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.
Highlights
GD (Gaucher disease) is a rare genetic lysosomal storage disorder caused by the functional deficiency of β-glucocerebrosidase that results in multiple organ malfunction [1]. β-glucocerebrosidase catalyses the hydrolysis of glucocerebroside into ceramide and glucose
Imiglucerase (Genzyme Corporation, a Sanofi company) is a β-glucocerebrosidase produced in a mammalian CHO (Chinese-hamster ovary) system, and modified post-production with exoglycosidase enzymes to expose mannose residues [5,6,7]
This study is the first attempt to evaluate the impact of the different glycosylation profiles on the performance of the three commercially available recombinant β-glucocerebrosidase enzymes
Summary
GD (Gaucher disease) is a rare genetic lysosomal storage disorder caused by the functional deficiency of β-glucocerebrosidase that results in multiple organ malfunction [1]. β-glucocerebrosidase catalyses the hydrolysis of glucocerebroside into ceramide and glucose. In GD, the enzyme malfunction results in accumulation of excessive glucocerebroside in lysosomal compartments of tissue macrophages (Gaucher cells) [2]. The results were disappointing [3] with limited therapeutic value, because exogenously administered, unmodified human β-glucocerebrosidase, derived from placenta, did not effectively enter the target cells in the body, due to the lack of exposed mannose residues. In order to produce β-glucocerebrosidase with exposed mannose residues, three alternative production methods have been developed and are used today for ERT of GD. Imiglucerase (Genzyme Corporation, a Sanofi company) is a β-glucocerebrosidase produced in a mammalian CHO (Chinese-hamster ovary) system, and modified post-production with exoglycosidase enzymes to expose mannose residues [5,6,7].
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