First-in-human study of a potent anti-HBsAg neutralizing antibody

Project Summary
Hepatitis B virus (HBV) remains a major global health problem and chronic HBV (CHB) is a major cause of
liver cirrhosis and hepatocellular carcinoma. While antiviral therapies achieve long-term viral suppression, they
can rarely clear the infection or achieve a state of functional cure where long-term viral suppression is
maintained in the absence of treatment. Along with persistence of viral antigens, impaired HBV-specific
immunity contributes to the chronicity of infection. Chronic exposure to high levels of HBsAg may render HBV-
specific immune cells overly activated and functionally tolerized Thus, decreasing serum HBsAg could be a
valuable therapeutic strategy, due to its potential to alleviate functional exhaustion and confer immune control.
Passive transfer of antibodies is a potential strategy in CHB for their dual functionality. Antibodies differ from
direct-acting antivirals in that they can recruit immune effector functions through their Fc domains to accelerate
clearance of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster
development of host immune responses. HepB monoclonal antibody (mAb)19 is a human monoclonal antibody
to the a-determinant of the extracellular loop of HBsAg and binds the major HBV serotypes. HepB mAb19
showed exceptional in vitro neutralization activity with IC50 in the nanogram range and in vivo antiviral activity
in an animal model of infection. The object of this proposal is to conduct a first-in-human dose-escalation study
of a long-acting variant of HepB mAb19 in individuals with CHB on antiviral nucleos(t)ide analogue (NRTI)
therapy. The hypothesis to be tested is that the administration of HepB mAb19-LS during suppressive NRTI
therapy will be safe and well tolerated, will lead to decreased levels of circulating HBsAg, and enhance host
innate and adaptive immune responses to HBV.

Grant Number: 5U01AI167786-04
NIH Institute/Center: NIH
Principal Investigator: Marina Caskey