Modulation of Mannose and Asialoglycoprotein Receptor Expression Determines Glycoprotein Hormone Half-life at Critical Points in the Reproductive Cycle

Abstract

Background: Unique glycan structures on glycoprotein hormones are recognized by glycan-specific receptors that control hormone half-life in the blood. Results: Clearance rates for recognized glycoproteins are determined by the level of receptor expression in the liver. Conclusion: Expression of glycan-specific receptors is modulated at critical points in the reproductive cycle. Significance: Glycans and glycan-specific receptors play critical roles in reproduction.

What Have We Learned from Glycosyltransferase Knockouts in Mice?

“…Deletion of GalNAc-4-sulfotransferase 1 (CHST8) increases the levels of circulating LH, leading to precocious sexual maturity in females with increased fecundity, and premature maturation of testis and seminal vesicles in males [139]. The generation of complex N-glycans terminating with GalNAc-4-SO 4 on LH depends on regulated expression of GalNAc- and sulfo-transferases and liver receptors that recognize these N-glycans, and clear them from the circulation [140]. Another sulfated glycan epitope with biological significance is HNK-1, expressed at the termini of N- and O-glycans and glycolipids, and generated by the action of GlcA-transferases and sulfotransferases.…”

Structure–Function Relationships of Glycoprotein Hormones and Their Subunits’ Ancestors

“…Nevertheless, liver mannose receptors appear to be involved in the removal from circulation of glycoprotein with glycans terminated by β1,4-linked GalNAc-4-SO4 such as in LH mainly (84, 85). …”

Antibody Glycosylation and Its Impact on the Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies and Fc-Fusion Proteins

“…Glycan receptors that have been attributed to the removal of glycoproteins in vivo include the mannose receptor (ManR) and the asialoglycoprotein receptor (ASGPR). The ASGPR and the ManR are carbohydrate‐specific, endocytic receptors expressed by hepatic parenchymal (hepatocytes) and nonparenchymal (such as Kupffer) cells and sinusoidal endothelial cells, respectively . Glycosylated mAbs with terminal high‐mannose glycans have been shown to exhibit fast clearance from the blood .…”

“…The AS-GPR and the ManR are carbohydrate-specific, endocytic receptors expressed by hepatic parenchymal (hepatocytes) and non-parenchymal (such as Kupffer) cells and sinusoidal endothelial cells, respectively. 85,86 Glycosylated mAbs with terminal highmannose glycans have been shown to exhibit fast clearance from the blood. 18,78,87-90 A rabbit antibody with exposed terminal Gal (after removal of sialic acid) has also been shown to be rapidly cleared from the blood and localized in the liver.…”