State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Science & School of Public Health, Xiamen University, Xiamen, China National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science & School of Public Health, Xiamen University, Xiamen, China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Science & School of Public Health, Xiamen University, Xiamen, China National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science & School of Public Health, Xiamen University, Xiamen, China Xiamen Blood Services, Xiamen 361002, China.
Gut. 2016 Apr;65(4):658-71. doi: 10.1136/gutjnl-2014-308964. Epub 2015 Sep 30.
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.
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.
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 Fcγ 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.
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.
本研究旨在探讨针对乙型肝炎病毒（HBV）的单克隆抗体（mAb）作为一种新型治疗方法在慢性乙型肝炎（CHB）小鼠模型中的治疗潜力。
在模拟持续性 HBV 感染的小鼠中，评估了针对病毒表面蛋白不同表位的 mAb 的治疗效果。系统研究了 mAb 介导的病毒清除的免疫机制。
在 11 种测试的 mAb 中，一种新型 mAb E6F6 在几种 HBV 持续感染的小鼠中表现出最显著的治疗效果。单次给予 E6F6 可在乙型肝炎转基因小鼠中数周内显著抑制乙型肝炎表面抗原（HBsAg）和 HBV DNA 的水平。E6F6 方案可有效预防初始 HBV 感染，并减少人肝嵌合小鼠中受感染肝细胞内的病毒传播。E6F6 为基础的免疫疗法促进了基于水力注射（HDI）的乙型肝炎载体小鼠中抗 HBV T 细胞反应的恢复。免疫分析表明，Fcγ 受体依赖性吞噬作用在 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，仅形成与有限的颗粒间交联的较小的抗体-病毒颗粒免疫复合物。E6F6 与 HBV 的这种独特结合特征可能与其有效体内调理吞噬作用以清除病毒有关。
这些结果为理解针对持续性病毒感染的抗体的治疗作用和机制提供了新的见解。E6F6 样 mAb 可能为人类慢性乙型肝炎感染提供一种新型免疫治疗药物。
