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Blockade of ccl18 signaling via ccr6 as a therapeutic option in fibrotic diseases and cancer

a fibrotic disease and cancer technology, applied in the field of ccr6 receptor polypeptide isolation, can solve the problems of irreversible lung damage, poorly understood molecular mechanisms driving their pathogenesis, and elusive etiology of said diseases, and achieve the effect of significantly increasing the percentage of lymphocytes

Inactive Publication Date: 2013-05-02
UNIVERSITATSKLINIKUM FREIBURG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides an isolated soluble CCR6 receptor polypeptide that can bind to CCL18 and CCL20, and a method for quantifying the concentration of this polypeptide in a liquid sample from a subject. The invention also provides a pharmaceutical composition comprising a compound that can inhibit the activity and expression of CCR6, and a method for detecting and / or prognosticating interstitial lung disease or cancer in a subject. The invention also provides a method for identifying a compound that can inhibit the activity of CCR6 by using a CCR6 receptor agonist and a detecting agent. The invention further provides a method for detecting an interstitial lung disease or cancer in a subject by measuring the level of CCR6 gene expression.

Problems solved by technology

The aetiology of said diseases has remained elusive and the molecular mechanisms driving their pathogenesis are poorly understood.
Said symptoms often don't appear until the disease is advanced, and irreversible lung damage has already occurred.
The prognosis of IPF is rather poor with an average survival time of 3 years from the time of diagnosis.
At present no effective treatments and no cure for pulmonary fibrosis are available.
Often treatment is limited to treating the inflammatory response that occurs in the lungs.
IPF, however, is refractory to most of these therapeutic options.
Experimental therapy studies using IFNγ, Bosentan® (endothelin antagonist), Aviptadil® (vasoactive intestinal peptide, VIP) or the tyrosine kinase inhibitor Imatinib® did also not reveal any profound beneficial effect of these drugs.
However, exact analysis of signaling events and possible therapeutic interventions in CCL18 signalling is hampered by the fact that its receptor is not known.
Furthermore, they have the potential to act at a distance, such that they may be administered far from the site of action.
Cancer is a major health problem causing about 13% of all deaths worldwide.
Despite of advantages in new technologies and developing of new drugs contributing to a much earlier diagnosis and a more sufficient treatment, NSCLC remains a life threatening disease.
The poor prognosis is due to the highly aggressive behavior of the tumor as demonstrated by a fast tumor growth and an early metastasis.

Method used

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  • Blockade of ccl18 signaling via ccr6 as a therapeutic option in fibrotic diseases and cancer
  • Blockade of ccl18 signaling via ccr6 as a therapeutic option in fibrotic diseases and cancer
  • Blockade of ccl18 signaling via ccr6 as a therapeutic option in fibrotic diseases and cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

Phage Display Library

[0503]For the identification of a CCL18-binding motif an established phage-display library was used (1).

Cells and Cell Lines

[0504]Fibroblast lines were established either from surgical material from pneum-ectomies or lobe-ectomies from patients suffering from various tumours or from remaining material obtained from fibrotic lungs by video-assisted thoracoscopies (VATS). The patients suffered either from adenocarcinoma of the lung, non-small cell carcinoma or squamous carcinoma. Fibrosis resulted from idiopathic pulmonary fibrosis (UIP), non-specific interstitial pneumonia, sarcoidosis, hypersensitivity pneumonitis, pneumoconiosis or systemic scleroderma. The tissue was cut in small peaces (app. 0.5 cm edge length) and placed in 6-well plates containing 1 ml Quantum 333 (PAA, Pasching, Austria) with 1% penicillin / streptomycin. Outgrowing fibroblasts were harvested when they reached approximately 80% confluence by trypsinisation, cultured in 7...

