Amylin Family Peptides And Methods For Making And Using Them

• US 20080274952A1
• Filed: 02/11/2005
• Published: 11/06/2008
• Est. Priority Date: 02/11/2004
• Status: Active Grant

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Ghosh, Soumitra, Hanley, Michael R., Lin, Qing, Prickett, Kathryn S., Mack, Christine Marie, Jodka, Carolyn Marie, Parkes, David Geoffrey, Lewis, Diana Yvonne, Soares, Christopher J
• Granted Patent: US 8,114,958 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/22 for decreasing, blocking or antagonising the activity of calcitonin
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

Abstract

The present invention relates to obesity related polypeptides (ORPs), related nucleic acids, expression constructs, host cells, and processes production of the obesity related polypeptides. The ORPs of the invention include one or more amino acid sequence modifications. In addition, methods and compositions are disclosed to treat and prevent metabolic disorders such as obesity, diabetes, and increased cardiovascular risk.

Claims

1. An amylin family peptide, said peptide comprising:

a loop region of amylin, calcitonin, or an analog of amylin or calcitonin, wherein said loop region is at the N-terminal end of said peptide;

an α

helix region of a) at least a portion of a calcitonin α

helix region or an analog thereof or b) a combination of at least a portion of a calcitonin α

helix region or an analog thereof and at least a portion of an amylin α

helix region or an analog thereof; and

a C-terminal tail of amylin, calcitonin, or an analog of amylin or calcitonin;

with the proviso that when the loop region is from a calcitonin or a calcitonin analog and the α

helix region is from a calcitonin or a calcitonin analog, the last position of the C-terminal tail is not proline, hydroxyproline, homoserine or derivative of homoserine.

2. The peptide of claim 1 wherein said amylin is a human amylin or an analog thereof.

3. The peptide of claim 1 wherein said calcitonin is a salmon calcitonin.

4. The peptide of claim 2 wherein said calcitonin is salmon calcitonin.

5. The peptide of claim 1 comprising an amino acid sequence of formula I:

6. The peptide of claim 5 wherein said intramolecular linkage of X and Y is a disulfide, an amide, an imine, an amine, an alkyl, an alkene, an alkynyl, an alkenyl, an ether or a thioether bond.

7. The peptide of claim 5 further comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, modifications of substitutions, insertions, deletions, elongations and/or derivatizations.

8. The peptide of claim 1 comprising an amino acid sequence of formula II:

Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 Xaa27 Xaa28 Xaa29 Xaa30 Xaa31 Xaa32 (SEQ ID NO;

35)

wherein

Xaa1 is A, C, D, F, I, K, S, T, or absent;

Xaa2 is C, D, S, or absent;

Xaa3 is A, D, N, or absent;

Xaa4 is A, L, T, or absent;

Xaa5 is A or S;

Xaa6 is T, A, S, or V;

Xaa7 is C, K, or A;

Xaa8 is A, V, L, or M;

Xaa9 is L or T;

Xaa10 is G, H, or Q;

Xaa11 is K, R, Q, or hArg;

Xaa12 is L, W, or Y;

Xaa13 is A, F, N, Q, S, or T;

Xaa14 is A, D, E, G, N, K, Q, or R;

Xaa15 is A, D, E, F, L, S, or Y;

Xaa16 is L, or F;

Xaa17 is H, Q, S, or V;

Xaa18 is K, R, hArg, u (Cit), or n (Orn);

Xaa19 is F, L, S, or absent;

Xaa20 is H, Q, or absent;

Xaa21 is T, N, or absent;

Xaa22 is F, L, M, V, or Y;

Xaa23 is P;

Xaa24 is P or R;

Xaa25 is T;

Xaa26 is N;

Xaa27 is T or V;

Xaa28 is G;

Xaa29 is S;

Xaa30 is E, G, K, or N;

Xaa31 is A or T; and

Xaa32 is F, P, or Y.

