NOTCH inhibition in the treatment and prevention of a metabolic disease or disorder and cardiovascular complications thereof

• US 8,889,131 B2
• Filed: 05/01/2012
• Issued: 11/18/2014
• Est. Priority Date: 11/01/2009
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Aikawa, Masanori, Miyazaki, Tetsuro, Fukuda, Daiju, Aikawa, Elena
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US13/461,365
• Publication Number:
  US 20130064832A1
• Time in Patent Office: 931 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 5/50 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 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/20 characterized by taxonomic origin
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 : interfering N.A.

Abstract

The present invention is directed to methods of treating or preventing a metabolic disease or disorder and cardiovascular complications and other complications thereof by administering agents that inhibit the NOTCH signaling pathway. In addition, the invention encompasses methods for determining whether a patient is at increased risk for developing these conditions by determining the amount, function, or activity of NOTCH pathway components in biological samples derived from the patient or in imaging analysis.

Claims

1. A method of treating a patient for metabolic syndrome comprising administering to said patient a therapeutically effective amount of an antibody that binds to Delta-like 4 (DLL4) and inhibits the NOTCH signaling pathway.

2. The method of claim 1, wherein said patient is treated for a sufficient period of time to reduce or eliminate one or more symptoms associated with metabolic syndrome, wherein said symptoms are selected from the group consisting of:

a waist circumference ≧

40 inches in men or ≧

35 inches in women;

blood pressure ≧

130/85 mmHg;

triglycerides ≧

150 mg/dL;

HDL cholesterol ≦

40 mg/dL in men and 50 mg/dL in women; and

glucose ≧

100 mg/dL.

3. The method of claim 2, wherein said patient is treated for a sufficient period of time to reduce or eliminate more than one of said symptoms.

4. The method of claim 1, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

atherosclerosis;

acute myocardial infarction;

chronic kidney disease;

arterial calcification;

valvular calcification;

valvular stenosis;

restenosis after coronary intervention;

accelerated tissue damage or delayed healing after coronary intervention;

failure of vein grafts for coronary bypass surgery;

diabetic nephropathy;

vasculitis;

retinopathy;

erectile dysfunction;

stroke and heart failure.

5. The method of claim 1, wherein said patient is treated by administering a pharmaceutical composition comprising said antibody and a pharmaceutically acceptable carrier.

6. The method of claim 5, wherein said patient is treated for a sufficient period of time to reduce or eliminate one or more symptoms associated with metabolic syndrome, wherein said symptoms are selected from the group consisting of:

a waist circumference >

40 inches in men or >

35 inches in women;

blood pressure >

130/85 mmHg;

triglycerides >

150 mg/dL;

HDL cholesterol 40 mg/dL in men and 50 mg/dL in women; and

glucose >

100 mg/dL.

7. The method of claim 6, wherein said patient is treated for a sufficient period of time to reduce or eliminate more than one of said symptoms.

8. The method of claim 6, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

acute myocardial infarction;

arterial calcification;

valvular calcification;

valvular stenosis;

restenosis after coronary intervention;

accelerated tissue damage or delayed healing after coronary intervention;

failure of vein grafts for coronary bypass surgery;

stroke and heart failure.

9. The method of claim 6, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

chronic kidney disease;

diabetic nephropathy;

vasculitis;

retinopathy; and

erectile dysfunction.

10. The method of claim 5, wherein said pharmaceutical composition is in unit dosage form.

11. The method of claim 10, wherein said patient is treated for a sufficient period of time to reduce or eliminate one or more symptoms associated with metabolic syndrome, wherein said symptoms are selected from the group consisting of:

a waist circumference >

40 inches in men or >

35 inches in women;

blood pressure >

130/85 mmHg;

triglycerides >

150 mg/dL;

HDL cholesterol 40 mg/dL in men and 50 mg/dL in women; and

glucose >

100 mg/dL.

12. The method of claim 11, wherein said patient is treated for a sufficient period of time to reduce or eliminate more than one of said symptoms.

13. The method of claim 11, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

acute myocardial infarction;

arterial calcification;

valvular calcification;

valvular stenosis;

restenosis after coronary intervention;

accelerated tissue damage or delayed healing after coronary intervention;

failure of vein grafts for coronary bypass surgery;

stroke and heart failure.

14. The method of claim 11, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

chronic kidney disease;

diabetic nephropathy;

vasculitis;

retinopathy; and

erectile dysfunction.

15. A method of treating a patient for metabolic syndrome comprising administering to said patient a therapeutically effective amount of a compound that inhibits the NOTCH signaling pathway wherein:

a) said patient is treated for a sufficient period of time to reduce or eliminate one or more symptoms associated with metabolic syndrome, wherein said one or more symptoms are selected from the group consisting of;

a waist circumference ≧

40 inches in men or ≧

35 inches in women;

blood pressure ≧

130/85 mmHg;

triglycerides ≧

150 mg/dL;

HDL cholesterol ≦

40 mg/dL in men and 50 mg/dL in women; and

glucose ≧

100 mg/dL;

b) said compound is an antibody that binds to Delta-like 4 (DLL4) and inhibits said NOTCH signaling pathway; and

c) said compound is administered by injection.

16. The method of claim 15, wherein said patient is treated by administering a pharmaceutical composition comprising said antibody and a pharmaceutically acceptable carrier.

17. The method of claim 16, wherein said pharmaceutical composition is in unit dosage form.

18. The method of claim 17, wherein said compound is administered intravenously.

19. The method of claim 15, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

acute myocardial infarction;

arterial calcification;

valvular calcification;

valvular stenosis;

restenosis after coronary intervention;

accelerated tissue damage or delayed healing after coronary intervention;

failure of vein grafts for coronary bypass surgery;

stroke and heart failure.

20. The method of claim 15, wherein said metabolic syndrome is accompanied by one or more complications selected from the group consisting of:

chronic kidney disease;

diabetic nephropathy;

vasculitis;

retinopathy; and

erectile dysfunction.