Abstract
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
Competing Interest Statement
F.A.L, E.C., F.B., J.Z, L.E.R., J.N., F.Z., H.K., S.B., G.L., S.J., H.I., L.B.S., N.P., M.L., A.T., A.L.C., G.S., L.A.P., C.M.H., D.C., M.A.S are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. L.A.P. is a former employee and shareholder in Regeneron Pharmaceuticals. D.M.B. received funding from Vir Biotechnology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. SU is inventor and holder on patents protecting bulevirtide.
Abbreviations
- Anti-HBs
- Antibody directed against HBsAg
- AGL
- Antigenic loop
- BL
- Base line
- BLI
- Bio-layer interferometry
- CHB
- Chronic hepatitis B
- ETV
- Entecavir
- FcRn
- Neonatal Fc receptor
- FcγRs
- Fc gamma receptors
- HBIG
- Hepatitis B immunoglobulins
- HBsAg
- Hepatitis B surface antigen
- HBV
- Hepatitis B virus
- HDV
- Hepatitis delta virus
- HSPG
- Heparan sulfate proteoglycan
- mAb
- Monoclonal antibody
- NRTIs
- Nucleos(t)ide reverse transcriptase inhibitors
- NTCP
- Sodium taurocholate co-transporting polypeptide
- PEG-IFNa
- Pegylated-interferon alpha
- PHH
- Primary human hepatocytes
- SD
- Standard deviation
- SVP
- Subviral particle
- TEM
- Transmission electron microscopy
- USG
- uPA/SCID beige
