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Title IgX informs engineering strategies of IgM and IgG hexamers.
Journal, issue, pagesSci Adv, Vol. 11, Issue 45, Page eaea3737, Year 2025
Publish dateNov 7, 2025
AuthorsRuixue Zhang / Chenggong Ji / Shuhan Li / Ningning Li / Ning Gao / Junyu Xiao /
PubMed AbstractPolymeric immunoglobulins are essential components of the immune system in jawed vertebrates. While mammalian immunoglobulin M (IgM) typically forms a pentamer linked by the joining chain (J-chain), ...Polymeric immunoglobulins are essential components of the immune system in jawed vertebrates. While mammalian immunoglobulin M (IgM) typically forms a pentamer linked by the joining chain (J-chain), IgX can assemble into a J-chain-independent polymer. Here, we present the cryo-electron microscopy (cryo-EM) structure of IgX, revealing its hexameric configuration. By incorporating the IgX tailpiece into human IgM, we achieved efficient IgM hexamer formation. Truncating IgM's natural tailpiece to a range of 11 to 16 residues also substantially enhanced hexamerization efficiency. Furthermore, introducing a shortened IgM tailpiece to IgG resulted in effective IgG hexamer formation. We further show that the engineered IgM and IgG hexamers targeting CD20 demonstrated robust complement-dependent cytotoxicity (CDC) against several B lymphoma cells. In addition, the IgG-Fc hexamer functioned as a decoy, attenuating CDC in cell cultures. These findings deepen our understanding of polymeric immunoglobulin evolution and introduce innovative strategies for the development of IgM- and IgG-based biologics.
External linksSci Adv / PubMed:41191733 / PubMed Central
MethodsEM (single particle)
Resolution2.75 - 3.29 Å
Structure data

64371

9uo3

EMDB-64371, PDB-9uo3:
Cryo-EM structure of the human IgM-Fc hexamer
Method: EM (single particle) / Resolution: 3.17 Å

64372

9uo4

EMDB-64372, PDB-9uo4:
Cryo-EM structure of the chimeric human IgM-Fc hexamer
Method: EM (single particle) / Resolution: 3.29 Å

64373

9uo5

EMDB-64373, PDB-9uo5:
Cryo-EM structure of the human IgG-Fc hexamer
Method: EM (single particle) / Resolution: 2.75 Å

64375

9uo6

EMDB-64375, PDB-9uo6:
Cryo-EM structure of the Xenopus IgX-Fc hexamer
Method: EM (single particle) / Resolution: 3.29 Å

Source
  • homo sapiens (human)
  • xenopus laevis (African clawed frog)
KeywordsIMMUNE SYSTEM / Complex / polymeric antibody

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