慢性乙型肝炎病毒感染是全球严重的公共卫生问题之一，其临床最佳治疗终点是HBsAg血清学阴转，然而现有药物的疗效十分有限，需发展新的治疗手段。前期研究中，我们发现E6F6抗体具有很好的HBsAg清除能力，具有成为抗体药物的潜力。在此基础上，我们获得E6F6人源化抗体并通过成药性评估；对人源化抗体进行Fc区改造，得到半衰期显著延长的抗体分子和细胞吞噬能力增强的抗体分子；在抗体CDR区引入组氨酸组合突变，初步筛选出具有pH依赖性抗原结合能力的抗体分子。本研究拟通过抗体工程方法，对抗体CDR区和Fc区进行改造，将pH依赖性抗原结合特性和Fc受体介导的细胞内吞相结合，在细胞模型和动物模型中验证功能，进一步将E6F6人源化抗体改造成一种能高效清除循环系统中高滴度HBsAg的sweeping抗体，长期抑制HBsAg的回升，从而降低抗体药物剂量和给药频率，提高药效，为慢性乙肝病人治疗提供新手段。

Chronic HBV infection is one of the major global health problems. The ideal endpoint for anti-HBV therapy is the loss of hepatitis B surface antigen (HBsAg); however, treatment options based on current drugs rarely result in HBsAg clearance. Development of more effective new drugs is need to improve the clinical management of this disease. In previous study, we identified an E6V6 mAb that showed a potent viral suppression effect in vivo and was a superior candidate for further development towards therapeutic antibody for CHB treatment. Then we generated E6F6 humanized antibody and performed druggability assessment. Furthermore, antibodies with markedly prolonged half-life or enhanced phagocytosis were generated through engineering in the Fc region of humanized antibody. Antibodies with pH–dependent antigen binding character were screened out from phage antibody library constructed by introduction of histidine to CDR regions of the humanized antibody. In the present study, to combine the character of pH–dependent antigen binding and cell phagocytosis via Fc receptors, antibody engineering will be carries out in the CDR region and Fc region of the E6F6 humanized antibody. The function of the resulting antibodies will be test in cell model and animal model. We propose to obtain a novel sweeping antibody which can efficiently eliminate high level HBsAg from circulation and suppress its rebound for a long time. The novel antibody with lower dosage and less frequent dosing would be a new method to treatment of chronic HBV infection.