Long lasting insulinotropic peptides

• US 6,593,295 B2
• Filed: 06/06/2001
• Issued: 07/15/2003
• Est. Priority Date: 05/17/1999
• Status: Expired due to Fees

• Current Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Original Assignee: ConjuChem, Inc. (Colabor Group, Inc.)
• Inventors: Bridon, Dominique P., Ezrin, Alan M., St. Pierre, Serge, Leblanc, Anouk, Holmes, Darren L., LʼArcheveque, Benoit
• Primary Examiner(s): Horlick, Kenneth R.
• Assistant Examiner(s): STRZELECKA, TERESA E
• Application Number:
  US09/876,388
• Publication Number:
  US 20020049153A1
• Time in Patent Office: 769 Days
• Field of Search: 514/2, 514/12
• US Class Current: 514/6.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C12N 2740/16122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Abstract

Modified insulinotropic peptides are disclosed. The modified insulinotropic peptides are capable of forming a peptidase stabilized insulinotropic peptide. The modified insulinotropic peptides are capable of forming covalent bonds with one or more blood components to form a conjugate. The conjugates may be formed in vivo or ex vivo. The modified peptides are administered to treat humans with diabetes and other related diseases.

Claims

1. A modified insulinotropic peptide comprising an insulinotropic peptide provided with a maleimide group which reacts with thiol groups on blood components to form a stable covalent bond.

2. A modified peptide as claimed in claim 1 wherein the insulinotropic peptide is selected from the group consisting of GLP-1, exendin-3, exendin-4, or a derivative thereof.

3. A modified insulinotropic peptide as claimed in claim 1, wherein the peptide is GLP-1 or a derivative thereof.

4. A modified insulinotropic peptide as claimed in claim 1, selected from the group consisting of GLP-1(1-36)-Lys³⁷(ε

-(AEEA)_n-MPA)-NH₂;

GLP-1 (7-36)-Lys³⁷ (ε

-(AEEA)_nMPA)-NH₂;

exendin-4 (1-39)-Lys40 (ε

-(AEEA)_n-MPA)-NH₂;

exendin-3 (1-39)-Lys⁴⁰ (ε

-(AEEA)_n-MPA)-NH₂;

exendin-4 (1-39)-Lys40 (ε

-(AEEA)_n-MPA)-NH₂;

Lys²⁶ ε

-(AEEA)_n-MPA GLP-1 (7-36)-NH₂;

GLP-1 (7-36)-EDA-MPA; and

exendin 4 (1-39)-EDA-MPA, wherein n=0-2.

5. A modified insulinotropic peptide as claimed in claim 4, selected from the group consisting of GLP-1 (1-36)-Lys³⁷(ε

-MPA)-NH₂, GLP-1 (1-36)-Lys³⁷(ε

-AEEA-AEEA-MPA)-NH₂, GLP-1 (7-36)-Lys³⁷ (ε

-MPA)-NH₂, GLP-1 (7-36)-Lys³⁷ (ε

-AEEA-AEEA-MPA)-NH₂exendin-4 (1-39)-Lys⁴⁰ (ε

-MPA)-NH₂, exendin-4 (1-39)-Lys⁴⁰ (ε

-AEEA-AEEA-MPA)-NH₂, exendin-3(1-39)-Lys⁴⁰ (ε

-MPA)-NH₂ and exendin-3(1-39)-Lys⁴⁰ (ε

-AEEA-AEEA-MPA).

6. A method for treating diabetes in a patient, comprising administering to the patient an effective amount of a modified insulinotropic peptide as claimed in claim 1.

7. A method for treating diabetes in a patient, comprising administering to the patient an effective amount of a modified insulinotropic peptide as claimed in claim 3.

8. A method for treating diabetes in a patient, comprising administering to the patient an effective amount of a modified insulinotropic peptide as claimed in claim 4.

9. A method for enhancing the expression of insulin in a patient, comprising administering to the patient an effective amount of a modified insulinotropic peptide as claimed in claim 1.

10. A method for enhancing the expression of insulin in a patient, comprising administering to the patient an effective amount of a modified insulinotropic peptide as claimed in claim 3.

11. A method for enhancing the expression of insulin in a patient, comprising administering to the patient an effective amount of a modified insulinotropic peptide as claimed in claim 4.

12. A conjugate comprising a modified insulinotropic peptide as claimed in claim 1 covalently bonded to a blood component.

13. A conjugate comprising a modified insulinotropic peptide as claimed in claim 3 covalently bonded to a blood component.

14. A conjugate comprising a modified insulinotropic peptide as claimed in claim 4 covalently bonded to a blood component.

15. A conjugate as claimed in claim 12 wherein the blood component is serum albumin.

16. A conjugate as claimed in claim 13 wherein the blood component is serum albumin.

17. A conjugate as claimed in claim 14 wherein the blood component is serum albumin.

21. A pharmaceutical composition comprising a modified insulinotropic peptide as claimed in claim 1 in association with a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a modified insulinotropic peptide as claimed in claim 3 in association with a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a modified insulinotropic peptide as claimed in claim 4 in association with a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a conjugate as claimed in claim 12 in association with a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a conjugate as claimed in claim 13 in association with a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a conjugate as claimed in claim 14 in association with a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising a conjugate as claimed in claim 15 in association with a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising a conjugate as claimed in claim 16 in association with a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising a conjugate as claimed in claim 17 in association with a pharmaceutically acceptable carrier.

18. A method for extending the in vivo half-life of an insulinotropic peptide comprising coupling to the peptide a maleimide group that forms a covalent bond with a blood component in vivo, thereby forming a modified insulinotropic peptide having an in vivo half-life longer than the in vivo half-life of the insulinotropic peptide.

19. A method as claimed in claim 18 wherein the insulinotropic peptide is selected from the group consisting of GLP-1, exendin-3, exendin-4 or a derivative thereof.

20. A method as claimed in claim 19 wherein the GLP-1 peptide is selected from the group consisting of GLP-1 (1-36)-Lys³⁷, GLP-1(7-36)-Lys³⁷ and D-Ala⁸ GLP-1(7-36)-Lys³⁷, exendin-4 (1-39)-Lys⁴⁰ and exendin-3(1-39)-Lys⁴⁰.