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

• Published in: Journal of the American Chemical Society Vol. 143; no. 2; pp. 593 - 598
• Main Authors: Cotton, Adam D, Nguyen, Duy P, Gramespacher, Josef A, Seiple, Ian B, Wells, James A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20-01-2021
• Subjects: Antibodies - chemistry; Antibodies - immunology; B7-H1 Antigen - chemistry; B7-H1 Antigen - immunology; Communication; Humans; Proteolysis
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.0c10008

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.