Long lasting glucagon-like peptide2(glp-2)for the treatment of gastrointestinal diseases and disorders

• US 20040248782A1
• Filed: 08/12/2002
• Published: 12/09/2004
• Est. Priority Date: 02/16/2001
• Status: Active Grant

• Current Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Original Assignee: ConjuChem Biotechnologies, Inc. /Old/ (Colabor Group, Inc.)
• Inventors: Leger, Roger, Carette, Julie, Boudjellab, Nissab, Robitaille, Martin, Bridon, Dominique P., Thibaudeau, Karen
• Granted Patent: US 7,112,567 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

This invention relates to glucagon-like peptide 2 (GLP-2) derivatives. In particular, this invention relates to GLP-2 peptide derivatives having an extended in vivo half-life, for the treatment or prevention of gastrointestinal disorders or diseases such as inflammatory bowel disease and other gastrointestinal functions, from any segment of the gastrointestinal tract, from the oesophagus to the anus.

Claims

1. An gastrointestinal tissue growth promoter derivative comprising

a GLP-2 peptide or an analog or fragment thereof having gastrointestinal tissue growth promoting activity;

and

a reactive entity coupled to the peptide,

the derivative being capable of covalently bonding in vivo with a functionality on a blood component.

2. A derivative as claimed in claim 1 wherein the GLP-2 is of the sequence R₁-(Y₁)_m-X₁-X₂-X₃-X₄-X₅-Phe₆-Ser₇-Asp₈-(P₁)-X₁₄-Asp₁₅-X₁₆-X₁₇-Ala₁₈-X₁₉-X₂₀-X₂₁-Phe₂₂-(P₂)-Trp₂₅-Leu₂₆-X₂₇-X₂₈-Thr₂₉-Lys₃₀-P₃-(Y₂)_n-R₂

wherein

X₁ is His or Tyr;

X₂ is Ala, Gly, D-Ala, Pro, Ile, Nor-Val, α

-aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

X₃ is Asp, Glu, Pro HPro;

or X₂-X₃ are X_2ψ

(CH(OH)CH₂)X₃;

X_2ψ

(CH₂NH₂)X₃ or X_2ψ

(CHCH)X₃ wherein X₂ and X₃ are as defined above;

X₄ is Gly or Ala;

X₅ is Ser or Ala;

P₁ is Glu-X₁₀-Asn-Thr-Ile, Gly-X₁₀-Asn-Thr-Val or Tyr-Ser-Lys-Tyr;

X₁₀ is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X₁₄ is Leu or Lys;

X₁₆ is Asn, Lys or Ala;

X₁₇ is Leu or Lys;

X₁₉ is Ala or Thr;

X₂₀ is Arg, Lys, His or Ala;

X₂₁ is Asp or Lys;

X₂₇ is Ile or Leu;

X₂₈ is Gln or His;

P₂ is Ile-Asn, Ile-Ala or Val-Gln;

P₃ is a covalent bond, or is Ile, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R₁ is NH₂ or a N-terminal blocking group;

R₂ is COOH, CONH₂ or a C-terminal blocking group;

Y₁ is one or two of Arg, Lys, and His;

Y₂ is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.

3. A derivative as claimed in claim 2 wherein X₁ is His;

X₂ is Ala or Gly, X₃ is Asp;

X₄ is Gly;

X₅ is Ser, P₁ is Glu-X₁₀-Asn-Thr-Ile;

X₁₀ is Met;

X₁₆ is Asn or Lys;

X₁₉ is Ala;

X₂₀ is Arg;

X₂₇ is Ile;

X₂₈ is Gln;

P₂ is Ile-Asn;

P₃ is Ile-Thr-Asp and R₂ is CONH₂.

4. A derivative as claimed in claim 1 wherein the reactive entity is a maleimide or a maleimido-containing group.

5. A derivative as claimed in claim 3 wherein the GLP-2 is selected from the group consisting of:

6. A derivative as claimed in claim 1 selected from the group consisting of:

7. A derivative as claimed in claim 1 wherein the blood component comprises blood proteins.

8. A pharmaceutical composition comprising a derivative as claimed in claim 1 in combination with a pharmaceutically acceptable carrier.

9. A composition as claimed in claim 8 for the treatment of prevention of gastrointestinal disorders or diseases.

10. A method for the treatment of prevention of gastrointestinal disorders or diseases in a subject comprising administering to a subject an effective amount of a derivative as claimed in claim 1, alone or in combination with a pharmaceutically acceptable carrier.

11. A method for the promotion of gastrointestinal tissue growth in a subject comprising administering to a subject an effective amount of a derivative as claimed in claim 1, alone or in combination with a pharmaceutical carrier.

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

13. A conjugate as claimed in claim 12 wherein the reactive entity is a maleimide or a maleimido-containing group and the blood component is a blood protein.

14. A conjugate as claimed in claim 13 wherein the blood protein is serum albumin.

15. A conjugate as claimed in claim 12 wherein the derivative is as defined in claim 6.

19. A method for the treatment of prevention of gastrointestinal disorders or diseases in a subject comprising administering to a subject an effective amount of a conjugate as claimed in claim 12, alone or in combination with a pharmaceutical carrier.

16. A method for extending the in vivo half-life of a GLP-2 peptide having gastrointestinal tissue growth promoting activity, the method comprising covalently bonding the peptide to a blood component.

17. A method as claimed in claim 16 wherein the peptide comprises GLP-2 or an analog or fragment thereof having gastrointestinal tissue growth promoting activity.

18. A method as claimed in claim 16 wherein the GLP-2 peptide is as defined in claim 5.