A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein

被引:0
|
作者
Yan Li
Yuhua Wan
Peipei Liu
Jincun Zhao
Guangwen Lu
Jianxun Qi
Qihui Wang
Xuancheng Lu
Ying Wu
Wenjun Liu
Buchang Zhang
Kwok-Yung Yuen
Stanley Perlman
George F Gao
Jinghua Yan
机构
[1] CAS Key Laboratory of Pathogenic Microbiology and Immunology,Departments of Microbiology and Pediatrics
[2] Institute of Microbiology,Department of Microbiology
[3] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,undefined
[4] Chinese Academy of Sciences,undefined
[5] School of Life Sciences,undefined
[6] Anhui University,undefined
[7] CAS Key Laboratory of Microbial and Metabolic engineering,undefined
[8] Institute of Microbiology,undefined
[9] Chinese Academy of Sciences,undefined
[10] University of Iowa,undefined
[11] State Key Laboratory of Biotherapy and Cancer Center,undefined
[12] West China Hospital,undefined
[13] West China Medical School,undefined
[14] Sichuan University,undefined
[15] Laboratory Animal Center,undefined
[16] Chinese Center for Disease Control and Prevention (China CDC),undefined
[17] State Key Laboratory for Emerging Infectious Diseases,undefined
[18] The University of Hong Kong,undefined
[19] National Institute for Viral Disease Control and Prevention,undefined
[20] Chinese Center for Disease Control and Prevention (China CDC),undefined
[21] China-Japan Joint Laboratory of Molecular Microbiology and Molecular Immunology,undefined
[22] Institute of Microbiology,undefined
[23] Chinese Academy of Sciences,undefined
[24] Office of Director-General,undefined
[25] Chinese Center for Disease Control and Prevention (China CDC),undefined
[26] State Key Laboratory of Respiratory Diseases,undefined
[27] Guangzhou Institute of Respiratory Disease,undefined
[28] The First Affiliated Hospital of Guangzhou Medical University,undefined
来源
Cell Research | 2015年 / 25卷
关键词
MERS-CoV; neutralizing monoclonal antibody; humanization; crystal structure;
D O I
暂无
中图分类号
学科分类号
摘要
The newly-emerging Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe and fatal acute respiratory disease in humans. Despite global efforts, the potential for an associated pandemic in the future cannot be excluded. The development of effective counter-measures is urgent. MERS-CoV-specific anti-viral drugs or vaccines are not yet available. Using the spike receptor-binding domain of MERS-CoV (MERS-RBD) to immunize mice, we identified two neutralizing monoclonal antibodies (mAbs) 4C2 and 2E6. Both mAbs potently bind to MERS-RBD and block virus entry in vitro with high efficacy. We further investigated their mechanisms of neutralization by crystallizing the complex between the Fab fragments and the RBD, and solved the structure of the 4C2 Fab/MERS-RBD complex. The structure showed that 4C2 recognizes an epitope that partially overlaps the receptor-binding footprint in MERS-RBD, thereby interfering with the virus/receptor interactions by both steric hindrance and interface-residue competition. 2E6 also blocks receptor binding, and competes with 4C2 for binding to MERS-RBD. Based on the structure, we further humanized 4C2 by preserving only the paratope residues and substituting the remaining amino acids with the counterparts from human immunoglobulins. The humanized 4C2 (4C2h) antibody sustained similar neutralizing activity and biochemical characteristics to the parental mouse antibody. Finally, we showed that 4C2h can significantly abate the virus titers in lungs of Ad5-hCD26-transduced mice infected with MERS-CoV, therefore representing a promising agent for prophylaxis and therapy in clinical settings.
引用
收藏
页码:1237 / 1249
页数:12
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