Ramesh Ashwin Kumar, Sivaccumar Jwala Priyadarsini, Ye Xiaohua, Yang Luona, Guo Hailong, Chin Chen-Ni, Ha Sha, Shiver John W, Strohl William R, Xu Yan, Du Haijuan, Zhou Tongqing, Zhang Ningyan, Xu Kai, Liu Xinli, Fu Tong-Ming, An Zhiqiang
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China.
Nat Commun. 2025 Apr 29;16(1):4025. doi: 10.1038/s41467-025-59294-0.
Engineering broadly neutralizing monoclonal antibodies (mAbs) targeting the hemagglutinin (HA) of Influenza A virus (IAV) is a promising approach for intervention of seasonal flu. However, HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here we hypothesize that multimerization of anti-IAV antibodies as IgMs can enhance coverage and neutralization potency. Here, we construct 18 IgM antibodies from known broadly neutralizing IgGs targeting different IAV HA epitopes and evaluate their breadth and potency of neutralization against distinct H1N1 and H3N2 IAVs. The IgM version of receptor binding site-specific IgG F045-092 shows increased breadth and antiviral potency compared to its parental IgG. Engineered IgM molecules overcome IAV strain resistance by expanded avidity, providing potent neutralization in vitro at sub-nanomolar ranges while retaining parental IgG specificity. Intranasal delivery of engineered IgM-F045-092 in female mice demonstrates efficient bio-retention in nasal cavities and lungs, offering protection against lethal doses of H1N1 and H3N2 IAV when administered prophylactically. Optimal epitope selection, trans-crosslinking, decavalent avidity, and intranasal administration contribute to the broader protection and potency of engineered IgM antibodies against diverse IAV subtypes.
工程化针对甲型流感病毒（IAV）血凝素（HA）的广泛中和单克隆抗体（mAb）是干预季节性流感的一种有前景的方法。然而，HA的可塑性常常导致产生耐药毒株，这些毒株会削弱作为二价IgG的mAb效力。在此，我们假设作为IgM的抗IAV抗体多聚化可以增强覆盖范围和中和效力。在此，我们从针对不同IAV HA表位的已知广泛中和IgG构建了18种IgM抗体，并评估了它们对不同H1N1和H3N2 IAV的中和广度和效力。与亲本IgG相比，受体结合位点特异性IgG F045 - 092的IgM版本显示出增加的广度和抗病毒效力。工程化的IgM分子通过扩大亲和力克服了IAV毒株抗性，在亚纳摩尔范围内提供体外强效中和作用，同时保留亲本IgG的特异性。在雌性小鼠中鼻内递送工程化的IgM - F045 - 092证明在鼻腔和肺部有高效的生物保留，在预防性给药时能提供针对致死剂量H1N1和H3N2 IAV的保护。最佳表位选择、反式交联、十价亲和力和鼻内给药有助于工程化IgM抗体对多种IAV亚型具有更广泛的保护作用和效力。
