Expanding the Repertoire of Lysosomal Degradation of Membrane Proteins: A Generalizable Strategy Using Multivalent...

Targeted protein degradation enables the removal of undesired proteins via proteasomal or lysosomal pathways without genomic alteration. Existing lysosomal strategies rely on chimeras that concurrently engage the protein of interest (POI) and a receptor that inherently directs bound proteins to the lysosome. We posit here that multivalent noncovalent interactions can trigger endosomal uptake and lysosomal degradation of specific membrane proteins in combination with an ancillary membrane protein, where the ancillary protein does not need to possess endogenous lysosome-directing characteristics. We demonstrate this relaxation of the ancillary protein characteristics using antibody-polymer conjugates, namely Polymeric Lysosome-Targeting Chimeras (PolyTACs), bearing ligands that polyvalently bind to membrane proteins. Using membrane carbonic anhydrase and PD-L1 as examples, we show the possibility of expanding the repertoire of lysosomal degradation of membrane POIs, which in turn opens up opportunities for new therapeutic possibilities.