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Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees

Trevor J. Morin, University of Massachusetts Medical School
Teresa J. Broering, University of Massachusetts Medical School
Brett A. Leav, University of Massachusetts Medical School
Barbara M. Blair, University of Massachusetts Medical School
Kirk J. Rowley, University of Massachusetts Medical School
Elisabeth N. Boucher, University of Massachusetts Medical School
Yang Wang, University of Massachusetts Medical School
Peter S. Cheslock, University of Massachusetts Medical School
Michael Knauber, University of Massachusetts Medical School
David B. Olsen, Merck Research Laboratories
Steve W. Ludmerer, Merck Research Laboratories
Gyongyi Szabo, University of Massachusetts Medical School
Robert W. Finberg, University of Massachusetts Medical School
Robert H. Purcell, National Institutes of Health
Robert E. Lanford, Texas Biomedical Research Institute
Donna M. Ambrosino, University of Massachusetts Medical School
Deborah C. Molrine, University of Massachusetts Medical School
Gregory J. Babcock, University of Massachusetts Medical School

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Citation: PLoS Pathog. 2012 Aug;8(8):e1002895. Epub 2012 Aug 30. Link to article on publisher's site

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log(10) reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.

Suggested Citation

Trevor J. Morin, Teresa J. Broering, Brett A. Leav, Barbara M. Blair, Kirk J. Rowley, Elisabeth N. Boucher, Yang Wang, Peter S. Cheslock, Michael Knauber, David B. Olsen, Steve W. Ludmerer, Gyongyi Szabo, Robert W. Finberg, Robert H. Purcell, Robert E. Lanford, Donna M. Ambrosino, Deborah C. Molrine, and Gregory J. Babcock. "Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees" PLoS pathogens 8.8 (2012).
Available at: http://works.bepress.com/gyongyi_szabo/140