LYTACs Target Extracellular and Membrane Proteins for Degradation

Therapeutics that target specific proteins without directly inhibiting them or blocking ligand binding have generated considerable interest; however, existing options, such as proteolysis-targeting chimeras (PROTAC), are not able to effectively target membrane or extracellular proteins, including many cancer-related proteins. This limitation motivated Banik and colleagues to develop lysosome-targeting chimeras, dubbed LYTACs, which are composed of an antibody specific to the targeted protein conjugated to a synthetic oligoglycopeptide ligand that binds the cation-independent mannose-6-phosphate receptor CI-M6PR, a transmembrane glycoprotein responsible for trafficking proteins to lysosomes for degradation. Cell-based assays using fluorescently labeled streptavidin and biotinylated M6P—a system chosen because of the high-affinity binding of avidins to biotin—demonstrated the feasibility of using this approach to direct extracellular proteins to the lysosome. A CRISPR interference screen revealed that knockdown of IGF2R (encoding CI-M6PR) decreased lysosomal targeting, as expected, as did knockdown of genes encoding protein components of the exocyst complex, which is thought to be involved in localizing vesicles to the plasma membrane. This effect appeared to be due to decreased transport of CI-M6PR to the plasma membrane, revealing a previously unknown essential role for the exocyst complex in this pathway. Further experiments provided proof-of-concept that LYTACs can be used to target therapeutically relevant soluble extracellular proteins and membrane proteins and increase their rate of lysosomal degradation. In particular, LYTACs successfully targeted apolipoprotein E4 (involved in Alzheimer disease) along with the cancer-relevant proteins EGFR, CD71, and PD-1. In summary, this work provides a novel approach to targeting extracellular and membrane proteins and demonstrates the promise of pursuing further testing of this method in targeting such proteins—particularly those that are not amenable to targeting by traditional drugs.

Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 2020;584:291–7.

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