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<p>Out of all human antibodies, IgG4 stands out by its ability to dissociate in half-molecules and reassemble forming novel bivalent antibodies. Although this so-called Fab-arm exchange mechanism is acknowledged, detailed analysis of whether all IgG4 clones in serum are involved in such processes is not known. Here, by introducing a liquid chromatography-mass spectrometry-based approach enabling the analysis of serum IgG4 clonal repertoires, we show that widespread Fab-arm exchange occurs in serum of healthy donors and leads to a massive explosion in the molecular diversity of the IgG4 clonal repertoire. These findings provide new insight into IgG4, which plays a critical role in allergy, autoimmunity and vaccination settings, and may also impact the use of IgG4 as scaffold for therapeutics.</p>

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Widespread Fab-arm exchange affects all endogenous serum IgG4

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Linus Wollenweber,
  • Albert Bondt,
  • Gestur Vidarsson,
  • Maartje G. Huijbers,
  • Albert J. R. Heck

摘要

Out of all human antibodies, IgG4 stands out by its ability to dissociate in half-molecules and reassemble forming novel bivalent antibodies. Although this so-called Fab-arm exchange mechanism is acknowledged, detailed analysis of whether all IgG4 clones in serum are involved in such processes is not known. Here, by introducing a liquid chromatography-mass spectrometry-based approach enabling the analysis of serum IgG4 clonal repertoires, we show that widespread Fab-arm exchange occurs in serum of healthy donors and leads to a massive explosion in the molecular diversity of the IgG4 clonal repertoire. These findings provide new insight into IgG4, which plays a critical role in allergy, autoimmunity and vaccination settings, and may also impact the use of IgG4 as scaffold for therapeutics.