The potent broadly neutralizing antibody VIR-3434 controls Hepatitis B and D Virus infection and reduces HBsAg in humanized mice
Journal of Hepatology(2022)
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
### 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.
* 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
MoreTranslated text
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined