Methods of treatment with DLL4 antagonists and an anti-hypertensive agent

1. A method of treating cancer comprising: administering to a human subject in need thereof a delta like ligand-4 (DLL4) antagonist, wherein the DLL4 antagonist is an antibody that specifically binds human DLL4, and further administering a therapeutically effective amount of one or more anti-hypertensive agents to the human subject to control hypertension caused by the antibody.

2. The method of claim 1 , wherein the human subject suffers from hypertension, is at risk for development of hypertension, or is a human subject in which the prevention or inhibition of hypertension is desirable.

3. The method of claim 1 , wherein the human subject is at risk for cardiovascular disease or cannot otherwise be treated with an appropriate dose of the DLL4 antagonist without developing hypertension.

4. The method of claim 1 , wherein the antibody and the anti-hypertensive agent are administered separately or simultaneously.

5. The method of claim 1 , wherein the antibody is encoded by the plasmid having ATCC deposit no. PTA-8425.

6. The method of claim 1 , wherein the antibody competes for specific binding to human DLL4 with an antibody encoded by the plasmid deposited with ATCC, having deposit no. PTA-8425.

7. The method of claim 1 , wherein the antibody is selected from the group consisting of: monoclonal, humanized, chimeric, human, Fab, Fv and scFv.

8. The method of claim 7 , wherein the antibody is a monoclonal antibody.

9. The method of claim 1 , wherein the antibody comprises: (i) a heavy chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:1); CDR2 (SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4); and CDR3 (SEQ ID NO:5), and (ii) a light chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:7); CDR2 (SEQ ID NO:8); and CDR3 (SEQ ID NO:9).

10. The method of claim 9 , wherein the heavy chain variable region comprises CDR amino acid sequences CDR1 (SEQ ID NO:1), CDR2 (SEQ ID NO:3), and CDR3 (SEQ ID NO:5), and the light chain variable region comprises CDR amino acid sequences CDR1 (SEQ ID NO:7); CDR2 (SEQ ID NO:8); and CDR3 (SEQ ID NO:9).

11. The method of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6.

12. The method of claim 1 , wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:10.

13. The method of claim 1 , wherein the anti-hypertensive agent is selected from the group consisting of a diuretic, an adrenergic receptor antagonist, an adrenergic receptor agonist, a calcium channel blocker, an ACE inhibitor, an angiotensin II receptor antagonist, an aldosterone antagonist, a vasodilator, a renin inhibitor, and combinations thereof.

14. The method of claim 13 , wherein the anti-hypertensive agent is a diuretic selected from the group, consisting of: furosemide, bumetanide, ethacrynic acid, torsemide, epitizide, hydrochlorothiazide, hydroflumethiazide, chlorothiazide bendroflumethiazide, polythiazide, trichlormethiazide cyclopenthiazide, methyclothiazide, cyclothiazide, mebutizide, indapamide, chlortalidone, metolazone, quinethazone, clopamide, mefruside, clofenamide, meticrane, xipamide, clorexolone, fenquizone, amiloride, triamterene, eplerenone, benzamil, potassium canrenoate, canrenone, spironolactone mannitol, glucose, urea, conivaptan, relcovaptan, nelivaptan, lixivaptan, mozavaptan, satavaptan, tolvaptan, demeclocycline, mersalyl acid, meralluride, mercaptomerin, mercurophyllme, merethoxyllme procaine, calomel, caffeine, theobromine, paraxanthine, theophylline, acetazolamide, methazolamide, dorzolamide, sulfonamide, topiramate, amanozine, arbutin, chlorazanil etozolin, hydracarbazine, isosorbide, metochalcone, muzohmme, perhexiline, and ticrynafen.

15. The method of claim 13 , wherein the anti-hypertensive agent is an adrenergic receptor antagonist selected from the group consisting of: atenolol, metoprolol, nadolol oxprenolol, pindolol, propranolol, timolol, acebutolol, bisoprolol, esmolol, labetalol, carvedilol, bucindolol, nebivolol, amosulalol, arotinolol, befunolol, betaxolol, bevantolot, bopindolol, bucumolol, bufetolol, bufuralol, bumtrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, celiprolol, cetamolol, cloranololdilevalol, epanolol, indenolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol, nipradilol, penbutolol, practolol, pronethalol, sotalol, sulfmalol, talinolol, tertatolol, tilisolol, toliprolol, xibenolol, phenoxybenzamine, prazosin, doxazosin, terazosin, trimazosin, phentolamine, amosulalol, arotinolol, dapiprazole, fenspinde, indoramin, labetalol, naftopidil, nicergolme, tamsulosin, tolazolme, moxonidine, reserpine, and yohimbine.

16. The method of claim 13 , wherein the anti-hypertensive agent is an adrenergic receptor agonist selected from the group consisting of: clonidine, methyldopa, guanfacine, methoxamine, methylnorepinephrine, oxymetazoline, phenylephrine, guanabenz, guanoxabenz, guanethidine, xylazine, and tizanidme.

17. The method of claim 13 , wherein the anti-hypertensive agent is a calcium channel blocker selected from the group consisting of: amlodipine, felodipine, nicardipine, nifedipine, nimodipine, isradipine, nitrendipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, lacidipine, lercanidipine, manidipine, nilvadipine, nisoldipine, diltiazem, verapamil, bepridil, clentiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, and perhexiline.

18. The method of claim 13 , wherein the anti-hypertensive agent is an ACE inhibitor.

19. The method of claim 18 , wherein the ACE inhibitor is selected from the group consisting of: captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lismopril, benazepril, fosinopril, ceronapril, casokinins, lactokinins, teprotide, alacepril, cilazapril, delapril, imidapnl, moexipnl, rentiapril, spirapril, temocapril, moveltipnl and trandolapril.

