An anti–IL-13 antibody reverses epithelial-mesenchymal transition biomarkers in eosinophilic esophagitis: Phase 2 trial results

Peter H. Gann*, Ryan J. Deaton, Nathan McMahon, Margaret H. Collins, Evan S. Dellon, Ikuo Hirano, Steven Ye Hua, Cristian Rodriguez, Sarah Harris

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Background: Fibrostenosis, the most serious eosinophilic esophagitis (EoE) complication, is mediated by epithelial-mesenchymal transition (EMT). Transitioned cells contribute to pathogenesis by overproducing extracellular matrix. Objective: Our aim was to determine whether RPC4046 (anti‒IL-13 mAb) modulates EMT biomarkers in biopsy samples from adults with active EoE in a substudy of a double-blind, placebo-controlled phase 2 trial. Methods: Baseline and week 16 esophageal biopsy samples were taken from 69 patients who were randomized to weekly treatment with subcutaneous RPC4046, 180 mg (n = 19), 360 mg (n = 26), or placebo (n = 24). Duplex immunofluorescence slides stained for E-cadherin and vimentin were digitally analyzed by mapping each epithelial cell and recording fluorescence intensities. End points included change from baseline to week 16 in percentage of vimentin-positive epithelial cells (primary), total E-cadherin expression, and vimentin-to–E-cadherin ratio per cell (an average of 47,000 cells per biopsy sample analyzed). Results: The mean percentage of vimentin-positive cells decreased by 0.94%, 2.75%, and 4.24% in the placebo, low-dose, and high-dose groups, respectively (P =.032 for the high-dose vs placebo group). Mean E-cadherin expression per cell increased 5.6-fold in both dose groups versus in the placebo group (high-dose group P =.047). The increases in E-cadherin expression per cell from baseline to week 16 were correlated with improvements in histology, eosinophil counts, endoscopic findings, and symptoms. Conclusion: RPC4046 significantly reduced EMT markers in adults with active EoE, with greater effects at 360 mg. Together with results for eosinophil density and clinical end points from the main trial, these data support the hypothesis that pharmacologic IL-13 inhibition ameliorates both inflammatory and remodeling pathways and could potentially reduce the risk of fibrostenotic complications.

Original languageEnglish (US)
Pages (from-to)367-376.e3
JournalJournal of Allergy and Clinical Immunology
Volume146
Issue number2
DOIs
StatePublished - Aug 2020

Keywords

  • Eosinophilic esophagitis
  • IL-13 antibody
  • epithelial-mesenchymal transition

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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