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Antiviral Res. 2019 Feb;162:136-141. doi: 10.1016/j.antiviral.2018.12.018. Epub 2018 Dec 30.

In vivo combination of human anti-envelope glycoprotein E2 and -Claudin-1 monoclonal antibodies for prevention of hepatitis C virus infection.

Author information

1
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France.
2
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France; Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France.
3
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
4
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
5
University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, USA; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA.
6
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Universitaire de France, Paris, France. Electronic address: thomas.baumert@unistra.fr.

Abstract

Despite the development of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection remains a major cause for liver disease and cancer worldwide. Entry inhibitors block virus host cell entry and, therefore, prevent establishment of chronic infection and liver disease. Due to their unique mechanism of action, entry inhibitors provide an attractive antiviral strategy in organ transplantation. In this study, we developed an innovative approach in preventing HCV infection using a synergistic combination of a broadly neutralizing human monoclonal antibody (HMAb) targeting the HCV E2 protein and a host-targeting anti-claudin 1 (CLDN1) humanized monoclonal antibody. An in vivo proof-of-concept study in human liver-chimeric FRG-NOD mice proved the efficacy of the combination therapy at preventing infection by an HCV genotype 1b infectious serum. While administration of individual antibodies at lower doses only showed a delay in HCV infection, the combination therapy was highly protective. Furthermore, the combination proved to be effective in preventing infection of primary human hepatocytes by neutralization-resistant HCV escape variants selected during liver transplantation, suggesting that a combination therapy is suited for the neutralization of difficult-to-treat variants. In conclusion, our findings suggest that the combination of two HMAbs targeting different steps of virus entry improves treatment efficacy while simultaneously reducing treatment duration and costs. Our approach not only provides a clinical perspective to employ HMAb combination therapies to prevent graft re-infection and its associated liver disease but may also help to alleviate the urgent demand for organ transplants by allowing the transplantation of organs from HCV-positive donors.

KEYWORDS:

Antivirals; Entry inhibitors; HCV; Humanized liver-chimeric mice; Synergy; Transplantation

PMID:
30599173
PMCID:
PMC6463510
[Available on 2020-02-01]
DOI:
10.1016/j.antiviral.2018.12.018

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