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Here we constructed an IgM antibody (20\u2010IgM) based on our previous discovery to address the resistance encountered by IgG\u2010based immunotherapy. Although binding to the same conserved neutralizing epitope within the GH loop of EV\u2010As VP1, the antiviral breath and potency of 20\u2010IgM are still higher than its parental 20\u2010IgG1. The\u00a020\u2010IgM blocks the interaction between the EV\u2010As and its receptors, scavenger receptor class B, member 2 (SCARB2) and Kringle\u2010containing transmembrane protein 1(KREMEN1) of the host cell. The\u00a020\u2010IgM also neutralizes the EV\u2010As at the post\u2010attachment stages, including postattachment neutralization, uncoating and RNA release inhibition after internalization. Mechanistically, the dual blockage effect of 20\u2010IgM is dependent on both a conserved site targeting and high affinity binding. Meanwhile, 20\u2010IgM provides cross\u2010antiviral efficacy in EV\u2010As orally infected neonatal ICR mice. Collectively, 20\u2010IgM and its property exhibit excellent antiviral activity with a dual\u2010blockage inhibitory effect at both the pre\u2010 and post\u2010attachment stages. The finding enhances our understanding of IgM\u2010mediated immunity and highlights the potential of IgM subtype antibodies against enterovirus infections.<\/jats:p>","DOI":"10.1111\/imm.13629","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T05:20:11Z","timestamp":1675315211000},"page":"292-308","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dual blockages of a broad and potent neutralizing <scp>IgM<\/scp> antibody targeting <scp>GH<\/scp> loop of <scp>EV\u2010As<\/scp>"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9210-1439","authenticated-orcid":false,"given":"Wenbing","family":"Zhu","sequence":"first","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College  Kunming 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