A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
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 become...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
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Elsevier
2017
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| Online Access: | https://eprints.nottingham.ac.uk/48357/ |
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| author | 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 |
| author_facet | 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 |
| author_sort | Desombere, Isabelle |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:08:46Z |
| format | Article |
| id | nottingham-48357 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:08:46Z |
| publishDate | 2017 |
| publisher | Elsevier |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-483572020-05-04T19:24:54Z https://eprints.nottingham.ac.uk/48357/ 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 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. Elsevier 2017-12-31 Article PeerReviewed 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 and Meuleman, Philip (2017) A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo. Antiviral Research, 148 . pp. 53-64. ISSN 1872-9096 Hepatitis C virus; envelope protein; neutralizing antibody; chimeric mice; liver transplantation; vaccine http://www.sciencedirect.com/science/article/pii/S0166354217304308?via%3Dihub doi:10.1016/j.antiviral.2017.10.015 doi:10.1016/j.antiviral.2017.10.015 |
| spellingShingle | Hepatitis C virus; envelope protein; neutralizing antibody; chimeric mice; liver transplantation; vaccine 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 A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo |
| title | A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo |
| title_full | A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo |
| title_fullStr | A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo |
| title_full_unstemmed | A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo |
| title_short | A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo |
| title_sort | novel neutralizing human monoclonal antibody broadly abrogates hepatitis c virus infection in vitro and in vivo |
| topic | Hepatitis C virus; envelope protein; neutralizing antibody; chimeric mice; liver transplantation; vaccine |
| url | https://eprints.nottingham.ac.uk/48357/ https://eprints.nottingham.ac.uk/48357/ https://eprints.nottingham.ac.uk/48357/ |