Engineered polypeptides having enhanced duration of action and reduced immunogenicity
View Patent ↗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 (ABD) polypeptide and
a first peptide hormone domain (HD1) comprising a leptin, a leptin analog or an active fragment thereof,
wherein said ABD comprises
at least 95% indentity to SEQ ID:300,
with the proviso that X 7 is not L, E or D;
or alternatively,
with the proviso that the amino acid sequence is not (SEQ ID NO:679).
2. The engineered polypeptide according to claim 1 , further comprising a first linker (L1) covalently linked to said HD1.
3. The engineered polypeptide according to claim 1 , wherein said HD1 comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, 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:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:664, SEQ ID NO:665, SEQ ID NO:666, SEQ ID NO:667, SEQ ID NO:668, SEQ ID NO:669, SEQ ID NO:670, SEQ ID NO:671, SEQ ID NO:672, SEQ ID NO:673, SEQ ID NO:674, SEQ ID NO:675, SEQ ID NO:676, SEQ ID NO:677, and SEQ ID NO:680.
4. The engineered polypeptide according to claim 1 , wherein the ABD polypeptide is selected from any one of SEQ ID NO:301-452, 455-463, and 500-593.
5. The engineered polypeptide according to claim 1 , wherein said engineered polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 594 to 663 and 681.
6. The engineered polypeptide according to claim 1 , having affinity for serum albumin with a dissociation constant less than about 10 −6 mol/L.
7. A method for treating a disease or disorder in a subject, comprising administering an a engineered polypeptide according to claim 1 to a subject in need thereof in an amount effective to treat said disease or disorder.
8. The method according to claim 7 , wherein said disease or disorder is lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease, diabetes, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X or Huntington's Disease.
9. A pharmaceutical composition comprising an engineered polypeptide according to claim 1 and a pharmaceutically acceptable excipient.
10. An engineered polypeptide comprising an amino acid sequence of SEQ ID NO: 595.
11. A polynucleotide encoding an engineered polypeptide according to claim 1 .
12. An expression vector comprising a polynucleotide according to claim 11 .
13. A host cell comprising an expression vector according to claim 12 .
14. A method for preparing the engineered polypeptide of claim 1 , the method comprising expressing a polynucleotide encoding the engineered polypeptide or synthesizing the polypeptide by non-biological peptide synthesis.