Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody

Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer1. Cell entry of HCV2 and other pathogens3-5 is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model6 we show that a monoclonal antibody specific for TJ protein claudin-17 eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection via host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

Strategies to Preclude Hepatitis C Virus Entry

“…A CLDN1 mAb OM-7D3-B3 targeting CLDN1 extracellular loop was found to be effective in inhibiting HCV isolates in vitro [85]. Further experiments in human liver-chimeric mouse models confirmed its potency in preventing HCV infection and eliminating persistent infection in vivo [86]. Pretreatment of another anti-CLDN1 mAb 3A2 targeting CLDN1 extracellular loop also showed protective effect in a chimeric mouse model [87].…”

Enfermé dehors

“…Nous avons utilisé le modèle de souris chimériques afin de tester l'efficacité de cet anticorps anti-CLDN1 in vivo [11]. Contrairement aux études précédentes, nous avons évalué l'efficacité de l'anticorps à la fois dans la prévention de l'infection par le VHC et dans le traitement d'une infection persistante, en administrant l'anticorps petites molécules.…”

Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

“…1). Interestingly, several recent studies provided in vivo proof of the concept that interference with HCV cell entry by broadly virus-neutralizing antibodies or by host receptor-targeting antibodies is a viable therapeutic strategy capable of eliminating HCV (13,14), which stimulated attempts to develop HCV entry inhibitors as antiviral agents. The molecules that emerged as HCV entry inhibitors in the abovementioned screenings can be grouped into four basic chemical scaffolds, namely, the diphenyl-piperazines or diphenyl-piperidines, the phenothiazines, the thioxanthenes, and the cycloheptene-piperidines (Fig.…”