Kidney Week

Abstract: SA-PO713

Reducing Proteinuria by Antagonizing αVβ3 Integrin with a Novel Inducible Co-stimulator Ligand-Based Peptide

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | 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, Universitatsmedizin Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany

Felix Kliewe

• Endlich, Nicole, Universitatsmedizin Greifswald, Greifswald, Mecklenburg-Vorpommern, 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

Activation of α_Vβ₃ integrin has been linked to early stages of glomerular diseases, leading to podocyte injury and proteinuria. To date, no α_Vβ₃ antagonists have been successful in clinical trials. Our group has recently discovered a novel protective role for the inducible co-stimulator ligand (ICOSL) in the kidney, functioning as an antagonist of α_Vβ₃integrin independently of its canonical immune function and mitigating glomerular damage through its RGD-motif. Here, we developed a 19-mer peptide based on the human ICOSL structure (hICOSL-19) and evaluated its therapeutic potential in vitro and in vivo

Methods

Data were obtained from the Nephroseq database. The interactions between ICOSL or its derived peptide and integrins were analyzed using surface plasmon resonance (SPR) and proximity ligation assay (PLA). The antagonistic effects of peptides were evaluated through podocyte adhesion, cancer cell proliferation and invasion assays, and western blotting. PEGylation was applied to extend the peptide half-life. The in vivo efficacy of ICOSL-based peptides was tested in mice injected with lipopolysaccharide (LPS) or nephrotoxic serum (NTS).

Results

Analysis of the Nephroseq database confirmed the reduction of ICOSL expression in the glomeruli across several kidney diseases. SPR analysis revealed the preferential binding of ICOSL to α_Vβ₃ integrin over other RGD-binding integrins. PLA tests confirmed this ICOSL-α_Vβ₃ interaction at both cellular and tissue levels. Similar to the full-length hICOSL protein, hICOSL-19 demonstrated a high affinity for α_Vβ₃ integrin. In vitro assays demonstrated that hICOSL-19 effectively blocks α_Vβ₃ integrin-mediated downstream signaling. Additionally, unlike cRGDfV, hICOSL-19 maintained its antagonistic effects even at low concentrations. Treatment with hICOSL-19 peptide reduced proteinuria in a mouse model of LPS-induced kidney damage. PEGylation of this hICOSL-19 extended its plasma half-life and maintained its antagonistic effect against α_Vβ₃ integrin in vitro and in vivo.

Conclusion

The hICOSL-19 peptide is a promising therapeutic option for treating glomerular disease associated with α_Vβ₃activation. Its applications might also extend to conditions involving α_Vβ₃ integrin activation, including cancer and fibrotic disease.

Funding

• NIDDK Support