A Longitudinal Study of Glycosylation of a Human IgG3 Paraprotein in a Patient with Multiple Myeloma

Abstract

The IgG antibody molecule is a structural paradigm for members of the immuoglobulin super family¹. Whilst the oligosaccharide moiety of the IgG molecule accounts for only 23% of its mass it has been shown to be essential for optimal activation of effector mechanisms leading to the clearance and destruction of pathogens², ³, ⁴. Human antibody molecules of the IgG class have N-linked oligosaccharide attached at the amide side chain of Asn-297 in the heavy chain⁵. The oligosaccharide moiety is of the complex bianntennary type having a heptasaccharide “core” structure (GlcNAc₂Man₃GlcNAc₂) and variable outer arm “non-core” sugar residues, such as fucose, bisecting N-acetylglucosamine, galactose and sialic acid (Figure 1). The number of variant oligosaccharides that may be attached to heavy chains is 32 (Figure 2) and the total number of possible glycoforms >800^6,7. This level of heterogeneity is evident for polyclonal IgG whilst a more restricted heterogeneity may be observed for monoclonal proteins⁴. In addition, ~30% of polyclonal IgG has been reported to bear a complex N- linked oligosaccharide in the Fab region⁸. It is apparent, therefore, that glycosylation is a post-translational modification that can introduce a very significant structural and, possibly, functional heterogeneity into the IgG molecule, such that glycoforms can alter the biological activity⁹.