The asialoglycoprotein receptor clears glycoconjugates terminating with sialic acidα2,6GalNAc

Abstract

Endogenous ligands have not, to date, been identified for the asialoglycoprotein receptor (ASGP-R), which is abundantly expressed by parenchymal cells in the liver of mammals. On the basis of the rapid clearance of BSA bearing multiple chemically coupled sialic acid (Sia)␣2,6GalNAc␤1,4GlcNAc␤1,2Man tetrasaccharides (SiaGGnM-BSA) from the circulation, and the ability of the ASGP-R hepatic lectin-1 subunit to bind SiaGGnM-BSA, we previously proposed that glycoproteins modified with structures terminating with Sia␣2,6GalNAc may represent previously unrecognized examples of endogenous ligands for this receptor. Here, we have taken a genetic approach using wild-type and ASGP-R-deficient mice to determine that the ASGP-R in vivo does indeed account for the rapid clearance of glycoconjugates terminating with Sia␣2,6GalNAc. We have also determined that the ASGP-R is able to bind core-substituted oligosaccharides with the terminal sequence Sia␣2,6Gal␤1,4GlcNAc but not those with the terminal Sia␣2,3Gal␤1,4GlcNAc. We propose that glycoproteins bearing terminals Sia␣2,6GalNAc and Sia␣2,6Gal are endogenous ligands for the ASGP-R, and that the ASGP-R helps to regulate the relative concentration of serum glycoproteins bearing ␣2,6-linked Sia.clearance ͉ galactose ͉ N-acetylgalactosamine ͉ hepatic lectin ͉ serum glycoproteins

A comparison of anti-HER2 IgA and IgG1 in vivo efficacy is facilitated by high N-glycan sialylation of the IgA

“…35 Since mouse ASGPR also seems to bind to a2,6-sialylated glycans in addition to ß-linked galactose and N-acetylgalactosamine, the human a2,3-sialyltransferase ST3GAL4 -and not an ST6GAL1 -was selected for increasing the level of antibody sialylation. 36,37 In contrast, in human serum IgA1 more than 95% of sialic acids were linked in the a2,6-configuration.…”

Production of Highly Sialylated Monoclonal Antibodies

“…Sialic acid can be linked to the galactose either with α2,3 or α2,6 linkage. Recent studies showed that α2,3 sialylation provides a better protection to the protein than α2,6 sialylation, as ASGPR recognizes Siaα2,6Gal and Siaα2,6GalNAc moieties in addition to the well-known Gal and GalNAc residues [14,15]. However, Fc-glycans have no apparent impact on IgG half-life [16].…”

Functionalized magnetic iron oxide/alginate core-shell nanoparticles for targeting hyperthermia

“…[15][16][17] For example, asialoglycoprotein receptors are located on liver cancer cells and can specifically bind with glycoprotein on/in galactose residues, leading to internalization and subsequent degradation of glycoprotein inside the cells. 18 Such active targeting strategies can not only effectively deliver drugs into cancer cells, but also reduce the amounts of anticancer agents used.…”