Anti-Nectin4 monoclonal antibodies attenuate airway inflammation and epithelial barrier dysfunction in asthma

Objective Nectin4 is an epithelial cell-adhesion molecule that may be involved in airway inflammatory responses. However, the effects of Nectin4 targeting in asthma has not yet been investigated. Methods Here we engineered anti-Nectin4 monoclonal antibody, N-1T1C8Ab or N-1T3H9Ab, their effects on airway epithelial dysfunction and inflammation. Dermatophagoides pteronyssinus 1 ( Der p 1)–stimulated normal human bronchial epithelial (NHBE) cells and ovalbumin-induced asthmatic BALB/c mice were used as experimental models. Results Anti-Nectin4 antibody treatment restored epithelial barrier dysfunction and was associated with changes in IL-33-related, MyD88/IRAK, and Afadin/Rac1 signaling in NHBE cells. In the murine asthma model, administration of N-1T1C8Ab or N-1T3H9Ab reduced airway inflammation, airway resistance, and immune cell infiltration in bronchoalveolar lavage fluid. Histological analysis demonstrated decreased inflammatory cell infiltration, goblet cell hyperplasia, and fibrosis in lung tissues. Anti-Nectin4 antibody treatment was also associated with modulation of IL-33/MyD88-related signaling components. Conclusion These findings indicate that anti-Nectin4 monoclonal antibodies attenuate airway inflammation and improve epithelial barrier function. Further preclinical studies are warranted to determine the potential of Nectin4 targeting in asthma.