IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins

Lysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on a large scale. Here, we report on the development of pure protein LYTACs based on the non-glycosylated IGF2 peptides, which can be readily produced in virtually any facility capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and, in our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous to immune checkpoint blockade. Results from in vitro assays significantly exceed the effects of anti-PD-L1 antibodies alone.

Automated summary

Lysosome-targeting chimeras (LYTACs) have been developed to facilitate the degradation of specific molecular targets. In this study, pure protein LYTACs based on non-glycosylated IGF2 peptides were developed, which can be easily produced in facilities capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and effectively target programmed death ligand 1 (PD-L1) with superior results compared to anti-PD-L1 antibodies alone in vitro assays.