Use of IL-1 beta Binding Antibodies

Abstract

The present invention relates to an IL-1β binding antibody or a functional fragment thereof for use in preventing or reducing risk of experiencing a recurrent cardiovascular (CV) event or a cerebrovascular event in a patient that has suffered of a qualifying CV event.

1 . A method of preventing or reducing risk of experiencing a recurrent cardiovascular (CV) event or a cerebrovascular event in a stable patient who has had a prior myocardial infarction (MI) comprising administering about 25 mg to about 300 mg of an IL-1β binding antibody or functional fragment thereof, wherein the patient has an hsCRP level of ≥ about 1 mg/L before administration of the antibody or functional fragment thereof. 
     
     
         2 . The method according to  claim 1 , wherein the level is ≥ about 2 mg/L. 
     
     
         3 .- 5 . (canceled) 
     
     
         6 . The method according to  claim 1 , wherein the IL-1β binding antibody or functional fragment thereof is administered every 2 weeks, monthly, every 6 weeks, bimonthly (every 2 months), quarterly (every 3 months), every 5 months, or every 6 months from the first administration. 
     
     
         7 . The method according to  claim 1 , wherein the recurrent CV event is selected from the group consisting of cardiovascular death, and myocardial infarction (MI). 
     
     
         8 . The method according to  claim 1 , wherein the recurrent CV event is selected from the group consisting of hospitalization for unstable angina, acute coronary syndrome, other non-coronary ischemic event (transient ischemic attack or limb ischemia), any revascularization procedure (coronary and non-coronary), limb amputation, stent thrombosis (definite or probable), hospitalization or prolongation of hospitalization for heart failure, and coronary revascularization procedures (PCI or CABG). 
     
     
         9 . The method according to  claim 1 , wherein the cerebrovascular event is stroke. 
     
     
         10 . (canceled) 
     
     
         11 . The method according to  claim 1 , further comprising administering an additional dose of about 25 mg to about 300 mg of the IL-1β binding antibody or functional fragment thereof to the patient at week 2, week 4 or week 6 from the first administration. 
     
     
         12 . The method according to  claim 1 , wherein the method comprises administering about 50 mg of the IL-1β binding antibody or functional fragment thereof. 
     
     
         13 . The method according to  claim 1 , wherein the method comprises: administering about 150 mg of the IL-1β binding antibody or functional fragment thereof. 
     
     
         14 . The method according to  claim 1 , wherein the method comprises: administering about 300 mg of the IL-1β binding antibody or functional fragment thereof. 
     
     
         15 . The method according to  claim 1 , wherein the method comprises administering about 25, 75, 100, 125, 175, 200, 225, 250, 275, 300 mg or any combination thereof of the IL-1β binding antibody or functional fragment thereof. 
     
     
         16 . The method according to  claim 1 , wherein the IL-1β binding antibody or functional fragment thereof is an IL-1β binding antibody. 
     
     
         17 . The method according to  claim 1 , wherein the IL-1β binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-1β to its receptor and has a K D  for binding to IL-1β of about 50 pM or less. 
     
     
         18 . The method according to  claim 1 , wherein the IL-1β binding antibody is selected from the group consisting of:
 a) an IL-1β binding antibody directed ton antigenic epitope of human IL-1β which includes the loop comprising the Glu64 residue of the mature IL-1β, wherein the IL-1β binding antibody is capable of inhibiting the binding of IL-1β to its receptor, and further wherein the IL-1β binding antibody has a K D  for binding to IL-1β of about 50 pM or less; 
 b) an IL-1β binding antibody that competes with the binding of an IL-1β binding antibody comprising a VH domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2; 
 c) an anti-IL-1β binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5; 
 d) an anti-IL-1β binding antibody comprising the three CDRs of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8; 
 e) an anti-IL-1β binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8; 
 f) an anti-IL-1β binding antibody comprising a VH domain comprising SEQ ID NO:1; 
 g) an anti-IL-1β binding antibody comprising a VL domain comprising SEQ ID NO:2; and 
 h) an anti-IL-1β binding antibody comprising a VH domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2. 
 
