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Abstract: FR-OR104

A Novel Small Therapeutic Peptide with Potential for Treating αvβ3-Mediated Glomerular Damage

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Xu, Yan, Rush University Medical Center, Chicago, Illinois, United States
  • Spear, Ryan, Rush University Medical Center, Chicago, Illinois, United States
  • Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
  • Koh, Kwi Hye, Morphic Therapeutic, Boston, Massachusetts, United States
  • Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
  • Jimenez Uribe, Alexis P., Rush University Medical Center, Chicago, Illinois, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States

Group or Team Name

  • Dr. Eunsil Hahm's Lab.
Background

αvβ3-mediated podocyte injury represents an initial pathological event observed in several glomerular diseases. However, effective clinical strategies targeting αvβ3 integrin remains elusive. Our recent research has unveiled a new function of inducible costimulatory ligand (ICOSL), which acts as an endogenous antagonist of αvβ3 integrin through its RGD motif. In this study, we identified a novel 19-mer peptide derived from ICOSL and evaluated its therapeutic potential for mitigating αvβ3-mediated podocyte injury.

Methods

The binding affinity of human ICOSL and its small linear peptide (hICOSL-peptide) to αvβ3 Integrin was assessed using surface plasmon resonance (SPR) at the molecular level, along with podocyte adhesion assays at the cellular level. Subsequently, we evaluated the therapeutic potential of hICOSL-peptide in proteinuric mice challenged with LPS by measuring ACR and BUN. To improve the pharmacokinetics (PK), a PEG12 molecule was introduced to the N terminal of hICOSL-peptide and the resulting PEG12-hICOSL-peptide was analyzed for its PK profile using ELISA.

Results

Our study showed that ICOSL binding favored the active αvβ3 integrin rather than the inactive form and showed no or weak affinity for other integrins. Through the analysis of ICOSL's crystal structure, we have successfully identified a 19-mer peptide possessing an RGD sequence. This peptide exhibited robust binding to the active form of αvβ3 integrin and exerted a strong influence on integrin-dependent podocyte adhesion. Moreover, administration of hICOSL-peptide effectively mitigated albuminuria in LPS-challenged ICOSL knockout (KO) mice, highlighting the therapeutic potential of hICOSL-peptide. Importantly, PEGylation process did not compromise the functional interaction of these peptides with αvβ3 integrin, but significantly enhanced the pharmacokinetic profile of hICOSL-peptide by a five-fold increment, further emphasizing its augmented therapeutic promise.

Conclusion

We identified a novel 19-mer linear peptide derived from ICOSL. This peptide exhibited the ability to specifically target αvβ3 integrin in podocytes and effectively reverse proteinuria in mice. These finding suggests that ICOSL and ICOSL-based small peptides hold significant promise as novel and safe therapeutic options for treating αvβ3-mediated glomerular diseases.

Funding

  • NIDDK Support