Rapid restoration of potent neutralization activity against the latest Omicron variant JN.1 via AI rational design and antibody engineering
Abstract
The rapid evolution of the viral genome has led to the continual generation of new variants of SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It is promising but challenging to develop therapeutic neutralizing antibodies (nAbs) through in vitro evolution based on antigen–antibody binding interactions. From an early B cell antibody repertoire, we isolated antibody 8G3 that retains its nonregressive neutralizing activity against Omicron BA.1 and various other strains in vitro. 8G3 protected ACE2 transgenic mice from BA.1 and WA1/2020 virus infection without adverse clinical manifestations and completely cleared viral load in the lungs. Similar to most IGHV3–53 antibodies, the binding sites of 8G3 and ACE2 largely overlap, enabling competition with ACE2 for binding to RBD. By comprehensively considering the binding free energy changes of the antigen–antibody complexes, the biological environment of their interactions, and the evolutionary direction of the antibodies, we were able to select 50 mutants. Among them, 11 were validated by experiments showing better neutralizing activities. Further, a combination of four mutations were identified in 8G3 that increased its neutralization potency against JN.1, the latest Omicron mutant, by approximately 1,500-fold, and one of the mutations led to an improvement in activity against multiple variants to a certain extent. Together, we established a procedure of rapid selection of neutralizing antibodies with potent SARS-CoV-2 neutralization activity. Our results provide a reference for engineering neutralizing antibodies against future SARS-CoV-2 variants and even other pandemic viruses.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (40)
Yunji Liao
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Hang Ma
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Zhenyu Wang
Institute of Environmental Processes and Pollution Control, School of Environment and Ecology
Shusheng Wang
Jecho Laboratories, Inc.
Yang He
Yunsong Chang
Jecho Biopharmaceuticals Co., Ltd
Huifang Zong
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Haoneng Tang
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Lei Wang
Yong Ke
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Huiyu Cai
BioGeometry
Ping Li
Jian Tang
Hua Chen
Department of Chemical Engineering, Delft University of Technology, Van der Maasweg 9, 2629 HZ Delft, The Netherlands
Aleksandra Drelich
Department of Microbiology & Immunology Centers for Biodefense and Emerging Diseases, The University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555, United States
Bi-Hung Peng
Department of Neurosciences, Cell Biology, and Anatomy, University of Texas Medical Branch
Jason Hsu
Department of Neurosciences, Cell Biology, and Anatomy, University of Texas Medical Branch
Vivian Tat
Department of Pathology, University of Texas Medical Branch
Chien-Te K. Tseng
Department of Microbiology and Immunology, University of Texas Medical Branch
Jingjing Song
Jecho Biopharmaceuticals Co., Ltd
Yunsheng Yuan
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Mingyuan Wu
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Junjun Liu
Techshake Biotechnology Co., Ltd., Xi’an, Shaanxi, China.
Yali Yue
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Xiaoju Zhang
Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, University People’s Hospital
Ziqi Wang
Division of Advanced Materials
Li Yang
Jing Li
Xiaodan Ni
Shuimu BioSciences Ltd. F4, Bio² Innovation Center, Life Science Park
Hongshi Li
Shuimu BioSciences Ltd. F4, Bio² Innovation Center, Life Science Park
Yuning Xiang
Shuimu BioSciences Ltd. F4, Bio² Innovation Center, Life Science Park
Yanlin Bian
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Baohong Zhang
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Haiyang Yin
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University
Dimiter S. Dimitrov
Center for Antibody Therapeutics, University of Pittsburgh School of Medicine
John Gilly
Jecho Biopharmaceuticals Co., Ltd
Lei Han
Hua Jiang
Yueqing Xie
Jecho Laboratories, Inc.
Jianwei Zhu
Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University