二肽基肽酶-1抑制剂布伦索卡特对支气管扩张症的广泛免疫调节作用：来自2期双盲、安慰剂对照的柳树试验的数据

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

作者信息

Johnson Emma D, Long Merete B, Perea Lidia, Shih Vivian H, Fernandez Carlos, Teper Ariel, Cipolla David, McIntosh Eve, Galloway Rachel, Eke Zsofia, Shuttleworth Morven, Hull Rebecca, Spinou Arietta, De Soyza Anthony, Ringshausen Felix C, Goeminne Pieter, Lorent Natalie, Haworth Charles, Loebinger Michael R, Blasi Francesco, Shteinberg Michal, Aliberti Stefano, Polverino Eva, Sibila Oriol, Shoemark Amelia, Mange Kevin, Huang Jeffrey T J, Stobo Jamie, Chalmers James D

机构信息

University of Dundee, Division of Molecular and Clinical Medicine, Dundee, United Kingdom of Great Britain and Northern Ireland.

August Pi i Sunyer Institute of Biomedical Research, Inflammation and repair in respiratory diseases, Barcelona, Spain.

出版信息

Am J Respir Crit Care Med. 2025 Feb 12. doi: 10.1164/rccm.202408-1545OC.

RATIONALE

In the WILLOW trial, the Dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease (NSP) activity and prolonged time to first exacerbation in patients with bronchiectasis.

OBJECTIVES

We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.

METHODS

The WILLOW trial was a phase 2 randomized trial of brensocatib (10mg and 25mg) versus placebo. Sputum was collected at baseline, week 4, week 24 (end of treatment) and week 28 (4 weeks post-treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured by ELISA, mucin-5AC (MUC5AC) by liquid chromatography mass spectrometry, myeloperoxidase by immunoassay and 45 inflammatory cytokines by Olink Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the EMBARC-BRIDGE bronchiectasis cohort.

MEASUREMENTS AND MAIN RESULTS

Of 82 patients randomized to 10mg brensocatib, 87 to 25mg brensocatib, and 87 to placebo, 71, 71 and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared to placebo at both week 4 and week 24. MUC5AC reduced in response to treatment. Sub-analysis showed this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. 15 cytokines and chemokines increased significantly compared to placebo at week 4 or 28. CXCL10, CCL8, CCL7, CCL3 and IL-6 increased at both doses at both timepoints. In the EMBARC-BRIDGE cohort neutrophil elastase correlated inversely with SLPI, CCL13, IL7, CCL11, CXCL10, CCL8, CCL7, all markers increased by brensocatib.

CONCLUSIONS

Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www.

CLINICALTRIALS

gov, ID: NCT03218917.

理论依据

在柳树试验中，二肽基肽酶 -1抑制剂布伦索卡特ib降低了支气管扩张症患者的中性粒细胞丝氨酸蛋白酶（NSP）活性，并延长了首次病情加重的时间。

目的

我们假设，通过降低NSPs，布伦索卡特ib会在整个炎症级联反应中影响抗菌肽、粘蛋白和细胞因子。

方法

柳树试验是一项布伦索卡特ib（10mg和25mg）与安慰剂对比的2期随机试验。在基线、第4周、第24周（治疗结束）和第28周（治疗后4周）收集痰液。通过酶联免疫吸附测定法测量抗菌肽分泌型白细胞蛋白酶抑制剂（SLPI）和α-防御素-3，通过液相色谱质谱法测量粘蛋白-5AC（MUC5AC），通过免疫测定法测量髓过氧化物酶，并通过Olink Target 48测定法测量45种炎症细胞因子。使用EMBARC - BRIDGE支气管扩张症队列验证这些标志物与痰液中性粒细胞弹性蛋白酶之间的关系。

测量指标及主要结果

随机分配至10mg布伦索卡特ib组的82例患者、25mg布伦索卡特ib组的87例患者和安慰剂组的87例患者中，纳入了71例、71例和73例至少有两个时间点痰液样本的患者。与安慰剂相比，在第4周和第24周时，布伦索卡特ib组的SLPI和α-防御素-3均显著增加。MUC5AC对治疗有反应而降低。亚组分析表明，这主要发生在基线中性粒细胞弹性蛋白酶水平高的患者中。髓过氧化物酶没有变化。与安慰剂相比，在第4周或第28周时，15种细胞因子和趋化因子显著增加。CXCL10、CCL8、CCL7、CCL3和IL - 6在两个时间点的两种剂量下均增加。在EMBARC - BRIDGE队列中，中性粒细胞弹性蛋白酶与SLPI、CCL13、IL7、CCL11、CXCL10、CCL8、CCL7呈负相关，所有这些标志物均因布伦索卡特ib而增加。

结论

布伦索卡特ib除了对丝氨酸蛋白酶有已知作用外，还具有广泛的抗炎作用。临床试验注册信息可在www.CLINICALTRIALS.gov查询，ID：NCT03218917。