Antibody engineering improves neutralization activity against K417 spike mutant SARS-CoV-2 variants

Lili Li; Meiling Gao; Peng Jiao; Shulong Zu; Yong-Qiang Deng; Dingyi Wan; Yang Cao; Jing Duan; Saba R Aliyari; Jie Li; Yueyue Shi; Zihe Rao; Cheng-Feng Qin; Yu Guo; Genhong Cheng; Heng Yang

doi:10.1186/s13578-022-00794-7

Antibody engineering improves neutralization activity against K417 spike mutant SARS-CoV-2 variants

Cell Biosci. 2022 May 17;12(1):63. doi: 10.1186/s13578-022-00794-7.

Authors

Lili Li^#^{1

2}, Meiling Gao^{1

2}, Peng Jiao³, Shulong Zu^{1

2}, Yong-Qiang Deng⁴, Dingyi Wan⁵, Yang Cao⁶, Jing Duan⁵, Saba R Aliyari⁷, Jie Li⁸, Yueyue Shi^{1

2}, Zihe Rao^{3

9}, Cheng-Feng Qin¹⁰, Yu Guo¹¹, Genhong Cheng⁷, Heng Yang^{12

13}

Affiliations

¹ Institute of Systems Medicine, Chinese Academy of Medical Science & Peking Union College, Beijing, 100005, China.
² Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
³ State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, China.
⁴ Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing, 100071, China.
⁵ AtaGenix Laboratories (Wuhan) Co., Ltd, Wuhan, 430075, China.
⁶ Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
⁷ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.
⁸ Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
⁹ Guangzhou Laboratory, B1, Standard Property Unite 4, Guangzhou international bio-island, Guangzhou, 510320, China.
¹⁰ Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing, 100071, China. chengfeng_qin@126.com.
¹¹ State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, China. guoyu@nankai.edu.cn.
¹² Institute of Systems Medicine, Chinese Academy of Medical Science & Peking Union College, Beijing, 100005, China. yhmyt@hotmail.com.
¹³ Suzhou Institute of Systems Medicine, Suzhou, 215123, China. yhmyt@hotmail.com.

^# Contributed equally.

Abstract

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.

Keywords: Antibody engineering; COVID-19; Neutralizing antibody; Phage display library; SARS-CoV-2 variants.

Abstract

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