Targeting Claudin-1 in Crescentic Glomerulonephritis

A study by Jean-Daniel Delbet and others examined the functional role of claudin-1 (CLDN1) in crescentic glomerulonephritis (CrGN) and the potential benefit of targeting CLDN1 in CrGN. Their results were presented at the 61st European Renal Association Congress.

In CrGN, extensive glomerular parietal epithelial cells (PECs) multiply and form crescents that are progressively replaced by fibrosis. CLDN1 is a transmembrane protein involved in epithelial tight junctions that is highly expressed by glomerular PECs. CLDN1 can be exposed outside the tight junctions and mediate profibrotic pathways and extracellular matrix (ECM) remodeling. The monoclonal antibody lixudebart targets and blocks exposed CLDN1 in injured epithelial cells. The drug is the subject of a phase 2 clinical trial involving patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with rapidly progressive glomerulonephritis.

Delbet and fellow researchers used kidney multicolor immunofluorescence staining and spatial transcriptomics to analyze CLDN1 expression in the renal tissues of patients with CrGN. They then examined the association between CLDN1 expression and clinical end points (estimated glomerular filtration rate [eGFR], proteinuria), disease biomarkers, and crescent progression. Finally, they developed a spatially resolved molecular roadmap from CLDN1-positive crescentic glomeruli and conducted proof-of-concept studies of an anti-CLDN1 monoclonal antibody in preclinical models of CrGN.

Immunofluorescence of 150 patients with AAV and IgA nephropathy (IgAN) showed upregulated CLDN1 expression by cellular and fibrocellular crescents. The extent of expression of both CLDN1 and CD44 at the surface of active PECs was associated with poor renal outcome (eGFR <30 ml/min) in AAV (median follow-up, 2.5 years) and IgAN patients (3.7 years). The researchers found an association between CLDN1-positive crescentic glomeruli and ECM genes.

In mice, treatment with anti-CLDN1 mAb reduced albuminuria, increased kidney function, and decreased fibrosis biomarkers in nephrotoxic serum-induced CrGN. In sum, the authors wrote, “Our results suggest a functional role of CLDN1 in the pathogenesis of CrGN, providing preclinical proof-of-concept for anti-CLDN1 antibodies as a novel therapeutic approach in patients with CrGN.”

Source: Delbet J-D, Anquetil V, Saitoski K, et al. Novel therapeutic for crescentic glomerulonephritis through targeting CLDN1 in parietal epithelial cells. Abstract #2837. Presented at the 61st European Renal Association Congress; May 23-26, 2024; Stockholm, Sweden.