Article

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

Adam D. CottonDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United StatesDuy NguyenDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United StatesJosef A. GramespacherDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United StatesIan B. SeipleCardiovascular Research Institute, University of California, San Francisco, California 94143, United StatesJames A. WellsDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States

2021en

ABI

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.

Identifiers

DOI: 10.1021/jacs.0c10008

Citations and references

Cited by 20 references

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