Glycobiology Advance Access originally published online on January 24, 2007
Glycobiology 2007 17(5):467-478; doi:10.1093/glycob/cwm008
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Effect of mannose chain length on targeting of glucocerebrosidase for enzyme replacement therapy of Gaucher disease
2 Cell and Protein Therapeutics, Genzyme Corp., Framingham, MA 01701-9322
1 To whom correspondence should be addressed; Tel: +1-508-270-2409; Fax: +1-508-872-9080; e-mail: Scott.Vanpatten{at}genzyme.com
Received on August 29, 2006; revised on December 14, 2006; accepted on January 18, 2007
Recombinant human glucocerebrosidase (imiglucerase, Cerezyme®) is used in enzyme replacement therapy for Gaucher disease. Complex oligosaccharides present on Chinese hamster ovary cell-expressed glucocerebrosidase (GCase) are enzymatically remodeled into a mannose core, facilitating mannose receptor-mediated uptake into macrophages. Alternative expression systems could be used to produce GCase containing larger oligomannose structures, offering the possibility of an improvement in targeting to macrophages. A secondary advantage of these expression systems would be to eliminate the need for carbohydrate remodeling. Here, multiple expression systems were used to produce GCase containing primarily terminal oligomannose, from Man2 to Man9. GCase from these multiple expression systems was compared to Cerezyme® with respect to affinity for mannose receptor and serum mannose-binding lectin (MBL), macrophage uptake, and intracellular half-life. In vivo studies comparing clearance and targeting of Cerezyme® and the Man9 form of GCase were carried out in a Gaucher mouse model (D409V/null). Mannose receptor binding, macrophage uptake, and in vivo targeting were similar for all forms of GCase. Increased MBL binding was observed for all forms of GCase having larger mannose structures than those of Cerezyme®, which could influence pharmacokinetic behavior. These studies demonstrate that although alternative cell expression systems are effective for producing oligomannose-terminated glucocerebrosidase, there is no biochemical or pharmacological advantage in producing GCase with an increased number of mannose residues. The display of alternative carbohydrate structures on GCase expressed in these systems also runs the risk of undesirable consequences, such as an increase in MBL binding or a possible increase in immunogenicity due to the presentation of non-mammalian glycans.
Key words: mannose receptor-directed uptake / glucocerebrosidase / lysosomal storage disease / enzyme replacement therapy / macrophage targeting
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