SM17, an anti-IL-17RB antibody, ameliorates pathogenesis of CRSwNP and IPF <i>via</i> Th2/Th17 dual modulation

Background Chronic respiratory diseases (CRDs), driven by dysregulated Th2/Th17 inflammations, represent a global health challenge with limited therapeutic options. Interleukin-25 (IL-25) has emerged as a key upstream regulator of both pathways, yet its exact role in CRDs’ pathogenesis remains underexplored. Here, our aim is to evaluate the efficacies of SM17, a novel anti-IL-25 receptor (IL-17RB) antibody, in preclinical models of chronic rhinosinusitis with nasal polyps (CRSwNP) and idiopathic pulmonary fibrosis (IPF). Methods Eosinophil, peripheral blood mononuclear cell, primary macrophage and lung fibroblast cultures were utilized to define the mechanism of action for how SM17 could ameliorate CRSwNP and IPF related phenotypes in vitro . CRSwNP murine model was induced by co-administration of ovalbumin and staphylococcus enterotoxin B for comparing SM17's efficacy with dexamethasone. Furthermore, IPF model was conducted using bleomycin stimulation for differentiating beneficial effects of SM17 with two FDA approved IPF drugs, nintedanib and pirfenidone. Results In vitro studies demonstrated that SM17 could attenuate eosinophilic activities via Th2 modulation and Th17 differentiation through inhibition of macrophage activation. Simultaneously, SM17 could also prevent IL-25 driven myofibroblast differentiation. The in vitro efficacies were successfully translated to animal studies. SM17 administration restored olfactory function through suppression of eosinophilic inflammation in the nasal epithelium of CRSwNP murine model and attenuated lung fibrosis through Th17 modulation in IPF model. In both animal experiments, SM17 showed trend of improvements than the comparison drugs. Conclusion Our findings suggest SM17 is a potential therapeutic agent to treat CRDs such as CRSwNP and IPF through Th2/Th17 dual modulation and anti-fibrotic function.