PT - JOURNAL ARTICLE AU - Eric G. Stefanich AU - Song Ren AU - Dimitry M. Danilenko AU - Amy Lim AU - An Song AU - Suhasini Iyer AU - Paul J. Fielder TI - Evidence for an Asialoglycoprotein Receptor on Nonparenchymal Cells for <em>O</em>-Linked Glycoproteins AID - 10.1124/jpet.108.142232 DP - 2008 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 308--315 VI - 327 IP - 2 4099 - http://jpet.aspetjournals.org/content/327/2/308.short 4100 - http://jpet.aspetjournals.org/content/327/2/308.full SO - J Pharmacol Exp Ther2008 Nov 01; 327 AB - 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. The American Society for Pharmacology and Experimental Therapeutics