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Glycobiology Advance Access originally published online on January 3, 2003
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Glycobiology, 2003, Vol. 13, No. 4 305-313
© 2003 Oxford University Press

A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease

Karen Lee, Xiaoying Jin, Kate Zhang, Lorraine Copertino, Laura Andrews, Jennifer Baker-Malcolm, Laura Geagan, Huawei Qiu, Keirsten Seiger, Debra Barngrover, John M. McPherson and Tim Edmunds1

Cell and Protein Therapeutics, Genzyme Corporation, P.O. Box 9322, Framingham, MA 01701-9322, USA

Received on October 8, 2002; revised on November 19, 2002; accepted on November 22, 2002

Fabry disease is a lysosomal storage disease arising from deficiency of the enzyme {alpha}-galactosidase A. Two recombinant protein therapeutics, Fabrazyme (agalsidase beta) and Replagal (agalsidase alfa), have been approved in Europe as enzyme replacement therapies for Fabry disease. Both contain the same human enzyme, {alpha}-galactosidase A, but they are produced using different protein expression systems and have been approved for administration at different doses. To determine if there is recognizable biochemical basis for the different doses, we performed a comparison of the two drugs, focusing on factors that are likely to influence biological activity and availability. The two drugs have similar glycosylation, both in the type and location of the oligosaccharide structures present. Differences in glycosylation were mainly limited to the levels of sialic acid and mannose-6-phosphate present, with Fabrazyme having a higher percentage of fully sialylated oligosaccharides and a higher level of phosphorylation. The higher levels of phosphorylated oligomannose residues correlated with increased binding to mannose-6-phosphate receptors and uptake into Fabry fibroblasts in vitro. Biodistribution studies in a mouse model of Fabry disease showed similar organ uptake. Likewise, antigenicity studies using antisera from Fabry patients demonstrated that both drugs were indistinguishable in terms of antibody cross-reactivity. Based on these studies and present knowledge regarding the influence of glycosylation on protein biodistribution and cellular uptake, the two protein preparations appear to be functionally indistinguishable. Therefore, the data from these studies provide no rationale for the use of these proteins at different therapeutic doses.

1 To whom correspondence should be addressed; e-mail: tim.edmunds{at}genzyme.com


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