Polypeptides and uses thereof

Abstract

The present invention provides polypeptides comprising or consisting of an amino acid sequence derived from a naturally occurring protein which modulates blood coagulation, or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof, for use in the treatment or prevention of inflammation and/or excessive coagulation of the blood. Related aspects of the invention provide isolated polypeptides comprising or consisting of an amino acid sequence of SEQ ID NOs: 1 to 11, or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof which exhibit an anti-inflammatory and/or anti-coagulant activity, together with isolated nucleic acid molecules, vectors and host cells for making the same. Additionally provided are pharmaceutical compositions comprising a polypeptide of the invention, as well as methods of use of the same in the treatment and/or prevention of inflammation and/or excessive coagulation.

1 . A method for treating or preventing inflammation and/or excessive coagulation of the blood in a patient, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising an amino acid sequence derived from a tissue factor pathway inhibitor (TFPI), or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof,
 wherein the tissue factor pathway inhibitor is selected from the group consisting of TFPI-1 and TFPI-2, and   wherein the fragment, variant, fusion or derivative exhibits an anti-inflammatory and/or anti-coagulant activity.   
     
     
         2 - 14 . (canceled) 
     
     
         15 . The method according to  claim 1 , wherein the tissue factor pathway inhibitor is TFPI-1. 
     
     
         16 . The method according to  claim 15 , wherein the TFPI-1 is Swiss Port Accession No. P10646. 
     
     
         17 . The method according to  claim 1  wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:4: 
       
         
           
                 
                 
               
                     
                   “GGL27”: 
                 
                     
                   [SEQ ID NO: 4] 
                 
                     
                   GGLIKTKRKRKKQRVKIAYEEIFVKNM 
                 
             
                
                
                
               
            
           
         
       
       or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof, which retains an anti-inflammatory and/or anti-coagulant activity of SEQ ID NO:4. 
     
     
         18 . The method according to  claim 17 , wherein the polypeptide consists of the amino acid sequence of SEQ ID NO:4. 
     
     
         19 . The method according to  claim 1 , wherein the tissue factor pathway inhibitor is TFPI-2. 
     
     
         20 . The method according to  claim 19  wherein the TFPI-2 is Swiss Port Accession No. P48307. 
     
     
         21 . The method according to  claim 19 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:8: 
       
         
           
                 
                 
               
                     
                   “EDC34”: 
                 
                     
                   [SEQ ID NO: 8] 
                 
                     
                   EDCKRACAKALKKKKKMPKLRFASRIRKIRKKQF 
                 
             
                
                
                
               
            
           
         
       
       or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof, which retains an anti-inflammatory and/or anti-coagulant activity of SEQ ID NO:8. 
     
     
         22 . The method according to  claim 21 , wherein the polypeptide consists of the amino acid sequence of SEQ ID NO:8. 
     
     
         23 - 48 . (canceled) 
     
     
         49 . The method according to  claim 1 , wherein said inflammation and/or or excessive coagulation of the blood in a patient is associated with a disease, condition or indication selected from the following:
 i) Acute systemic inflammatory disease, with or without an infective component, such as systemic inflammatory response syndrome (SIRS), ARDS, sepsis, severe sepsis, and septic shock. Other generalized or localized invasive infective and inflammatory disease, including erysipelas, meningitis, arthritis, toxic shock syndrome, diverticulitis, appendicitis, pancreatitis, cholecystitis, colitis, cellulitis, burn wound infections, pneumonia, urinary tract infections, postoperative infections, and peritonitis;   ii) Chronic inflammatory and or infective diseases, including cystic fibrosis, COPD and other pulmonary diseases, gastrointestinal disease including chronic skin and stomach ulcerations, other epithelial inflammatory and or infective disease such as atopic dermatitis, oral ulcerations (aphtous ulcers), genital ulcerations and inflammatory changes, parodontitis, eye inflammations including conjunctivitis and keratitis, external otitis, mediaotitis, genitourinary inflammations;   iii) Postoperative inflammation. Inflammatory and coagulative disorders including thrombosis, DIC, postoperative coagulation disorders, and coagulative disorders related to contact with foreign material, including extracorporeal circulation, and use of biomaterials. Furthermore, vasculitis related inflammatory disease, as well as allergy, including allergic rhinitis and asthma;   iv) Excessive contact activation and/or coagulation in relation to, but not limited to, stroke; or   v) Excessive inflammation in combination with antimicrobial treatment.   
     
     
         50 - 55 . (canceled) 
     
     
         56 . An isolated polypeptide comprising an amino acid sequence derived from a tissue factor pathway inhibitor (TFPI), or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof, which polypeptide exhibits an anti-inflammatory and/or anti-coagulant activity,
 wherein the tissue factor pathway inhibitor is selected from the group consisting of TFPI-1 and TFPI 2,   with the proviso that the polypeptide is not a naturally occurring protein.   
     
     
         57 - 70 . (canceled) 
     
     
         71 . The polypeptide according to  claim 56 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:4: 
       
         
           
                 
                 
               
                     
                   “GGL27”: 
                 
                     
                   [SEQ ID NO: 4] 
                 
                     
                   GGLIKTKRKRKKQRVKIAYEEIFVKNM 
                 
             
                
                
                
               
            
           
         
       
       or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof, which retains an anti-inflammatory and/or anti-coagulant activity of SEQ ID NO:4. 
     
     
         72 . The polypeptide according to  claim 71 , wherein the polypeptide consists of the amino acid sequence of SEQ ID NO:4. 
     
     
         73 - 74 . (canceled) 
     
     
         75 . The polypeptide according to  claim 56 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:8: 
       
         
           
                 
                 
               
                     
                   “EDC34”: 
                 
                     
                   [SEQ ID NO: 8] 
                 
                     
                   EDCKRACAKALKKKKKMPKLRFASRIRKIRKKQF 
                 
             
                
                
                
               
            
           
         
       
       or a fragment, variant, fusion or derivative thereof, or a fusion of said fragment, variant or derivative thereof, which retains an anti-inflammatory and/or anti-coagulant activity of SEQ ID NO:8. 
     
     
         76 . The polypeptide according to  claim 75 , wherein the polypeptide consists of the amino acid sequence of SEQ ID NO:8. 
     
     
         77 - 102 . (canceled) 
     
     
         103 . A pharmaceutical composition comprising a polypeptide according to  claim 56  together with a pharmaceutically acceptable excipient, diluent, carrier, buffer or adjuvant. 
     
     
         104 . The pharmaceutical composition according to  claim 103 , wherein said composition is suitable for administration via a route selected from the group consisting of topical, ocular, nasal, pulmonar, buccal, parenteral (intravenous, subcutaneous, intrathecal and intramuscular), oral, vaginal and rectal. 
     
     
         105 . The pharmaceutical composition according to  claim 103 , wherein said composition is suitable for administration via an implant. 
     
     
         106 . The pharmaceutical composition according to  claim 103 , wherein the pharmaceutical composition is associated with a device or material to be used in medicine. 
     
     
         107 . (canceled) 
     
     
         108 . The pharmaceutical composition according to  claim 103 , wherein the pharmaceutical composition is coated, painted, sprayed or otherwise applied to a suture, prosthesis, implant, wound dressing, catheter, lens, skin graft, skin substitute, fibrin glue or bandage. 
     
     
         109 - 137 . (canceled)