Glycobiology Advance Access published online on January 24, 2007
Glycobiology, 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
Cell and Protein Therapeutics, Genzyme Corp., Framingham, MA 01701-9322, USA
* Corresponding author: Phone: 508-270-2409, Fax: 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 as an enzyme replacement therapy for Gaucher disease. Complex oligosaccharides present on CHO cell-expressed glucocerebrosidase (GCase) are enzymatically remodeled to 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 improved 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 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 alternate carbohydrate structures on GCase expressed in these systems also runs the risk of undesirable consequences, such as the increased MBL binding seen here or possible increased 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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