贝那利珠单抗治疗重度嗜酸性粒细胞性哮喘：迈向疾病控制与不断演变的治疗范式

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中文摘要

重度嗜酸性粒细胞性哮喘（SEA）是一种由持续性嗜酸性粒细胞增多驱动的2型炎症表型，其特征为频繁急性加重、肺功能进行性下降以及显著的口服糖皮质激素（OCS）依赖，而传统治疗在相当一部分患者中仍不充分。贝那利珠单抗——一种人源化、去岩藻糖基化的抗白介素-5受体α（IL-5Rα）单克隆抗体——通过双重受体阻断和去岩藻糖基化增强的抗体依赖性细胞介导的细胞毒性（ADCC）实现嗜酸性粒细胞和嗜碱性粒细胞的近乎完全耗竭，在目前获批的生物制剂中产生最广泛的抗嗜酸性粒细胞效应之一。关键3期试验（SIROCCO、CALIMA、ZONDA）显示年急性加重率降低高达51%，稳健的OCS节约效应，52.7%的OCS依赖患者实现完全停用，以及第1秒用力呼气容积（FEV1）的显著改善。五年以上的长期扩展数据（MELTEMI）证实了持续疗效和安全性，未发现可归因于慢性嗜酸性粒细胞耗竭的不良后果。包括PONENTE、SHAMAL和ABRA在内的里程碑式研究进一步扩展了贝那利珠单抗的临床影响：实现结构化的OCS停用，证明控制良好的患者可将吸入性糖皮质激素减至按需治疗，并确立基于生物制剂的急性嗜酸性粒细胞加重治疗为一种可行的新方法。真实世界证据持续印证试验发现，临床缓解——定义为无急性加重、OCS独立、症状控制和肺功能保留的复合达成——在12个月时报告于17-44%的患者中，在选定的长期队列中高达91%。除哮喘外，贝那利珠单抗在共病的慢性鼻窦炎伴鼻息肉、嗜酸性肉芽肿性多血管炎和嗜酸性食管炎中显示出有意义的活性。本综述全面审视贝那利珠单抗的分子药理学、关键与真实世界临床证据、共病管理，及其在推动重度嗜酸性气道疾病从症状控制向临床缓解范式转变中的核心作用。

英文摘要

Severe eosinophilic asthma (SEA) is a type-2 inflammatory phenotype driven by persistent eosinophilia, characterized by frequent exacerbations, progressive lung function decline, and substantial oral corticosteroid (OCS) dependence, for which conventional therapies remain insufficient in a significant minority of patients. Benralizumab-a humanized, afucosylated anti-interleukin-5 receptor alpha (IL-5Rα) monoclonal antibody-achieves near-complete depletion of eosinophils and basophils through dual receptor blockade and afucosylation-enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), producing one of the most extensive anti-eosinophilic effects among currently approved biologics. Pivotal Phase 3 trials (SIROCCO, CALIMA, ZONDA) demonstrated annual exacerbation rate reductions of up to 51%, robust OCS-sparing with complete elimination in 52.7% of OCS-dependent patients, and significant improvements in forced expiratory volume in 1 second (FEV1). Long-term extension data over five years (MELTEMI) confirmed sustained efficacy and safety, without evidence of adverse consequences attributable to chronic eosinophil depletion. Landmark studies including PONENTE, SHAMAL, and ABRA have further extended benralizumab's clinical impact: enabling structured OCS elimination, demonstrating that well-controlled patients can reduce inhaled corticosteroids to as-needed therapy, and establishing biologic-based treatment of acute eosinophilic exacerbations as a viable new approach. Real-world evidence consistently corroborates trial findings, with clinical remission-defined as the composite achievement of exacerbation freedom, OCS independence, symptom control, and preserved lung function-reported in 17-44% of patients at 12 months and up to 91% in selected longer-term cohorts. Beyond asthma, benralizumab demonstrates meaningful activity in comorbid chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis, and eosinophilic esophagitis. This review comprehensively examines benralizumab's molecular pharmacology, pivotal and real-world clinical evidence, comorbidity management, and its central role in driving the paradigm shift from symptom control toward clinical remission in severe eosinophilic airway disease.