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

doi:10.1016/j.jaci.2020.03.045

Journal of Allergy and Clinical Immunology

Volume 146, Issue 2, August 2020, Pages 367-376.e3

https://doi.org/10.1016/j.jaci.2020.03.045 Get rights and content

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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.

Graphical abstract

Key words

Eosinophilic esophagitis

epithelial-mesenchymal transition

IL-13 antibody

Abbreviations used

EMT

Epithelial-mesenchymal transition

EoE

Eosinophilic esophagitis

MET

Mesenchymal-epithelial transition

RHTIC

Research Histology and Tissue Imaging Core

Cited by (0)

: This study was sponsored by Celgene. Support for third-party writing assistance for this article was provided by CodonMedical (an Ashfield Company that is part of UDG Healthcare and Peloton Advantage, an OPEN Health Company) and was funded by Celgene Corporation.

: Disclosure of potential conflict of interest: M. H. Collins has served as a consultant for Allakos, AstraZeneca, Celgene Corporation, Esocap, GlaxoSmithKline, Regeneron, and Shire and has received grant/research support from Celgene Corporation, Regeneron, and Shire. E. S. Dellon has served as a consultant for Adare, Alivio, Allakos, AstraZeneca, Banner, Calypso, Celgene Corporation, Enumeral, Esocap, Gossamer Bio, GSK, Regeneron, Robarts, and Shire; has received grant/research support from Adare, Allkos, Celgene Corporation, GSK, Meritage, Miraca, Nutricia, Regeneron, and Shire; and has received educational grants from Allakos, Banner, and Holoclara. I. Hirano has served as a consultant for Adare, Allakos, Celgene Corporation, Regeneron, and Shire and has received grant/research support from Adare, Allakos, Celgene Corporation, Regeneron, and Shire. S. Ye Hua, C. Rodriguez, and S. Harris are employees of Celgene Corporation and may own stock and/or stock options in the company. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: Nathan McMahon's present affiliation is Oregon Health Sciences University, Portland, Oregon.