Burm Rani, Van Houtte Freya, Verhoye Lieven, Mesalam Ahmed Atef, Ciesek Sandra, Roingeard Philippe, Wedemeyer Heiner, Leroux-Roels Geert, Meuleman Philip
Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), Dokki, Cairo 12622, Egypt.
JHEP Rep. 2022 Dec 5;5(3):100646. doi: 10.1016/j.jhepr.2022.100646. eCollection 2023 Mar.
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.
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.
The antibody could effectively prevent HBV/HDV infection in a dose-dependent manner with IC 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.
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.
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.
消除慢性乙型肝炎病毒（HBV）/丁型肝炎病毒（HDV）感染仍是一项重大的全球卫生挑战。针对过量乙肝表面抗原（HBsAg）的释放可能提供一个有趣的机会窗口，以打破免疫耐受，并使用其他抗病毒药物实现功能性治愈。
我们评估了一种HBsAg特异性人单克隆抗体，作为预防或治疗策略的一部分，在细胞培养模型和人肝嵌合小鼠中对抗HBV/HDV感染。为评估预防效果，在感染HBV或HBV/HDV（同时感染和重叠感染情况）之前对小鼠进行被动免疫。在接受4周治疗的HBV和HBV/HDV同时感染的小鼠中评估治疗效果。在小鼠血浆中评估病毒参数（HBV DNA、HDV RNA和HBsAg）。
该抗体能够以剂量依赖的方式有效预防HBV/HDV感染，IC值约为3.5 ng/ml。被动免疫显示小鼠对HBV和HBV/HDV同时感染均有完全保护作用。此外，在HBV感染的小鼠中，HDV重叠感染要么被完全预防，要么至少得到减轻。最后，对已建立HBV/HDV感染的小鼠进行抗体治疗导致病毒血症显著下降，同时治疗期间的HBsAg下降，停药后病毒有中度反弹。
我们展示了关于一种有价值的抗体候选物的数据，该抗体可在旨在实现慢性HBV和HDV感染功能性治愈的策略中补充其他抗病毒药物。
慢性感染HBV的患者最终可能发展为肝癌，并且有很大的重叠感染HDV的风险，这会使疾病进展恶化和加速。不幸的是，目前的治疗方法很少能从慢性感染患者体内清除这两种病毒。在本研究中，我们展示了关于一种新型抗体的数据，该抗体能够在人源化肝脏的小鼠模型中预防慢性HBV/HDV感染。此外，对HBV/HDV感染的小鼠进行抗体治疗在治疗期间能强烈降低病毒载量。这种抗体是进一步临床开发的有价值候选物。
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