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Abstract
Objective 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.
Design 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.
Results 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.
Conclusions 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.
- HEPATITIS C
- ANTIVIRAL THERAPY
- TIGHT JUNCTION
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Footnotes
CCC and RGT contributed equally as co-first authors.
Contributors CCC and RGT contributed equally. TFB initiated and supervised the study. CCC, RGT, LM, CT, LH, SCD, FX and ER performed the experiments. PP provided essential reagents. CCC, RGT, MBZ and TFB analysed data. CCC, RGT, MZB and TFB wrote the manuscript.
Funding This study was supported by funding from the European Union (FP7 HEPAMAB GAN 305600, ERC-2014-AdG-HEPCIR, EU H2020 HEPCAR and Interreg IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012), the Agence Nationale de Recherche sur le SIDA (ANRS) (2012/318, 2013/108) the Direction Générale de l'Offre de Soins (A12027MS) and the US National Institutes of Health (1U19AI123862-01). This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the Future programme. CCC is supported by fellowships from the Canadian Institutes of Health Research (201411MFE-338606-245517) and the Canadian Network on Hepatitis C.
Competing interests TFB is a co-inventor on a patent application on monoclonal anti-claudin1 antibodies for the inhibition of HCV infection (US patent no. 8,518,408; WO2010034812; PCT/EP 08 305 597 0).
Patient consent Obtained.
Ethics approval Strasbourg University Hospitals (CPP 10-17).
Provenance and peer review Not commissioned; externally peer reviewed.