Antibody-Proteolysis Targeting Chimera Conjugate Enables Selective Degradation of Receptor-Interacting Serine/Threonine-Protein Kinase 2 in HER2+ Cell Lines

Bioconjug Chem. 2023 Nov 15;34(11):2049-2054. doi: 10.1021/acs.bioconjchem.3c00366. Epub 2023 Nov 2.

Abstract

Proteolysis targeting chimeras (PROTACs) are a family of heterobifunctional molecules that are now realizing their promise as a therapeutic strategy for targeted protein degradation. However, one limitation of existing designs is the lack of cell-selective targeting of the protein degrading payload. This manuscript reports a cell-targeted approach to degrade receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in HER2+ cell lines. An antibody-PROTAC conjugate is prepared containing a protease-cleavable linkage between the antibody and the corresponding degrader. Potent RIPK2 degradation is observed in HER2+ cell lines, whereas an equivalent anti-IL4 antibody-PROTAC conjugate shows no degradation at therapeutically relevant concentrations. No RIPK2 degradation was observed in HER2- cell lines for both bioconjugates. This work demonstrates the potential for the cell-selective delivery of PROTAC scaffolds by engaging with signature extracellular proteins expressed on the surface of particular cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Immunoconjugates*
  • Proteolysis
  • Proteolysis Targeting Chimera*
  • Serine
  • Threonine
  • Ubiquitin-Protein Ligases

Substances

  • Proteolysis Targeting Chimera
  • Immunoconjugates
  • Threonine
  • Serine
  • Ubiquitin-Protein Ligases