胸腺基质淋巴细胞生成素单克隆抗体在重度哮喘治疗中的研究进展

doi:10.16138/j.1673-6087.2026.02.13

摘要/Abstract

摘要：

本文综述了抗胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin，TSLP）单克隆抗体特泽利尤单抗（tezepelumab）在重度哮喘治疗中的研究进展。哮喘是一种慢性气道炎症性疾病，全球患病率高且控制率低，尤其是重度哮喘患者对常规治疗反应不佳。TSLP作为上皮来源的警报素，位于炎症级联反应顶端，可驱动多种哮喘表型的病理过程。特泽利尤单抗作为全人源抗TSLP单克隆抗体，通过特异性结合TSLP并阻断其与TSLP受体（TSLP receptor，TSLPR）的相互作用，减少白介素（interleukin，IL）4、IL-5、IL-13等2型炎症因子的产生。多项动物实验及临床试验表明，抗TSLP抗体能显著减轻气道炎症，降低气道高反应性，抑制气道重塑，降低哮喘年化急性加重率，延长至首次发作持续时间，改善肺功能[如第1秒用力呼气量（forced expiratory volume in the first second，FEV₁）]，降低血嗜酸性粒细胞计数、呼出气一氧化氮（fractional exhaled nitric oxide，FeNO）及总免疫球蛋白E（immunoglobulin E，IgE）水平，并在不同炎症表型患者中均显示出疗效。

关键词: 抗胸腺基质淋巴细胞生成素, 重度哮喘, 单克隆抗体, 生物靶向治疗

Abstract:

This article reviews the research progress on tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) monoclonal antibody, in the treatment of severe asthma. Asthma is a chronic inflammatory airway disease with high global prevalence and low control rate, especially in patients with severe asthma who respond poorly to conventional therapies. TSLP, an epithelial-derived alarmin, sits at the apex of the inflammatory cascade and drives the pathological processes of multiple asthma phenotypes. Tezepelumab, a fully human anti-TSLP monoclonal antibody, specifically binds TSLP and prevents its interaction with TSLP receptor (TSLPR), thereby reducing the production of type 2 inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13. Multiple animal experiments and clinical trials have shown that anti-TSLP antibodies can significantly alleviate airway inflammation, reduce airway hyperresponsiveness, inhibit airway remodeling, decrease annualized rate of acute asthma exacerbation, prolong time to first exacerbation, improve lung function [e.g., forced expiratory volume in the first second (FEV₁)], lower blood eosinophil count, fractional exhaled nitric oxide (FeNO) as well as total immunoglobulin E (IgE) level, and demonstrate efficacy across patients with different inflammatory phenotypes.

Key words: anti-thymic stromal lymphopoietin, severe asthma, monoclonal antibody, biological targeted therapy

张敏, 邓贤坤. 胸腺基质淋巴细胞生成素单克隆抗体在重度哮喘治疗中的研究进展[J]. 内科理论与实践, 2026, 21(02): 183-187.

ZHANG Min, DENG Xiankun. Research progress on the application of thymic stromal lymphopoietin monoclonal antibody in the treatment of severe asthma[J]. Journal of Internal Medicine Concepts & Practice, 2026, 21(02): 183-187.

