IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility

Mengxin Xu¹, Zhaoyong Zhang², Yuzhu Sun¹, Haoting Mai¹, Siqi Liu³, Shuning Liu¹, Kexin Lv¹, Feiyang Yu⁴, Yuanyuan Wang¹, Xinyu Yue¹, Jiayi Zhang¹, Xiaoyu Cai¹, Ruixin Zhao¹, Hongjie Lu¹, Lin Liu¹, Huanle Luo¹, Haiyan Zhao⁴, Yanqun Wang⁵, Peng Gong⁶, Shoudeng Chen⁷, Xuping Jing⁸, Jincun Zhao⁹, Yao-Qing Chen¹⁰

Affiliations

¹ School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
² State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
³ Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China.
⁴ State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China; Clinical Laboratory Medicine Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁶ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China.
⁷ Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China; Central Laboratory, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China. Electronic address: chenshd5@mail.sysu.edu.cn.
⁸ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China. Electronic address: jingxuping@wh.iov.cn.
⁹ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Guangzhou National Laboratory, Bio-Island, Guangzhou, China; Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, the Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China. Electronic address: zhaojincun@gird.cn.
¹⁰ School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China; Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen, China. Electronic address: chenyaoqing@mail.sysu.edu.cn.

PMID: 39828085
DOI: 10.1016/j.antiviral.2025.106082

IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility

Mengxin Xu et al. Antiviral Res. 2025 Mar.

. 2025 Mar:235:106082.

doi: 10.1016/j.antiviral.2025.106082. Epub 2025 Jan 17.

Authors

Affiliations

¹ School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
² State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
³ Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China.
⁴ State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China; Clinical Laboratory Medicine Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁶ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China.
⁷ Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China; Central Laboratory, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China. Electronic address: chenshd5@mail.sysu.edu.cn.
⁸ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.262 Jin Long Street, Wuhan, Hubei 430207, China. Electronic address: jingxuping@wh.iov.cn.
⁹ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Guangzhou National Laboratory, Bio-Island, Guangzhou, China; Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, the Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China. Electronic address: zhaojincun@gird.cn.
¹⁰ School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China; Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen, China. Electronic address: chenyaoqing@mail.sysu.edu.cn.

PMID: 39828085
DOI: 10.1016/j.antiviral.2025.106082

Erratum in

Corrigendum to "IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility" [Antiv. Res. (2025) 106082].
Xu M, Zhang Z, Sun Y, Mai H, Liu S, Liu S, Lv K, Yu F, Wang Y, Yue X, Zhang J, Cai X, Zhao R, Lu H, Liu L, Luo H, Zhao H, Wang Y, Gong P, Chen S, Jing X, Zhao J, Chen YQ. Xu M, et al. Antiviral Res. 2025 May;237:106146. doi: 10.1016/j.antiviral.2025.106146. Epub 2025 Mar 20. Antiviral Res. 2025. PMID: 40118704 No abstract available.

Abstract

IgA antibodies are critical components of the mucosal immune barrier, providing essential first-line defense against viral infections. In this study, we investigated the impact of antibody class switching on neutralization efficacy by engineering recombinant antibodies of different isotypes (IgA1, IgG1) with identical variable regions from SARS-CoV-2 convalescent patients. A potent, broad-spectrum neutralizing monoclonal antibody CAV-C65 exhibited a ten-fold increase in neutralization potency upon switching from IgG1 to IgA1 monomer. Structural analysis revealed that this antibody binds to two adjacent receptor binding domains on the spike protein. Enhanced neutralization by IgA1 was attributed to the combined effects of increased affinity, unique hinge region properties, and potential cross-linking of viral particles. Inhaled CAV-C65 IgA1 demonstrated prophylactic efficacy against lethal SARS-CoV-2 infection in hACE2 mice. These findings highlight the pivotal role of IgA in antiviral immunity and inform the development of IgA-based therapeutics.

Keywords: Antibody hinge; Class switching; Immunoglobulin A (IgA); Immunoglobulin G (IgG); Neutralization enhancement.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility

Affiliations

IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous