Abstract
Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients.
Highlights
Infection with hepatitis B virus (HBV) is one of the most serious global public health issues, insofar as approximately 296 million people are chronic carriers of HBV and 820,000 individuals die each year due to HBV-associated liver diseases [1]
Vimentin Was Induced by HBV In Vitro and vi-VIM Presence Was Increased in the Liver of HBV-Infected Patients and woodchuck hepatitis virus (WHV)-Infected Woodchucks
For testing VIM upregulation by HBV, HepG2 cells were infected with increasing doses of HBV and vi-VIM was detected via binding to the humanized hzVSF antibody by Western blot (Figure 2). hzVSF-bound vi-VIM increased dose-dependently during 2–12 h pi
Summary
Infection with hepatitis B virus (HBV) is one of the most serious global public health issues, insofar as approximately 296 million people are chronic carriers of HBV and 820,000 individuals die each year due to HBV-associated liver diseases [1]. DNA synthesis and lower the risk of liver disease progression, but require prolonged or even lifelong administration, because the persistent HBV covalently-closed circular (ccc) DNA genome within the nucleus of infected hepatocytes is not targeted, and viral replication typically rebounds after treatment discontinuation [3]. Novel drugs are wanted for incorporation into already applied treatment regimens for enhancing the HBV cure rate after a finite course of treatment. These new treatment regimens are thought to improve the survival of HBV-infected patients by preventing liver disease progression to cirrhosis and hepatocellular carcinoma (HCC), and subsequent death due to inoperable liver cancer
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