Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland.
Ann Allergy Asthma Immunol. 2024 Jul;133(1):33-42. doi: 10.1016/j.anai.2024.03.002. Epub 2024 Mar 14.
IgE signaling through its high-affinity receptor FcεRI is central to the pathogenesis of numerous allergic disorders. Oral inhibitors of Bruton's tyrosine kinase (BTKis), which are currently Food and Drug Administration-approved for treating B cell malignancies, broadly inhibit the FcεRI pathway in human mast cells and basophils, and therefore may be effective allergen-independent therapies for a variety of allergic diseases. The application of these drugs to the allergy space was previously limited by the low kinase selectivity and subsequent toxicities of early-generation compounds. Fortunately, next-generation, highly selective BTKis in clinical development appear to have more favorable risk-benefit profiles, and their likelihood of being Food and Drug Administration-approved for an allergy indication is increasing. Recent clinical trials have indicated the remarkable and rapid efficacy of the second-generation BTKi acalabrutinib in preventing clinical reactivity to peanut ingestion in adults with peanut allergy. In addition, next-generation BTKis including remibrutinib effectively reduce disease activity in patients with antihistamine-refractory chronic spontaneous urticaria. Finally, several BTKis are currently under investigation in early clinical trials for atopic dermatitis and asthma. In this review, we summarize recent data supporting the use of these drugs as novel therapies in food allergy, anaphylaxis, urticaria, and other allergic disorders. We also discuss safety data derived from trials using both short-term and chronic dosing of BTKis.
IgE 信号通过其高亲和力受体 FcεRI 是许多过敏性疾病发病机制的核心。布鲁顿酪氨酸激酶(BTK)的口服抑制剂目前已获得美国食品和药物管理局批准用于治疗 B 细胞恶性肿瘤,广泛抑制人类肥大细胞和嗜碱性粒细胞中的 FcεRI 途径,因此可能是治疗多种过敏性疾病的有效过敏原非依赖性疗法。这些药物在过敏领域的应用以前受到第一代化合物激酶选择性低和随后毒性的限制。幸运的是,目前正在临床开发的新一代高选择性 BTK 抑制剂似乎具有更好的风险效益比,它们获得美国食品和药物管理局批准用于过敏适应症的可能性正在增加。最近的临床试验表明,第二代 BTKi acalabrutinib 可显著快速预防花生过敏成人对花生摄入的临床反应。此外,包括 remibrutinib 在内的新一代 BTK 抑制剂可有效降低抗组胺难治性慢性自发性荨麻疹患者的疾病活动度。最后,几种 BTK 抑制剂目前正在早期临床试验中用于特应性皮炎和哮喘。在这篇综述中,我们总结了支持将这些药物作为新型疗法用于食物过敏、过敏反应、荨麻疹和其他过敏性疾病的最新数据。我们还讨论了从短期和慢性 BTK 给药试验中获得的安全性数据。
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