Targeted Degradation of Cell‐Surface Proteins via Chaperone‐Mediated Autophagy by Using Peptide‐Conjugated Antibodies

Cell‐surface proteins are important drug targets but historically have posed big challenges for the complete elimination of their functions. Herein, we report antibody–peptide conjugates (Ab‐CMAs) in which a peptide targeting chaperone‐mediated autophagy (CMA) was conjugated with commercially available monoclonal antibodies for specific cell‐surface protein degradation by taking advantage of lysosomal degradation pathways. Unique features of Ab‐CMAs, including cell‐surface receptor‐ and E3 ligase‐independent degradation, feasibility towards different cell‐surface proteins (e.g., epidermal growth factor receptor (EGFR), programmed cell death ligand 1 (PD‐L1), human epidermal growth factor receptor 2 (HER2)) by a simple change of the antibody, and successful tumor inhibition in vivo, make them attractive protein degraders for biomedical research and therapeutic applications. As the first example employing CMA to degrade proteins from the outside in, our findings may also shed new light on CMA, a degradation pathway typically targeting cytosolic proteins. A modular strategy for targeted degradation of cell‐surface proteins with an antibody–peptide conjugate (Ab‐CMA) is reported, in which a peptide targeting chaperone‐mediated autophagy (CMA) was conjugated with commercially available antibodies for CMA‐based lysosomal degradation of the corresponding antigen independent of specific cell‐surface receptors or E3 ligases, with useful implications for both biochemical research and for therapeutics.