Engineered polypeptides having enhanced duration of action

Abstract

Compounds are provided having inter alia good duration of action, high potency and/or convenient dosing regimens including oral administration. The compounds are engineered polypeptides which incorporate an albumin binding domain in combination with one or more biologically active polypeptides. Also provided are pharmaceutical compositions and methods of treatment for diseases and disorders including obesity and overweight, diabetes, dyslipidemia, hyperlipidemia, Alzheimer's disease, fatty liver disease, short bowel syndrome, Parkinson's disease, cardiovascular disease, and other and disorders of the central nervous system.

What is claimed is: 
     
         1 . An engineered polypeptide comprising: an albumin binding domain polypeptide (ABD) sequence, and a first peptide hormone domain (HD1) sequence selected from an exendin sequence, an exendin analog sequence, an exendin active fragment sequence or an exendin analog active fragment sequence. 
     
     
         2 . The engineered polypeptide according to  claim 1 , further comprising a first linker (L1) covalently linking said ABD sequence and said HD1 sequence. 
     
     
         3 . The engineered polypeptide according to  claim 1 , wherein said engineered polypeptide comprises said ABD sequence as a C-terminal moiety and said HD1 sequence as an N-terminal moiety. 
     
     
         4 . The engineered polypeptide according to  claim 1 , wherein said HD1 sequence consists of said exendin sequence or said exendin analog sequence. 
     
     
         5 . The engineered polypeptide according to  claim 4 , wherein said exendin sequence is exendin-4 sequence. 
     
     
         6 . The engineered polypeptide according to  claim 4 , wherein said exendin active fragment sequence is the sequence of exendin-4(1-28), exendin-4(1-29), exendin-4(1-30), exendin-4(1-31) or exendin-4(1-32) (SEQ ID NO:2). 
     
     
         7 . The engineered polypeptide according to  claim 1 , wherein said ABD sequence comprises an albumin binding motif (ABM) sequence. 
     
     
         8 . The engineered polypeptide according to  claim 1 , wherein said ABD sequence comprises an albumin binding motif (ABM) sequence that consists of amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 119) 
                 
                     
                   GVSD X 5  YK X 8  X 9  I X 11  X 12  A X 14  TVEGV X 20  AL 
                 
                     
                   X 23  X 24  X 25  I 
                 
             
                
                
                
               
            
           
         
       
       wherein,
 X 5  is selected from Y and F; 
 X 8  is selected from N, R and S; 
 X 9  is selected from V, I, L, M, F and Y; 
 X 11  is selected from N, S, E and D; 
 X 12  is selected from R, K and N; 
 X 14  is selected from K and R; 
 X 20  is selected from D, N, Q, E, H, S, R and K; 
 X 23  is selected from K, I and T; 
 X 24  is selected from A, S, T, G, H, L and D; and 
 X 25  is selected from H, E and D. 
 
     
     
         9 . The engineered polypeptide according to  claim 1 , wherein said ABD sequence comprises an albumin binding motif (ABM) sequence that does not consist of the amino acid sequence GVSDYYKNLINNAKTVEGVKALIDEI (SEQ ID NO:120). 
     
     
         10 . The engineered polypeptide according to  claim 1 , wherein said ABD sequence comprises the amino acid sequence:
 LAEAK X a  X b  A X, X d  EL X e  KY (SEQ ID NO:182) covalently linked to an albumin binding motif (ABM) sequence which is further covalently linked to amino acid sequence LAALP (SEQ ID NO:183),   
       wherein
 X a  is selected from V and E; 
 X b  is selected from L, E and D; 
 X c  is selected from N, L and I; 
 X d  is selected from R and K; and 
 X e  is selected from D and K. 
 
     
     
         11 . The engineered polypeptide according to  claim 1 , wherein said ABD sequence has at least 85% identity with the sequence of an ABD selected from the group consisting of (SEQ ID NO:23), (SEQ ID NO:24), (SEQ ID NO:25), (SEQ ID NO:26), (SEQ ID NO:27), (SEQ ID NO:28), (SEQ ID NO:29), (SEQ ID NO:30), (SEQ ID NO:31), (SEQ ID NO:32), (SEQ ID NO:33), (SEQ ID NO:34), (SEQ ID NO:35), (SEQ ID NO:122), (SEQ ID NO:123) and (SEQ ID NO:124). 
     
     
         12 . The engineered polypeptide according to  claim 2 , wherein said linker L1 is a peptide linker of from 1 to 30 amino acids. 
     
     
         13 . The engineered polypeptide according to  claim 2 , wherein said linker L1 comprises the sequence (Gly) 3 , (Gly) 4  (SEQ ID NO:196), or (Gly) 5  (SEQ ID NO:197). 
     
     
         14 . The engineered polypeptide according to  claim 2 , wherein said linker L1 comprises the sequence (Gly) 3 Lys(Gly) 4  (SEQ ID NO:131); (Gly) 3 AsnGlySer(Gly) 2  (SEQ ID NO:132); (Gly) 3 Cys(Gly) 4  (SEQ ID NO:133); or GlyProAsnGlyGly (SEQ ID NO:134). 
     
     
         15 . The engineered polypeptide according to  claim 2 , wherein said linker L1 comprises an N-terminal TG dipeptide. 
     
     
         16 . The engineered polypeptide according to  claim 2 , wherein said linker L1 comprises a C-terminal AS dipeptide. 
     
     
         17 . The engineered polypeptide according to  claim 2 , wherein said linker L1 comprises a sequence selected from the group consisting of TG-(GGGS) 1  (SEQ ID NO:198), TG-(GGGS) 2  (SEQ ID NO:199), TG-(GGGS) 3  (SEQ ID NO:200), TG-(GGGS) 4  (SEQ ID NO:201), TG-(GGGS) 5  (SEQ ID NO:202), (GGGS) 1 -AS (SEQ ID NO:203), (GGGS) 2 -AS (SEQ ID NO:204), (GGGS) 3 -AS (SEQ ID NO:205), (GGGS) 4 -AS (SEQ ID NO:206), (GGGS) 5 -AS (SEQ ID NO:207), TG-(GGGS) 1 -AS (SEQ ID NO:208), TG-(GGGS) 2 -AS (SEQ ID NO:209), TG-(GGGS) 3 -AS (SEQ ID NO:210), TG-(GGGS) 4 -AS (SEQ ID NO:211), and TG-(GGGS) 5 -AS (SEQ ID NO:212). 
     
     
         18 . The engineered polypeptide of  claim 1  comprising (SEQ ID NO:40), (SEQ ID NO:41), (SEQ ID NO:42), (SEQ ID NO:43), (SEQ ID NO:51), (SEQ ID NO:163), (SEQ ID NO:99), (SEQ ID NO:169), (SEQ ID NO:170), (SEQ ID NO: 95), (SEQ ID NO: 97), (SEQ ID NO: 96), (SEQ ID NO:55), (SEQ ID NO:53), (SEQ ID NO:62), (SEQ ID NO:67), (SEQ ID NO:166), (SEQ ID NO:167), (SEQ ID NO:51), (SEQ ID NO:52), (SEQ ID NO:53), (SEQ ID NO:54), (SEQ ID NO:55), (SEQ ID NO:56), (SEQ ID NO:57), (SEQ ID NO:58), (SEQ ID NO:59), (SEQ ID NO:60), (SEQ ID NO:61), (SEQ ID NO:62), (SEQ ID NO:63), (SEQ ID NO:64), (SEQ ID NO:65), (SEQ ID NO:66), (SEQ ID NO:67), (SEQ ID NO:68), (SEQ ID NO:70), (SEQ ID NO:71), (SEQ ID NO:72), (SEQ ID NO:73), (SEQ ID NO:74), (SEQ ID NO:75), (SEQ ID NO:76), (SEQ ID NO:77), (SEQ ID NO:78), (SEQ ID NO:79), (SEQ ID NO:80), (SEQ ID NO:81), (SEQ ID NO:82), (SEQ ID NO:83), (SEQ ID NO:84), (SEQ ID NO:85), (SEQ ID NO:86), (SEQ ID NO:87), (SEQ ID NO:88), (SEQ ID NO:89), (SEQ ID NO:90), (SEQ ID NO:91), (SEQ ID NO:92), (SEQ ID NO:93), (SEQ ID NO:94), (SEQ ID NO:95), (SEQ ID NO:96), (SEQ ID NO:97), (SEQ ID NO:98), (SEQ ID NO:99), (SEQ ID NO:100) (SEQ ID NO:101), (SEQ ID NO:102), (SEQ ID NO:103), (SEQ ID NO:104), (SEQ ID NO:105), (SEQ ID NO:106), (SEQ ID NO:107), (SEQ ID NO:108) or (SEQ ID NO:109). 
     
     
         19 . A method for treating a disease or disorder in a subject, comprising administering a engineered polypeptide according to  claim 1  to a subject in need thereof in an amount effective to treat said disease or disorder, wherein said disease or disorder is diabetes, overweight, obesity, Alzheimer's disease, short bowel syndrome, fatty liver disease, dyslipidemia, coronary artery disease, stroke, hyperlipidemia or Parkinson's disease. 
     
     
         20 . A pharmaceutical composition comprising an engineered polypeptide according to  claim 1  and a pharmaceutically acceptable excipient.