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

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.

1 . An isolated soluble CCR6 receptor polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of:
 (a) an amino acid sequence which exhibits at least 80% identity to the sequence according to SEQ ID NO.: 1; and   (b) a fragment of the amino acid sequence according to (a);   
       wherein said isolated soluble CCR6 receptor polypeptide is capable of binding to CCL18 and/or CCL20. 
     
     
         2 . The isolated soluble CCR6 receptor polypeptide according to  claim 1 , wherein the amino acid sequence according to (a) comprises at least 8 consecutive amino acids of the sequence according to SEQ ID NO.:1. 
     
     
         3 . The isolated soluble CCR6 receptor polypeptide according to  claim 1 , wherein said isolated soluble CCR6 receptor polypeptide does not comprise a transmembrane domain. 
     
     
         4 . A pharmaceutical composition comprising a compound capable of inhibiting the activity and/or the expression of CCL18 or CCL20. 
     
     
         5 . A pharmaceutical composition according to  claim 4 , wherein the compound capable of inhibiting the activity and/or the expression of CCL18 or CCL20 is selected from the group consisting of the isolated soluble CCR6 receptor polypeptide according to  claim 1 , a small molecule capable of binding to CCL18 or CCL20, an aptamer specific for CCL18 or CCL20, an antibody specific for CCL18 or CCL20, an antisense molecule suitable for reducing or inhibiting the expression of CCL18 or CCL20 and an siRNA molecule suitable for reducing or inhibiting the expression of CCL18 or CCL20. 
     
     
         6 . A pharmaceutical composition according to  claim 4 , wherein the composition comprises a further active compound suitable for the treatment or prevention of an interstitial lung disease and/or cancer. 
     
     
         7 . (canceled) 
     
     
         8 . A method of treating or preventing an interstitial lung disease and/or cancer by administering to a subject in need thereof an effective amount of the isolated soluble CCR6 receptor polypeptide according to  claim 1  or a pharmaceutical composition according to  claim 4 . 
     
     
         9 . (canceled) 
     
     
         10 . The method according to  claim 8 , wherein the interstitial lung disease is selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamtive interstitial pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia. 
     
     
         11 . The method according to  claim 8 , wherein the cancer is selected from the group consisting of adenocarcinoma, preferably adenocarcinoma of the lung, pleuramesothelioma, colorectal carcinoma, prostate carcinoma, mamma carcinoma, renal cell carcinoma, hepatocellular carcinoma, Non-Hodgkin-Lymphoma and Hodgkin-Lymphoma. 
     
     
         12 . An isolated polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of:
 (a) an amino acid sequence which exhibits at least 80% identity to the sequence according to SEQ ID NO.: 9, 22 or 23; and   (b) a fragment of the amino acid sequence according to (a);   
       wherein said isolated polypeptide is capable of binding to and inhibiting the activity of the CCR6 receptor. 
     
     
         13 . The isolated polypeptide according to  claim 12 , wherein the amino acid sequence according to (a) comprises at least 8 consecutive amino acids of the sequence according to SEQ ID NO.:9, 22 or 23. 
     
     
         14 . An isolated polynucleotide encoding the polypeptide according to  claim 12 . 
     
     
         15 . The isolated polynucleotide according to  claim 14 , wherein said polynucleotide comprises or consists of a sequence which exhibits at least 80% identity to the sequence according to SEQ ID NO.:24, SEQ ID NO.:25 or SEQ ID NO.:26. 
     
     
         16 . A pharmaceutical composition comprising a compound capable of inhibiting the activity and/or the expression of the CCR6 receptor. 
     
     
         17 . A pharmaceutical composition according to  claim 16 , wherein the compound capable of inhibiting the activity and/or the expression of the CCR6 receptor is selected from the group consisting of the isolated polypeptide according to  claim 12 , a small molecule capable of binding to the CCR6 receptor, the isolated polynucleotide according to  claim 14 , an aptamer specific for CCR6 receptor, an antibody specific for CCR6 receptor, an antisense molecule suitable for reducing or inhibiting the expression of the CCR6 receptor and an siRNA molecule suitable for reducing or inhibiting the expression of the CCR6 receptor. 
     
     
         18 . A pharmaceutical composition according to  claim 16 , wherein the composition comprises a further active compound suitable for the treatment or prevention of an interstitial lung disease and/or cancer. 
     
     
         19 . A method of treating or preventing an interstitial lung disease and/or cancer by administering to a subject in need thereof an effective amount of the pharmaceutical composition according to  claim 16 . 
     
     
         20 . (canceled) 
     
     
         21 . The method according to  claim 19 , wherein the interstitial lung disease is selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamtive interstitial pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia. 
     
     
         22 . The method according to  claim 19 , wherein the cancer is selected from the group consisting of adenocarcinoma, preferably adenocarcinoma of the lung, pleuramesothelioma, colorectal carcinoma, prostate carcinoma, mamma carcinoma, renal cell carcinoma, hepatocellular carcinoma, Non-Hodgkin-Lymphoma and Hodgkin-Lymphoma.