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

作者：Yuan Zhao, Yaxian Liao, Pengyun Li, R. González, Xuankun Chen, Nicholas S. Nieto, Florence M. Brunel, Nick Cox, Joseph R. Stock, Matthew McHenry, Guangsen Fu, Penghsuan Huang, Wenxin Wu, Deqin Cai, Lingjun Li, Alexander N. Zaykov, Weiping Tang · 发表于：Advanced Science · 年份：2026 · DOI：10.1002/advs.202518793 · 被引用次数：2 · 研究领域：Protein Degradation and Inhibitors、Click Chemistry and Applications、Lysosomal Storage Disorders Research

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.