Auflistung nach Autor:in "AL-Sheakly, Baraa Khalid Salah"

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Innovative anti-IL-33 receptor blocking
(2025-07-28) AL-Sheakly, Baraa Khalid Salah
Severe asthma remains a critical healthcare challenge due to its complex pathophysiology and poor response to corticosteroids. IL-33, a potent alarmin, plays a central role in promoting airway inflammation through its receptor, ST2. Targeting the IL-33/ST2 axis is emerging as a promising therapeutic strategy for severe asthma. While monoclonal anti-ST2 antibodies such as astegolimab show potential in severe asthma, their high cost, limited tissue penetration, and immunogenicity highlight the need for innovative alternatives. This study addresses these limitations by developing novel anti-ST2 nanobodies and evaluating their therapeutic potential through intrapulmonary delivery, which offers localized treatment with superior tissue penetration, reduced side effects, and enhanced efficiency. Mechanistic studies revealed that IL-33/ST2 signaling drives steroid hypo-responsiveness by activating MAPK/ERK and NF-κB pathways and disrupting the GRα/GRβ balance. To counteract these effects, we generated a high-affinity anti-ST2 nanobody library using phage display technology. NB7, the top-performing nanobody, demonstrated exceptional binding specificity and affinity for ST2. Functional evaluations in primary human lung epithelial cells confirmed NB7's ability to block ST2, reduced MAPK/ERK and NF-κB activation, and suppress key pro-inflammatory cytokines, including IL-17 and IL-8. Notably, NB7 restored the GRα/GRβ balance and reversed steroid hypo-responsiveness in vitro. In vivo, intrapulmonary delivery of NB7 demonstrated enhanced localized action, significantly reducing airway inflammation, mucus production, and cytokine levels, while improving lung mechanics and restoring steroid responsiveness with lower systemic exposure and side effects. NB7 demonstrated superior efficacy to astegolimab across multiple parameters at a lower dose. This research is the first to develop anti-ST2 nanobodies that specifically target the IL-33 receptor and evaluate their efficacy via intrapulmonary delivery compared to monoclonal antibodies. By addressing key limitations of existing therapies, this study offers a transformative and localized approach to improving the management of severe asthma.