title: Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb.
abstract: Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver carcinoma and new therapies based on novel targets are needed. The tight junction protein claudin 1 (CLDN-1) is essential for HCV cell entry and spread, and anti-CLDN-1 rat and mouse mAbs are safe and effective in preventing and treating HCV infection in a human liver chimeric mouse model. To accelerate translation of these observations into a novel approach to treat HCV infection and disease in humans, we screened a phage display library of human single-chain antibody fragments by using a panel of CLDN-1-positive and -negative cell lines and identified phage specifically binding to CLDN-1. The 12 clones showing the highest levels of binding were converted into human IgG4. Some of these mAbs displayed low-nanomolar affinity, and inhibited infection of human hepatoma Huh7.5 cells by different HCV isolates in a dose-dependent manner. Cross-competition experiments identified six inhibitory mAbs that recognized distinct epitopes. Combination of the human anti-SRB1 mAb C-1671 with these anti-CLDN-1 mAbs could either increase or reduce inhibition of cell culture-derived HCV infection in vitro. These novel human anti-CLDN-1 mAbs are potentially useful to develop a new strategy for anti-HCV therapy and lend support to the combined use of antibodies targeting the HCV receptors CLDN-1 and SRB1, but indicate that care must be taken in selecting the proper combination.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.|Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.
authors.forename: Rolando
authors.initials: R
authors.lastname: Paciello
authors.affiliation: School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.|NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Urbanowicz
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.|Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Riccio
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.|Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sasso
authors.affiliation: School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.|NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: McClure
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.|Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.affiliation: School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.|NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Ball
authors.affiliation: Keires AG, Bäumleingasse 18, CH 4051 Basel, Switzerland.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.|Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.affiliation: Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: De Lorenzo
mesh_terms: D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000378:metabolism*; D000998:Antiviral Agents / Q000302:isolation & purification / Q000378:metabolism*; D002460:Cell Line; D062445:Claudin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008962:Models, Theoretical; D019151:Peptide Library; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors* / Q000276:immunology; D057127:Single-Chain Antibodies / Q000302:isolation & purification / Q000378:metabolism*; D019562:Viral Load; D014776:Virus Cultivation; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D062445:Claudin-1; D019151:Peptide Library; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D057127:Single-Chain Antibodies