Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems
Open Access
- 25 September 2013
- journal article
- Published by Portland Press Ltd. in Bioscience Reports
- Vol. 33 (5), 771-781
- https://doi.org/10.1042/bsr20130081
Abstract
The glycosylation of recombinant β-glucocerebrosidase, and in particular the exposure of mannose residues, has been shown to be a key factor in the success of ERT (enzyme replacement therapy) for the treatment of GD (Gaucher disease). Macrophages, the target cells in GD, internalize β-glucocerebrosidase through MRs (mannose receptors). Three enzymes are commercially available for the treatment of GD by ERT. Taliglucerase alfa, imiglucerase and velaglucerase alfa are each produced in different cell systems and undergo various post-translational or post-production glycosylation modifications to expose their mannose residues. This is the first study in which the glycosylation profiles of the three enzymes are compared, using the same methodology and the effect on functionality and cellular uptake is evaluated. While the major differences in glycosylation profiles reside in the variation of terminal residues and mannose chain length, the enzymatic activity and stability are not affected by these differences. Furthermore, the cellular uptake and in-cell stability in rat and human macrophages are similar. Finally, in vivo studies to evaluate the uptake into target organs also show similar results for all three enzymes. These results indicate that the variations of glycosylation between the three regulatory-approved β-glucocerebrosidase enzymes have no effect on their function or distribution.This publication has 36 references indexed in Scilit:
- Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic responseBlood, 2011
- Protective and pathogenic functions of macrophage subsetsNature Reviews Immunology, 2011
- How I treat Gaucher diseaseBlood, 2011
- Development of Monocytes, Macrophages, and Dendritic CellsScience, 2010
- Characterization of gene-activated human acid- -glucosidase: Crystal structure, glycan composition, and internalization into macrophagesGlycobiology, 2009
- Use of Dynasore, the Small Molecule Inhibitor of Dynamin, in the Regulation of EndocytosisMethods in Enzymology, 2008
- Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell systemPlant Biotechnology Journal, 2007
- Dexamethasone-Mediated Up-Regulation of the Mannose Receptor Improves the Delivery of Recombinant Glucocerebrosidase to Gaucher MacrophagesThe Journal of pharmacology and experimental therapeutics, 2003
- Heterogeneity of the complex N‐linked oligosaccharides at specific glycosylation sites of two secreted carrot glycoproteinsJBIC Journal of Biological Inorganic Chemistry, 1991
- Establishment and characterization of a human histiocytic lymphoma cell line (U‐937)International Journal of Cancer, 1976