Engineered polypeptides having enhanced duration of action
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. An engineered polypeptide comprising: an albumin binding domain polypeptide (ABD) having the sequence of SEQ ID NO: 114, a first peptide hormone domain (HD1) having the sequence of SEQ ID NO: 20, and a linker L1 having the sequence of SEQ ID NO: 215.
2. The engineered polypeptide according to claim 1 , wherein the ABD is located N-terminal to the HD1.
3. The engineered polypeptide according to claim 1 , wherein the HD1 is located N-terminal to the ABD.
4. 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.
5. The method according to claim 4 , wherein said disease or disorder is disease or disorder can be 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.
6. A pharmaceutical composition comprising an engineered polypeptide according to claim 1 and a pharmaceutically acceptable excipient.
7. A method of treating obesity in a subject in need thereof comprising peripherally administering therapeutically effective amounts of at least two different anti-obesity agents, wherein at least one anti-obesity agent is an amylin, an amylin analog, an amylin agonist, or an amylin derivative; and at least one anti-obesity agent is the engineered polypeptide of claim 1 .
8. A method of reducing body weight in a subject in need thereof comprising peripherally administering therapeutically effective amounts of at least two different anti-obesity agents, wherein at least one anti-obesity agent is an amylin, an amylin analog, an amylin agonist, or an amylin derivative; and at least one anti-obesity agent is the engineered polypeptide of claim 1 .