Topical delivery of human single-domain antibody targeting IL-33 for inhibiting mucosal inflammation

Addressing mucosal inflammatory disorders in the ocular surface or respiratory system remains a formidable challenge due to limited penetration of biological therapeutics across epithelial barriers. In this study, we explored the potential of human single-domain antibodies (UdAbs) as topical therapeutics for the targeted modulation of interleukin-33 (IL-33) in two mucosal-associated inflammatory disorders. The anti-IL-33 UdAb, designated A12, demonstrated potent inhibition of the IL-33-mediated signaling pathway, despite not blocking IL-33 receptor interaction. The topical delivery of A12 achieved significantly elevated corneal concentrations in vivo compared to anti-IL-33 control IgG Itepekimab, which exhibited negligible ocular penetration. Meanwhile, A12 ameliorated the dry eye disease severity considerably by exerting anti-inflammatory effects. Furthermore, in another murine model of allergic asthma, inhaled A12 substantially reduced overall lung inflammation. Our findings revealed the capacity of UdAbs to penetrate mucosal barriers following non-invasive localized delivery, highlighting their potential as an innovative therapeutic strategy for modulating mucosal inflammation.