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

• Published in: Mucosal immunology Vol. 12; no. 5; pp. 1174 - 1186
• Main Authors: Karmele, Erik P., Pasricha, Trisha S., Ramalingam, Thirumalai R., Thompson, Robert W., Gieseck, Richard L., Knilans, Kayla J., Hegen, Martin, Farmer, Mark, Jin, Fang, Kleinman, Aaron, Hinds, David A., Almeida Pereira, Thiago, de Queiroz Prado, Rafael, Bing, Nan, Tchistiakova, Lioudmila, Kasaian, Marion T., Wynn, Thomas A., Vannella, Kevin M.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.09.2019; Nature Publishing Group US; Elsevier Limited
• Subjects: Affinity; Allergology; Animal models; Animals; Anti-Inflammatory Agents - pharmacology; Antibodies; Antibodies, Monoclonal - pharmacology; Bioavailability; Biomedical and Life Sciences; Biomedicine; Colitis; Colon; Crohn Disease - etiology; Crohn Disease - metabolism; Crohn Disease - pathology; Crohn's disease; Cytokines; Dextran; Dextran Sulfate - adverse effects; Disease Models, Animal; Disease Susceptibility; Drug development; Eosinophils - immunology; Eosinophils - metabolism; Gain of Function Mutation; Gastroenterology; Genetic Variation; Humans; Immunity; Immunology; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - etiology; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; Interleukin 1; Interleukin 10; Interleukin 13; Interleukin-13 Receptor alpha2 Subunit - antagonists & inhibitors; Interleukin-13 Receptor alpha2 Subunit - genetics; Interleukin-13 Receptor alpha2 Subunit - metabolism; Intestine; Mice; Odds Ratio; Remission; Sodium sulfate; Stat6 protein
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/s41385-019-0189-6

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.