Abstract: FR-PO0774
Inducible Costimulator Ligand-Based Peptide Treatment Targeting αVβ3 Integrin Reduces Proteinuria and Alleviates CKD
Session Information
- Top Trainee Posters - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 01:06 PM - 01:12 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Jimenez Uribe, Alexis P., Rush University Medical Center, Chicago, Illinois, United States
- Xu, Yan, Rush University Medical Center, Chicago, Illinois, United States
- Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
- Spear, Ryan, Rush University Medical Center, Chicago, Illinois, United States
- Koh, Kwi Hye, Morphic Therapeutic Inc, Waltham, Massachusetts, United States
- Mansini, Adrian P., Rush University Medical Center, Chicago, Illinois, United States
- Alcantar, Ariana G., Rush University Medical Center, Chicago, Illinois, United States
- Kliewe, Felix, Universitat Greifswald, Greifswald, MV, Germany
- Endlich, Nicole, Universitat Greifswald, Greifswald, MV, Germany
- Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
- Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
Background
The activation of αVβ3 integrin is linked to the development of glomerular diseases leading to podocyte injury and proteinuria. Recently, a novel protective role for the inducible co-stimulator ligand (ICOSL) has been reported. Independent of its canonical immune function, ICOSL antagonizes activated αVβ3 integrin and mitigates glomerular damage through its arginine-glycine-aspartic acid (RGD)-motif. Leveraging therapeutic peptides as an effective strategy to treat disease here, we report the generation of a 19-residue peptide based on the human ICOSL structure (hICOSL-19) and its use in antagonizing αVβ3 integrin to mitigate proteinuria and reducing glomerular damage in mice.
Methods
Surface plasmon resonance (SPR) assays were used to determine binding affinities. The X-ray crystal structure of human ICOSL was used for the design of the hICOSL-19 peptide. Proliferation, invasion, and western blot assays were performed for antagonistic function evaluation. Adhesion assays were used for evaluating specificity in podocytes. Nephrotoxic serum (NTS)-glomerulonephritis and diabetic nephropathy were used as CKD models. ACR, histology and electron microscopy were used to evaluate the efficacy of hICOSL-19.
Results
We demonstrated a high affinity between hICOSL-19 peptide and αVβ3 integrin. The affinity was similar to full-length hICOSL and in an RGD-motif dependent manner. hICOSL-19 peptide was able to act as an αVβ3 integrin antagonist as determined by its efficacy to inhibit cell proliferation and invasion of cancer cells in vitro. Moreover, hICOSL-19 decreased focal adhesion kinase (FAK) phosphorylation induced by αVβ3 integrin activators in human podocytes. Adhesion assays demonstrated that hICOSL-19 was able to target podocytes. Finally, treatment with hICOSL-19 peptide or its PEGylated form (PhICOSL-19) effectively reduced proteinuria and decreased glomerular injury in mice.
Conclusion
The hICOSL-19 peptide is a feasible therapeutic option for treating glomerular diseases associated with αVβ3 activation, and kidney diseases with loss of glomerular ICOSL expression such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN).