Broadly neutralizing anti‐HBV antibody binds to non‐epitope regions of preS1

Abstract

a b s t r a c tBroadly neutralizing anti-hepatitis B virus (HBV) antibody HzKR127 undergoes a fairly large conformational change of CDR H3 loop upon binding to HBV preS1 epitope peptide. In this study, we identified low-affinity antibody-binding sites in the largely unstructured preS1 region by nuclear magnetic resonance and biochemical studies, indicating that the antibody binds to the preS1 region outside the major immune epitope with low affinity. Surface plasma resonance experiments showed that the full-length preS1 has approximately three fold higher affinity for HzKR127 Fab than the preS1 epitope peptide, suggesting that the presence of low-affinity sites in the preS1 region increases the antibody-binding affinity. Therefore, the low-affinity binding of the antibody to non-epitope regions of preS1 may contribute to effective neutralization.

Decreased CD27 on B Lymphocytes in Patients with Primary Hepatocellular Carcinoma

“…The interaction between HBV and B lymphocytes might be explained by defects in humoral immunity in individuals who develop HCC. 22 Chi et al 23 demonstrated that effective neutralization of HBV might be achieved by low-affinity binding of antibody to nonepitope regions of preS1. Naïve B lymphocytes can be bound to and activated by HBV capsid (core antigen), which stimulates them to become efficient antigenpresenting cells that can prime T lymphocytes and induce an effective immune response.…”

Inhibition of preS1-hepatocyte interaction by an array of recombinant human antibodies from naturally recovered individuals

“…The presence of disease concomitantly with an apparently neutralizing antibody response has been an argument against the use of anti-HBs antibodies in therapy. However neutralizing efficacy of anti-HBV antibodies has been demonstrated in non-human primates 9 10 11 12 .…”

“…NTCP can therefore serve as a target for developing therapeutic anti-HBV agents 21 22 23 . However the classical target, the viral hepatocyte binding domain has shown that anti-preS1(21–47 a.a.) agents such as antibodies are quite effective in neutralizing the virus by blocking its attachment, endocytosis and possibly membrane penetration into the hepatocyte 9 10 11 24 . A number of highly specific murine and humanized preS1-specific monoclonal antibodies that effectively neutralize HBV infection in non-human primates have been generated 9 10 .…”

“…However the classical target, the viral hepatocyte binding domain has shown that anti-preS1(21–47 a.a.) agents such as antibodies are quite effective in neutralizing the virus by blocking its attachment, endocytosis and possibly membrane penetration into the hepatocyte 9 10 11 24 . A number of highly specific murine and humanized preS1-specific monoclonal antibodies that effectively neutralize HBV infection in non-human primates have been generated 9 10 . The preS1 component has, therefore been incorporated into the third generation hepatitis B vaccines to achieve a stronger neutralizing response against the virus 25 .…”