A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection

Rani Burm; Freya Van Houtte; Lieven Verhoye; Ahmed Atef Mesalam; Sandra Ciesek; Philippe Roingeard; Heiner Wedemeyer; Geert Leroux-Roels; Philip Meuleman

doi:10.1016/j.jhepr.2022.100646

A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection

JHEP Rep. 2022 Dec 5;5(3):100646. doi: 10.1016/j.jhepr.2022.100646. eCollection 2023 Mar.

Authors

Rani Burm¹, Freya Van Houtte¹, Lieven Verhoye¹, Ahmed Atef Mesalam^{1

2}, Sandra Ciesek^{3

4

5}, Philippe Roingeard⁶, Heiner Wedemeyer⁷, Geert Leroux-Roels⁸, Philip Meuleman¹

Affiliations

¹ Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
² Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), Dokki, Cairo 12622, Egypt.
³ Institute for Medical Virology, University Hospital, Goethe University, Frankfurt am Main, Germany.
⁴ German Center for Infection Research, DZIF, External Partner Site, Frankfurt am Main, Germany.
⁵ Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Theodor Stern Kai 7, Frankfurt am Main, Germany.
⁶ INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France.
⁷ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
⁸ Center for Vaccinology, Faculty of Medicine and Health Sciences, Ghent University and University Hospital, Ghent, Belgium.

Abstract

Background & aims: Elimination of chronic HBV/HDV infection remains a major global health challenge. Targeting excessive hepatitis B surface antigen (HBsAg) release may provide an interesting window of opportunity to break immune tolerance and to achieve a functional cure using additional antivirals.

Methods: We evaluated a HBsAg-specific human monoclonal antibody, as part of either a prophylactic or therapeutic strategy, against HBV/HDV infection in cell culture models and in human-liver chimeric mice. To assess prophylactic efficacy, mice were passively immunized prior to infection with HBV or HBV/HDV (coinfection and superinfection setting). Therapeutic efficacy was assessed in HBV and HBV/HDV-coinfected mice receiving 4 weeks of treatment. Viral parameters (HBV DNA, HDV RNA and HBsAg) were assessed in mouse plasma.

Results: The antibody could effectively prevent HBV/HDV infection in a dose-dependent manner with IC₅₀ values of ∼3.5 ng/ml. Passive immunization showed complete protection of mice from both HBV and HBV/HDV coinfection. Moreover, HDV superinfection was either completely prevented or at least attenuated in HBV-infected mice. Finally, antibody treatment in mice with established HBV/HDV infection resulted in a significant decline in viremia and a concomitant drop in on-treatment HBsAg, with a moderate viral rebound following treatment cessation.

Conclusion: We present data on a valuable antibody candidate that could complement other antivirals in strategies aimed at achieving functional cure of chronic HBV and HDV infection.

Impact and implications: Patients chronically infected with HBV may eventually develop liver cancer and are at great risk of being superinfected with HDV, which worsens and accelerates disease progression. Unfortunately, current treatments can rarely eliminate both viruses from chronically infected patients. In this study, we present data on a novel antibody that is able to prevent chronic HBV/HDV infection in a mouse model with a humanized liver. Moreover, antibody treatment of HBV/HDV-infected mice strongly diminishes viral loads during therapy. This antibody is a valuable candidate for further clinical development.

Keywords: HBsAg, hepatitis B surface antigen; IC50, half maximal inhibitory concentration; IP, intraperitoneally; LLOQ, lower limit of quantification; LOD, limit of detection; NTCP, sodium taurocholate co-transporting polypeptide; Viral hepatitis; hepatitis B; hepatitis B surface antigen; hepatitis D; hu-mAb, human monoclonal antibody; human monoclonal antibody; human-liver chimeric mouse model; neutralization; prevention.