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Mucosal Immunol. 2019 Jul 15. doi: 10.1038/s41385-019-0189-6. [Epub ahead of print]

Anti-IL-13Rα2 therapy promotes recovery in a murine model of inflammatory bowel disease.

Author information

1
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
2
Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA.
3
Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, MA, USA.
4
Biomedicine Design, Pfizer Inc., Cambridge, MA, USA.
5
23andMe, Mountain View, CA, USA.
6
Human Genetics, Pfizer Inc., Cambridge, MA, USA.
7
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. kevin.vannella@nih.gov.

Abstract

There continues to be a major need for more effective inflammatory bowel disease (IBD) therapies. IL-13Rα2 is a decoy receptor that binds the cytokine IL-13 with high affinity and diminishes its STAT6-mediated effector functions. Previously, we found that IL-13Rα2 was necessary for IBD in mice deficient in the anti-inflammatory cytokine IL-10. Here, we tested for the first time a therapeutic antibody specifically targeting IL-13Rα2. We also used the antibody and Il13ra2-/- mice to dissect the role of IL-13Rα2 in IBD pathogenesis and recovery. Il13ra2-/- mice were modestly protected from induction of dextran sodium sulfate (DSS)-induced colitis. Following a 7-day recovery period, Il13ra2-/- mice or wild-type mice administered the IL-13Rα2-neutralizing antibody had significantly improved colon health compared to control mice. Neutralizing IL-13Rα2 to increase IL-13 bioavailability promoted resolution of IBD even if neutralization occurred only during recovery. To link our observations in mice to a large human cohort, we conducted a phenome-wide association study of a more active variant of IL-13 (R130Q) that has reduced affinity for IL-13Rα2. Human subjects carrying R130Q reported a lower risk for Crohn's disease. Our findings endorse moving anti-IL-13Rα2 into preclinical drug development with the goal of accelerating recovery and maintaining remission in Crohn's disease patients.

PMID:
31308480
DOI:
10.1038/s41385-019-0189-6

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