     
     
         19 . The method according to  claim 1 , wherein the 3 CDRs of of the VH domain of the anti-IL-1β binding antibody are set forth in SEQ ID NO:3, 4, and 5, and wherein the 3 CDRs of of the VL domain of the anti-IL-1β binding antibody are set forth in SEQ ID NO:6, 7, and 8. 
     
     
         20 . The method according to  claim 1 , wherein the IL-1β binding antibody is canakinumab. 
     
     
         21 . The method according to  claim 1 , wherein the IL-1β binding antibody or functional fragment thereof is selected from the group consisting of XOMA 052 or gevokizumab, LY-2189102 or AMG-108. 
     
     
         22 . The method according to  claim 1 , wherein the IL-1β binding antibody or functional fragment thereof is administered subcutaneously. 
     
     
         23 .- 25 . (canceled) 
     
     
         26 . The method according to  claim 1 , wherein the patient is concomitantly receiving standard of care treatment for preventing or reducing risk of experiencing recurrent CV events or a cerebrovascular event. 
     
     
         27 . The method according to  claim 26 , wherein standard of care treatment is a lipid lowering agent such as a HMG-CoA reductase inhibitor, e.g., a statin such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, pitavastatin, rosuvastatin or mixtures thereof or mixtures with ezetimibe, niacin, amlodipine besylate), anti-hypertensives such as a calcium channel blocker (e.g., amlodipine, diltiazem, nifedipine, nicardipine, verapamil) or beta-adrenergic blocking drugs such as esmolol, metoprolol, nadolol, penbutolol or anti-hypertensives such as labetalol, metoprolol, hydralazine, nitroglycerin, nicardipine, sodium nitroprusside, clevidipine or a diuretic such as a thiazide diuretic, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone, am iloride hydrochloride, spironolactone, triamterene, or an angiotensin-converting enzyme (ACE) inhibitor such as ramipril, ramiprilat, captopril, lisinopril or an angiotensin II receptor blocker such as losartan, valsartan, olmesartan, irbesartan, candesartan, telmisartan, eprosartan or an anticoagulant such as acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumacetate, phenprocoumon, warfarin heparin, low molecular weight heparin such as bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin or an inhibitor of platelet aggregation such clopidogrel, elinogrel, prasugrel, cangrelor, ticagrelor, ticlopidine, cilostazol, dipyridamole, picodamide eptifibatide, abciximab, eptifibatide, tirofiban or terutroban or a Prostaglandin analogue (PGI2) such as beraprost, prostacyclin, iloprost or treprostinil, or COX inhibitors such as aspirin, aloxiprin or carbasalate calcium, indobufen or triflusal or cloricromen or ditazole or 1,3-Indandiones such as clorindione, diphenadione or phenindion, or tioclomarol, or direct thrombin (II) inhibitors such as hirudin, bivalirudin, lepirudin, desirudin (bivalent) or argatroban or dabigatran (monovalent) or oligosaccharides such as fondaparinux, idraparinux, or an heparinoids such as danaparoid, sulodexide, dermatan sulfate or direct Xa inhibitors xabans such as apixaban, betrixaban, edoxaban, otamixaban, rivaroxaban or REG1 or defibrotide or ramatroban or antithrombin III or protein C (drotrecogin alfa) or fibrinolytics plasminogen activators: r-tPA such as alteplase, reteplase, tenecteplase or UPA such as urokinase or saruplase) or streptokinase or anistreplase or monteplase or other serine endopeptidases or ancrod or fibrinolysin; or brinase or citrate or EDTA or oxalate or digitalis, or digoxin, or nesiritide, or oxygen, or a nitrate such as glyceryl trinitrate (GTN)/nitroglycerin, isosorbide dinitrate, isosorbide mononitrate or an analgesic such as morphine sulfate or a renin inhibitor such as aliskiren or an endothelin A receptor inhibitor or an aldosterone inhibitor. 
     
     
         28 .- 71 . (canceled)