title: A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease.
abstract: 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.
authors.affiliation: Cell and Protein Therapeutics, Genzyme Corporation, PO Box 9322, Framingham, MA 01701-9322, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Lee
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jin
authors.forename: Kate
authors.initials: K
authors.lastname: Zhang
authors.forename: Lorraine
authors.initials: L
authors.lastname: Copertino
authors.forename: Laura
authors.initials: L
authors.lastname: Andrews
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baker-Malcolm
authors.forename: Laura
authors.initials: L
authors.lastname: Geagan
authors.forename: Huawei
authors.initials: H
authors.lastname: Qiu
authors.forename: Keirsten
authors.initials: K
authors.lastname: Seiger
authors.forename: Debra
authors.initials: D
authors.lastname: Barngrover
authors.forename: John M
authors.initials: JM
authors.lastname: McPherson
authors.forename: Tim
authors.initials: T
authors.lastname: Edmunds
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D000795:Fabry Disease / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors; D014018:Tissue Distribution; D000519:alpha-Galactosidase / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D011994:Recombinant Proteins; C000627036:agalsidase alfa; D000519:alpha-Galactosidase; C459420:agalsidase beta