title: Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice.
abstract: Direct-acting antivirals (DAAs) have led to a high cure rate in treated patients with chronic hepatitis C virus (HCV) infection, but this still leaves a large number of treatment failures secondary to the emergence of resistance-associated variants (RAVs). To increase the barrier to resistance, a complementary strategy is to use neutralizing human monoclonal antibodies (HMAbs) to prevent acute infection. However, earlier efforts with the selected antibodies led to RAVs in animal and clinical studies. Therefore, we identified an HMAb that is less likely to elicit RAVs for affinity maturation to increase potency and, more important, breadth of protection. Selected matured antibodies show improved affinity and neutralization against a panel of diverse HCV isolates. Structural and modeling studies reveal that the affinity-matured HMAb mediates virus neutralization, in part, by inducing conformational change to the targeted epitope, and that the maturated light chain is responsible for the improved affinity and breadth of protection. A matured HMAb protected humanized mice when challenged with an infectious HCV human serum inoculum for a prolonged period. However, a single mouse experienced breakthrough infection after 63 days when the serum HMAb concentration dropped by several logs; sequence analysis revealed no viral escape mutation.
  
  
  
  The findings suggest that a single broadly neutralizing antibody can prevent acute HCV infection without inducing RAVs and may complement DAAs to reduce the emergence of RAVs. (Hepatology 2016;64:1922-1933).
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Zhen-Yong
authors.initials: ZY
authors.lastname: Keck
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lau
authors.affiliation: KMT Hepatech, Inc, Edmonton, Alberta, Canada.
authors.forename: Garry
authors.initials: G
authors.lastname: Lund
authors.affiliation: University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD.|Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD.
authors.forename: Sneha
authors.initials: S
authors.lastname: Rangarajan
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fauvelle
authors.affiliation: Integrated BioTherapeutics, Inc, Rockville, MD.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Liao
authors.affiliation: Integrated BioTherapeutics, Inc, Rockville, MD.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtsberg
authors.affiliation: Integrated BioTherapeutics, Inc, Rockville, MD.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: Integrated BioTherapeutics, Inc, Rockville, MD.
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
authors.affiliation: University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Pierce
authors.affiliation: University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Fuerst
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Bailey
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hépato-Digestif, Hôpitaux Universitaires de Strasbourg, Institut Hospitalo-universitaire (IHU), Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD.|Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD.
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
authors.affiliation: Departments of Surgery and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.|Department of Surgery and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Norman M
authors.initials: NM
authors.lastname: Kneteman
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Steven K H
authors.initials: SK
authors.lastname: Foung
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D000915:Antibody Affinity; D002478:Cells, Cultured; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000517:prevention & control*; D006801:Humans; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing