Claudin-1 is a potential antibody target for crescent glomerulonephritis

Claudin-1, the target of lixudebart, showed mechanistic involvement in decreasing kidney function and preclinical data support claudin 1 as a therapeutic target in crescent glomerulonephritis.

Claudin-1 is a transmembrane protein involved in fibrotic pathways and extracellular matrix remodelling in immune-mediated kidney disease. It is targeted by lixudebart, a drug currently assessed for its potential in anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis) in the phase 2 RENAL-F02 (NCT06047171) trial.

Dr Jean-Daniel Delbet (Paris Centre de Recherche Cardiovasculaire, Paris, France) and his team investigated the mechanistic role of claudin 1 in crescentic glomerulonephritis, which is characterised by extensive glomerular parietal epithelial cell proliferation forming a crescent, which evolves into fibrotic lesions.  Using the OPAL multiplex technique, the researchers determined claudin 1 expression in parietal epithelial cells in two cohorts (33 participants with ANCA-associated vasculitis and 29 with IgA nephropathy). Separately, an anti-claudin 1 antibody was tested in a nephrotoxic nephritis mouse model of crescentic glomerulonephritis (knockout mice expressing human claudin 1, n=20 each receiving control and the antibody) [1].

“We found that the proportion of claudin 1-positive cells increases with the development of histological extra-capillary glomerular lesions and we identified a subpopulation of activated parietal epithelial cells that express both claudin 1 and CD44”, explained Dr Delbet. This subpopulation of claudin 1 and CD44 double-positive cells was associated with lowered eGFR (<30 mL/min) at diagnosis for both participants with IgA nephropathy (P<0.01) and ANCA-associated vasculitis (P=0.02). Transcriptome analysis of the activated parietal epithelial cells compared to normal kidney samples (junctional claudin 1 in Bowman’s capsule) and participants with ANCA-associated vasculitis (exposed claudin 1 from cellular crescents) revealed that the activated parietal epithelial cells overexpressed genes related to the extracellular matrix and fibrosis. In the mouse model of crescentic glomerulonephritis, the anti-claudin 1 antibody led to a significantly decreased urine albumin-creatinine ratio and significantly blunted glomerular scarring by decreasing collagen IV deposition.

“We showed that parietal epithelial cells retain claudin 1 expression when forming extra-capillary glomerular crescents and that the subpopulation of double-positive (claudin 1 and CD44) cells may be associated with poor renal outcomes in human glomerulonephritis,” concluded Dr Delbet.

1. Delbet JD, et al. Novel therapeutic for crescentic glomerulonephritis through targeting CLDN1 in parietal epithelial cells. Abstract #2837 ERA 2024, 23–26 May, Stockholm, Sweden.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 20 June 202424 June 2024