Combination Treatment with the Vimentin-Targeting Antibody hzVSF and Tenofovir Suppresses Woodchuck Hepatitis Virus Infection in Woodchucks

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.

Removal of Extracellular Vimentin in Blood Confers Resistance to Viral Infection

“…Considering the fact that current therapeutic agents such as Molnupiravir and Nirmatrelvir/ritonavir are limited to preventative use from progression to severe COVID-19 and remdesivir is the only antiviral drug for sever COVID-19 [46][47][48] , this work supports the pursuit for the development of hzVSF-v13 as a therapeutic agent for severe COVID-19. Also, this work provides an in vivo foundation for development of hzVSF-v13 as antiviral drugs to various viral infections such as SARS-CoV-1, cowpea mosaic virus, Japanese encephalitis virus, dengue virus, and human papillomavirus, in which eVIM plays an important pathogenic role [49][50][51] .…”

Extracellular vimentin as a modulator of the immune response and an important player during infectious diseases

“…Targeting eVim–pathogen interactions could be integrated into combination therapies alongside conventional antimicrobial agents. The combined therapeutic approach utilizing the vimentin‐targeting antibody hzVSF and tenofovir demonstrated significant efficacy in suppressing woodchuck hepatitis virus infection in woodchucks 96 . This approach holds promise for enhancing the effectiveness of existing treatments and reducing the likelihood of pathogen resistance development.…”

Double-Blind, Randomized, Placebo-Controlled Study on hzVSF-v13, a Novel Anti-Vimentin Monoclonal Antibody Drug as Add-on Standard of Care in the Management of Patients with Moderate to Severe COVID-19

“…In a woodchuck hepatitis virus (WHV) model, when hzVSF was provided, together with tenofovir (TAF), which is a conventional therapy for treatment of hepatitis infection, the antiviral effect was enhanced with a more profound suppression of WHV markers in serum and liver than when either drug was used alone. Because the TAF-induced antiviral effect was always transient, this emphasizes the significance of the sustained antiviral response mediated by combination treatment in half of the tested animals [ 10 ]. The compound also showed a good safety profile in a Phase I clinical trial in healthy volunteers.…”