Therapeutic uses of modified FGF-21 polypeptides

• US 10,189,883 B2
• Filed: 03/16/2017
• Issued: 01/29/2019
• Est. Priority Date: 10/24/2014
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Morin, Paul E., Cohen, Daniel, Mukherjee, Ranjan, Reilly, Timothy P., Christian, Rose C., Lipovsek, Dasa, Camphausen, Ray, Krupinski, John
• Primary Examiner(s): Saoud, Christine J
• Application Number:
  US15/460,917
• Publication Number:
  US 20170189486A1
• Time in Patent Office: 684 Days
• Field of Search: None
• 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 method of decreasing or inhibiting fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a modified FGF-21 polypeptide comprising a polypeptide having at least 96% amino acid sequence identity to the amino acid sequence of SEQ ID NO:

202.

2. The method of claim 1, wherein said modified FGF-21 polypeptide comprises a polypeptide having at least 97% amino acid sequence identity to the amino acid sequence of SEQ ID NO:

202.

3. The method of claim 1, wherein said modified FGF-21 polypeptide comprises a polypeptide having at least 98% amino acid sequence identity to the amino acid sequence of SEQ ID NO:

202.

4. The method of claim 1, wherein said modified FGF-21 polypeptide comprises a polypeptide having at least 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO:

202.

5. The method of claim 1, wherein said modified FGF-21 polypeptide comprises a polypeptide having the amino acid sequence of SEQ ID NO:

202.

6. The method of claim 1, wherein said modified FGF-21 polypeptide is linked to a half-life extending moiety.

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

8. The method of claim 7, wherein said poly(ethylene glycol) has an average molecular weight between 10 kDa and 40 kDa.

9. The method of claim 8, wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa.

10. The method of claim 6, wherein said modified FGF-21 polypeptide is linked to a half-life extending moiety via a para-acetyl-L-phenylalanine in the modified FGF-21 polypeptide.

11. The method of claim 1, wherein said method treats a disease selected from NASH, liver fibrosis, cirrhosis, diabetic kidney disease, chronic kidney disease, renal fibrosis, lung fibrosis, cardiac fibrosis, heart failure, or metabolic heart failure in said patient.

12. The method of claim 1, wherein said method treats a disease selected from NASH or liver fibrosis in said patient.

13. A method of decreasing or inhibiting fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of a modified FGF-21 polypeptide comprising a polypeptide having the amino acid sequence of (a) SEQ ID NO:

202 without the N-terminal methionine or (b) SEQ ID NO;

202, wherein said modified FGF-21 polypeptide is linked to poly(ethylene glycol).

14. The method of claim 13, wherein said poly(ethylene glycol) has an average molecular weight between 10 kDa and 40 kDa.

15. The method of claim 14, wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa.

16. The method of claim 13, wherein said method treats a disease selected from NASH, liver fibrosis, cirrhosis, diabetic kidney disease, chronic kidney disease, renal fibrosis, lung fibrosis, cardiac fibrosis, heart failure, or metabolic heart failure in said patient.

17. The method of claim 13, wherein said method treats a disease selected from NASH or liver fibrosis in said patient.

18. The method of claim 13, further comprising the administration of at least one other active agent to said patient.

19. A method of reducing the incidence of or treating NASH in a patient in need thereof, comprising administering to the patient an effective amount of a modified FGF-21 polypeptide comprising a polypeptide having the amino acid sequence of SEQ ID NO:

202, wherein said modified FGF-21 polypeptide is linked to poly(ethylene glycol).

20. The method of claim 19, wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa.