A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo

Desombere, Isabelle; Mesalam, Ahmed Atef; Urbanowicz, Richard A.; Van Houtte, Freya; Verhoye, Lieven; Keck, Zhen-Yong; Farhoudi, Ali; Vercauteren, Koen; Weening, Karin E.; Baumert, Thomas F.; Patel, Arvind H.; Foung, Steven K.H.; Ball, Jonathan; Leroux-Roels, Geert; Meuleman, Philip

Abstract

Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the effi cacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. Conclusion : mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.

Citation

Desombere, I., Mesalam, A. A., Urbanowicz, R. A., Van Houtte, F., Verhoye, L., Keck, Z.-Y., Farhoudi, A., Vercauteren, K., Weening, K. E., Baumert, T. F., Patel, A. H., Foung, S. K., Ball, J., Leroux-Roels, G., & Meuleman, P. (2017). A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo. Antiviral Research, 148, https://doi.org/10.1016/j.antiviral.2017.10.015

• Journal Article Type: Article
• Acceptance Date: Oct 16, 2017
• Online Publication Date: Oct 23, 2017
• Publication Date: Dec 31, 2017
• Deposit Date: Nov 24, 2017
• Publicly Available Date: Nov 24, 2017
• Journal: Antiviral Research
• Print ISSN: 0166-3542
• Electronic ISSN: 1872-9096
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 148
• DOI: https://doi.org/10.1016/j.antiviral.2017.10.015
• Keywords: Hepatitis C virus; envelope protein; neutralizing antibody; chimeric mice; liver transplantation; vaccine
• Public URL: https://nottingham-repository.worktribe.com/output/902458
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S0166354217304308?via%3Dihub
• Contract Date: Nov 24, 2017