GLP-1 fusion proteins

• US 7,271,149 B2
• Filed: 11/29/2001
• Issued: 09/18/2007
• Est. Priority Date: 12/07/2000
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Glaesner, Wolfgang, Micanovic, Radmila, Tschang, Sheng-Hung Rainbow
• Primary Examiner(s): Wax; Robert A
• Application Number:
  US10/433,108
• Publication Number:
  US 20040053370A1
• Time in Patent Office: 2,119 Days
• Field of Search: None
• US Class Current: 514/7.2
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 14/765 Serum albumin, e.g. HSA
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/31 fusions, other than Fc, for prolonged plasma life, e.g. albumin
• CPC Class Codes: C07K 2319/735 containing a domain for self-assembly, e.g. a viral coat protein (includes phage display)
• CPC Class Codes: C12N 15/62 DNA sequences coding for fusion proteins

Abstract

The present invention relates to glucagon-like-1 compounds fused to proteins that have the effect of extending the in vivo half-life of the peptides. These fusion proteins can be used to treat non-insulin dependent diabetes mellitus as well as a variety of other conditions.

Claims

1. A heterologous fusion protein comprising a first polypeptide with a N-terminus and a C-terminus fused to a second polypeptide with a N-terminus and a C-terminus wherein the first polypeptide is a GLP-1 compound and the second polypeptide is selected from the group consisting of

a) human albumin;

b) human albumin analogs; and

c) fragments of human albumin,

and wherein the C-terminus of the first polypeptide is fused to the N-terminus of the second polypeptide.

4. The heterologous fusion protein of claims 1, 2, or 3 wherein the GLP-1 compound comprises the sequence of formula 1 [SEQ ID NO:

2]

5. The heterologous fusion protein of claims 1, 2, or 3 wherein the GLP-1 compound comprises the sequence of formula II (SEQ ID NO:

3);

6. The heterologous fusion protein of claims 1, 2, or 3 wherein the GLP-1 compound comprises the sequence of formula III (SEQ ID NO:

4);

7. The heterologous fusion protein of claim 1 wherein the GLP-1 compound has no more than 6 amino acids that are different from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)OH, or Exendin-4.

8. The heterologous fusion protein of claim 7 wherein the GLP-1 compound has no more than 5 amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)OH, or Exendin-4.

9. The heterologous fusion protein of claim 8 wherein the GLP-1 compound has no more than 4 amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)OH, or Exendin-4.

10. The heterologous fusion protein of claim 9 wherein the GLP-1 compound has no more than 3 amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)OH, or Exendin-4.

11. The heterologous fusion protein of claim 10 wherein the GLP-1 compound has no more than 2 amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)OH, or Exendin-4.

12. A method of treating a patient with non-insulin dependent diabetes mellitus comprising the administration of a therapeutically effective amount of the heterologous fusion protein of claim 1.

13. A method of treating obesity comprising the administration of a therapeutically effective amount of the heterologous fusion protein of claim 1.

2. A heterologous fusion protein comprising a first polypeptide with a N-terminus terminus and a C-terminus fused to a second polypeptide with a N-terminus and a C-terminus wherein the first polypeptide is a GLP-1 compound and the second polypeptide is selected from the group consisting of

a) human albumin;

b) human albumin analogs; and

c) fragments of human albumin,

and wherein the C-terminus of the first polypeptide is fused to the N-terminus of the second polypeptide via a peptide linker.

3. The heterologous fusion protein of the claim 2 wherein the peptide linker is selected from the group consisting of:

a) a glycine rich peptide;

b) a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]_n where n is 1, 2, 3, 4, 5 or 6; and

c) a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]₃.