Broad Immunomodulatory Effects of the Dipeptidyl Peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial.

Objectives: We hypothesized that by reducing neutrophil serine proteases, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.

目的：我们假设通过减少中性粒细胞丝氨酸蛋白酶，brensocatib将影响整个炎症级联反应中的抗菌肽、粘蛋白和细胞因子。

Methods: The WILLOW trial was a phase 2 randomized trial of brensocatib (10 and 25 mg) versus placebo.

方法：WILLOW试验是一项II期随机试验，比较了brensocatib（10毫克和25毫克）与安慰剂。

Sputum was collected at baseline, Week 4, Week 24 (end of treatment), and Week 28 (4 wk after treatment).

在基线时、第4周、第24周（治疗结束时）和第28周（治疗结束后4周）收集了痰液。

The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured using ELISA, MUC5AC (mucin-5AC) using liquid chromatography-mass spectrometry, myeloperoxidase using immunoassay, and 45 inflammatory cytokines using the Olink Target 48 assay.

抗菌肽分泌性白细胞蛋白酶抑制剂（SLPI）和α-防御素-3采用ELISA方法测量，MUC5AC（粘蛋白-5AC）采用液相色谱-质谱法测量，髓过氧化物酶采用免疫测定法测量，以及45种炎症细胞因子采用Olink Target 48测定法测量。

The relationship between these markers and sputum neutrophil elastase was validated using the European Multicentre Bronchiectasis Audit and Research Collaboration BRIDGE (Bronchiectasis Research Involving Databases, Genomics and Endotyping) bronchiectasis cohort.

这些标志物与痰液中性粒细胞弹性蛋白酶之间的关系通过使用欧洲多中心支气管扩张症审计和研究合作组织BRIDGE（支气管扩张症研究涉及数据库、基因组学和内型学）支气管扩张症队列进行了验证。

Measurements and Main Results: Of 82 patients randomized to 10 mg brensocatib, 87 to 25 mg brensocatib, and 87 to placebo, 71, 71, and 73 with sputum available for at least two time points were included.

测量和主要结果：在被随机分配到10毫克brensocatib的82名患者、25毫克brensocatib的87名患者和安慰剂的87名患者中，分别有71、71和73名患者的痰液样本在至少两个时间点上可用。

SLPI and α-defensin-3 increased significantly with brensocatib compared with placebo at both Week 4 and Week 24.

与安慰剂相比，brensocatib在第4周和第24周显著增加了SLPI和α-防御素-3的水平。

MUC5AC was reduced in response to treatment.

治疗后，MUC5AC的表达有所降低。

Subanalysis showed that this was primarily among patients with high baseline neutrophil elastase.

亚组分析显示，这主要发生在基线时中性粒细胞弹性蛋白酶水平较高的患者中。

Myeloperoxidase did not change.

髓过氧化物酶没有变化。

Fifteen cytokines and chemokines increased significantly compared with placebo at Week 4 or 28.

与安慰剂相比，15种细胞因子和趋化因子在第4周或第28周显著增加。

CXCL10, CCL8, CCL7, CCL3, and IL-6 increased at both doses at both time points.

CXCL10、CCL8、CCL7、CCL3和IL-6在两个剂量和两个时间点均有所增加。

In the BRIDGE cohort, neutrophil elastase correlated inversely with SLPI, CCL13, IL-7, CCL11, CXCL10, CCL8, and CCL7, all markers increased by brensocatib.

在BRIDGE队列中，中性粒细胞弹性蛋白酶与SLPI、CCL13、IL-7、CCL11、CXCL10、CCL8和CCL7呈负相关，这些标志物均因brensocatib的使用而增加。

Conclusions: Brensocatib exerts broad antiinflammatory effects beyond its known effects on serine proteases.

结论：Brensocatib具有广泛的抗炎作用，超出了其对丝氨酸蛋白酶已知效应的范围。

Clinical trial registered with www.clinicaltrials.gov (NCT03218917).

临床试验已在www.clinicaltrials.gov注册（NCT03218917）。