图/表 2

表1

抗TSLP抗体改善哮喘的动物实验

作者及年份	动物品系	抗TSLP抗体剂量及持续时间	结果
IFN-γ：干扰素γ（interferon γ）；OVA：卵清蛋白（ovalbumin）；mRNA：信使RNA（messenger RNA）；TGF-β1：转化生长因子-β1（transforming growth factor-beta 1）。
Shi等^[25] （2008）	8~10周龄雌性BALB/c哮喘小鼠模型	20 μg抗TSLPR或Ig经气管内注射；致敏前30 min	局部使用抗TSLPR抗体可减少气道炎症、Th2偏移和黏液产生，降低IL-4和IL-5水平，上调IFN-γ产生；阻断改变气道DC的成熟和迁移；阻断损害DC在体外启动Th2反应能力
Zhang等^[26] （2011）	雌性BALB/c过敏性哮喘小鼠模型	20 μg TSLPR-Ig；致敏前30 min	TSLPR-Ig抑制共刺激分子表达；显著降低炎症细胞浸润水平和过敏性气道反应的严重程度；抑制OVA-DC诱导哮喘小鼠Th2偏移的能力；抑制过敏原特异性IgE合成
Chen等^[27] （2013）	6~8 周龄雌性BALB/c哮喘小鼠模型	20 μg抗TSLP mAb；致敏前1 h	抗TSLP mAb处理显著抑制肺中TSLP mRNA和蛋白水平的增加；消除气道EOS炎症，降低气道高反应性；通过抑制支气管周围胶原沉积和杯状细胞增生，预防气道结构重塑；下调TGF-β1水平；调节Th1/Th2平衡；抑制气道CD11c⁺细胞表面标志物表达
Lee等^[28] （2020）	7~8周龄雌性 BALB/c哮喘小鼠模型	1 mg/kg抗TSLP抗体；激发前2 h	抗TSLP治疗显著降低对乙酰甲胆碱的呼吸系统阻力；显著减少总炎性细胞和EOS计数；减少炎症细胞积聚，减少上皮和杯状细胞增生及黏液分泌；有效抑制肺组织中TSLP、IL-33、IL-5和IL-13表达；降低总IgE和OVA特异性IgG1水平
Cheng等^[29] （2013）	3~10 kg经猪蛔虫抗原致敏的食蟹猴	每周7.5 mg/kgTSLP mAb；持续6周	TSLP mAb处理组BALF中EOS浸润水平、IL-13细胞因子均显著降低，且过敏原诱导的气道阻力经TSLP处理也显著降低

表1

表2

特泽利尤单抗改善哮喘的临床试验

作者及年份	队列名称	特泽利尤单抗剂量及持续时间	结果
AQLQ(S)+12：12周岁及以上标准化AQLQ（standardized AQLQ for 12 years and older）；HRQoL：健康相关生命质量（health-related quality of life）。
Corren等^[30]（2017）	2期临床试验，18~75岁，患有哮喘的非吸烟者	70 mg/4周、210 mg/4周、 280 mg/2周，持续52周	特泽利尤单抗组哮喘加重年化率比安慰剂组降低，其首次哮喘急性发作的发生时间较安慰剂组更长，52周时支气管舒张剂前FEV₁的变化比安慰剂组更大。血液EOS计数、FeNO水平均出现显著且持续下降，总血清IgE也呈逐步下降趋势
Diver等^[31]（2021）	2期临床试验，18~75岁，中重度未控制哮喘	210 mg/4周，持续28周	特泽利尤单抗治疗组的气道黏膜下EOS明显减少，且这一差异在所有基线生物标志物亚组中均可见（中性粒细胞、CD3⁺T细胞、CD4⁺T细胞、胰蛋白酶⁺肥大细胞和糜蛋白酶⁺肥大细胞）
Menzies-Gow等^[32]（2021）	3期临床试验，12~80岁，哮喘患者	210 mg/4周，持续52周	特泽利尤单抗治疗后哮喘急性发作年化率明显降低；首次哮喘急性发作的发生时间延长。52周时，支气管舒张剂前FEV₁的变化在特泽利尤单抗组更明显，同时，特泽利尤单抗组的ACQ-6、AQLQ(S)+12、ASD评分均较安慰剂组有改善。血液EOS计数、FeNO水平均出现持续下降，总血清IgE也逐步下降
Menzies-Gow等^[33]（2023）	3期临床试验， 18~80岁成人及12~17岁的青少年重度未控制性哮喘	210 mg/4周，持续104周	特泽利尤单抗治疗在2年内均耐受良好，并在重度未控制性哮喘患者中持续、显著减少哮喘恶化
Lugogo等^[34]（2025）	4期临床试验，＞12岁的重度哮喘患者	210 mg/4周，持续48周	接受特泽利尤单抗治疗的美国重度哮喘多样化患者群体急性发作显著减少，同时肺功能、哮喘控制、鼻窦炎症状和HRQoL获得临床上有意义的改善

表2

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