Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen

Objective This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models.Methods Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated.Results Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV-persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fc gamma receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody-viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance.Conclusions These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection.

目的 本研究旨在探讨抗乙肝病毒（HBV）单克隆抗体（mAb）作为一种新型治疗方法在小鼠模型中对慢性乙型肝炎（CHB）的治疗潜力。 方法 在模拟持续性HBV感染的小鼠中评估针对病毒表面蛋白不同表位的mAbs的治疗效果。系统研究了mAb介导的病毒清除的免疫机制。 结果 在11种测试的mAbs中，一种新型mAb E6F6在几只HBV持续感染的小鼠中表现出最显著的治疗效果。在HBV转基因小鼠中，单次给予E6F6可在数周内显著抑制乙肝表面抗原（HBsAg）和HBV DNA的水平。E6F6方案有效地预防了初始HBV感染，并减少了人 - 肝嵌合小鼠中感染肝细胞的病毒传播。基于E6F6的免疫疗法促进了基于 hydrodynamic注射（HDI）的HBV携带小鼠中抗HBV T细胞反应的恢复。免疫学分析表明，Fcγ受体依赖的吞噬作用在E6F6介导的病毒抑制中起主要作用。分子分析表明，E6F6识别一个进化上保守的表位（GPCK(R)TCT），并且当它与病毒颗粒结合时仅形成一个较小的抗体 - 病毒颗粒免疫复合物，颗粒间交联有限。E6F6与HBV的这种独特结合特性可能与其在体内有效调理吞噬以清除病毒有关。 结论 这些结果为理解抗体在持续性病毒感染中的治疗作用和机制提供了新的见解。类似E6F6的mAbs可能为人类慢性HBV感染提供一种新型免疫治疗剂。