Peptide-based carrier devices for stellate cells

Abstract

A compound includes a carrier molecule wherein the carrier molecule is linked to a further molecule, wherein the further molecule is at least one cyclic peptide in which the cyclic peptide portion thereof contains at least one sequence encoding a cell receptor recognizing peptide (RRP) and with the proviso that the compound is not a naturally occurring receptor agonist or antagonist. Preferably, the RRP is a receptor specific for Hepatic Stellate Cells (HSC) or a receptor that is up-regulated on HSC during disease. The RFP may be chosen from among a PDGF receptor, a collagen type VI receptor, cytokine receptor(s) such as TGBβ, INFα and interleukinβ. The cyclic portion of the peptide can contain at least one amino acid sequence RGD or KPT. The compounds can be used as an active targeting ingredient for manufacturing a pharmaceutical composition for therapy, prophylaxis or diagnosis of a disease chosen from fibrotic disease, sclerotic disease, and chronic or acute inflammatory processes including glomeruloscherosis, interstitial fibrosis, lung fibrosis, atherosclerosis, rheumatoid arthritis, Crohns disease, colitis ulcerosa, glomerulonephritis and sepsis, and particularly for targeting HSC. Pharmaceutical compositions contain the above-compound(s).

1 . (canceled) 
     
     
         2 - 26 . (canceled) 
     
     
         27 . A compound comprising a carrier molecule linked to at least one further molecule selected from the group consisting of:
 (a) a carrier molecule linked to at least 10 molecules capable of recognising and capable of binding mannose-6-phosphate receptor are linked to said carrier molecule, with the proviso the compound is not a naturally occurring peptide with terminal mannose-6-phosphate residues, latent growth factor beta, thyroglobulin or lyosomal protein,   (b) a carrier molecule linked to at least one further molecule which is X*YRGDYX* wherein X* represents the location of cyclisation and Y represents at least one amino acid or a sequence of amino acids up to a length such that the target receptor binding capacity of the further molecule is retained,   (c) a carrier molecule linked to at least one further molecule wherein said further molecule is X*YKPTYX*, wherein X* represents the location of cyclisation and Y represents at least one amino acid or a sequence of amino acids up to a length such that the target receptor binding capacity of the further molecule is retained, and   (d) a carrier molecule linked to at least one further molecule wherein said at least one further molecule is X*RKKPX*, wherein X* represents the location of cyclisation.   
     
     
         28 . A compound according to  claim 27 , wherein the molecule capable of recognising and capable of binding to mannose-6-phosphate receptor is mannose-6-phosphate. 
     
     
         29 . A compound according to  claim 27 , wherein said further molecule is X*GRGDSPX*, wherein X* represents the location of cyclisation. 
     
     
         30 . A compound according to  claim 27 , wherein said further molecule is X*DKPTLX*, wherein X* represents the location of cyclisation. 
     
     
         31 . A compound according to  claim 27 , wherein X* is a cystein residue. 
     
     
         32 . A compound according to  claim 27 , wherein X* represents the location of cyclisation and attachment to the carrier molecule. 
     
     
         33 . A compound according to  claim 27 , wherein in the further molecule of (b)-(d), the cyclic portion of the cyclic peptide comprises multiple receptor binding sequences. 
     
     
         34 . A compound according to  claim 27 , wherein of the further molecule the cyclic portion of the cyclic peptide comprises multiple receptor binding sequences directed at least two different types of receptors. 
     
     
         35 . A compound according to  claim 27 , wherein the further molecule in (b)-(d) comprises multiple cyclic peptides directed at the same or different types of receptors. 
     
     
         36 . A compound according to  claim 27 , wherein the carrier molecule is selected from the group of carrier molecules consisting of proteins, oligo or polypeptides, immunoglobulins or parts thereof, oligonucleotides, disaccharides, polysaccharides, biodegradable synthetic polymers, liposomes, lipid particles, biocompatible polymers in the form of microspheres or nanoparticles, endogenous plasma proteins, lactoferrin, alkaline phosphatase, superoxide dismutase, alpha2 macroglobulin and fibronectin. 
     
     
         37 . A compound according to  claim 27 , wherein the carrier molecule comprises additional drugs or chemicals linked thereto. 
     
     
         38 . A compound according to  claim 27 , wherein the carrier molecule comprises a diagnostic marker attached thereto. 
     
     
         39 . A compound according to  claim 27 , wherein said compound is a targeting ingredient and is in combination with one or more pharmaceutically acceptable carriers. 
     
     
         40 . A method selected from the group consisting of:
 (a) a method comprising using a compound according to  claim 27  in vitro diagnosis of a sclerotic and/or fibrotic disease selected from the group consisting of liver fibrosis, kidney fibrosis, lung fibrosis, atherosclerosis and chronic or acute inflammatory processes Crohns disease, colitis ulcerosa, glomerulonephritis, sepsis and tumor-cell proliferation associated pathology, fibroblast proliferation associated pathology, endothelial cell proliferation associated pathology and osteoblast proliferation associated pathology;   (b) a method comprising using a compound according to  claim 27  for the preparation of a medicament for in vivo diagnosis, prophylaxis and/or therapy of a sclerotic and/or fibrotic disease selected from the group consisting of liver fibrosis, kidney fibrosis, lung fibrosis, atherosclerosis and chronic or acute inflammatory processes, Crohns disease, colitis ulcerosa, glomerulonephritis, sepsis and tumor-cell proliferation associated pathology, fibroblast proliferation associated pathology, endothelial cell proliferation associated pathology and osteoblast proliferation associated pathology.   
     
     
         41 . The method of  claim 40 , wherein said method is (a) a method for in vitro diagnosis of a sclerotic and/or fibrotic disease, said method comprising the steps of providing a tissue sample of a subject and administering a compound according to  claim 31  to said tissue sample, wherein said disease is selected from the group consisting of liver fibrosis, kidney fibrosis, lung fibrosis, atherosclerosis and chronic or acute inflammatory processes, Crohns disease, colitis ulcerosa, glomerulonephritis, sepsis and tumor-cell proliferation associated pathology, fibroblast proliferation associated pathology, endothelial cell proliferation associated pathology and osteoblast proliferation associated pathology.