Asymmetric N-Glycosylation in the Tailpiece of Recombinant IgA1

J Am Chem Soc. 2024 Dec 18;146(50):34720-34732. doi: 10.1021/jacs.4c13156. Epub 2024 Dec 6.

Abstract

Here, we employed a variety of mass spectrometry (MS)-based approaches, both (glyco)peptide-centric and protein-centric, to resolve the complex glycoproteoform landscape of recombinant IgA1 produced in HEK293 cells. These key immunoglobulins harbor several N- and O-glycosylation sites, making them considerably more heterogeneous than their IgG counterparts. We provide quantitative data on the occupancy and glycan composition for each IgA1 glycosylation site. Combining all data, we revealed that IgA1 molecules consist of at least three distinct populations with varying N-glycosylation site occupancies at the C-terminal tailpiece, namely, one with both glycosylation sites occupied, another with both glycosylation sites unoccupied, and a third asymmetric population with one glycosylation site occupied and the other unoccupied, challenging the prevailing acceptance that IgA1 N-glycosylation is symmetrical. This finding is significant, given that the tailpiece is involved in interactions with the J-chain and the Polymeric Immunoglobulin Receptor, and in general as antibody glycosylation is a quality attribute that needs to be carefully monitored, as the presence and nature of these modifications can affect the antibody's efficacy, lifetime, stability, and binding and/or neutralizing capacities. Optimizing strategies to produce recombinant IgA1 requires efficient and specific quality control analytical strategies, as presented here, which is essential for therapeutic IgA1-based antibody development. We expect that the integrated MS-based strategy presented here may be beneficial to comprehensively characterize the glycoproteoform profiles of IgA1-based therapeutics, thereby improving their production and optimization processes and facilitating the pathway to bring more IgA1-based therapeutics into clinical applications.

MeSH terms

  • Glycosylation
  • HEK293 Cells
  • Humans
  • Immunoglobulin A* / chemistry
  • Mass Spectrometry
  • Polysaccharides / chemistry
  • Polysaccharides / metabolism
  • Recombinant Proteins* / chemistry

Substances

  • Immunoglobulin A
  • Recombinant Proteins
  • Polysaccharides