Modified FGF-21 polypeptides comprising an internal deletion and uses thereof

• US 9,434,778 B2
• Filed: 10/23/2015
• Issued: 09/06/2016
• Est. Priority Date: 10/24/2014
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Reilly, Timothy P., Christian, Rose C., Krupinski, John, Morin, Paul E., Cohen, Daniel, Mukherjee, Ranjan, Lipovsek, Dasa, Camphausen, Ray
• Primary Examiner(s): Saoud, Christine J
• Application Number:
  US14/921,796
• Publication Number:
  US 20160115213A1
• Time in Patent Office: 319 Days
• Field of Search: None
• US Class Current: 1/1
• 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: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 14/50 : Fibroblast growth factor [FGF]
• 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

Abstract

Modified FGF-21 polypeptides and uses thereof are provided, for example, for the treatment of diseases associated with fibrosis. Modified FGF-21 polypeptides are disclosed that contain an internal deletion and optionally replacement peptide, optionally modified with at least one non-naturally-encoded amino acid, and/or optionally fused to a fusion partner.

Claims

1. A modified FGF-21 polypeptide comprising a polypeptide having an amino acid sequence having at least 98% amino acid sequence identity to SEQ ID NO:

102.

2. The modified FGF-21 polypeptide of claim 1, wherein said amino acid sequence comprises at least one non-naturally encoded amino acid.

3. The modified FGF-21 polypeptide of claim 2, wherein said at least one non-naturally encoded amino acid comprises a phenylalanine derivative.

4. The modified FGF-21 polypeptide of claim 3, wherein said at least one non-naturally encoded amino acid comprises para-acetyl-L-phenylalanine.

5. The modified FGF-21 polypeptide of claim 4, wherein said amino acid sequence comprises para-acetyl-L-phenylalanine at a position corresponding to amino acid 109 in SEQ ID NO:

102 which corresponds to amino acid 108 in SEQ ID NO;

1.

6. The modified FGF-21 polypeptide of claim 2, wherein said at least one non-naturally encoded amino acid is linked to a half-life extending moiety.

7. The modified FGF-21 polypeptide of claim 6, wherein said half-life extending moiety comprises a poly(ethylene glycol).

8. The modified FGF-21 polypeptide of claim 7, wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa.

9. The modified FGF-21 polypeptide of claim 1, wherein said amino acid sequence comprises at least one non-naturally encoded amino acid at a position corresponding to amino acid 109 in SEQ ID NO:

102 which corresponds to amino acid 108 in SEQ ID NO;

1.

10. The modified FGF-21 polypeptide of claim 1, wherein said amino acid sequence has at least 99% amino acid sequence identity to SEQ ID NO:

102.

11. The modified FGF-21 polypeptide of claim 1, wherein said modified FGF-21 polypeptide sequence is fused to a fusion partner.

12. The modified FGF-21 polypeptide of claim 11, wherein the fusion partner comprises an Fc domain or fragment thereof.

13. A composition comprising the modified FGF-21 polypeptide of claim 1 and a pharmaceutically acceptable carrier or excipient.

14. A modified FGF-21 polypeptide comprising a polypeptide having the amino acid sequence of SEQ ID NO:

202.

15. The modified FGF-21 polypeptide of claim 14, wherein said modified FGF-21 polypeptide is linked to a half-life extending moiety.

16. The modified FGF-21 polypeptide of claim 15, wherein said half-life extending moiety comprises a poly(ethylene glycol).

17. The modified FGF-21 polypeptide of claim 16, wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa.

18. A composition comprising the modified FGF-21 polypeptide of claim 14 and a pharmaceutically acceptable carrier or excipient.

19. A modified FGF-21 polypeptide comprising a polypeptide having the amino acid sequence of SEQ ID NO:

202, wherein the para-acetyl-L-phenylalanine in SEQ ID NO;

202 is linked to a poly(ethylene glycol) having an average molecular weight of about 30 kDa.

20. A composition comprising the modified FGF-21 polypeptide of claim 19 and a pharmaceutically acceptable carrier or excipient.