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

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2025-01-17 DOI:10.1016/j.antiviral.2025.106082

Mengxin Xu, Zhaoyong Zhang, Yuzhu Sun, Haoting Mai, Siqi Liu, Shuning Liu, Kexin Lv, Feiyang Yu, Yuanyuan Wang, Xinyu Yue, Jiayi Zhang, Xiaoyu Cai, Ruixin Zhao, Hongjie Lu, Lin Liu, Huanle Luo, Haiyan Zhao, Yanqun Wang, Peng Gong, Shoudeng Chen, Xuping Jing, Jincun Zhao, Yao-Qing Chen

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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.

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IgA类转换通过增加抗体铰链灵活性增强对SARS-CoV-2的中和效力。

IgA抗体是粘膜免疫屏障的重要组成部分，为抵抗病毒感染提供了必要的第一线防御。在这项研究中，我们通过从SARS-CoV-2恢复期患者中获得具有相同可变区的不同同工型（IgA1, IgG1）的工程重组抗体，研究了抗体类别转换对中和效果的影响。一种有效的广谱中和单克隆抗体CAV-C65在从IgG1切换到IgA1单体后，其中和效力增加了10倍。结构分析表明，该抗体结合到刺突蛋白上两个相邻的受体结合域。IgA1增强的中和作用归因于病毒颗粒的亲和力增加、独特的铰链区特性和潜在的交联的综合作用。在hACE2小鼠中，吸入CAV-C65 IgA1对致命的SARS-CoV-2感染具有预防作用。这些发现强调了IgA在抗病毒免疫中的关键作用，并为基于IgA的治疗方法的发展提供了信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Antiviral research 医学-病毒学

CiteScore

17.10

自引率

3.90%

发文量

157

审稿时长

34 days

期刊介绍： Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.