Synthetic Site-Specific Antibody-Ligand Conjugates Promote Asialoglycoprotein Receptor-Mediated Degradation of Extracellular Human PCSK9.

ABSTRACT: Targeted degradation using cell-specific lysosome targeting receptors is emerging as a new therapeutic strategy for the elimination of disease-associated proteins. The liver-specific human asialoglycoprotein receptor (ASGPR) is a particularly attractive lysosome targeting receptor leveraged for targeted protein degradation (TPD). However, the efficiency of different glycan ligands for ASGPR-mediated lysosomal delivery remains to be further characterized. In this study, we applied a chemoenzymatic Fc glycan remodeling method to construct an array of site-specific antibody-ligand conjugates carrying natural bi- and tri-antennary N-glycans as well as synthetic tri-GalNAc ligands. Alirocumab, an anti-PCSK9 (proprotein convertase subtilisin/kexin type 9) antibody, and cetuximab (an anti-

SUBMITTER: Donahue TC 

PROVIDER: S-EPMC10530246 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature