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Kidney Week

Abstract: TH-PO531

Claudin-1 Is a Therapeutic Target for Crescentic Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Teixeira, Geoffrey, Alentis Therapeutics, Allschwil, Switzerland
  • Delbet, Jean-Daniel, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
  • Anquetil, Vincent, Alentis Therapeutics, Allschwil, Switzerland
  • Toso, Alberto, Alentis Therapeutics, Allschwil, Switzerland
  • Toovey, Stephen, Alentis Therapeutics, Allschwil, Switzerland
  • Manenti, Luigi, Alentis Therapeutics, Allschwil, Switzerland
  • Iacone, Roberto, Alentis Therapeutics, Allschwil, Switzerland
  • Kers, Jesper, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Rabelink, Ton J., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Saitoski, Kevin, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
  • Baumert, Thomas F., Universite de Strasbourg, Strasbourg, Grand Est, France
  • Benigni, Ariela, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Lombardia, Italy
  • Tomasoni, Susanna, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Lombardia, Italy
  • Remuzzi, Giuseppe, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Lombardia, Italy
  • Cagarelli, Thomas, Hopitaux Universitaires Geneve, Geneve, Genève, Switzerland
  • Prunotto, Marco, Universite de Geneve Section des Sciences Pharmaceutiques, Geneve, GE, Switzerland
  • Moll, Solange, Hopitaux Universitaires Geneve, Geneve, Genève, Switzerland
  • Tharaux, Pierre-Louis, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
Background

Crescentic glomerulonephritis (CGN), encompasses a large spectrum of kidney diseases characterized by extensive epithelial cell proliferation forming crescents and renal fibrosis. Current therapies for CGN do not directly target the deleterious response of resident kidney cells. Claudin-1 (CLDN1), a transmembrane protein involved in epithelial tight junctions, can, in pathological conditions, be exposed outside the tight junctions and mediate pro-fibrotic pathways and extracellular matrix (ECM) remodelling. We have developed ALE.F02, a first-in-class monoclonal antibody (mAb) highly specific in targeting CLDN1 exposed outside the tight junctions. ALE.F02 exhibited an excellent safety profile with evidence of on-target biological activity in first-in-human clinical trial. This study investigated the functional role of CLDN1 in proliferative glomerular parietal epithelial cells (PEC) as a therapeutic target for ANCA-associated vasculitis (AAV), Lupus Nephritis (LN) and crescentic IgA nephropathy (IgAN).

Methods

CLDN1 expression in renal tissues of CGN patients was analyzed using immunohistochemistry, immunofluorescence and spatial transcriptomics. Correlations between CLDN1 expression, disease biomarkers and crescent evolution were studied. Spatially resolved molecular roadmap from CLDN1+ crescentic glomeruli were conducted. Proof-of-concept studies using anti-CLDN1 mAb were performed in preclinical models of CGN.

Results

In tissues (n=100+) of CGN patients, exposed CLDN1 was highly expressed by cellular and fibro-cellular crescents. Multi-color immunofluorescence of CGN patients revealed up-regulated CLDN1 expression by activated PEC. CLDN1 upregulation was associated with high plasma levels of renal disease biomarkers (CD44, CXCL12, MMP7). Spatial transcriptomics analysis highlighted the association between CLDN1+ crescentic glomeruli and ECM proteins. Proof-of-concept studies in CGN mouse models showed that treatment with anti-CLDN1 mAb reduced proteinuria and fibrosis biomarkers.

Conclusion

Our results suggest a functional role for CLDN1 in the pathogenesis of CGN, providing preclinical proof-of-concept for ALE.F02 as a novel therapeutic approach in patients with CGN.