The potent broadly neutralizing antibody VIR-3434 controls Hepatitis B and D Virus infection and reduces HBsAg in humanized mice
Authors: Lempp Florian A. , Volz Tassilo , Cameroni Elisabetta , Benigni Fabio , Zhou Jiayi , Rosen Laura E. , Noack Julia , Zatta Fabrizia , Kaiser Hannah , Bianchi Siro , Lombardo Gloria , Jaconi Stefano , Imam Hasan , Soriaga Leah B. , Passini Nadia , Belnap David M. , Schulze Andreas , Lütgehetmann Marc , Telenti Amalio , Cathcart Andrea L. , Snell Gyorgy , Purcell Lisa A. , Hebner Christy M. , Urban Stephan , Dandri Maura , Corti Davide , Schmid Michael A. 
Published: September 2022

Background & Aims

Chronic hepatitis B is a major 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 promote functional cure of chronic hepatitis B and D to address this unmet medical need.

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 three 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 putative conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with >12,000-fold 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 intrahepatic HBV RNA and cccDNA increase. 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

This in vitro and in vivo characterization identified the potent anti-HBs mAb VIR-3434, which 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.

Lay summary

Chronic infection with hepatitis B virus places approximately 290 million individuals worldwide at risk for severe liver disease and cancer. Currently 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.

Highlights

Identification of a human mAb VIR-3434 that potently neutralizes HBV and HDV

VIR-3434 targets a conserved, conformational epitope of the HBsAg antigenic loop

VIR-3434 treatment blocks intrahepatic HBV spread in human liver-chimeric mice

VIR-3434 treatment reduces circulating HBsAg and HDV RNA in co-infected mice

Data have enabled clinical development of VIR-3434 against chronic hepatitis B/D