Bispecific domain antibody attenuates airway hyperresponsiveness and pulmonary inflammation in ovalbumin-lipopolysaccharide induced asthma model by inhibiting IL-23 and TNF-α

Abstract

Asthma, a chronic multi-factorial pulmonary inflammatory condition with a high morbidity rate, is characterized by airway hyperresponsiveness and persistent pulmonary inflammation. There is a need to develop more effective treatment(s) for the management of asthma. In this study, we have investigated the therapeutic potential of BiSpekDAb (an engineered bispecific antibody comprising an anti-IL-23 domain antibody and an anti-TNF-α domain antibody fused together via flexible linkers to a half-life extension partner) in asthma. Asthma was established by sensitization and challenge of female Wistar rats with the combination of ovalbumin and lipopolysaccharide and the efficacy of BiSpekDAb was investigated by its subcutaneous administration for 11 days on each alternative day (6 doses) during the challenge phase. Significant deterioration of pulmonary functions, enhanced airway hyperresponsiveness, increase in the number of immune cells such as lymphocytes, eosinophils, neutrophils in blood circulation as well as in lungs, enhanced production of inflammatory cytokines (IL-23, TNF-α, IL-1β, IL-6, IL-22), allergic IgE antibodies, oxidative stress markers, and histopathological changes (thickening of epithelial lining, infiltration of immune cells, mast cell degranulation, and overproduction of mucus) were observed in asthma animals, and administration of BiSpekDAb attenuated airway hyperresponsiveness (AHR), pulmonary inflammation and other pathological changes. BiSpekDAb significantly inhibited IL-23 and TNF-α levels in the lungs of asthmatic rats. Our results suggest that targeting IL-23 and TNF-α simultaneously opens a new therapeutic window for biologics development aimed at mitigating pulmonary inflammation such as asthma.