Procollagen (III) Propeptides and Related Substances for Treating Fibrotic Diseases

Abstract

A medicament for treating or preventing fibrotic diseases contains an antifibrotic substance that is a (poly) peptide having antifibrotic activity and comprising at least one of an N-terminal procollagen (III) propeptide and a C-terminal procollagen (III) propeptide, or a fragment of the (poly) peptide defined having antifibrotic activity or a derivative of the (poly) peptide having antifibrotic activity. The antifibrotic substance is combined with a pharmaceutically tolerable carrier or dilutant.

What is claimed is:  
     
         1 . A medicament comprising: 
 A) an antifibrotic substance selected from the group consisting of: 
 a) a (poly) peptide having antifibrotic activity and being selected from the group consisting of at least one of an N-terminal procollagen (III) propeptide and a C-terminal procollagen (III) propeptide;  
 b) a fragment of the (poly) peptide defined under a) having the antifibrotic activity; and  
 c) a derivative of the (poly) peptide defined under a) having the antifibrotic activity;  
   B) a pharmaceutically tolerable carrier or dilutant.    
     
     
         2 . The medicament according to  claim 1 , wherein the antifibrotic substance comprises a recognition sequence of procollagen-N-proteinase type III or a recognition sequence of procollagen-C-proteinase type III or recognition sequences of procollagen-N-proteinase type III and procollagen-C-proteinase type III.  
     
     
         3 . The medicament according to  claim 1 , wherein the antifibrotic substance comprises a sequence for affinity purification.  
     
     
         4 . The medicament according to  claim 3 , wherein the antifibrotic substance comprises a His-tag.  
     
     
         5 . A method of producing at least one of a renatured N-terminal procollagen (III) propeptide and a renatured C-terminal procollagen (III) propeptide, comprising the steps of: 
 a) producing inclusion bodies in  E. coli , wherein the inclusion bodies are dissolved in a 0.5 to 8 M denaturing buffer;    b) pipetting the buffer of step a) dropwise into a limited dilution buffer, buffered around neutral pH and containing L-arginine in a final concentration between 200 to 1,000 nM and a disulifide bridge-reducing coupled redox system, until a volume ratio of maximally 1:3 is reached of the denaturing buffer and the limited dilution buffer, respectively;    c) dialyzing the buffer mixture of step b) for at least 2 hours against a physiological buffer that contains L-arginine at a final concentration of 50 to 200 nM and a disulifide bridge-reducing coupled redox system;    d) dialyzing the buffer mixture of step c) for at least 2 hours against a physiological buffer that contains a disulfide bridge-reducing coupled redox system;    e) dialyzing the buffer mixture according to step d) against a physiological buffer for at least 2 hours.    
     
     
         6 . A method of treating or preventing fibrotic diseases, the method comprising the steps of: 
 a) producing at least one of an N-terminal procollagen (III) propeptide and C-terminal procollagen (III) propeptide according to  claim 5;     b) administering an effective amount of a product of step a) to a patient.    
     
     
         7 . The method according to  claim 6 , wherein the fibrotic diseases are selected from the group consisting of systemic or localized scleroderma, liver fibrosis of various etiologies, alcoholic cirrhosis, e.g. alcoholic liver cirrhosis, biliary cirrhosis, hepatitis of viral or other origin, veno-occlusive disease, idiopathic interstitial fibrosis, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, acute pulmonary fibrosis, acute respiratory distress syndrome, perimuscular fibrosis, pericentral fibrosis, dermatofibroma, kidney fibrosis, diabetic nephropathy, glomerulonephritis, keloids, hypertrophic scars, joint adhesions, arthrosis, myelofibrosis, corneal scaring, cystic fibrosis, muscular fibrosis, Duchenne's muscular dystrophy, esophageal stricture, retroabdominal scaring, Crohn's disease, ulcerative colitis, atherosclerotic alterations, pulmonary hypertension, angiopathy of the arteries and veins, aneurysms of large vessels or are induced or initiated by scar revisions, plastic surgeries, glaucoma, cataract fibrosis, corneal scaring, graft vs. host disease, tendon surgery, nerve entrapment, Dupuytren's contracture, OB/GYN adhesions, pelvic adhesions, infertility, peridural fibrosis, diseases of the thyroid gland or the parathyroids, metastatic bone disease, multiple myeloma, or restenosis.