Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in a liver cell line specifically by these degraders. We also observed that more efficient delivery could be achieved for smaller degrader/target complexes. This work will add a new dimension to the TPD with cell type specificity.