LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation

  • Nat Chem Biol. 2021 Sep;17(9):937-946. doi: 10.1038/s41589-021-00770-1.
Green Ahn  1 ,  Steven M Banik  1 ,  Caitlyn L Miller  2 ,  Nicholas M Riley  1 ,  Jennifer R Cochran  2 ,  Carolyn R Bertozzi  3  4
Affiliations
  • 1. Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA, USA.
  • 2. Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 3. Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
  • 4. Howard Hughes Medical Institute, Stanford, CA, USA. [email protected].
PMID: 33767387 DOI: 10.1038/s41589-021-00770-1
Abstract

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-GalNAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GalNAc-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-GalNAc ligand degrades integrins and reduces Cancer cell proliferation. Degradation with a single tri-GalNAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GalNAc-LYTACs in vivo. GalNAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation.

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