NOTCH inhibition in the treatment of cardiovascular disease

• US 9,289,489 B2
• Filed: 05/28/2013
• Issued: 03/22/2016
• Est. Priority Date: 03/07/2006
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Aikawa, Masanori
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US13/903,288
• Publication Number:
  US 20130336958A1
• Time in Patent Office: 1,029 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention is directed to methods of treating or preventing atherosclerosis and other cardiovascular diseases by administering agents that inhibit or modulate the NOTCH signaling pathway. In addition, the invention encompasses methods for assaying compounds for their ability to treat atherosclerosis based upon their effects on NOTCH signaling, and for measuring levels of amount, function, or activity of NOTCH pathway components in biological samples.

Claims

1. A method of treating a patient for atherosclerosis, comprising administering, systemically or locally, to said patient a therapeutically effective amount of an antibody that binds to Delta like 4 ligand (Dll4) and thereby inhibits the binding of Dll4 to NOTCH receptors.

2. The method of claim 1, wherein said antibody inhibits the binding of the Dll4 to NOTCH-3 receptors in macrophages.

3. The method of claim 2, wherein said antibody is administered systemically by injection.

4. The method of claim 2, wherein said antibody is administered by local injection.

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

6. A method of treating a patient for atherosclerosis, comprising administering, systemically or locally, to said patient a therapeutically effective amount of an antibody that binds to Delta like 4 ligand (Dll4) and thereby inhibits the binding of Dll4 to NOTCH receptors, wherein said patient is selected for treatment because one or more assays have indicated that NOTCH activity is elevated in said patient relative to a control group.

7. The method of claim 6, wherein said antibody inhibits the binding of the Dll4 to NOTCH-3 receptors in macrophages.

8. The method of claim 7, wherein said control group is made up of:

a) individuals believed to be free of atherosclerosis;

b) individuals believed to be free of cardiovascular disease;

or c) individuals from the general population.

9. The method of claim 8, wherein said antibody is administered systemically by injection.

10. The method of claim 8, wherein said antibody is administered by local injection.

11. The method of claim 8, wherein said patient is administered a pharmaceutical composition comprising said antibody and a pharmaceutically acceptable carrier.

12. A method of treating a patient for atherosclerosis, comprising administering, systemically or locally, to said patient a therapeutically effective amount of a blocking antibody that binds to Delta like 4 ligand (Dll4) and thereby inhibits the binding of Dll4 to macrophages, wherein said patient is selected for treatment because, relative to a control group, said patient has a greater amount of NOTCH activity in proinflammatory cells.

13. The method of claim 12, wherein said proinflammatory cells are macrophages.

14. The method of claim 12, wherein said control group is made up of:

a) individuals believed to be free of atherosclerosis;

b) individuals believed to be free of cardiovascular disease;

or c) individuals from the general population.

15. The method of claim 12, wherein said blocking antibody is administered systemically by injection.