一种新型人源化抗HBV抗体的结构指导成熟及其临床前开发

StephenW

Antiviral Res. 2020 Mar 11:104757. doi: 10.1016/j.antiviral.2020.104757. [Epub ahead of print]
Structure guided maturation of a novel humanized anti-HBV antibody and its preclinical development.
Zhou B1, Xia L2, Zhang T3, You M3, Huang Y3, He M3, Su R3, Tang J3, Zhang J3, Li S3, An Z4, Yuan Q5, Luo W6, Xia N3.
Author information

1
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Science, Xiamen University; Xiamen, 361105, China; The 2nd Affiliated Hospital, South University of Science and Technology, 29 Bulan Road, Longgang District, Shenzhen, 518112, China.
2
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Science, Xiamen University; Xiamen, 361105, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361105, China.
3
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Science, Xiamen University; Xiamen, 361105, China.
4
    The Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
5
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Science, Xiamen University; Xiamen, 361105, China. Electronic address: [email protected].
6
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Science, Xiamen University; Xiamen, 361105, China. Electronic address: [email protected].

Abstract

We have reported that E6F6, a mouse monoclonal antibody, is a promising treatment option for patients with chronic hepatitis B (CHB). A humanized E6F6 antibody B11 with affinity loss was obtained by CDR-grafting approach. To address this issue, in silico affinity maturation through scanning mutagenesis using CHARMM force field methods was performed on an predicted immune complex model of the B11:HBsAg. We chose four variants with top increased interaction energy for further characterization. The antibody huE6F6-1 within two point mutations (Heavy Chain: Asp65Val; His66Leu) was identified to restore the parental antibody's high binding affinity, neutralization activity, and potent efficacy of viral suppression in vivo. Crystal structure (1.8 Å resolution) based molecular docking proved more stabilized and compact hydrogen bond interactions formed in huE6F6-1.The smaller and dispersed HBV immune complexes of huE6F6-1 by electron microscopy suggested it will have the same therapeutic efficacy as the parental E6F6 mAb. Preclinical study and pharmacokinetics of huE6F6-1 demonstrated that it is a stable and desirable lead candidate to improve the clinical management of CHB. Notably, our structure guided approach may facilitate the humanization and affinity maturation of other rodent antibody candidates during drug development.

Copyright © 2020. Published by Elsevier B.V.
KEYWORDS:

Chronic hepatitis B infection; Druggability; Humanized antibody; Structural guided maturation

PMID:
    32171857
DOI:
    10.1016/j.antiviral.2020.104757

StephenW

抗病毒水库。 2020年3月11日：104757。Doi：10.1016 / j.antiviral.2020.104757。 [Epub提前发行]
一种新型人源化抗HBV抗体的结构指导成熟及其临床前开发。
周B1，夏L2，张T3，尤M3，黄Y3，何M3，苏R3，唐J3，张J3，李S3，安Z4，袁Q5，罗W6，夏N3。
作者信息

1个
厦门大学生命科学学院公共卫生学院，国家传染病诊断和疫苗开发研究所，分子疫苗学和分子诊断学国家重点实验室；厦门361105;南方科技大学第二附属医院，深圳市龙岗区不兰路29号，邮政编码518112
2
厦门大学生命科学学院公共卫生学院，国家传染病诊断和疫苗开发研究所，分子疫苗学和分子诊断学国家重点实验室；厦门361105;厦门大学药学院，厦门361105
3
厦门大学生命科学学院公共卫生学院，国家传染病诊断和疫苗开发研究所，分子疫苗学和分子诊断学国家重点实验室；厦门361105
4
美国得克萨斯州休斯敦市德克萨斯健康医学中心德克萨斯大学健康科学中心，德克萨斯大学治疗学研究所，布朗基金会分子医学研究所，美国，77030。
5
厦门大学生命科学学院公共卫生学院，国家传染病诊断和疫苗开发研究所，分子疫苗学和分子诊断学国家重点实验室；厦门361105电子地址：[email protected]。
6
厦门大学生命科学学院公共卫生学院，国家传染病诊断和疫苗开发研究所，分子疫苗学和分子诊断学国家重点实验室；厦门361105电子地址：[email protected]。

抽象

我们已经报道，小鼠单克隆抗体E6F6对于慢性乙型肝炎（CHB）患者是一种有希望的治疗选择。通过CDR移植法获得了具有亲和力丧失的人源化E6F6抗体B11。为了解决这个问题，在B11：HBsAg的预测免疫复合物模型上通过使用CHARMM力场方法进行扫描诱变，进行了计算机亲和力成熟。我们选择了四种具有最大相互作用能量的变体进行进一步表征。鉴定出两个点突变（重链：Asp65Val； His66Leu）内的抗体huE6F6-1可恢复亲本抗体的高结合亲和力，中和活性和体内病毒抑制的有效功效。基于晶体结构（1.8Å分辨率）的分子对接证明在huE6F6-1中更稳定且形成了紧密的氢键相互作用。通过电子显微镜观察，huE6F6-1较小且分散的HBV免疫复合物表明，它将具有与亲本E6F6 mAb相同的治疗功效。 huE6F6-1的临床前研究和药代动力学证明，它是改善CHB临床管理的稳定且理想的潜在候选药物。值得注意的是，我们的结构指导方法可能有助于药物开发过程中其他啮齿动物抗体候选物的人源化和亲和力成熟。

版权所有©2020。由Elsevier B.V.发布。
关键字：

慢性乙型肝炎感染；可药用性；人源化抗体；结构导向成熟

PMID：
32171857
DOI：
10.1016 / j.antiviral.2020.104757

乙肝人1949

人源?，那需要多少人的血液提取啊