title: Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape.
abstract: HCV infection is a leading cause of chronic liver disease and a major indication for liver transplantation. Although direct-acting antivirals (DAAs) have much improved the treatment of chronic HCV infection, alternative strategies are needed for patients with treatment failure. As an essential HCV entry factor, the tight junction protein claudin-1 (CLDN1) is a promising antiviral target. However, genotype-dependent escape via CLDN6 and CLDN9 has been described in some cell lines as a possible limitation facing CLDN1-targeted therapies. Here, we evaluated the clinical potential of therapeutic strategies targeting CLDN1.
  
  
  
  We generated a humanised anti-CLDN1 monoclonal antibody (mAb) (H3L3) suitable for clinical development and characterised its anti-HCV activity using cell culture models, a large panel of primary human hepatocytes (PHH) from 12 different donors, and human liver chimeric mice.
  
  
  
  H3L3 pan-genotypically inhibited HCV pseudoparticle entry into PHH, irrespective of donor. Escape was likely precluded by low surface expression of CLDN6 and CLDN9 on PHH. Co-treatment of a panel of PHH with a CLDN6-specific mAb did not enhance the antiviral effect of H3L3, confirming that CLDN6 does not function as an entry factor in PHH from multiple donors. H3L3 also inhibited DAA-resistant strains of HCV and synergised with current DAAs. Finally, H3L3 cured persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy.
  
  
  
  Overall, these findings underscore the clinical potential of CLDN1-targeted therapies and describe the functional characterisation of a humanised anti-CLDN1 antibody suitable for further clinical development to complement existing therapeutic strategies for HCV.
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Che C
authors.initials: CC
authors.lastname: Colpitts
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Rajiv G
authors.initials: RG
authors.lastname: Tawar
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mailly
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Thumann
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Heydmann
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Durand
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Robinet
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.|Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Patrick
authors.identifier: 0000-0001-5635-7437
authors.initials: P
authors.lastname: Pessaux
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|University of Strasbourg, Strasbourg, France.|Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D062445:Claudin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; C568108:CLDN1 protein, human; D062445:Claudin-1; D007155:Immunologic Factors
keywords: ANTIVIRAL THERAPY; HEPATITIS C; TIGHT JUNCTION