An inducible co-stimulator ligand (ICOSL)-based peptide therapy for proteinuric kidney diseases targeting αvβ3 integrin

Abstract Dysregulated αvβ3 integrin activation in podocytes contributes to proteinuric kidney disease by disrupting podocyte architecture and the glomerular filtration barrier. However, no treatments currently exist that therapeutically target this integrin. We previously identified inducible co-stimulator ligand (ICOSL) as an endogenous antagonist of αvβ3 integrin that protects kidney function through its arginine-glycine-aspartic acid (RGD) motif, independent of its canonical role in immunity. Leveraging the therapeutic advantages of small peptides and the renoprotective function of ICOSL, we used a structure-guided approach to design a 19-amino acid human ICOSL-derived peptide (hICOSL-19) containing the RGD motif and evaluated its therapeutic potential for proteinuric kidney disease. hICOSL-19 exhibited high-affinity binding to αvβ3 integrin, similar to full-length ICOSL, and retained its αvβ3-antagonistic activity. PEGylation of hICOSL-19 (PhICOSL-19) extended its circulating half-life while preserving its antagonistic function. In murine models of acute and chronic proteinuric kidney disease, including immune-mediated glomerulonephritis and diabetic nephropathy, PhICOSL-19 treatment significantly reduced proteinuria, limited glomerular injury, and preserved podocyte architecture. In vitro and in vivo safety assessments further showed no detectable podocyte cytotoxicity, T-cell activation, or anti-drug antibody response. These findings suggest that an ICOSL-derived peptide targeting αvβ3 integrin represents a potential therapeutic strategy for proteinuric kidney diseases associated with αvβ3 integrin activation.