MassIVE MSV000097341

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Widespread Fab-arm exchange affects all endogenous serum IgG4

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Description

Antibodies are key molecular elements of the human immune system and account for an increasingly large proportion of therapeutics. Next to the well-studied and explored IgG1, several other classes (e.g. IgA, IgM) and sub-classes (e.g., IgG2, IgG3 and IgG4) exist in humans. In particular IgG4 is worth a closer examination as it has unique natural properties and is regularly used as a scaffold in biologicals. In contrast to IgG1, endogenous IgG4 comes in two co-existing structural isomers, owing to the distinct properties of the hinge disulfide-bond connecting the two heavy chains. In one isomer, this disulfide bridge is opened, allowing the release and exchange of one half of the IgG4 molecule, and consequently the formation of bispecific IgG4. Here, we present a LC-MS-based approach enabling the analysis of IgG4 repertoires with clonal resolution, which we used to monitor endogenous serum IgG4 repertoires from seven healthy donors. Most strikingly, our data reveal the combinatorial explosion in diversity of the serum IgG4 clonal repertoire. This phenomenon is explained by the stochastic behavior of Fab-arm exchange, making virtually each IgG4 molecule in serum bispecific. Although the endogenous IgG4 clonal repertoire is therefore extremely diverse, we demonstrate that this IgG4 repertoire persists over time within an individual healthy donor, at least for more than one year. [doi:10.25345/C5CC0V585] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Antibody repertoire ; Clonal profiling ; IgG4 ; DatasetType:Other (Intact protein)

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Principal Investigators:
(in alphabetical order) 		Albert J.R. Heck, Utrecht University, The Netherlands
Submitting User: LinusWollenweber
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