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...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.展开更多
基金supported by grants from the National Natural Science Foundation of China(82394450,92459301,32270984)the Science and Technology Commission of Shanghai Municipality(23XD1400800)+10 种基金the Shanghai Municipal Health Commission(GWVI-11.2-YQ46)the Fund of Fudan University and Cao’ejiang Basic Research(24FCB09)supported by the National Science Fund for Distinguished Young Scholars(82425015)the National Natural Science Foundation of China(82171102)the National Key Research and Development Program of China(2023YFA0915003)the Shanghai Medical Innovation Research Program(22Y21900900)the“Dawn”Program of the Shanghai Municipal Education Commission(24SG11)the Shanghai Science and Technology Innovation Action Plan for Cell and Gene Therapy(24J22800500)the Shanghai Science and Technology Innovation Action Plan for Advanced Materials(24CL2900802)the Shanghai Municipal Commission of Health(20254Z0019)the Shanghai Medicine and Health Development Foundation.
文摘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.
