高效持久清除乙肝病毒的新型抗体研究

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.

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。

慢性乙型肝炎病毒（HBV）感染是全球性严重的公共卫生问题之一，然而现有药物在临床上实现理想治疗终点的疗效十分有限。作为能够有效清除HBsAg或大幅降低HBsAg水平的创新治疗性药物平台，由抗体介导的免疫治疗有望成为CHB病人对抗HBV病毒持续感染的新策略。本研究创新性地开发出能够高效清除循环系统中HBsAg的乙肝治疗性清道夫抗体，在实现长效病毒抑制的同时有效降低了给药剂量，可为大幅度提升慢性HBV感染的临床治疗疗效提供可靠的技术手段。具体结果如下：.（1）完成具有pH依赖性抗原结合特征的乙肝治疗性再循环抗体改造，可以实现血清病毒的长效抑制。.（2）初步探索乙肝治疗性清道夫抗体的构建形式，在pH依赖性抗原结合抗体的基础上，进一步探索Fc改造，明确增强Fc与鼠FcγR亲和力的清道夫抗体可以提升疗效，展现至少降低10倍剂量的优势，完成概念验证。.（3）多维度优化乙肝治疗性清道夫抗体。优化抗体可变区改造，维持强pH依赖性结合特征与广谱结合活性。进一步将能够延长半衰期的Fc点突变引入抗体的Fc区，有效提升体内抗原清除活性与抑制时间。.（4）新型乙肝治疗性抗体在食蟹猴体内展现显著延长的抗体半衰期，并且以皮下给药的途径可以进一步延长半衰期。抗体给药后食蟹猴的血生化和血常规指标正常，初步验证新型抗体的安全性。