Kidney Week

Abstract: FR-PO0774

Inducible Costimulator Ligand-Based Peptide Treatment Targeting αVβ3 Integrin Reduces Proteinuria and Alleviates CKD

Session Information

• Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Jimenez Uribe, Alexis P., Rush University, Chicago, Illinois, United States

Alexis P. Jimenez Uribe, MS, MSc, PhD, DVM

• Xu, Yan, Rush University, Chicago, Illinois, United States

Yan Xu, PhD

• Cao, Yanxia, Rush University, Chicago, Illinois, United States

Yanxia Cao, MS

• Spear, Ryan, Rush University, Chicago, Illinois, United States

Ryan Spear

• Koh, Kwi Hye, Morphic Therapeutic Inc, Waltham, Massachusetts, United States

Kwi Hye Koh, PhD

• Mansini, Adrian P., Rush University, Chicago, Illinois, United States

Adrian P. Mansini

• Alcantar, Ariana G., Rush University, Chicago, Illinois, United States

Ariana G. Alcantar, MS, MSc

• Kliewe, Felix, Universitat Greifswald, Greifswald, MV, Germany

Felix Kliewe

• Endlich, Nicole, Universitat Greifswald, Greifswald, MV, Germany

Nicole Endlich, PhD

• Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States

Jochen Reiser, MD, PhD

• Mangos, Steve, Rush University, Chicago, Illinois, United States

Steve Mangos, PhD

• Hahm, Eunsil, Rush University, Chicago, Illinois, United States

Eunsil Hahm, PhD

Background

The activation of α_Vβ₃ 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 α_Vβ₃ 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 α_Vβ₃ 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 α_Vβ₃ 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 α_Vβ₃ 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 α_Vβ₃ 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 α_Vβ₃ activation, and kidney diseases with loss of glomerular ICOSL expression such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN).

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025nth6znpe