Potent broadly neutralizing antibody VIR-3434 controls hepatitis B and D virus infection and reduces HBsAg in humanized mice

Florian A Lempp; Tassilo Volz; Elisabetta Cameroni; Fabio Benigni; Jiayi Zhou; Laura E Rosen; Julia Noack; Fabrizia Zatta; Hannah Kaiser; Siro Bianchi; Gloria Lombardo; Stefano Jaconi; Lucia Vincenzetti; Hasan Imam; Leah B Soriaga; Nadia Passini; David M Belnap; Andreas Schulze; Marc Lütgehetmann; Amalio Telenti; Andrea L Cathcart; Gyorgy Snell; Lisa A Purcell; Christy M Hebner; Stephan Urban; Maura Dandri; Davide Corti; Michael A Schmid

doi:10.1016/j.jhep.2023.07.003

Potent broadly neutralizing antibody VIR-3434 controls hepatitis B and D virus infection and reduces HBsAg in humanized mice

J Hepatol. 2023 Nov;79(5):1129-1138. doi: 10.1016/j.jhep.2023.07.003. Epub 2023 Jul 17.

Authors

Florian A Lempp¹, Tassilo Volz², Elisabetta Cameroni³, Fabio Benigni³, Jiayi Zhou⁴, Laura E Rosen⁴, Julia Noack⁴, Fabrizia Zatta³, Hannah Kaiser⁴, Siro Bianchi³, Gloria Lombardo³, Stefano Jaconi³, Lucia Vincenzetti³, Hasan Imam⁴, Leah B Soriaga⁴, Nadia Passini³, David M Belnap⁵, Andreas Schulze⁶, Marc Lütgehetmann⁷, Amalio Telenti⁴, Andrea L Cathcart⁴, Gyorgy Snell⁴, Lisa A Purcell⁴, Christy M Hebner⁴, Stephan Urban⁸, Maura Dandri², Davide Corti³, Michael A Schmid⁹

Affiliations

¹ Vir Biotechnology, San Francisco, California 94158, USA. Electronic address: flempp@vir.bio.
² Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems and Heidelberg Sites, Germany.
³ Humabs Biomed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
⁴ Vir Biotechnology, San Francisco, California 94158, USA.
⁵ School of Biological Sciences and Department of Biochemistry, University of Utah, Salt Lake City, Utah 84112, USA.
⁶ Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁷ German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems and Heidelberg Sites, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
⁸ German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems and Heidelberg Sites, Germany; Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁹ Humabs Biomed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland. Electronic address: mschmid@vir.bio.

PMID: 37459920
DOI: 10.1016/j.jhep.2023.07.003

Abstract

Background & aims: Chronic hepatitis B is a global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to treat chronic hepatitis B and chronic hepatitis D.

Methods: HBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting 3 weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase).

Results: From a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with higher potency than hepatitis B immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and the increase in intrahepatic HBV RNA and covalently closed circular DNA. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs.

Conclusions: The potently neutralizing anti-HBs mAb VIR-3434 reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D.

Impact and implications: Chronic infection with hepatitis B virus and co-infection with hepatitis D virus place approximately 290 million individuals worldwide at risk of severe liver disease and cancer. Available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D.

Keywords: HBsAg; Hepatitis B virus (HBV); Hepatitis delta virus (HDV); anti-HBs; chronic infection; human liver chimeric mice; monoclonal antibody (mAb); neutralization; virus spread.