Anti-PcrV antibody in cystic fibrosis: a novel approach targeting Pseudomonas aeruginosa airway infection.
Anti-PcrV antibody in cystic fibrosis: a novel approach targeting Pseudomonas aeruginosa airway infection.
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DOI：
10.1002/ppul.22890
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发表时间：
2014-07
影响因子：
3.1
通讯作者：
Geller, David E.
中科院分区：
文献类型：
--
作者：
Milla, Carlos E.;Chmiel, James F.;Accurso, Frank J.;VanDevanter, Donald R.;Konstan, Michael W.;Yarranton, Geoffrey;Geller, David E.
铜绿假单胞菌（Pa）气道感染与囊性纤维化（CF）发病率和死亡率增加相关。III型分泌系统是导致Pa毒力增加和促炎作用的因素之一。KB 001是一种PEG化的重组抗假单胞菌-PcrV抗体Fab'片段，可阻断Pa TTSS的功能。我们研究了KB 001在慢性Pa感染CF受试者中的安全性、药代动力学（PK）和药效学特性。27名合格的CF受试者（年龄≥ 12岁，FEV 1 ≥预测值的40%，痰Pa密度>105 CFU/gm）接受单次静脉内剂量的KB 001（3 mg/kg或10 mg/kg）或安慰剂。评估了安全性、PK、Pa密度、临床结局和炎症标志物。KB 001具有可接受的安全性特征，平均血清半衰期为11.9天。所有受试者的痰液中均有Pa TTSS表达。单次给药后，KB 001和安慰剂之间Pa密度、症状或肺功能测定的变化无显著差异。然而，与基线相比，在第28天，痰液髓过氧化物酶、IL-1和IL-8呈剂量依赖性降低趋势，痰液中性粒细胞弹性蛋白酶和中性粒细胞计数的变化存在显著的总体差异，有利于KB 001 10 mg/kg组与安慰剂组（分别为-0.61 log 10和-0.63 log 10; p<0.05）。这些结果支持用KB 001靶向Pa TTSS作为非抗生素策略，以减少患有慢性Pa感染的CF患者的气道炎症和损伤。重复给药研究是必要的，以评估抗炎作用的持久性以及如何转化为临床益处。（NCT00638365）
Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality in cystic fibrosis (CF). The type III secretion system is one of the factors responsible for the increased virulence and pro-inflammatory effects of Pa. KB001 is a PEGylated, recombinant, anti-Pseudomonas-PcrV antibody Fab’ fragment that blocks the function of Pa TTSS. We studied the safety, pharmacokinetic (PK), and pharmacodynamic properties of KB001 in CF subjects with chronic Pa infection. Twenty-seven eligible CF subjects (≥ 12 years of age, FEV1 ≥ 40% of predicted, and sputum Pa density >105 CFU/gm) received a single intravenous dose of KB001 (3 mg/kg or 10 mg/kg) or placebo. Safety, PK, Pa density, clinical outcomes and inflammatory markers were assessed. KB001 had an acceptable safety profile and a mean serum half-life of 11.9 days. All subjects had Pa TTSS expression in sputum. There were no significant differences between KB001 and placebo for changes in Pa density, symptoms, or spirometry after a single dose. However, compared to baseline, at Day 28 there was a trend towards a dose-dependent reduction in sputum myeloperoxidase, IL-1, and IL-8, and there were significant overall differences in change in sputum neutrophil elastase and neutrophil counts favoring the KB001 10 mg/kg group versus placebo (−0.61 log10 and −0.63 log10 respectively; p<0.05). These results support targeting Pa TTSS with KB001 as a non-antibiotic strategy to reduce airway inflammation and damage in CF patients with chronic Pa infection. Repeat-dosing studies are necessary to evaluate the durability of the anti-inflammatory effects and how that may translate into clinical benefit. (NCT00638365)
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DOI：
10.1165/ajrcmb.26.4.4473
发表时间：
2002-04-01
影响因子：
6.4
作者：
Fischer, BM;Voynow, JA
通讯作者：
Voynow, JA
影响因子：
5.2
作者：
Konstan, Michael W.;Wagener, Jeffrey S.;Morgan, Wayne J.
通讯作者：
Morgan, Wayne J.
影响因子：
3.1
作者：
HENRY, RL;MELLIS, CM;PETROVIC, L
通讯作者：
PETROVIC, L
影响因子：
9.6
作者：
Laguna, Theresa A.;Wagner, Brandie D.;Accurso, Frank J.
通讯作者：
Accurso, Frank J.
影响因子：
2.8
作者：
Feltman, H;Schulert, G;Hauser, AR
通讯作者：
Hauser, AR