example 2

Identification of a CCL18-Binding Peptide Using Phage Display

[0540]After 3 circles of binding of the phages of the phage library (as described in Example 1) to plate-bound human CCL18, phage-infected E. coli were plated on agar and 20 colonies were picked, expanded and DNA was isolated for sequencing. Some of the sequences were not informative or coded for non-human gene targets, however, one sequence with a clear relation to the CC-chemokine receptor 6 (CCR6) was identified.

example 3

Analysis of CCR6 Expression On Primary Human Fibroblast Line

PCR

[0541]Expression studies using primers for CCR6 revealed a high variability of CCR6 mRNA expression. Highest expression was found in fibroblast lines derived from lung of patients suffering from usual interstitial pneumonia (UIP). Lines derived from patients suffering from non-specific interstitial pneumonia (NSIP) or squamous carcinoma expressed only marginal levels of CCR6 mRNA (FIG. 1).

FACS

[0542]Flow-cytometric analyses of the established fibroblast lines revealed detectable CCR6 expression only on fibroblast lines derived from patients suffering from UIP. Lines generated from lungs of patients suffering from squamous carcinoma or NSIP do not express detectable CCR6 on their surface (FIG. 2). Increased CCR6 expression of fibroblasts from fibrotic lungs remained increased throughout all passages (data not shown).

Immunohistochemistry

[0543]Immunohistochemical studies on tissue sections taken from lungs of patients with I...

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Abstract

The present invention relates to an isolated soluble CCR6 receptor polypeptide capable of binding to CCL18 and / or CCL20 and to a method for quantifying the concentration of a soluble CCR6 receptor polypeptide in a liquid sample from a subject. The present invention also relates to a method for detecting and / or prognosticating an interstitial lung disease or a cancer in a subject by determining the level of a soluble CCR6 receptor polypeptide in a sample from said subject and further provides a pharmaceutical composition comprising a compound capable of inhibiting the activity and / or the expression of CCL18 or CCL20 for the treatment of said diseases. The present invention further relates to an isolated polypeptide capable of binding to and inhibiting the activity of the chemokine receptor CCR6 and to a method for identifying further inhibitors of CCR6 receptor activity. The present invention also relates to a method for detecting an interstitial lung disease or a cancer in a subject by determining the level of CCR6 gene expression in a sample from said subject and further provides pharmaceutical compositions comprising inhibitors of CCR6 receptor activity and / or expression for the treatment of said diseases.

Description

FIELD OF THE INVENTION[0001]The present invention relates to an isolated soluble CCR6 receptor polypeptide capable of binding to CCL18 and / or CCL20 and to a method for quantifying the concentration of a soluble CCR6 receptor polypeptide in a liquid sample from a subject. The present invention also relates to a method for detecting and / or prognosticating an interstitial lung disease or a cancer in a subject by determining the level of a soluble CCR6 receptor polypeptide in a sample from said subject and further provides a pharmaceutical composition comprising a compound capable of inhibiting the activity and / or the expression of CCL18 or CCL20 for the treatment of said diseases. The present invention further relates to an isolated polypeptide capable of binding to and inhibiting the activity of the chemokine receptor CCR6 and to a method for identifying further inhibitors of CCR6 receptor activity. The present invention also relates to a method for detecting an interstitial lung dise...

Claims

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Application Information

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IPC IPC(8): C07K14/715A61K45/06A61K38/16A61K38/17C07K14/00
CPCA61K9/0019A61K38/00C07K14/7158G01N33/57423G01N33/6863G01N2333/521C07K14/00G01N2500/02G01N2800/12A61K38/16A61K38/1793A61K45/06G01N2333/7158A61P1/04A61P1/16A61P11/00A61P13/08A61P13/12A61P15/00A61P35/00A61P43/00C07K14/47C07K16/24C07K16/2866C12N15/1136C12N15/1138C12N15/115C12N2310/11C12N2310/14C12N2310/16
Inventor ZISSEL, GERNOTMULLER-QUERNHEIM, JOACHIMPRASSE, ANTJE
Owner UNIVERSITATSKLINIKUM FREIBURG
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