Fusion protein of exendin-4 to a transferrin (Tf) polypeptide

• US 7,867,972 B2
• Filed: 07/24/2007
• Issued: 01/11/2011
• Est. Priority Date: 07/24/2006
• Status: Expired due to Fees

• Current Assignee: BioRexis Pharmaceutical Corp. (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company LLC (Pfizer Inc.)
• Inventors: Prior, Christopher P., Turner, Andrew J., Ballance, David James, Sadeghi, Homayoun
• Primary Examiner(s): Landsman; Robert
• Assistant Examiner(s): Chandra; Gyan
• Application Number:
  US11/782,030
• Publication Number:
  US 20090239795A1
• Time in Patent Office: 1,267 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 3/00 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/04 for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment

Abstract

The invention provides fusion proteins comprising an exendin-4 fused to a transferrin (Tf) via a polypeptide linker, as well as corresponding nucleic acid molecules, vectors, host cells, and pharmaceutical compositions. The invention also provides the use of the exendin-4/Tf fusion proteins for treatment of Type II diabetes, obesity, and to reduce body weight.

Claims

1. A fusion protein comprising an exendin-4 fused to a transferrin (Tf) via a polypeptide linker, wherein said Tf is modified to exhibit reduced glycosylation as compared to a native transferrin molecule, and further wherein said Tf has the amino acid sequence as shown in SEQ ID NO:

17.

2. The fusion protein of claim 1, wherein the linker is a nonhelical polypeptide.

3. The fusion protein of claim 1, wherein the linker is selected from the group consisting of PEAPTD (SEQ ID NO:

6), (PEAPTD)₂ (SEQ ID NO;

     5), PEAPTD (SEQ ID NO;

     6) in combination with an IgG hinge linker, and (PEAPTD)₂ (SEQ ID NO;

     5) in combination with an IgG hinge linker.

4. The fusion protein of claim 1, wherein said exendin-4 has the amino acid sequence as shown in SEQ ID NO:

4.

5. The fusion protein of claim 1, wherein the exendin-4 molecule is fused at the N-terminal end of the fusion protein, at the C-terminal end of the fusion protein or at both the N- and C-terminal ends of the fusion protein.

6. The fusion protein of claim 1, wherein the N-terminus of the fusion protein further comprises a secretion signal sequence.

7. The fusion protein of claim 6, wherein the signal sequence is a signal sequence from serum transferrin, lactoferrin, melanotransferrin, or a variant thereof.

8. The fusion protein of claim 6, wherein the signal sequence is a human scrum albumin (HS,A)/MFα

-1 hybrid leader sequence, a modified PISA/MFα

-1 hybrid leader sequence, or a Tf signal sequence.

9. The fusion protein of claim 6, wherein the signal sequence is the human Tf signal sequence as shown in SEQ ID NO:

1.8.

10. A pharmaceutical composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, wherein the composition is adapted to be administered via inhalation.