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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2807-2816
A Comparison of the Pharmacological Properties of Carbohydrate
Remodeled Recombinant and Placental-Derived  -Glucocerebrosidase:
Implications for Clinical Efficacy in Treatment of Gaucher Disease
BethAnn Friedman,
Kris Vaddi,
Constance Preston,
Elizabeth Mahon,
James R. Cataldo, and
John M. McPherson
From the Cell and Protein Therapeutics Department, Genzyme
Corporation, Framingham, MA.
The objective of these studies was to characterize the macrophage
mannose receptor binding and pharmacological properties of carbohydrate
remodeled human placental-derived and recombinant  -glucocerebrosidase (pGCR and rGCR, respectively). These are similar
but not identical molecules that were developed as enzyme replacement
therapies for Gaucher disease. Both undergo oligosaccharide remodeling
during purification to expose terminal mannose sugar residues.
Competitive binding data indicated carbohydrate remodeling improved
targeting to mannose receptors over native enzyme by two orders of
magnitude. Mannose receptor dissociation constants (Kd) for pGCR and rGCR were each 13 nmol/L. At
37°C, 95% of the total macrophage binding was mannose receptor
specific. In vivo, pGCR and rGCR were cleared from circulation by a
saturable pathway. The serum half-life (t1/2) was 3 minutes
when less than saturable amounts were injected intravenously (IV) into
mice. Twenty minutes postdose, -glucocerebrosidase activity
increased over endogenous levels in all tissues examined. Fifty percent
of the injected activity was recovered. Ninety-five percent of
recovered activity was in the liver. Parenchymal cells (PC), Kupffer
cells (KC), and liver endothelium cells (LEC) were responsible for
75%, 22%, and 3%, respectively, of the hepatocellular uptake of rGCR
and for 76%, 11%, and 12%, respectively, of the hepatocellular
uptake of pGCR. Both molecules had poor stability in LEC and relatively long terminal half-lives in PC (t1/2 = 2 days) and KC
(t1/2 = 3 days).
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