期刊
CELL AND BIOSCIENCE
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13578-022-00794-7
关键词
SARS-CoV-2 variants; COVID-19; Neutralizing antibody; Phage display library; Antibody engineering
资金
- National Natural Science Foundation of China [82102371, 91542201, 81925025, 81802870, 31870733, 81973243]
- Chinese Academy of Medical Sciences Initiative for Innovative Medicine [2021I2M-1-047, 2019-I2M-5-049]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2020PT310006, 2019XK310002]
- NIH [R01AI069120, AI158154, AI140718]
- University of California Los Angeles (UCLA) AI and Charity Treks, UCLA DGSOM BSCRC COVID19 Award Program
- National Key Research and Development Project [2020YFC0841700]
- Emergency Key Program of Guangzhou Laboratory [EKPGL2021008]
- Jiangsu Province
- Natural Science Foundation of Jiangsu Province [BK20211554]
This study identified and engineered neutralizing antibodies against SARS-CoV-2 variants, using an antibody phage display library made from COVID-19 patients. One specific antibody clone, R3P1-E4, was found to effectively suppress SARS-CoV-2 infection and rescue lethal phenotypes in infected mice. Crystal structural analysis revealed the reasons behind the reduced binding and neutralizing activity of R3P1-E4 towards SARS-CoV-2 variants with K417 mutations, and allowed for the engineering of mutant antibodies with improved neutralizing activity. This research provides a strategy for identifying and improving neutralizing antibodies against SARS-CoV-2 variants.
Background Neutralizing antibodies are approved drugs to treat coronavirus disease-2019 (COVID-19) patients, yet mutations in severe acute respiratory syndrome coronavirus (SARS-CoV-2) variants may reduce the antibody neutralizing activity. New monoclonal antibodies (mAbs) and antibody remolding strategies are recalled in the battle with COVID-19 epidemic. Results We identified multiple mAbs from antibody phage display library made from COVID-19 patients and further characterized the R3P1-E4 clone, which effectively suppressed SARS-CoV-2 infection and rescued the lethal phenotype in mice infected with SARS-CoV-2. Crystal structural analysis not only explained why R3P1-E4 had selectively reduced binding and neutralizing activity to SARS-CoV-2 variants carrying K417 mutations, but also allowed us to engineer mutant antibodies with improved neutralizing activity against these variants. Thus, we screened out R3P1-E4 mAb which inhibits SARS-CoV-2 and related mutations in vitro and in vivo. Antibody engineering improved neutralizing activity of R3P1-E4 against K417 mutations. Conclusion Our studies have outlined a strategy to identify and engineer neutralizing antibodies against SARS-CoV-2 variants.
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