LHO

Figure 12.15 Generalized structure of a glucocerebroside

Genzyme Corporation was granted marketing authorization in 1991 for a glucocerebrosidase preparation to be used for the treatment of Gaucher's disease. This Genzyme product (tradename Ceredase) was extracted from placentas (afterbirths) obtained from maternity hospital wards. The enzyme displays a molecular mass of 65 kDa and four of its five potential glycosylation sites are glycosylated. It had been estimated that a 1-year's supply of enzyme for an average patient required extraction of 27 000 placentas, which rendered treatment extremely expensive. Genzyme then gained regulatory approval for a recombinant version of glucocerebrosidase produced in CHO cells. This product (tradename Cerezyme) has been on the market since 1994, and the total world market for glucocerebrosidase is estimated to be in the region of US$200 million.

Cerezyme is produced in a CHO cell line harbouring the cDNA coding for human P-glucocer-ebrosidase. The purified product is presented as a freeze-dried powder, which also contains man-nitol, sodium citrate, citric acid and polysorbate 80 as excipients. It exhibits a shelf life of 2 years when stored at 2-8 °C.

An integral part of the downstream processing process entails the modification of cerezyme's oli-gosaccharide components. The native enzyme's sugar side-chains are complex and, for the most part, are capped with a terminal sialic acid or galactose residue. Animal studies indicate that in excess of 95 per cent of injected glucocerebrosidase is removed from the circulation by the liver via binding to hepatocyte surface lectins. As such, the intact enzyme is not available for uptake by the affected cell type, i.e. the tissue macrophages. These macrophages display high levels of surface mannose receptors. Treatment of native glucocerebrosidase with exoglycosidases, by removing terminal sugar residues, can expose mannose residues present in their sugar side-chains, resulting in their binding to and uptake by the macrophages. In this way, the 'mannose-engineered' enzyme is selectively targeted to the affected cells.

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