US2013203661A1PendingUtilityA1

Highly soluble leptins

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Assignee: AMYLIN PHARMACEUTICALS LLCPriority: Sep 28, 2010Filed: Mar 28, 2013Published: Aug 8, 2013
Est. expirySep 28, 2030(~4.2 yrs left)· nominal 20-yr term from priority
Inventors:Mary Erickson
A61P 3/06A61P 43/00A61P 3/10A61P 3/00A61P 3/04A61P 25/14A61P 25/28A61P 1/16A61P 15/08A61P 15/00A61P 1/18A61K 38/2264C07K 2319/33A61K 38/00C07K 14/5759C07K 14/00C07K 14/575
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Claims

Abstract

The disclosure provides chimeric polypeptides and nucleic acid molecules encoding chimeric 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.

Claims

exact text as granted — not AI-modified
1 . A chimeric polypeptide comprising a wild type seal leptin polypeptide wherein at least one contiguous region of 1-30 amino acids of a wild type seal leptin sequence has been replaced with a contiguous region of 1-30 amino acids of a mature human leptin sequence. 
     
     
         2 . The chimeric polypeptide of  claim 1 , wherein two or more contiguous regions of 1-30 amino acids of a wild type seal leptin sequence have been replaced at each region with a contiguous region of 1-30 amino acids of a mature human leptin sequence. 
     
     
         3 . The chimeric polypeptide of  claim 1 , wherein a wild type seal leptin sequence comprises the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:31. 
     
     
         4 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51. 
     
     
         5 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least one amino acid substitution at a position where divergence is observed in a corresponding position in a leptin from another species. 
     
     
         6 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least two amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         7 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least three amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         8 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least four amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         9 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least five amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         10 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least six amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         11 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least seven amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         12 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least eight amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         13 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least nine amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         14 . The chimeric polypeptide of  claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12, SEQ ID NO:13, 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:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, wherein the mature human leptin sequence has at least ten amino acid substitutions at positions where divergence is observed in corresponding positions in a leptin from another species. 
     
     
         15 . The chimeric polypeptide of  claim 1 , wherein the mature human leptin sequence comprises the amino acid sequence of SEQ ID NO:24. 
     
     
         16 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises an amino acid sequence with at least 80% identity with an amino acid sequence selected from the group consisting of: SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, 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:69, 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, ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, and SEQ ID NO:85. 
     
     
         17 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises an amino acid sequence with at least 80% identity with an amino acid sequence selected from the group consisting of: SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33. 
     
     
         18 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises an amino acid sequence with at least 80% identity the amino acid sequence of SEQ ID NO:33. 
     
     
         19 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises an amino acid sequence with at least 90% identity the amino acid sequence of SEQ ID NO:33. 
     
     
         20 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, 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:69, 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, ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, and SEQ ID NO:85. 
     
     
         21 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33. 
     
     
         22 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises the amino acid sequence of SEQ ID NO:29. 
     
     
         23 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises the amino acid sequence of SEQ ID NO:30. 
     
     
         24 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises the amino acid sequence of SEQ ID NO:32. 
     
     
         25 . The chimeric polypeptide of  claim 1 , wherein the chimeric polypeptide comprises the amino acid sequence of SEQ ID NO:33. 
     
     
         26 . A method for treating a disease or disorder in a subject, comprising administering a chimeric polypeptide of  claim 1  to a subject in need thereof in an amount effective to treat said disease or disorder. 
     
     
         27 . The method according to  claim 26 , wherein the disease or disorder is 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 (including type I and type II), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X and Huntington's Disease. 
     
     
         28 . The method of  claim 27 , wherein the disease or disorder is lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease or diabetes. 
     
     
         29 . The method of  claim 26 , wherein the disease or disorder is type I diabetes or type II diabetes. 
     
     
         30 . The method of  claim 26 , wherein the disease or disorder is obesity. 
     
     
         31 . The method of  claim 26 , wherein the disease or disorder is lipodystrophy or leptin deficiency. 
     
     
         32 . A pharmaceutical composition comprising a chimeric polypeptide according to  claim 1  and a pharmaceutically acceptable excipient.

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