A new Anticalin protein for IL-23 inhibits non-type 2 allergen-driven mouse lung inflammation and airway hyperresponsiveness

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 327; no. 5; pp. L624 - L633
• Main Authors: Brüggemann, Thayse R, Krishnamoorthy, Nandini, Hagner, Matthias, Matschiner, Gabriele, Jaquin, Thomas, Tavares, Luciana P, Peh, Hong Yong, Levy, Bruce D
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.11.2024
• Subjects: Allergens; Allergens - immunology; Animals; Antibodies, Monoclonal - pharmacology; Asthma; Asthma - immunology; Asthma - metabolism; Asthma - pathology; CD4 antigen; Eosinophils; Female; Helper cells; Inflammation; Interleukin 17; Interleukin 23; Interleukin 5; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukin-23 - immunology; Interleukin-23 - metabolism; Leukocytes (eosinophilic); Leukocytes (granulocytic); Leukocytes (neutrophilic); Lung - immunology; Lung - metabolism; Lung - pathology; Lungs; Lymphocytes; Lymphocytes T; Macrophages; Metaplasia; Methacholine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monoclonal antibodies; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Pneumonia - immunology; Pneumonia - metabolism; Pneumonia - pathology; Proteins; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - pathology; Respiratory tract; Th17 Cells - immunology; Th17 Cells - metabolism; Anticalin proteins; severe asthma; interleukin (IL)-23
• DOI: 10.1152/ajplung.00295.2023
• ISSN: 1040-0605; 1522-1504

Severe asthma is a syndromic label assigned to patients based on clinical parameters, yet there are diverse underlying molecular endotypes in severe asthma pathobiology. Immunophenotyping of asthma biospecimens commonly includes a mixture of granulocytes and lymphocytes. Recently, a subset of patients with severe asthma was defined as non-type 2 with neutrophil-enriched inflammation associated with increased Th17 CD4 T cells and IL-17 levels. Here, we used an allergen-driven mouse model of increased IL-17 and mixed granulocyte lung inflammation to determine the impact of upstream regulation by an Anticalin protein that specifically binds IL-23. Airway administration of the IL-23-binding Anticalin protein (AcIL-23) decreased lung neutrophils, eosinophils, macrophages, lymphocytes, IL-17 CD4 T cells, mucous cell metaplasia, and methacholine-induced airway hyperresponsiveness. Selective targeting of IL-23 with a monoclonal antibody (IL-23p19; αIL-23) also decreased macrophages, IL-17 CD4 T cells, and airway hyperresponsiveness. In contrast, a monoclonal antibody against IL-17A (αIL-17A) had no significant effect on airway hyperresponsiveness but did decrease lung neutrophils, macrophages, and IL-17 CD4 T cells. Targeting the IL-23 pathway did not significantly change IL-5 or IL-13 CD4 T cells. Together, these data indicate that airway AcIL-23 mirrored the activity of systemic anti-IL-23 antibody to decrease airway hyperresponsiveness in addition to mixed granulocytic inflammation and that these protective actions were broader than blocking IL-17A or IL-5 alone, which selectively decreased airway neutrophils and eosinophils, respectively. This is the first report of an Anticalin protein engineered to neutralize IL-23 (AcIL-23). Airway administration of AcIL-23 in mice regulated allergen-driven airway inflammation, mucous cell metaplasia, and methacholine-induced airway hyperresponsiveness. In mixed granulocytic allergic lung inflammation, immune regulation of IL-23 was broader than neutralization of either IL-17 or IL-5.