Document Detail


Evidence for an asialoglycoprotein receptor on nonparenchymal cells for O-linked glycoproteins.
MedLine Citation:
PMID:  18728239     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
B cell-activating factor receptor 3 (BR3)-Fc is an IgG1-receptor dimeric fusion protein that has multiple O-linked glycosylation sites and sialylation levels that can vary in the manufacturing process. Increased sialic acid levels resulted from increased site occupancy with the O-linked N-acetylgalactosamine (GalNAc-Gal), but because the ratio of sialic acid per mole of oligosaccharide remained approximately 1, this led to increased asialo terminal GalNAc. Previous studies have demonstrated an effect of terminal asialo Gal or GalNAc on the clearance of glycoproteins due to uptake and degradation by lectin receptors in the liver. However, the previous studies examined N-linked oligosaccharides, and there are less data regarding O-linked oligosaccharides. The objective of these studies was to determine the effects on the pharmacokinetics and distribution of the asialo terminal GalNAc and varying amounts of sialic acid residues on BR3-Fc. The results of the data presented here suggest that exposed Gal on the desialylated BR3-Fc led to rapid clearance due to uptake and degradation in the liver that was associated with nonparenchymal cells. It is interesting to note that the data indicated a decreased clearance and increased exposure of BR3-Fc as the sialic acid levels increased, even though increased sialic acid was associated with increased asialo GalNAc. Therefore, the exposed GalNAc did not seem to play a role in the clearance of BR3-Fc; although the Gal linked to the hydroxyl group at position 3 may have prevented an interaction. Because we did not see uptake of desialylated BR3-Fc in hepatocytes where the asialoglycoprotein receptor is localized, this nonparenchymal cell lectin may have preference for O-linked glycoproteins.
Authors:
Eric G Stefanich; Song Ren; Dimitry M Danilenko; Amy Lim; An Song; Suhasini Iyer; Paul J Fielder
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Publication Detail:
Type:  Journal Article     Date:  2008-08-26
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  327     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-10-20     Completed Date:  2008-11-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  308-15     Citation Subset:  IM    
Affiliation:
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA 94080, USA. erics@gene.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD19 / analysis
Asialoglycoprotein Receptor / pharmacokinetics*
B-Cell Activation Factor Receptor / chemistry,  pharmacokinetics*,  pharmacology
Female
Glycoproteins / metabolism*
Immunoglobulin Fc Fragments / metabolism,  pharmacology
Iodine Radioisotopes / diagnostic use
Liver / metabolism
Mice
Mice, Inbred BALB C
Recombinant Fusion Proteins / pharmacokinetics*,  pharmacology
Tissue Distribution
Chemical
Reg. No./Substance:
0/Antigens, CD19; 0/Asialoglycoprotein Receptor; 0/B-Cell Activation Factor Receptor; 0/Glycoproteins; 0/Immunoglobulin Fc Fragments; 0/Iodine Radioisotopes; 0/Recombinant Fusion Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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