7150\/ijbs.26520","article-title":"Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth","volume":"14","author":"Li","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67061","DOI":"10.18632\/oncotarget.11489","article-title":"Potent in Vitro and in Vivo Effects of Polyclonal Anti-Human-Myeloma Globulins","volume":"7","author":"Schieferdecker","year":"2016","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.exphem.2005.08.004","article-title":"Antithymocyte Globulin Induces Complement-Dependent Cell Lysis and Caspase-Dependent Apoptosis in Myeloma Cells","volume":"33","author":"Ayuk","year":"2005","journal-title":"Exp. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.exphem.2014.07.260","article-title":"Anti-Tumor Effects of Anti-T-Cell Globulin","volume":"42","author":"Westphal","year":"2014","journal-title":"Exp. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1038\/srep04984","article-title":"Polyclonal Rabbit Anti-Human Ovarian Cancer Globulins Inhibit Tumor Growth through Apoptosis Involving the Caspase Signaling","volume":"4","author":"Zhang","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1007\/s10495-010-0568-7","article-title":"Polyclonal Rabbit Anti-Murine Plasmacytoma Cell Globulins Induce Myeloma Cells Apoptosis and Inhibit Tumour Growth in Mice","volume":"16","author":"Mu","year":"2011","journal-title":"Apoptosis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1182\/blood-2005-06-2269","article-title":"Apoptosis and Complement-Mediated Lysis of Myeloma Cells by Polyclonal Rabbit Antithymocyte Globulin","volume":"107","author":"Zand","year":"2006","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.aohep.2019.11.011","article-title":"Role of CD98 in Liver Disease","volume":"19","author":"Canup","year":"2020","journal-title":"Ann. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Jin, M., Zhang, J., Sun, Y., Liu, G., and Wei, X. (2025). ANXA5: Related Mechanisms of Osteogenesis and Additional Biological Functions. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1553683"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Che, L., Paliogiannis, P., Cigliano, A., Pilo, M.G., Chen, X., and Calvisi, D.F. (2019). Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma. Front. Oncol., 9, Erratum in Front. Oncol. 2022, 12, 874053.","DOI":"10.3389\/fonc.2022.874053"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1002\/1878-0261.12358","article-title":"Nogo-B Promotes Tumor Angiogenesis and Provides a Potential Therapeutic Target in Hepatocellular Carcinoma","volume":"12","author":"Cai","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.neo.2017.02.007","article-title":"Knockout of the Nogo-B Gene Attenuates Tumor Growth and Metastasis in Hepatocellular Carcinoma","volume":"19","author":"Zhu","year":"2017","journal-title":"Neoplasia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00262-024-03827-x","article-title":"A Monoclonal Antibody Recognizing CD98 on Human Embryonic Stem Cells Shows Anti-Tumor Activity in Hepatocellular Carcinoma Xenografts","volume":"73","author":"Lim","year":"2024","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e002140","DOI":"10.1136\/jitc-2020-002140","article-title":"Immunotherapy Using IgE or CAR T Cells for Cancers Expressing the Tumor Antigen SLC3A2","volume":"9","author":"Pellizzari","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.jconrel.2012.04.045","article-title":"Opportunities and Challenges for Use of Tumor Spheroids as Models to Test Drug Delivery and Efficacy","volume":"164","author":"Mehta","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1097\/TP.0000000000003047","article-title":"In Vivo Analysis of Human Immune Responses in Immunodeficient Rats","volume":"104","author":"Ouisse","year":"2020","journal-title":"Transplantation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10-1128","DOI":"10.1128\/AAC.01237-21","article-title":"Pharmacokinetics and Safety of XAV-19, a Swine Glyco-Humanized Polyclonal Anti-SARS-CoV-2 Antibody, for COVID-19-Related Moderate Pneumonia: A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study","volume":"65","author":"Gaborit","year":"2021","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9185\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:16Z","timestamp":1760035576000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,20]]},"references-count":37,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26189185"],"URL":"https:\/\/doi.org\/10.3390\/ijms26189185","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,20]]}}}