9. The peptide of claim 8 further comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, modifications of substitutions, insertions, deletions, elongations and/or derivatizations.

10. The peptide of claim 1 comprising an amino acid sequence of formula III:

Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 Xaa27 Xaa28 Xaa29 Xaa30 Xaa31 Xaa32, (SEQ ID NO;

36)

wherein

Xaa1 is A, C, F, I, K, S, or absent;

Xaa2 is C, D, or S;

Xaa3 is A, D or N;

Xaa4 is A, L or T;

Xaa5 is A or S;

Xaa6 is T;

Xaa7 is C or K;

Xaa8 is A or V;

Xaa9 is L or T;

Xaa10 is G, H, or Q;

Xaa11 is K, R, or hArg;

Xaa12 is L;

Xaa13 is A, F, N, S, or T;

Xaa14 is A, D, E, G, N, Q, or R;

Xaa15 is A, E, F, L, S, or Y;

Xaa16 is L;

Xaa17 is H, S, or V;

Xaa18 is K, R, hArg, u (Cit), or n (Orn);

Xaa19 is F, L, or S;

Xaa20 is H or Q;

Xaa21 is T or N;

Xaa22 is F, L, M, V, or Y;

Xaa23 is P;

Xaa24 is P or R;

Xaa25 is T;

Xaa26 is N;

Xaa27 is T, or V;

Xaa28 is G;

Xaa29 is S;

Xaa30 is E, G, K, or N;

Xaa31 is A, or T; and

Xaa32 is F, P, or Y.

14. A method of treating eating disorders, insulin-resistance, obesity, abnormal postprandial hyperglycemia, diabetes of any kind, including Type I, Type II, and gestational diabetes, Metabolic Syndrome, Dumping Syndrome, hypertension, dyslipidemia, cardiovascular disease, hyperlipidemia, sleep apnea, cancer, pulmonary hypertension, cholecystitis, and osteoarthritis comprising administering to a subject in need thereof an effective amount of a peptide of claim 1.

15. A method of treating eating disorders, insulin-resistance, obesity, abnormal postprandial hyperglycemia, diabetes of any kind, including Type I, Type II, and gestational diabetes, Metabolic Syndrome, Dumping Syndrome, hypertension, dyslipidemia, cardiovascular disease, hyperlipidemia, sleep apnea, cancer, pulmonary hypertension, cholecystitis, and osteoarthritis comprising administering to a subject in need thereof an effective amount of a peptide of claim 5.

16. A method of treating eating disorders, insulin-resistance, obesity, abnormal postprandial hyperglycemia, diabetes of any kind, including Type I, Type II, and gestational diabetes, Metabolic Syndrome, Dumping Syndrome, hypertension, dyslipidemia, cardiovascular disease, hyperlipidemia, sleep apnea, cancer, pulmonary hypertension, cholecystitis, and osteoarthritis comprising administering to a subject in need thereof an effective amount of a peptide of claim 8.

18. The peptide of claim 1 wherein

the loop region comprises an amino acid sequence of

19. The peptide of claim 1 wherein

the loop region comprises an amino acid sequence of

11. The peptide of claim 11 further comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, modifications of substitutions, insertions, deletions, elongations and/or derivatizations.

12. An amylin family peptide, said peptide comprising a sequence of any one of SEQ ID NO:

40 to SEQ ID NO;

137.

13. The peptide of claim 12 wherein said peptide has at least 95% sequence identify to any one of SEQ ID NO:

40 to SEQ ID NO;

137.

17. A method of treating eating disorders, insulin-resistance, obesity, abnormal postprandial hyperglycemia, diabetes of any kind, including Type I, Type II, and gestational diabetes, Metabolic Syndrome, Dumping Syndrome, hypertension, dyslipidemia, cardiovascular disease, hyperlipidemia, sleep apnea, cancer, pulmonary hypertension, cholecystitis, and osteoarthritis comprising administering to a subject in need thereof an effective amount of a peptide of claim 12.