Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1

J Am Chem Soc. 2021 Jan 20;143(2):593-598. doi: 10.1021/jacs.0c10008. Epub 2021 Jan 4.

Abstract

Targeted protein degradation has emerged as a new paradigm to manipulate cellular proteostasis. Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein of interest, promoting its ubiquitination and subsequent degradation. Here, we report the development of antibody-based PROTACs (AbTACs), fully recombinant bispecific antibodies that recruit membrane-bound E3 ligases for the degradation of cell-surface proteins. We show that an AbTAC can induce the lysosomal degradation of programmed death-ligand 1 by recruitment of the membrane-bound E3 ligase RNF43. AbTACs represent a new archetype within the PROTAC field to target cell-surface proteins with fully recombinant biological molecules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / chemistry
  • Antibodies / immunology*
  • B7-H1 Antigen / chemistry
  • B7-H1 Antigen / immunology*
  • Humans
  • Proteolysis

Substances

  • Antibodies
  • B7-H1 Antigen
  • CD274 protein, human