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Abstract

Chronic infection with hepatitis B virus (HBV) is characterized by persistent expression of hepatitis B surface antigen (HBsAg), which is associated with profound immune tolerance. Although nucleos(t)ide analogue therapy effectively suppresses viral replication, it neither eliminates HBV nor reverses virus-specific immune dysfunction. Here, we report the results of two parallel first-in-human, dose-escalation studies evaluating a single infusion of mAb19-LS, a long-acting IgG1 monoclonal antibody targeting HBsAg, in individuals with chronic HBV infection receiving nucleos(t)ide analogue therapy. mAb19-LS was generally safe and well tolerated and induced a mean 11-fold increase in antigen clearance. The magnitude and duration of HBsAg suppression were dependent on both baseline antigen levels and mAb19-LS dose, with suppression maintained for more than 36 weeks in individuals receiving the highest dose. Reduction of circulating HBsAg was associated with uptake of HBsAg-IgG immune complexes by monocytes and dendritic cells and inflammatory reprogramming of these antigen-presenting cells. Notably, proliferation of both CD4+ and CD8+ T cells, as well as interferon-{gamma} and TNF- production in response to HBV antigens, were significantly increased 24 weeks after infusion. Together, these findings demonstrate that mAb19-LS is generally safe and effectively accelerates HBsAg clearance while activating antigen presenting cells and enhancing antiviral T cell responses.

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