Widespread Fab-arm exchange affects all endogenous serum IgG4

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. Among the antibody subclasses, IgG4 is unique in its capability to fragment-antigen-binding (Fab)-arm exchange, a process that renders IgG4 bispecific for antigen binding. Here authors analyse serum IgG4 clonal repertoires of healthy human donors to show that Fab-arm exchange is widespread and affects all IgG4 clones.