Glucagon-like peptide-2 and its therapeutic use

• US 5,834,428 A
• Filed: 06/28/1996
• Issued: 11/10/1998
• Est. Priority Date: 04/14/1995
• Status: Expired due to Term

• Current Assignee: 1149336 Ontario Inc.
• Original Assignee: 1149336 Ontario Inc.
• Inventors: Drucker, Daniel J.
• Primary Examiner(s): Huff, Sheela
• Application Number:
  US08/669,790
• Time in Patent Office: 865 Days
• Field of Search: 514/2, 514/3, 514/12, 530/324, 530/308, 530/303, 935/52, 935/55, 935/66, 935/70, 935/71, 435/366, 435/371
• US Class Current: 514/6.9
• CPC Class Codes: A61K 38/26 Glucagons
• 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: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Glucagon-like peptide 2, a product of glucagon gene expression, and analogs of glucagon-like peptide 2, have been identified as gastrointestinal tissue growth factors. Their effects on the growth of small bowel and pancreatic islets are described. Their formulation as a pharmaceutical, and their therapeutic use in treating disorders of the bowel, are described.

Claims

1. A pharmaceutical composition, comprising a GLP-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which has the formula (SEQ ID NO. 1):

R1-(Y)m-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-aa1-Leu-Asp-aa2-Leu-Ala-aa3-aa4-Asp-Phe-Ile-Asn-Trp-Leu-aa5-aa6-Thr-Lys-Ile-Thr-Asp-(X)n-R2

wherein;

aa1 is Met, Leu, Ile, Val or Cys;

aa2 is Ala, Ser, Thr, Pro, Gly, Asn, Asp, Glu or Gln;

aa3 is Ala, Ser, Thr, Pro or Gly;

aa4 is His, Arg or Lys;

aa5 is Met, Leu, Ile, Val or Cys;

aa6 is Asn, Asp, Glu, Gln, His, Arg or Lys;

X is one or two amino acids selected from the group consisting of His, Arg and Lys;

Y is one or two amino acids selected from the group consisting of His, Arg and Lys;

m is 0 or 1;

n is 0 or 1;

R1 is H or an N-terminal blocking group; and

R2 is OH or a C-terminal blocking group, and wherein the GLP-2 or salt thereof is not a naturally occurring GLP-2.

2. The pharmaceutical composition according to claim 1, wherein the GLP-2 or salt thereof is present in an amount effective to promote the growth of gastrointestinal tissue.

3. A method for promoting the growth of bowel tissue in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition as claimed in claim 1 to promote the growth of bowel tissue.

4. The pharmaceutical composition according to claim 1, wherein the GLP-2 or salt thereof is present in an amount effective to promote the growth of pancreatic islets.

5. A method for promoting the growth of pancreatic islets in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition as claimed in claim 1 to promote the growth of pancreatic islets.

6. A method for treating a gastrointestinal disease selected from the group consisting of ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn'"'"'s disease), small intestinal damage due to toxic or chemotherapeutic agents, and short bowel syndrome, and wherein the method comprises administering to a patient having the gastrointestinal disease an effective amount of a pharmaceutical composition as claimed in claim 1 to reduce a pathological effect or symptom of the gastrointestinal disease.

7. A method for treating diabetes, comprising administering to a patient having diabetes an effective amount a pharmaceutical composition as claimed in claim 1 to increase the levels of insulin in the patient.

8. The pharmaceutical composition according to claim 1, wherein the GLP-2 or salt thereof has the amino acid sequence (SEQ ID NO. 2):

R1-(Y)m-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-aa3-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-(X)n-R2.

9. The pharmaceutical composition according to claim 8, wherein the GLP-2 or salt thereof is present in an amount effective to promote the growth of gastrointestinal tissue.

10. A method for promoting the growth of bowel tissue in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition as claimed in claim 8 to promote the growth of bowel tissue.

11. The pharmaceutical composition according to claim 8, wherein the GLP-2 or salt thereof is present in an amount effective to promote the growth of pancreatic islets.

12. A method for promoting the growth of pancreatic islets in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition as claimed in claim 8 to promote the growth of pancreatic islets.

13. A method for treating a gastrointestinal disease selected from the group consisting of ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis (Crohn'"'"'s disease), small intestinal damage due to toxic or chemotherapeutic agents, and short bowel syndrome,

and wherein the method comprises administering to a patient having the gastrointestinal disease an effective amount of a pharmaceutical composition as claimed in claim 8 to reduce a pathological effect or symptom of the gastrointestinal disease.

14. A method for treating diabetes, comprising administering to a patient having diabetes an effective amount of a pharmaceutical composition as claimed in claim 8 to increase the levels of insulin in the patient.

15. A method according to any of claims 3, 5, 6, 7, 10 or 12-14, wherein the patient is a human.

16. A method to identify intestinotrophic peptides, comprising:

a) obtaining an analog of an intestinotrophic vertebrate GLP-2, the analog having at least one amino acid substitution, deletion, addition, or an amino acid with a blocking group;

b) administering to a mammal the analog using a regimen capable of eliciting an intestinotrophic effect when utilized for rat GLP-2; and

c) determining the effect of the analog on small bowel weight and/or on the crypt plus villus height and/or pancreatic islet size relative to a mock treated control mammal, whereby the intestinotrophic peptide is identified as an analog which elicits an increase in the weight and/or the height and/or the size.