Potent and Selective IGF‐IIR‐Recruiting Bifunctional Molecules for Targeted Lysosomal Degradation of Extracellular and Membrane Proteins

Lysosome targeting chimeras (LYTACs) represent a promising strategy to harness lysosomal degradation for eliminating extracellular and membrane disease-causing proteins. These bifunctional molecules link a target protein to a lysosome targeting receptor (LTR), forming a ternary complex that drives internalization and degradation. The first generation of LYTAC used cation-independent mannose-6-phosphate receptor (CI-M6PR), also known as Type II insulin-like growth factor receptor (IGF-IIR), as the LTR, with polymeric glycopeptides as the ligands. However, their complex and heterogeneous composition limits therapeutic potential. To improve specificity and efficacy, natural IGF-II has been explored as an alternative ligand. However, wild-type IGF-II activates both Type I insulin-like growth factor receptor (IGF-IR) and insulin receptor isoform A (IR-A), posing off-target risks. In this study, we engineered a novel IGF-II mutant (mutIGF-II) with two mutations (Del1-7 and Y27L), which confer high affinity for IGF-IIR while minimizing binding to IGF-IR and IR-A. The mutIGF-II-based bifunctional degraders significantly enhanced internalization and degradation of both secreted and membrane-bound proteins. Additionally, we developed a practical all-protein mutIGF-II LYTAC by genetically encoding mutIGF-II into a mammalian expression vector and transfecting it into cancer-relevant cell lines. The secreted mutIGF-II-based PD-L1 degrader effectively induced PD-L1 degradation.