Structure guided maturation of a novel humanized anti-HBV antibody and its preclinical development

Zhou，Bing1,2; Xia，Lin1,3; Zhang，Tianying1; You，Min1; Huang，Yang1; He，Maozhou1; Su，Ruopeng1; Tang，Jixian1; Zhang，Juan1; Li，Shaowei1; An，Zhiqiang4; Yuan，Quan1; Luo，Wenxin1; Xia，Ningshao1

2020-08-01

10.1016/j.antiviral.2020.104757

ANTIVIRAL RESEARCH   影响因子和分区

0166-3542

1872-9096

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.

Chronic hepatitis B infection Druggability Humanized antibody Structural guided maturation

SCI

英语

其他

National Natural Science Foundation of China[31600748][81702006][31870925] ; National Key Program for Infectious Disease of China[2017ZX10202203] ; Science and Technology Innovation project grant from Fujian province[2017J01066] ; Fujian Provincial Medical Innovation Foundation[2017-CXB20] ; Fundamental Research foundation of Xiamen University[20720190124]

Pharmacology & Pharmacy ; Virology

Pharmacology & Pharmacy ; Virology

WOS:000553379200001

ELSEVIER

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85086094477

Scopus

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
2.The 2nd Affiliated Hospital,South University of Science and Technology,Shenzhen,29 Bulan Road, Longgang District,518112,China
3.School of Pharmaceutical Sciences,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,77030,United States

Zhou，Bing,Xia，Lin,Zhang，Tianying,et al. Structure guided maturation of a novel humanized anti-HBV antibody and its preclinical development[J]. ANTIVIRAL RESEARCH,2020,180.

Zhou，Bing.,Xia，Lin.,Zhang，Tianying.,You，Min.,Huang，Yang.,...&Xia，Ningshao.(2020).Structure guided maturation of a novel humanized anti-HBV antibody and its preclinical development.ANTIVIRAL RESEARCH,180.

Zhou，Bing,et al."Structure guided maturation of a novel humanized anti-HBV antibody and its preclinical development".ANTIVIRAL RESEARCH 180(2020).