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J Gen Virol. 2016 Jan;97(1):82-94. doi: 10.1099/jgv.0.000330. Epub 2015 Oct 29.

Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb.

Author information

1
1​Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy 2​Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy.
2
3​School of Life Sciences, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK 4​NIHR Nottingham Digestive Diseases Centre, Biomedical Research Unit, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.
3
5​Keires AG, Bäumleingasse 18, CH 4051 Basel, Switzerland.
4
2​Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145 Napoli, Italy 1​Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', via Pansini 5, 80131 Napoli, Italy.

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.

PMID:
26519290
PMCID:
PMC5478175
DOI:
10.1099/jgv.0.000330
[Indexed for MEDLINE]
Free PMC Article

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