In the consortium PharmIgA, supported by the growth fund program PharmaNL and ZonMw, we explore new avenues to use the immunoglobulin A (IgA) class as a format for next-generation biotherapeutics, inspired by the fact that the human body does use this IgA format even more so than IgG. However, IgA is structurally more complex and versatile than IgG. Human immunoglobulin A (IgA) naturally occurs in multiple molecular forms—monomers, dimers, and even higher-order polymers—that are differentially distributed across serum, breastmilk and mucosal surfaces. The C-terminal tailpiece of IgA is essential to its polymerization mediated by the joining chain (J-chain) and thus also an important determinant of its extensive structural heterogeneity, yet its features remain somewhat poorly defined.
In our latest publication in JACS, Weiwei Wang et al. show a variety of proteoform properties of the IgA tailpiece. We had observed before that the tailpiece can be found with and without the C-terminal tyrosine, Tyr472. Here, we looked a bit deeper at the tailpiece in different circulatory and secretory configurations. Specifically, we investigated circulatory monomeric IgA and J-chain-coupled dimers, as well as milk-derived secretory IgA dimers.
It turns out that the parts coupled to a J-chain mostly retain the Tyr472, and that their glycosylation is less 'mature': high-mannose type glycans, hybrids, or low levels of galactosylation, sialylation and bisection. The free tailpieces often lack Tyr472 and come with mature biantennary glycans. Interestingly, the other IgA-Fc N-glycosylation sites are barely affected by the IgA configuration. Together, this suggests that the J-chain is added to the IgA heavy chains early in the Golgi, and that its presence hinders glycosyltransferases to continue editing the N-glycans on the tailpiece.
Overall, our results advance the understanding of IgA structure and will offer a much-needed molecular basis to assist future bioengineering of IgA-based therapeutics, the major aim of PharmIgA.
