Huang Keke, Wu Yuqing, Kong Yu, Xu Qingyuan, Lv Mingwei, Zhang Yirou, Lu Yiteng, Li Quanxiao, Li Cheng, Song Wenping, Zhu Xiaoyi, Yang Zhenlin, Xin Changchang, Zhou Xujiao, Ying Tianlei, Wu Yanling, Hong Jiaxu
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Institute of Infectious Disease and Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, Fudan University, Shanghai, China.
Cell Mol Immunol. 2025 Jun 11. doi: 10.1038/s41423-025-01305-7.
Addressing mucosal inflammatory disorders in the ocular surface or respiratory system remains a formidable challenge owing to the 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 A12 demonstrated potent inhibition of the IL-33-mediated signaling pathway, despite not potently blocking the IL-33 receptor interaction. Compared with the anti-IL-33 control IgG itepekimab, the topical delivery of A12 resulted in significantly elevated corneal concentrations in vivo, which resulted in negligible ocular penetration. Moreover, A12 considerably ameliorated dry eye disease severity 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 noninvasive localized delivery, highlighting their potential as an innovative therapeutic strategy for modulating mucosal inflammation.
由于生物治疗药物穿透上皮屏障的能力有限，治疗眼表或呼吸系统的黏膜炎症性疾病仍然是一项艰巨的挑战。在本研究中，我们探索了人单域抗体（UdAbs）作为局部治疗药物，在两种黏膜相关炎症性疾病中靶向调节白细胞介素-33（IL-33）的潜力。抗IL-33 UdAb A12尽管不能有效阻断IL-33受体相互作用，但仍表现出对IL-33介导的信号通路的有效抑制。与抗IL-33对照IgG依特佩单抗相比，A12的局部给药导致体内角膜浓度显著升高，而眼内渗透率可忽略不计。此外，A12通过发挥抗炎作用，显著改善了干眼症的严重程度。此外，在另一种过敏性哮喘小鼠模型中，吸入A12可显著减轻肺部整体炎症。我们的研究结果揭示了UdAbs在无创局部给药后穿透黏膜屏障的能力，突出了它们作为调节黏膜炎症的创新治疗策略的潜力。
