A Longitudinal Study of Glycosylation of a Human IgG3 Paraprotein in a Patient with Multiple Myeloma
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 >8006,7. 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.
KeywordsMultiple Myeloma Sialic Acid Plateau Phase HPLC Profile Amide Side Chain
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- 3.R. Jefferis and J. Lund, Molecular characterisation of IgG antibody Fc effector sites, In protein engineering of antibody molecules for prophylactic and therapeutic applications in man, M. Clarke, Ed. Academic press NY p115 (1995)Google Scholar
- 9.R. Malhotra, M. R. Wormald, P. M. Rudd, P. B. Fischer, R. A. Dwek and R. B. Sim, Glycosylation changes of IgG associated rheumatoid arthritis can activate complement via the MBP, Nature Medicine. vol 1 No 6: 599Google Scholar
- 10.R. B. Parekh, R. A. Dwek, B. J. Sutton, D. L. Fernandes, A. Leung, D. Stanworth, T. W. Rademacher, T. Mizuochi, T. Taniguchi, K. Matsuta, F. Takeuchi, Y. Nagano, T. Miyamoto and A. Kobata, Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG, Nature. 316:452–457 (1985).PubMedCrossRefGoogle Scholar
- 13.G. A. W. Rook, J. Steele, R. Brearley, A. Whyte, D. A. Isenburg, N. Sumar, J. L. Nelson, K. B. Bodman, A. Young, I. M. Roitt, P. Williams, I. Scragg, C. J. Edge, P. D. Arkwright, D. Ashford, M. Wormald, P. Rudd, C. W. G. Redman, R. A. Dwek, and T. W. Rademacher, Changes in the IgG glycoform levels are associated with remission of arthritis during pregnancy, J. Autoimmunity. 779–794 (1991).Google Scholar
- 17.M. Farooq, N. Takahashi, H. Arrol, M. Drayson, and R. Jefferis, Glycosylation of IgG antibody molecules in multiple myeloma, Glycoconjugate J. In press (1996).Google Scholar
- 21.S. Narasimhan, J. C. Freed, and H. Schachter, Control of glycoprotein synthesis. Bovine milk UDP-galactose: N-acetylglucosamine β-4-Galactosyltransferase catalyzes the preferential transfer of galactose to the GlcNAcβ1,2Manα1,3-branch of both bisected and non-bisected complex biantennary asparagine-linked oligosaccharides, Biochemistry. 24: 1694–1700 (1985).PubMedCrossRefGoogle Scholar