Role of sialylation in determining the pharmacokinetics of neutrophil inhibitory factor (NIF) in the Fischer 344 rat

Webster, Robert O.; Taberner, J; Edgington, A.; Guhan, S; Varghese, J; Feeney, H; Blocker, L; Jezequel, Sylvie

doi:10.1080/004982599238010

Cited by 10 publications

(8 citation statements)

References 16 publications

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“…Consequently, glycosylation improved the pharmaceutical properties of GLP-1, because the liver is one of the major organs to metabolize and excrete exogenous GLP-1 5,9 , and DPP-IV is abundant in hepatocytes 31 .Our results were consistent with previous reports 29,30 . In the case of recombinant neutrophil inhibitory factor (NIF), which is a glycoprotein with a mean molecular weight of 41 kDa, an increase in the number of sialylation reduces hepatic extraction of NIF 29 .…”

Section: Discussionsupporting

confidence: 83%

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Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

et al. 2011

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Objective Glycosylation is generally applicable as a strategy for increasing the activity of bioactive proteins. In this study, we examined the effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1 (GLP-1) as a bioactive peptide for type 2 diabetes.Methods Noninvasive imaging studies were performed using a gamma camera after the Conclusions This study demonstrated that glycosylation significantly decreased the distribution of radiolabeled GLP-1 into the liver and increased the concentration of 2 radiolabeled GLP-1 in plasma. These results suggested that glycosylation is a useful strategy for decreasing the distribution into the liver of bioactive peptides as desirable pharmaceuticals.

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Section: Discussionsupporting

confidence: 83%

“…In the case of recombinant neutrophil inhibitory factor (NIF), which is a glycoprotein with a mean molecular weight of 41 kDa, an increase in the number of sialylation reduces hepatic extraction of NIF 29 . In addition, the sialic acid moiety contributes to an optimal inhibition of hepatic extraction of liposome 30 .…”

Section: Discussionmentioning

confidence: 99%

Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

et al. 2011

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“…Results suggest that BR3-Fc does have a sialic acid-dependent clearance consistent with the Webster et al (1999) study. The effects on clearance and exposure were greatest for the desialylated BR3-Fc; however, there was still a rela- Fig.…”

Section: Discussionsupporting

confidence: 75%

“…Although we do not have direct data demonstrating the presence or binding to a receptor in Kupffer cells, there are many previous studies demonstrating the presence of various lectin receptors on hepatocytes, Kupffer cells, and endothelial cells that internalize and degrade glycoproteins or cells bearing terminal sugar moieties. An ASGP receptor has been reported on liver hepatocytes (Ashwell and Harford, 1982;Matsuura et al, 1982;Steer et al, 1983;Webster et al, 1999), and there has also been evidence that a similar ASGP receptor is associated with Kupffer cells (Kolb-Bachofen et al, 1982;Ii et al, 1990;Ozaki et al, 1992). The mannose/ N-GlcNAc receptor has been described previously as being associated with sinusoidal/Kupffer cells, but no binding has been reported with glycoproteins bearing terminal GalNAcGal residues such as those in BR3-Fc (Ashwell and Harford, 1982).…”

Section: Discussionmentioning

confidence: 99%

Evidence for an Asialoglycoprotein Receptor on Nonparenchymal Cells forO-Linked Glycoproteins

Stefanich¹,

Ren²,

Danilenko³

et al. 2008

J Pharmacol Exp Ther

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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.B cell-activating factor receptor 3 (BR3)-Fc is an IgG1-receptor dimeric fusion protein that is directed against B cell-activating factor (BAFF of the tumor necrosis factor ligand superfamily) (Gordon et al., 2003;Mackay and Ambrose, 2003;. BR3-BAFF interaction seems to be particularly important for the regulation of B cell survival and maturation in the spleen (Ng et al., 2004). Prevention of BAFF binding to BR3 on B cells by neutralizing BAFF via BR3-Fc results in notable peripheral and tissue B cell reduction in rodents and monkeys due to apoptosis (Vugmeyster et al., 2006;Lin et al., 2007). BR3-Fc consists of two polypeptide chains, each containing 299 amino acids, with sequences from the extracellular domain of the human BAFF receptor BR3 and the Fc domain of human IgG1. The two chains are joined by two disulfide bonds located in the IgG1 Fc domain near the junction between the BR3 extracellular domain and the IgG1 Fc region.In addition, BR3-Fc has multiple O-linked glycosylation sites with sialylation on the glycoproteins that can vary in the manufacturing process. There are six potential sites per BR3 domain and two BR3 domains per molecule. The monosaccharide analyses of BR3-Fc lots indicate that, on average, less than half of the identified O-linked sites are occupied and th...

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“…Sialylation on fragment variable (Fv) glycans may be important for binding to the target antigen, affecting the efficacy of the protein (103). In non-immunoglobulins, sialylation is often a key determinant of the PK profile, acting as a cap on terminal galactose residues that are responsible for protein clearance via binding to the asialoglycoprotein receptor (104). Further, additional sialylation has also been shown to extend the PK half-life of smaller proteins (105).…”

Section: Sialylationmentioning

confidence: 98%

Heterogeneity of IgGs: Role of Production, Processing, and Storage on Structure and Function

Barton¹,

Spencer²,

Levitskaya³

et al. 2014

ACS Symposium Series

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Detailed monoclonal antibody (mAb) characterization tools have enabled the discovery of structural variations, including many that compromise functionality or have other undesired properties. Size, charge, glycosylation, and disulfide bonding variants; oxidized amino acid residues; and polypeptide chain truncations, extensions, and cleavage points have been identified. Product quality attributes, including detection techniques, published knowledge about the process origins, and quality impacts of these variants are summarized.

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Role of sialylation in determining the pharmacokinetics of neutrophil inhibitory factor (NIF) in the Fischer 344 rat

Cited by 10 publications

References 16 publications

Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

Evidence for an Asialoglycoprotein Receptor on Nonparenchymal Cells forO-Linked Glycoproteins

Heterogeneity of IgGs: Role of Production, Processing, and Storage on Structure and Function

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