Pre-clinical characterization of an HBsAg-specific monoclonal antibody preventing HBV spreading and reducing HBV, HDV and HBsAg in serum of humanized mice

Treatment using monoclonal antibodies targeting the HBV surface proteins has the potential to induce functional cure not only in chronic HBV (CHB) patients but also in individuals coinfected with HDV, which depends on HBsAg for its life cycle. HBC34, the parental molecule of VIR-3434, is a human monoclonal antibody targeting the antigenic loop present in all HBV surface proteins (L-/M-/S-HBsAg). VIR-3434 is currently in Phase 1/2 clinical development.

Methods 3-weeks post HBV inoculation (spreading model) human liver chimeric mice received either HBC34 (1mg/kg/2-times/week), control antibodies, or entecavir for 6 weeks. Chronic HBV infected mice received HBC34, lamivudine or both drugs in combination (6-weeks). HBV/HDV coinfected mice received HBC34 (4-weeks). Viral markers were measured by ELISA, RT-qPCR and immunofluorescence.

Results HBV spreading and increase of intrahepatic viral markers were efficiently blocked in mice receiving HBC34 or entecavir. In chronic HBV monoinfected mice, HBC34, Lam or combination treatment caused 0.7log, 1.3log and 2.4log viremia reduction, respectively. HBsAg dropped 1.3log in mice receiving HBC34 alone and 2.6log in the combination group, but not in Lam treated mice. HBC34 administration in HBV/HDV coinfected mice efficiently reduced HBV (2.1log) and HDV (2.8log) viremia and HBsAg levels (2.7log), while HBeAg and intrahepatic viral loads remained unchanged.

Conclusion HBC34 potently blocked intrahepatic HBV spreading and lowered HBV and HDV viremia in chronically infected mice. The strong HBsAg reduction indicates that HBC34 could accelerate HBsAg clearance both in HBV and HBV/HDV infected patients. These data support the development of VIR-3434 for treatment of chronic HBV and HBV/HDV infection.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022