Human 3 relaxin

Abstract

Human H3 preprorelaxin, human H3 prorelaxin, human H3 relaxin, human relaxin analogues having a modified A chain and/or a modified B chain are described. Also described are nucleic acid sequences encoded human H3 preprorelaxin, human H3 prorelaxin, human H3 relaxin, human relaxin analogues. Also described are methods for the treatment of conditions responsive to administration of H3 relaxin or analogues thereof.

1 . A method for the treatment of one or more of: vascular disease; arterial hypertension; diseases related to uncontrolled or abnormal collagen or fibronectin formation; kidney disease; psychiatric disorders; depression or depressive disorders; neurologic or neurodegenerative diseases; disorders of learning, attention and motivation; addictive disorders; movement and locomotor disorders; immunological disorders; breast disorders; endometrial disorders; endocrine disorders; delayed onset of labour, impaired cervical ripening, and prevention of prolonged labour due to fetal dystocia; sinus bradycardia; hair loss; alopecia; disorders of water balance including impaired or inappropriate secretion of vasopressin; or placental insufficiency; which comprises administering to a subject in need of any such treatments a therapeutically effective amount of human H3 relaxin, or an analogue thereof, optionally in association with one or more pharmaceutically acceptable carriers and/diluents and/or excipients. 
     
     
         2 . A method according to  claim 1 , wherein the H3 relaxin or analogue thereof is human H3 relaxin, human H3 prorelaxin, human H3 preprorelaxin, or the constitutive A, B or C peptide chains thereof. 
     
     
         3 . A method according to  claim 2 , wherein the human H3 relaxin or a human H3 relaxin analogue thereof comprises an A chain and a B chain, the A chain having the amino acid sequence set forth in SEQ ID NO:4: 
       
         
           
                 
                 
               
                   (SEQ ID NO: 4) 
                     
                 
                 
                 
               
                   Asp Val Leu Ala Gly Leu Ser Ser Ser Cys Cys Lys 
                     
                 
                   1               5                   10 
                 
                     
                 
                   Trp Gly Cys Ser Lys Ser Glu Ile Ser Ser Leu Cys 
                 
                           15                  20 
                 
             
                
               
            
             
                
                
                
                
                
               
            
           
         
       
       or an amino acid sequence truncated by up to about 9 amino acids from N-terminus, the B chain having the amino sequence set forth in SEQ ID NO:2: 
       
         
           
                 
                 
               
                   (SEQ ID NO: 2) 
                     
                 
                 
                 
               
                   Arg Ala Ala Pro Tyr Gly Val Arg Leu Cys Gly Arg 
                     
                 
                   1               5                   10 
                 
                     
                 
                   Glu Phe Ile Arg Ala Val Ile Phe Thr Cys Gly Gly 
                 
                           15                  20 
                 
                     
                 
                   Ser Arg Trp 
                 
                   25 
                 
             
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       or an amino acid sequence truncated by up to 9 amino acids from the amino-terminus and/or up to about 5 amino acids from the carboxyl-terminus, the A and B chains are linked by disulphide bonds between A11-B10 and A24-B22, and wherein the human H3 relaxin or analogue thereof has relaxin bioactivity. 
     
     
         4 . A method according to  claim 1  wherein a human H3 relaxin analogue comprises a modified A chain and/or a modified B chain, the H3 relaxin A chain having the amino acid sequence set forth in SEQ ID NO:4: 
       
         
           
                 
                 
               
                   (SEQ ID NO: 4) 
                     
                 
                 
                 
               
                   Asp Val Leu Ala Gly Leu Ser Ser Ser Cys Cys Lys 
                     
                 
                   1               5                   10 
                 
                     
                 
                   Trp Gly Cys Ser Lys Ser Glu Ile Ser Ser Leu Cys 
                 
                           15                  20 
                 
             
                
               
            
             
                
                
                
                
                
               
            
           
         
       
       wherein the carboxyl-terminus is an amide derivative and/or Lys at position 12 is replaced with Glu, and/or Glu at position 19 is replaced with Gln, the H3 relaxin B chain having the amino acid sequence set forth in SEQ ID NO:2: 
       
         
           
                 
                 
               
                   (SEQ ID NO: 2) 
                     
                 
                 
                 
               
                   Arg Ala Ala Pro Tyr Gly Val Arg Leu Cys Gly Arg 
                     
                 
                   1               5                   10 
                 
                     
                 
                   Glu Phe Ile Arg Ala Val Ile Phe Thr Cys Gly Gly 
                 
                           15                  20 
                 
                     
                 
                   Ser Arg Trp 
                 
                   25 
                 
             
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein the carboxyl-terminus is an amide derivative, and/or Ala at position 2 is replaced with Pro, and/or Arg at position 8 is replaced with Lys, the A and B chains being linked by disulphide bonds between A11-B10 and A24-B22, and wherein the human H3 relaxin analogue has relaxin bioactivity. 
     
     
         5 . A method according to  claim 1 , which is a method for the treatment of arterial hypertension. 
     
     
         6 . A method according to  claim 1 , which is a method for the treatment of peripheral vascular disease including coronary artery disease, peripheral vascular disease, vasospasm including Raynaud's phenomenon, microvascular disease involving the central and peripheral nervous system, kidney, eye and other organs. 
     
     
         7 . A method according to  claim 1 , which is a method for the treatment of kidney disease including vascular disease, interstitial fibrosis, glomerulosclerosis, or other kidney disorders. 
     
     
         8 . A method according to  claim 1 , which is a method for the treatment of diseases related to uncontrolled or abnormal collagen or fibronectin formation including fibrosis of lung, heart and cardiovascular system, kidney and genitourinary tract, gastrointestinal system, cutaneous, rheumatologic and hepatobiliary systems.