重新思考慢性鼻窦炎伴鼻息肉中的单特异性抗体治疗：双特异性和多特异性抗体

文献信息

中文摘要

慢性鼻窦炎伴鼻息肉（CRSwNP）是一种异质性炎症性疾病，其中2型炎症占主导地位，但其局部组织、临床背景和下游组织效应各不相同。靶向白介素-4受体α、免疫球蛋白E、白介素-5/白介素-5受体轴和胸腺基质淋巴细胞生成素的生物制剂扩大了严重疾病的治疗选择，并可改善息肉负荷、鼻塞、嗅觉功能、生活质量以及皮质类固醇或手术相关结局。然而，不同患者和临床领域的反应仍然可变，不完全控制可能反映靶点不匹配、持续的平行炎症通路、共病气道疾病或已建立的组织重塑，而不仅仅是通路覆盖不足。在这篇综述中，我们总结了当前单特异性抗体的机制和临床证据，并探讨可能导致治疗反应变异的生物学背景，包括局部IgE活性、微生物和抗原扩增、非甾体抗炎药加重性呼吸疾病（N-ERD）、共病哮喘和持续的上皮重塑。然后，我们讨论了生物标志物、多维反应评估和生物治疗的临床定位，之后评估了双特异性和多特异性抗体的原理、边界、分子设计和当前研发管线。关注更广泛的通路靶向是否能在优化单特异性治疗的基础上提供增量获益，同时保持可接受的长期安全性、治疗实用性和经济价值。多特异性生物制剂在CRSwNP中的未来作用将取决于合理的靶点配对、比较性临床证据以及更好地识别最可能获益的患者。

英文摘要

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disorder in which type 2 inflammation predominates but varies in its local organization, clinical context, and downstream tissue effects. Biologics targeting interleukin-4 receptor alpha, immunoglobulin E, the interleukin-5/interleukin-5 receptor axis, and thymic stromal lymphopoietin have expanded treatment options for severe disease and can improve polyp burden, nasal obstruction, olfactory function, quality of life, and corticosteroid- or surgery-related outcomes. However, responses remain variable across patients and clinical domains, and incomplete control may reflect target mismatch, persistent parallel inflammatory pathways, comorbid airway disease, or established tissue remodeling rather than insufficient pathway coverage alone. In this review, we summarize the mechanisms and clinical evidence for current monospecific antibodies and examine biological contexts that may contribute to variable treatment responses, including local IgE activity, microbial and antigenic amplification, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), comorbid asthma, and persistent epithelial remodeling. We then discuss biomarkers, multidimensional response assessment, and clinical positioning of biologic therapy before evaluating the rationale, boundaries, molecular design, and current pipeline of dual- and multispecific antibodies. Attention is given to whether broader pathway targeting can provide incremental benefit over optimized monospecific therapy, while maintaining acceptable long-term safety, treatment practicality, and economic value. The future role of multispecific biologics in CRSwNP will depend on rational target pairing, comparative clinical evidence, and improved identification of patients most likely to benefit.