20. The method of claim 13 , wherein the anti-hypertensive agent is an angiotensin II receptor antagonist selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan.

21. The method of claim 13 , wherein the anti-hypertensive agent is an aldosterone antagonist selected from the group consisting of: eplerenone, canrenone, and spironolactone.

22. The method of claim 13 , wherein the anti-hypertensive agent is a vasodilator selected from the group consisting of: bencyclane, cinnarizine, citicoline, cyclandelate, ciclonicate, diisopropylamine dichloroacetate, eburnamonine, fasudil, fenoxedil, flunarizine, ibudilast, ifenprodil, lomerizine, nafronyl, nicametate, nicergoline, nimodipine, papaverine, tinofedrine, vincamine, vinpocetine, viquidil, amotriphene, bendazol, benfurodil hemisuccinate, benziodarone, chloracizme, chromonar, clobenfural, clonitrate, cloricromen, dilazep, dipyridamole, droprenilamine, efloxate, erythrityl tetranitrate, etafenone, fendiline, floredil, ganglefene, hexestrol bis(P-diethylaminoethyl) ether, hexobendine, itramin tosylate, khellin, lidoflazine, mannitol hexanitrate, medibazine, nitroglycerin, pentaerythritol tetranitrate, pentrinitrol, perhexiline, pimefylline, prenylamine, propatyl nitrate, trapidil, tricromyl, trimetazidine, trolnitrate phosphate, sildenafil, tadalafil, vardenafil, sodium nitroprusside, isosorbide mononitrate, isosorbide dinitrate, pentaerythritol, tetranitrate, theobromine, visnadine, aluminum nicotinate, bamethan, bencyclane, betahistine, brandykinin, brovincamine, bufeniode, buflomedil, butalamine, cetiedil, ciclonicate, cinepazide, cinnarizine, cyclandelate, diisopropylamine dichloroacetate, eledoisin, fenoxedil, flunarizine, hepronicate, ifenprodil, iloprost, inositol niacinate, isoxsuprine, kallidin, kallikrein, moxisylyte, nafronyl, nicametate, nicergoline, nicofuranose, nylidrin, pentifyllme, pentoxifylline, piribedil, prostaglandin E1, suloctidil, tolazoline, and xanthinol niacinate.

23. The method of claim 13 , wherein the anti-hypertensive agent is a renin inhibitor selected from the group consisting of: aliskiren and remikiren.

24. The method, of claim 13 , further comprising administering a third therapeutic agent.

25. The method of claim wherein the antibody is an antigen-binding antibody fragment.

26. The method of claim 1 , wherein the antibody is a bispecific antibody.

27. A method of ameliorating hypertension in a human patient receiving treatment with a delta like ligand-4 (DLL4) antagonist, wherein the DLL4 antagonist is an antibody that specifically binds human DLL4, said method comprising: administering to the human patient receiving treatment with the antibody, a therapeutically effective amount of one or more anti-hypertensive agents to control hypertension caused by the antibody.

28. The method of claim 27 , wherein the antibody and the anti-hypertensive agent are administered separately or simultaneously.

29. The method of claim 27 , wherein the anti-hypertensive agent is selected from the group consist of: a diuretic, an adrenergic receptor antagonist, an adrenergic receptor agonist, a calcium channel blocker, an ACE inhibitor, an angiotensin II receptor antagonist, an aldosterone antagonist, a vasodilator, a renin inhibitor, and combinations thereof.

30. The method of claim 27 , wherein the antibody is encoded by the plasmid having ATCC deposit no. PTA-8425.

31. The method of claim 27 , herein the antibody comprises: (i) a heavy chain variable region comprising CD R amino acid sequences CDR1 (SEQ ID NO:1); CDR2 (SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4); and CDR3 (SEQ ID NO:5), and (ii) a light chain variable region comprising CDR amino acid sequences CDR1 SEQ ID NO:7); CDR2 (SEQ ID NO:8); and CDR3 (SEQ ID NO:9).

32. The method of claim 27 , wherein the antibody competes for specific binding to human DLL4 with an antibody encoded by the plasmid deposited with ATCC, having deposit no. PTA-8425.

33. A method of reducing hypertension in a patient receiving treatment with a delta like ligand-4 (DLL4) antagonist, wherein the DLL4 antagonist is an antibody that specifically binds human DLL4, comprising: administering to the patient receiving treatment with the antibody a therapeutically effective amount of one or more anti-hypertensive agents to control hypertension caused by the antibody.

34. The method of claim 33 , wherein the anti-hypertensive agent is administered before, concurrently with, or after the administration of the antibody.

35. The method of claim 33 wherein the anti-hypertensive, agent is selected from the group consisting of: a diuretic, an adrenergic receptor antagonist, an adrenergic receptor agonist, a calcium channel blocker, an ACE inhibitor, an angiotensin II receptor antagonist, an aldosterone antagonist, a vasodilator, a renin inhibitor, and combinations thereof.

36. The method of claim 33 , wherein the antibody is encoded by the plasmid having ATCC deposit no. PTA-8425.

37. The method of claim 33 , wherein the antibody comprises: (i) a heavy chain variable region comprising CDR acid sequences CDR1 (SEQ ID NO:1); CDR2 (SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4); and CDR3 (SEQ ID NO:5), and (ii) a light chain variable region comprising CDR amino acid sequences CDR1 (SEQ ID NO:7); CDR2 (SEQ ID NO:8); and CDR3 (SEQ ID NO:9).

38. The method of claim 33 , wherein the anti body competes for specific binding to human DLL4 with an antibody encoded by the plasmid deposited with ATCC, having deposit no. PTA-8425.