Abstract
Hepatitis B virus (HBV) infection is a major global health problem. Currently-available therapies are ineffective in curing chronic HBV infection. HBV and its satellite hepatitis D virus (HDV) infect hepatocytes via binding of the preS1 domain of its large envelope protein to sodium taurocholate cotransporting polypeptide (NTCP). Here, we developed novel human monoclonal antibodies that block the engagement of preS1 with NTCP and neutralize HBV and HDV with high potency. One antibody, 2H5-A14, functions at picomolar level and exhibited neutralization-activity-mediated prophylactic effects. It also acts therapeutically by eliciting antibody-Fc-dependent immunological effector functions that impose durable suppression of viral infection in HBV-infected mice, resulting in reductions in the levels of the small envelope antigen and viral DNA, with no emergence of escape mutants. Our results illustrate a novel antibody-Fc-dependent approach for HBV treatment and suggest 2H5-A14 as a novel clinical candidate for HBV prevention and treatment of chronic HBV infection.
Highlights
Human hepatitis B virus (HBV) infects more people than does Hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV) combined (World Health Organization, 2016)
We discovered that the preS1 domain of the L protein binds to the liver bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP) in hepatocytes and thusly mediates viral entry of HBV and Hepatitis D virus (HDV) (Yan et al, 2012; Li, 2015)
To identify Neutralizing antibodies (nAbs) that block viral infection, we used preS1 peptides derived from the preS1 domain of the HBV L protein (Figure 1—figure supplement 1) as targets to select against a large nonimmune phage display antibody library
Summary
Human hepatitis B virus (HBV) infects more people than does Hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV) combined (World Health Organization, 2016). Despite the fact that there is an effective prophylactic HBV vaccine, 240 million people are chronically infected. HBV carriers are at high risk of developing severe liver diseases ranging from chronic hepatic insufficiency to cirrhosis and hepatocellular carcinoma (HCC) (World Health Organization, 2016; Schweitzer et al, 2015). 15 million of HBV carriers are co-infected with HDV, which accelerates disease progression and exacerbates disease severity. No effective therapies are currently available for HBV patients co-infected with HDV, and there are no anti-viral therapies that target HDV (Rizzetto, 2015; Hughes et al, 2011; Thomas et al, 2015)
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