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 once weekly 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 lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease or diabetes (including type I and type II). Additional diseases and disorders which can be treated by the compounds and methods described herein include nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X and Huntington's Disease.

1 - 32 . (canceled) 
     
     
         33 . An engineered polypeptide, comprising:
 (i) an albumin binding domain polypeptide (ABD), wherein the ABD comprises an albumin binding motif (ABM) that consists of the amino acid sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 34) 
                 
                   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, independently of each other, 
         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, Rand K; 
         X 23  is selected from K, I and T; 
         X 24  is selected from A, S, T, G, H, Land D; and 
         X 25  is selected from H, E and D; and 
         (ii) a first peptide hormone domain (HD1) selected from a leptin, a leptin analog or an active fragment thereof. 
       
     
     
         34 . The engineered polypeptide of  claim 33 , wherein the HD1 domain comprises the sequence of SEQ ID NO: 20. 
     
     
         35 . The engineered polypeptide of  claim 33 , wherein the HD1 domain comprises a sequence that is at least 95% identical to SEQ ID NO: 20. 
     
     
         36 . The engineered polypeptide of  claim 33 , wherein the HD1 domain has a sequence selected from the group consisting of SEQ ID NOS: 1-33 and 143-146. 
     
     
         37 . The engineered polypeptide of  claim 33 , having a sequence selected from any one of SEQ ID NOS: 53-64, 67-69, 76, and 104-107. 
     
     
         38 . The engineered polypeptide of  claim 33 , wherein the ABD is N-terminal to the HD1. 
     
     
         39 . The engineered polypeptide of  claim 33 , wherein the ABD is C-terminal to the HD1. 
     
     
         40 . The engineered polypeptide of  claim 33 , wherein the ABM comprises the amino acid sequence of SEQ ID NO: 114 or SEQ ID NO: 115. 
     
     
         41 . The engineered polypeptide of  claim 33 , further comprising a linker, wherein the linker is a polypeptide. 
     
     
         42 . A method for treating a disease or a disorder in a subject comprising administering the engineered polypeptide of  claim 33  to a subject in need thereof. 
     
     
         43 . The method of  claim 42 , wherein the disease or disorder is selected from the group consisting of: lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease, diabetes, type I diabetes, type II diabetes, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X, and Huntington's Disease. 
     
     
         44 . A pharmaceutical composition comprising the engineered polypeptide of  claim 33  and a pharmaceutically acceptable excipient. 
     
     
         45 . A method for treating obesity in a subject in need thereof comprising administering the engineered polypeptide of  claim 33 . 
     
     
         46 . The method of  claim 45 , further comprising administering an anti-obesity agent, wherein the anti-obesity agent is not the engineered polypeptide of  claim 33 . 
     
     
         47 . A method of reducing body weight in a subject in need thereof comprising administering the engineered polypeptide of  claim 33 . 
     
     
         48 . The method of  claim 47  comprising administering an anti-obesity agent, wherein the anti-obesity agent is not the engineered polypeptide of  claim 33 .