LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation

Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome-targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here, we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosome-targeting receptor, to degrade extracellular proteins in a cell-type-specific manner. We conjugated binders to a triantenerrary N-acetylgalactosamine (tri-GaINAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GaINAc-LYTAC attenuated EGFR signaling compared to inhibition with an antibody. Furthermore, we demonstrated that a LYTAC consisting of a 3.4-kDa peptide binder linked to a tri-GaINAc ligand degrades integrins and reduces cancer cell proliferation. Degradation with a single tri-GaINAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GaINAc-LYTACs in vivo. GaINAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation.