单位：[1]Guangzhou Laboratory, Guangzhou International Biotech Island, Guangzhou, China.[2]Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China.[3]Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.[4]State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.[5]Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.[6]Department of Infectious Diseases, The Third People’s Hospital of Changzhou, Changzhou, China.[7]Department of Medical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.浙江大学医学院附属第一医院[8]Guangzhou Institute of Respiratory Health, Guangzhou, China.[9]Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.华中科技大学同济医学院附属同济医院血液内科[10]Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.[11]Department of Thoracic Oncology and Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Many SARS-CoV-2 neutralizing antibodies (nAbs) lose potency against variants of concern. In this study, we developed 2 strategies to produce mutation-resistant antibodies. First, a yeast library expressing mutant receptor binding domains (RBDs) of the spike protein was utilized to screen for potent nAbs that are least susceptible to viral escape. Among the candidate antibodies, P5-22 displayed ultrahigh potency for virus neutralization as well as an outstanding mutation resistance profile. Additionally, P14-44 and P15-16 were recognized as mutation-resistant antibodies with broad betacoronavirus neutralization properties. P15-16 has only 1 binding hotspot, which is K378 in the RBD of SARS-CoV-2. The crystal structure of the P5-22, P14-44, and RBD ternary complex clarified the unique mechanisms that underlie the excellent mutation resistance profiles of these antibodies. Secondly, polymeric IgG enhanced antibody avidity by eliminating P5-22's only hotspot, residue F486 in the RBD, thereby potently blocking cell entry by mutant viruses. Structural and functional analyses of antibodies screened using both potency assays and the yeast RBD library revealed rare, ultrapotent, mutation-resistant nAbs against SARS-CoV-2.
基金：
This work was supported by the Emergency Key Program of Guangzhou
Laboratory (grant EKPG21-07), by the National Health and
Family Planning Commission Research Fund and Zhejiang Provincial
Medical and Health Major Science and Technology Plan Project
(grant KWJ-ZJ-2108), and the Public Welfare Technology Application
Research Project of Zhejiang Province (grant LGF20E030004).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2025]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者单位：[1]Guangzhou Laboratory, Guangzhou International Biotech Island, Guangzhou, China.[2]Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China.[*2]Innovent Biologics, Suzhou, Jiangsu, China.
共同第一作者：
通讯作者：
通讯机构：[1]Guangzhou Laboratory, Guangzhou International Biotech Island, Guangzhou, China.[2]Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China.[3]Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.[8]Guangzhou Institute of Respiratory Health, Guangzhou, China.[9]Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.[10]Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.[11]Department of Thoracic Oncology and Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.[*1]Guangzhou Laboratory, Guangzhou, China.[*2]Innovent Biologics, Suzhou, Jiangsu, China.[*3]Department of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.[*4]Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China.[*5]Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
推荐引用方式(GB/T 7714)：
Zou Jia,Li Li,Zheng Peiyi,et al.Ultrapotent neutralizing antibodies against SARS-CoV-2 with a high degree of mutation resistance.[J].The Journal of clinical investigation.2022,132(4):doi:10.1172/JCI154987.
APA：
Zou Jia,Li Li,Zheng Peiyi,Liang Wenhua,Hu Siyi...&He Jianxing.(2022).Ultrapotent neutralizing antibodies against SARS-CoV-2 with a high degree of mutation resistance..The Journal of clinical investigation,132,(4)
MLA：
Zou Jia,et al."Ultrapotent neutralizing antibodies against SARS-CoV-2 with a high degree of mutation resistance.".The Journal of clinical investigation 132..4(2022)
医学