Novel monkey mAbs induced by a therapeutic vaccine targeting the hepatitis B surface antigen effectively suppress hepatitis B virus in mice.
Novel monkey mAbs induced by a therapeutic vaccine targeting the hepatitis B surface antigen effectively suppress hepatitis B virus in mice.
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由针对乙型肝炎表面抗原的治疗性疫苗诱导的新型猴单克隆抗体可有效抑制小鼠体内的乙型肝炎病毒
DOI：
10.1093/abt/tbab020
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发表时间：
2021-10
影响因子：
--
通讯作者：
Xia N
中科院分区：
文献类型：
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作者：
Chen Y;Xiang X;Qi R;Wang Y;Huang Y;You M;Xian Y;Wu Y;Fu R;Kang C;Tang J;Yu H;Zhang T;Yuan Q;Luo W;Xia N
我们先前已经获得了具有持久血清HBsAg清除效果的小鼠抗B表面抗原（HBsAg）抗体E6 F6。食蟹猴中基于E6 F6表位的蛋白CR-T3-SEQ 13（HBsAg aa 113-135）疫苗接种疗法诱导HBV转基因（HBV-Tg）小鼠中HBsAg的长期多克隆抗体介导的清除。我们从CR-T3-SEQ 13免疫的食蟹猴中分离单克隆抗体，比较其与E6 F6的治疗效果，鉴定其在HBsAg上的表位，测定药代动力学并研究其物理性质。通过记忆B细胞刺激培养产生一组抗HBsAg mAb。两种先导性猴-人嵌合抗体C1-23和C3-23在HBV-Tg小鼠中有效抑制HBsAg和HBV DNA。两种抗体的人源化抗体和人源化小鼠反向嵌合抗体在HBV-Tg小鼠中表现出与E6 F6版本相当的HBsAg清除和病毒抑制功效。在HBV-Tg小鼠中，人源化抗体hu 1 -23在10和20 mg/kg的剂量水平下表现出比huE 6 F6 -1和hu 3 -23更有效的HBeAg抑制作用。结合位点的评价表明，hu 1 -23识别的表位位于HBsAg aa 118-125和hu 3 -23的121-125。物理性质研究表明，hu 1 -23和hu 3 -23足够稳定，可作为候选药物进一步开发。我们的数据表明，CR-T3-SEQ 13蛋白是一种有前途的HBV治疗性疫苗候选者，hu 1 -23和hu 3 -23是治疗慢性乙型肝炎B的治疗性候选者。此外，从基于表位的疫苗接种受试者产生抗体可能是新抗体药物发现的替代方法。
We have previously obtained a mouse anti-hepatitis B surface antigen (HBsAg) antibody E6F6 with long-lasting serum HBsAg clearance effects. The E6F6 epitope-based protein CR-T3-SEQ13 (HBsAg aa 113-135) vaccination therapy in cynomolgus monkeys induced long-term polyclonal antibodies-mediated clearance of HBsAg in the HBV transgenic (HBV-Tg) mice. We isolated monoclonal antibodies from CR-T3-SEQ13 vaccinated cynomolgus monkeys, compared their therapeutic effects with E6F6, identified their epitopes on HBsAg, determined the pharmacokinetics and studied their physical property. A panel of anti-HBsAg mAbs was generated through memory B cell stimulatory culture. Two lead monkey-human chimeric antibodies, C1-23 and C3-23, effectively suppressed HBsAg and HBV DNA in HBV-Tg mice. The humanized antibodies and humanized-mouse reverse chimeric antibodies of two antibodies exhibited comparable HBsAg clearance and viral suppression efficacy as those versions of E6F6 in HBV-Tg mice. Humanized antibody hu1-23 exhibited more efficacy HBsAg-suppressing effects than huE6F6-1 and hu3-23 in HBV-Tg mice at dose levels of 10 and 20 mg/kg. Evaluation of the binding sites indicates that the epitope recognized by hu1-23 is located in HBsAg aa 118-125 and 121-125 for hu3-23. Physical property study revealed that hu1-23 and hu3-23 are stable enough for further development as a drug candidate. Our data suggest that the CR-T3-SEQ13 protein is a promising HBV therapeutic vaccine candidate, and hu1-23 and hu3-23 are therapeutic candidates for the treatment of chronic hepatitis b. Moreover, the generation of antibodies from the epitope-based vaccinated subjects may be an alternative approach for novel antibody drug discovery.