Variants of tace pro-domain as tnf-a inhibitor and their medical use

Abstract

A method of treating an inflammatory disease is disclosed. The method comprises administering to the subject a therapeutically effective amount of a polypeptide comprising a pro-domain of TNF-alpha converting enzyme (TACE), said polypeptide being devoid of a catalytic domain of said TACE, said polypeptide comprising a modification at a site selected from the group consisting of R58, R56 and K57 which renders said polypeptide resistant to furin degradation said polypeptide being capable of downregulating an activity of TACE, thereby treating the inflammatory disease.

What is claimed is: 
     
         1 . A method of generating a TNF-α converting enzyme (TACE) pro-domain comprising expressing a pro-domain of TACE which is devoid of a catalytic domain of said TACE, said pro-domain of TACE comprising a modification at a site selected from the group consisting of R 58 , R 56  and K 57  which renders said polypeptide resistant to furin degradation the TACE pro-domain being capable of downregulating an activity of TACE. in a cell, thereby generating the TACE pro-domain. 
     
     
         2 . The method of  claim 1 , wherein said cell is a bacterial cell. 
     
     
         3 . The method of  claim 2 , wherein said bacterial cell is an  E. coli  cell. 
     
     
         4 . The method of  claim 1 , wherein said expressing is effected by introducing a nucleic acid construct comprising a nucleic acid sequence which encodes said polypeptide into said cell. 
     
     
         5 . A method of generating a TACE pro-domain comprising a modification at a position C184, the method comprising expressing the TACE pro-domain in a cytoplasm of a bacterial cell, thereby generating the TACE pro-domain. 
     
     
         6 . The method of  claim 5 , wherein said bacterial cell is an  E. coli  cell. 
     
     
         7 . The method of  claim 5 , wherein said expressing is effected by introducing a nucleic acid construct comprising a nucleic acid sequence which encodes said polypeptide into said cell. 
     
     
         8 . The method of  claim 7 , wherein said nucleic acid sequence is selected from the group consisting of SEQ ID NOs: 11-16. 
     
     
         9 . The method of  claim 5 , wherein said pro-domain is not expressed in an inclusion body. 
     
     
         10 . A method of treating small cell lung cancer of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a polypeptide comprising a pro-domain of TNF-α converting enzyme (TACE), said polypeptide being devoid of a catalytic domain of said TACE, said polypeptide comprising modifications at each of the sites R 58 , R 211 , R 214  and C 184  which render said polypeptide resistant to furin degradation, said polypeptide being capable of downregulating an activity of TACE, wherein the numbering of the modifications corresponds to the full length human TACE enzyme, thereby treating small cell lung cancer.