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

Paciello, Rolando; Urbanowicz, Richard A.; Riccio, Gennaro; Sasso, Emanuele; McClure, C. Patrick; Zambrano, Nicola; Ball, Jonathan K.; Cortese, Riccardo; Nicosia, Alfredo; De Lorenzo, Claudia

Authors

Rolando Paciello

Richard A. Urbanowicz

Gennaro Riccio

Emanuele Sasso

Nicola Zambrano

JONATHAN BALL jonathan.ball@nottingham.ac.uk
Professor of Molecular Virology

Riccardo Cortese

Alfredo Nicosia

Claudia De Lorenzo



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.

Citation

Paciello, R., Urbanowicz, R. A., Riccio, G., Sasso, E., McClure, C. P., Zambrano, N., …De Lorenzo, C. (2016). Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb. Journal of General Virology, 97(1), 82-94. https://doi.org/10.1099/jgv.0.000330

Journal Article Type Article
Acceptance Date Oct 27, 2015
Online Publication Date Jan 1, 2016
Publication Date Jan 1, 2016
Deposit Date Jan 27, 2017
Publicly Available Date Mar 28, 2024
Journal Journal of General Virology
Print ISSN 0022-1317
Electronic ISSN 1465-2099
Publisher Microbiology Society
Peer Reviewed Peer Reviewed
Volume 97
Issue 1
Pages 82-94
DOI https://doi.org/10.1099/jgv.0.000330
Public URL https://nottingham-repository.worktribe.com/output/767985
Publisher URL http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000330

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