Publication Date
3-1-2026
Journal
PLoS Pathogens
DOI
10.1371/journal.ppat.1014071
PMID
41880376
PMCID
PMC13043055
PubMedCentral® Posted Date
3-25-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong resistance. Cryo-electron microscopy analysis uncovered two distinct Fab-RBD interfaces: a primary interface overlapping the angiotensin-converting enzyme 2 (ACE2)-binding region, and a unique secondary interface formed only when the RBD adopts the ACE2-inaccessible "down" conformation, involving a neighboring spike protomer. Site-directed mutagenesis and structural modeling revealed a critical role of this secondary site in IgM-14-mediated neutralization. Unlike IgG-14, structural modeling suggested that IgM-14 can simultaneously engage both interfaces in diverse modes, indicating a noncanonical avidity mechanism. Collectively, these findings highlight the structural and functional uniqueness of IgM-14 and offer valuable insights into the rational design of next-generation spike-targeted antibody therapeutics with enhanced breadth and potency.
Keywords
SARS-CoV-2, Spike Glycoprotein, Coronavirus, Immunoglobulin M, Humans, Epitopes, Antibodies, Neutralizing, Antibodies, Viral, COVID-19, Angiotensin-Converting Enzyme 2, Cryoelectron Microscopy
Published Open-Access
yes
Recommended Citation
Wang, Yan; Hu, Yanping; Ku, Zhiqiang; et al., "Neutralization of SARS-CoV-2 by IgM-14 via Engagement of Two Distinct Spike Epitopes" (2026). The Brown Foundation: Institute of Molecular Medicine. 45.
https://digitalcommons.library.tmc.edu/molecular_med/45