METHODS FOR INHIBITING ATHEROSCLEROSIS BY ADMINISTERING AN INHIBITOR OF PCSK9
The present invention provides methods and compositions for inhibiting atherosclerotic plaque formation in a subject. In certain embodiments, the methods of the present invention comprise selecting a subject who has, or is at risk of developing, atherosclerosis, and administering to the subject a pharmaceutical composition comprising a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. In certain embodiments, this PCSK9 inhibitor is an anti-PCSK9 antibody, or antigen binding protein.
1 - 39 . (canceled)
40 . A method of inhibiting atherosclerotic plaque formation, the method comprising:
(a) selecting a subject who has atherosclerosis; and
(b) administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:86, 87, 88, 90, 91, and 92, such that the administration of the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, or instability of atherosclerotic plaques in the subject.
41 . The method of claim 40 , wherein the subject has suffered a stroke or myocardial infarction.
42 . The method of claim 40 , wherein the subject has one or more of the following conditions:
a) a disease or disorder selected from the group consisting of type I diabetes mellitus, type II diabetes mellitus, Kawasaki disease, chronic inflammatory disease, and hypertension;
b) heterozygous Familial Hypercholesterolemia (heFH); and
c) a form of hypercholesterolemia that is not Familial Hypercholesterolemia (nonFH).
43 . The method of claim 40 , wherein the subject has an elevated level of an inflammatory marker.
44 . The method of claim 43 , wherein the inflammatory marker is C-reactive protein or an inflammatory cytokine.
45 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:85 and an LCVR having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:89.
46 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof inhibits the increase of the number, total area, severity, or instability of atherosclerotic plaques in the subject by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
47 . The method of claim 40 , wherein the subject is on another lipid-modifying agent before and/or during administration of the antibody or antigen-binding fragment thereof.
48 . The method of claim 47 , wherein the therapeutic lipid-modifying agent is selected from the group consisting of a statin, ezetimibe, a fibrate, niacin, an omega-3 fatty acid, and a bile acid resin.
49 . The method of claim 48 , wherein the statin is selected from the group consisting of cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin and pravastatin.
50 . The method of claim 40 , wherein the subject is not on another lipid-modifying agent before and/or during administration of the antibody or antigen-binding fragment thereof.
51 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.
52 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof inhibits an increase in the number of atherosclerotic plaques.
53 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof inhibits an increase in the total area of atherosclerotic plaques.
54 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof inhibits an increase in the severity of atherosclerotic plaques.
55 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof inhibits an increase in the instability of atherosclerotic plaques.
56 . The method of claim 40 , wherein the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, and instability of atherosclerotic plaques.
57 . A method of inhibiting atherosclerotic plaque formation, the method comprising:
(a) selecting a subject who has atherosclerosis and hypercholesterolemia; and
(b) administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to PCSK9, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:86, 87, 88, 90, 91, and 92, such that the administration of the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, or instability of atherosclerotic plaques in the subject.
58 . The method of claim 57 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:85 and an LCVR having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:89.
59 . A method of inhibiting atherosclerotic plaque formation, the method comprising:
(a) selecting a subject who has atherosclerosis and hypercholesterolemia; and
(b) administering to the subject subcutaneously a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to PCSK9, wherein the antibody or antigen-binding fragment thereof comprises:
(i) an HCVR comprising heavy chain CDR amino acid sequences having SEQ ID NOs:86, 87, and 88, and having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:85; and
(ii) an LCVR comprising light chain CDR amino acid sequences having SEQ ID NOs: 90, 91, and 92, and having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:89,
such that the administration of the antibody or antigen-binding fragment thereof inhibits an increase in the number, total area, severity, or instability of atherosclerotic plaques in the subject.