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TitleNeutralization of SARS-CoV-2 by IgM-14 via engagement of two distinct spike epitopes.
Journal, issue, pagesPLoS Pathog, Vol. 22, Issue 3, Page e1014071, Year 2026
Publish dateMar 25, 2026
AuthorsYan Wang / Yanping Hu / Zhiqiang Ku / Jason Yeung / Jing Zou / Michael Woodson / Nikolai S Prokhorov / Ekaterina S Knyazhanskaya / Haiqing Zhao / Michael B Sherman / Zhiqiang An / Stephen F Carroll / Pei-Yong Shi / Petr G Leiman / Xuping Xie /
PubMed AbstractEngineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to ...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.
External linksPLoS Pathog / PubMed:41880376 / PubMed Central
MethodsEM (single particle)
Resolution3.01 - 4.1 Å
Structure data

73228

9ynr

EMDB-73228, PDB-9ynr:
Local refinement of Fab-14/SARS-CoV-2 D614G spike complex, Mode I
Method: EM (single particle) / Resolution: 3.55 Å

EMDB-73231: Cryo-EM map of D614G spike, 1-up-RBD
Method: EM (single particle) / Resolution: 3.38 Å

EMDB-73244: SARS-CoV-2 D614G spike, 3-RBD-downn
Method: EM (single particle) / Resolution: 3.32 Å

73245

9ynx

EMDB-73245, PDB-9ynx:
Local refinement of Fab-14/SARS-CoV-2 D614G spike complex, Mode IV, Subgroup I conformation
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-73247: Fab-14/SARS-CoV-2 D614G spike complex, Mode V conformation
Method: EM (single particle) / Resolution: 3.52 Å

73260

9yok

EMDB-73260, PDB-9yok:
Fab-14/SARS-CoV-2 D614G spike complex, Mode I conformation
Method: EM (single particle) / Resolution: 3.56 Å

EMDB-73263: Fab-14/SARS-CoV-2 D614G spike complex, Mode II, subgroup I conformation
Method: EM (single particle) / Resolution: 3.48 Å

EMDB-73265: Fab-14/SARS-CoV-2 D614G spike complex, Mode II, subgroup II conformation
Method: EM (single particle) / Resolution: 3.49 Å

EMDB-73267: Fab-14/SARS-CoV-2 D614G spike complex, Mode II, subgroup III conformation
Method: EM (single particle) / Resolution: 3.57 Å

EMDB-73270: Fab-14/SARS-CoV-2 Omicron BA.1 spike complex
Method: EM (single particle) / Resolution: 3.73 Å

EMDB-73271: SARS-CoV-2 Omicron BA.1 spike, 3-RBD-down
Method: EM (single particle) / Resolution: 3.01 Å

EMDB-73273: SARS-CoV-2 Omicron BA.1 spike, 1-RBD-up
Method: EM (single particle) / Resolution: 3.16 Å

EMDB-73290: Fab-14/SARS-CoV-2 D614G spike complex, Mode III conformation
Method: EM (single particle) / Resolution: 3.47 Å

EMDB-73291: Unbound SARS-CoV-2 D614G spike
Method: EM (single particle) / Resolution: 3.52 Å

73292

9ypb

EMDB-73292, PDB-9ypb:
Fab-14/SARS-CoV-2 D614G spike complex, Mode IV, subgroup II conformation
Method: EM (single particle) / Resolution: 3.5 Å

73306

9ypr

EMDB-73306, PDB-9ypr:
Fab-14/SARS-CoV-2 D614G spike complex, Mode IV, subgroup I conformation
Method: EM (single particle) / Resolution: 3.46 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / SARS-CoV-2 / neutralizing antibody / neutraling antibody / neutralizing anbitody

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