What question did this study set out to answer?

To engineer a mutant IGF‐II for selective lysosomal targeting that enhances the degradation of specific proteins.

February 2, 2026Advanced Science0 citationsOpen Access

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

Key Points

To engineer a mutant IGF‐II for selective lysosomal targeting that enhances the degradation of specific proteins.
Developed a novel IGF‐II mutant with specific mutations for targeting IGF‐IIR.
Formed bifunctional molecules linking target proteins to lysosome targeting receptors.
Transfected mutIGF‐II into cancer cell lines to assess degradation efficacy.
The engineered mutIGF‐II showed high affinity for IGF‐IIR with reduced off-target effects.
Significantly enhanced internalization and degradation of both extracellular and membrane proteins.
Demonstrated effective PD-L1 degradation in cancer cells using mutIGF‐II-based degraders.

Abstract

ABSTRACT 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.

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