Composition for treatment of CXCL8-mediated lung inflammation

A technology of pulmonary inflammation and IL-8, applied in the field of interleukin, can solve the problems of low efficiency and cannot reduce inflammation in COPD patients

Inactive Publication Date: 2012-07-18
PROTAFFIN BIOTECHNOLOGIE AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These therapies have some effect on controlling acute exacerbations, but results with traditional glucocorticosteroids are largely ineffective and fail to attenuate inflammation in COPD patients (Culpitt et al 1999; Fitzgerald et al 2007), which highlights There is a need to develop new anti-inflammatory strategies (Fabbri et al. 2004)

Method used

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  • Composition for treatment of CXCL8-mediated lung inflammation
  • Composition for treatment of CXCL8-mediated lung inflammation
  • Composition for treatment of CXCL8-mediated lung inflammation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Effect of PA401 on LPS-induced acute lung inflammation model in mice.

[0094] Various stimuli induce migration of neutrophils to the lung. Among the most commonly used and best characterized inducers of inflammation are endotoxins (lipopolysaccharide: LPS) of Gram-negative bacteria.

[0095] Intranasal instillation or nebulization of LPS induces dose- and time-dependent neutrophil infiltration in the pulmonary vasculature, interstitium, and BAL (Reutersshan et al 2005), with peak levels 4-8 hours post-challenge reached, and remained significantly above baseline in mice up to 24 hours.

[0096] The dose of LPS administered varied with the LPS serotype, method of application, and mouse strain used, with significant BAL neutropenia reported for LPS doses as low as 0.1 μg / hour and as high as 800 μg / mouse ( neutrophilia).

[0097] LPS inhalation is able to induce lung neutrophil infiltration across species (eg, mouse and rat, Chapman et al 2007; guinea pig; Wu et al 2002...

Embodiment 2

[0101] The second study was carried out using a slightly different model implying a different mouse strain and sex (male Balb / c instead of C57BL / 6), a different LPS strain and serotype (Salmonella enterica ) instead of E. coli) and different LPS administration (aerosol - 3.5mg / 7mL in 30 minutes - instead of intranasal). PA401 doses of 4, 40 and 400 μg / kg were administered by s.c. or i.v. route at t=-5 and t=+3 h from LPS exposure. BAL total and differential cytometry were assessed at t=8h, a later time point compared to previous studies.

[0102] Saline-nebulized mice and mice receiving intratracheal administration of dexamethasone (20 μg / 20 μl / mouse at t=−1 h) were used as controls.

[0103] Also in this case, PA401 induced a highly significant reduction in total cell number in BAL ( Figure 4 ), which is due to a decrease in the neutrophil count ( Figure 5 ). The activity of PA401 was more pronounced when administered by intravenous than subcutaneous route, achieving th...

Embodiment 3

[0106] PA401 effects in an acute model of cigarette smoke-induced lung inflammation.

[0107] Acute exposure of mice to cigarette smoke results in a lung response that at least partially mimics the lung inflammation observed in COPD patients. Different mouse lines exhibit varying degrees of lung inflammation after acute cigarette smoke exposure (Guerrassimov et al. 2004, Vlahos et al. 2006). This genetic variability in response in mice appears to fully represent the variable susceptibility to developing COPD in human smokers, and this model is therefore considered to be the most relevant for modeling human pathology.

[0108] Lung inflammation was induced in C57BL / 6J female mice (susceptible line) by exposure to cigarette smoke from 4 to 6 cigarettes over a 4-day period. The effect of subcutaneous PA401 treatment at doses of 4, 40 and 400 μg / kg administered at t=+30 min and t=+6 h from smoke exposure on cellular infiltrates on bronchoalveolar lavage was assessed 24 hours afte...

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Abstract

The present invention provides a composition comprising a modified interleukin 8 (IL-8) having increased GAG binding affinity and further inhibited or down-regulated GPCR activity compared to the respective wild type IL-8 for use in preventing or treating lung inflammation with neutrophilic infiltration, for example for the prevention or treatment of chronic obstructive pulmonary disease, cystic fibrosis, severe asthma, bronchitis, broncheolitis, acute lung injury and acute respiratory distress syndrome.

Description

[0001] The present invention relates to the use of modified interleukin 8 (IL-8, CXCL8) with increased GAG binding affinity and further inhibited or down-regulated receptor binding activity compared with the corresponding wild-type IL-8 for the prevention or treatment of Neutrophil-infiltrated lung inflammation, in particular new uses for the prevention or treatment of CXCL8-mediated lung inflammation. In particular, the use of modified IL-8 as an inhalant is provided. Background of the invention [0002] Pneumonic diseases are of particular relevance in terms of their predominance in the population and lack of effective therapies. Specifically, lung diseases shown to have elevated neutrophil infiltration are chronic obstructive pulmonary disease, cystic fibrosis, chronic severe asthma and Acute lung injury and its more severe form, acute respiratory distress syndrome. [0003] Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating disease that is pre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20C12N15/00
CPCC07K14/5421A61K38/00A61P11/00A61P11/06A61P29/00A61P37/02A61K38/20C12N15/00
Inventor A.孔格尔J.斯林斯比T.阿达格A.雷克
Owner PROTAFFIN BIOTECHNOLOGIE AG
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