PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE

• US 20150056223A1
• Filed: 03/08/2013
• Published: 02/26/2015
• Est. Priority Date: 03/09/2012
• Status: Active Application

• Current Assignee: Hanmi Science Co., Ltd
• Original Assignee: Hanmi Science Co., Ltd
• Inventors: Lim, Se Young, Park, Sung Hee, Choi, In Young, Kwon, Se Chang, Shin, Ryoung Ae
• Application Number:
  US14/383,954
• Publication Number:
  US 20150056223A1
• Time in Patent Office: Days
• US Class Current: 424/179.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 47/6883 Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to a pharmaceutical composition for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), including a conjugate prepared by covalently linking an insulinotropic peptide, a non-peptidyl polymer and an immunoglobulin Fc region. The composition of the present invention maintains the in-vivo activity of the peptide at a relatively high level, and remarkably increases the blood half-life, thereby preventing triglyceride accumulation which is a typical feature of non-alcoholic fatty liver disease. Ultimately, it can be desirably employed for the prevention and treatment of non-alcoholic fatty liver disease.

Claims

1. A pharmaceutical composition for the prevention or treatment of non-alcoholic fatty liver disease comprising an insulinotropic peptide drug conjugate prepared by covalently linking an insulinotropic peptide and an immunoglobulin Fc region via a non-peptidyl polymer as an active ingredient, wherein the insulinotropic peptide is selected from the group consisting of exendin-4, an exendin-4 derivative prepared by deleting the N-terminal amine group of exendin-4, an exendin-4 derivative prepared by substituting the N-terminal amine group of exendin-4 with a hydroxyl group, an exendin-4 derivative prepared by modifying the N-terminal amine group of exendin-4 with a dimethyl group, and an exendin-4 derivative prepared by deleting alpha-carbon of the N-terminal histidine residue of exendin-4 and the N-terminal amine group linked to the alpha-carbon, and

the non-peptidyl polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol-propylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, biodegradable polymers, lipid polymers, chitins, hyaluronic acid, and combinations thereof.

2. The pharmaceutical composition according to claim 1, wherein the non-peptidyl polymer is linked to the amino acid residue other than the N-terminus of the insulinotropic peptide.

3. The pharmaceutical composition according to claim 1, wherein the immunoglobulin Fc region and an amine group or a thiol group of the insulinotropic peptide are linked at both ends of the non-peptidyl polymer, respectively.

4. The pharmaceutical composition according to claim 1, wherein the non-peptidyl polymer is linked to the lysine residue of the insulinotropic peptide.

5. The pharmaceutical composition according to claim 1, wherein the non-peptidyl polymer is polyethylene glycol.

6. The pharmaceutical composition according to claim 1, wherein the immunoglobulin Fc region is aglycosylated.

7. The pharmaceutical composition according to claim 1, wherein the immunoglobulin Fc region is composed of one to four domains selected from the group consisting of CH1, CH2, CH3 and CH4 domains.

8. The pharmaceutical composition according to claim 7, wherein the immunoglobulin Fc region further include a hinge region.

9. The pharmaceutical composition according to claim 1, wherein the immunoglobulin Fc region is an Fc region that is derived from an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE and IgM.

10. The pharmaceutical composition according to claim 9, wherein the immunoglobulin Fc region is an IgG4 Fc region.

11. The pharmaceutical composition according to claim 10, wherein the immunoglobulin Fc region is a human non-glycosylated IgG4 Fc region.

12. The pharmaceutical composition according to claim 1, wherein the reactive group of the non-peptidyl polymer is selected from the group consisting of an aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group and a succinimide derivative.

13. The pharmaceutical composition according to claim 12, wherein the succinimide derivative is selected from the group consisting of succinimidyl propionate, succinimidyl carboxymethyl, hydroxy succinimidyl, and succinimidyl carbonate.

14. The pharmaceutical composition according to claim 1, wherein the non-peptidyl polymer has reactive aldehyde groups at both ends thereof.

15. The pharmaceutical composition according to claim 1, wherein the insulinotropic peptide drug conjugate increases the activity of PKC-ζ

(Protein Kinase C-ζ

) regulating the enzymatic activity involved in lipolysis.

16. The pharmaceutical composition according to claim 1, wherein the insulinotropic peptide drug conjugate increases expression of Glut2 (Glucose transporter protein-2) involved in lipolysis.

17. The pharmaceutical composition according to claim 1, wherein the non-alcoholic fatty liver disease is selected from the group consisting of simple steatosis, fatty liver diseases caused by malnutrition, starvation, obesity and diabetes, steatohepatitis, liver fibrosis and liver cirrhosis.

18. A method for preventing or treating non-alcoholic liver disease, comprising the step of administering to a subject the pharmaceutical composition of claim 1.