目前全球慢性乙型肝炎病毒感染者约为2.5亿，现有药物仅能缓解疾病的进展，无法实现有效治愈。我们在前期研究中发现抗体E6F6可通过FcγR介导的吞噬作用清除HBsAg，有望成为慢乙肝治疗的新手段。现有研究表明Fc段的糖基化会影响抗体与FcγR的结合，进而影响抗体在机体中的功能。我们已完成E6F6的人源化改造，并对其进行去岩藻糖基化，增强了抗体与FcγRIIb和FcγRIIIb的结合，在HBV-Tg小鼠中增强了抗体对HBsAg的清除。本项目拟进一步在多种细胞模型和动物模型中验证糖基改造抗体的生物学功能，利用多种分析技术对抗体进行成药性分析，并利用结构生物学技术研究抗体与FcγRs的结合模式，揭示去岩藻糖基增强抗体治疗效果的分子机制及与结构基础。本研究预期获得的去岩藻糖基抗体可更高效地清除机体中高滴度的HBsAg，将为慢乙肝病人的治疗提供新手段；也将为阐释抗体对持续性病毒感染的治疗机制提供依据。

At present, there are about 250 million people infected with chronic hepatitis b virus worldwide. However the existing drugs can only alleviate the disease progression, and cannot achieve effective cure. In previous study, we found that the antibody E6F6 can effectively clear HBsAg and inhibit HBsAg for a long time. The antibody cleared HBsAg through the phagocytosis mediated by FcγR. We have completed the humanization for E6F6. Existing studies have confirmed that the glycans of the Fc segment could affect the binding activity of the antibody with Fc receptors, and affect the function of the antibody in the body. In previous study, antibody with markedly enhanced the binding with FcγRs and improved the clearance efficiency of HBsAg in HBV transgenic mice through the defucosylation of humanized antibody. In order to accelerate the industrialization of defucosylated antibody, in this study, the biological function of defucosylated antibody will be verified in various cell models and animal models, and the druggability will be assayed by various analytical techniques. On this basis, the binding mode of antibody with FcγRs will be researched by structural biology technology, and the molecular mechanism and structural basis of defucosylation enhancing therapeutic effect will be revealed. We propose to obtain a novel antibody which can efficiently eliminate high level HBsAg from circulation. The novel antibody would be a new method to treatment of chronic HBV infection, and it will provide a scientific basis for elucidating the therapeutic effect and mechanism of antibodies on persistent viral infection.