METHODS AND COMPOSITIONS FOR TREATMENT OF METABOLIC DISORDERS

• US 20140079771A1
• Filed: 09/09/2013
• Published: 03/20/2014
• Est. Priority Date: 08/03/2010
• Status: Active Grant

• Current Assignee: Beth Israel Deaconess Medical Center, Inc. (Beth Israel Lahey Health, Inc.)
• Original Assignee: Beth Israel Deaconess Medical Center, Inc. (Beth Israel Lahey Health, Inc.)
• Inventors: O'Shea, Donal, Balk, Steven P., EXLEY, Mark A., Lynch, Lydia, O'Farrelly, Cliona
• Granted Patent: US 9,907,848 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7032 attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/4613 Natural-killer cells [NK or NK-T]
• CPC Class Codes: A61K 39/464 characterised by the antigen targeted or presented
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00

Abstract

The present invention relates to the discovery that increases in invariant NKT cell (iNKT) number and/or activity can reduce the incidence or severity of metabolic disorders such as obesity and diabetes. The invention accordingly features methods, kits, and compositions for the treatment of such metabolic disorders by administration of a composition capable of increasing iNKT activity.

Claims

1. A method of treating a subject suffering from a metabolic disorder, said method comprising administering to said subject a sufficient amount of a composition that increases invariant NKT (iNKT) cell activity.

2. The method of claim 1, wherein said composition comprises a glycolipid;

an antibody or an antigen-binding fragment thereof;

or an iNKT.

3. The method of claim 2, wherein said glycolipid is a bacterial glycolipid capable of activating iNKT.

4. The method of claim 2, wherein said glycolipid is α

-galactosylceramide or an analog thereof.

5. The method of claim 2, wherein said antibody or antigen-binding fragment thereof specifically binds to an iNKT and increases activity of said iNKT.

6. The method of claim 5, wherein said antibody or antigen-binding fragment thereof binds to the CDR3 loop or the α

-β

junction of said iNKT.

7. The method of claim 2, wherein said iNKT is an autologous iNKT.

8. The method of claim 1, wherein said composition further comprises a pharmaceutically acceptable carrier.

9. The method of claim 8, wherein said composition is administered intravenously, intramuscularly, orally, by inhalation, parenterally, intraperitoneally, intraarterially, transdermally, sublingually, nasally, transbuccally, liposomally, adiposally, ophthalmically, intraocularly, subcutaneously, intrathecally, topically, or locally.

18. The method of claim 1, wherein said metabolic disorder is diabetes, obesity, diabetes as a consequence of obesity, hyperglycemia, dyslipidemia, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, a cardiovascular disease, or hypertension.

19. The method of claim 18, wherein said diabetes is type I diabetes or type II diabetes.

20. The method of claim 1, wherein said subject is a human.

21. The method of claim 1, wherein said subject is further administered a second therapeutic for treating said metabolic disorder.

10. A method for treating a subject suffering from a metabolic disorder, said method comprising the steps:

(a) obtaining a biological sample from said subject, said sample containing a population of iNKT;

(b) contacting said sample with a sufficient amount of an agent capable of selectively expanding said iNKT; and

(c) administering said iNKT of step (b) to said subject in an amount sufficient to treat said metabolic disorder.

11. The method of claim 10, wherein said biological sample is a blood sample.

12. The method of claim 10, wherein said agent is a glycolipid or said agent is an antibody or an antigen-binding fragment thereof.

13. The method of claim 12, wherein said glycolipid is a bacterial glycolipid capable of activating iNKT.

14. The method of claim 12, wherein said glycolipid is α

-galactosylceramide or an analog thereof.

15. The method of claim 12, wherein said antibody or antigen-binding fragment thereof specifically binds to an iNKT and increases activity of said iNKT.

16. The method of claim 15, wherein said antibody or antigen-binding fragment thereof binds to the CDR3 loop or the α

-β

junction of said iNKT.

17. The method of claim 10, wherein said iNKT is administered intravenously, intramuscularly, orally, by inhalation, parenterally, intraperitoneally, intraarterially, transdermally, sublingually, nasally, transbuccally, liposomally, adiposally, opthalmically, intraocularly, subcutaneously, intrathecally, topically, or locally.

22. A kit comprising:

(a) a composition that increases iNKT activity

(b) a therapeutic for treating a metabolic disorder.

23. A composition comprising:

(a) a first agent that increases iNKT activity; and

(b) a second agent for treating a metabolic disorder, wherein said agents are together present in an amount sufficient to treat said metabolic disorder.