Methods and Monitoring of Treatment With A DLL4 Antagonist

Abstract

Methods for treating diseases such as cancer comprising administering a DLL4 antagonist, either alone or in combination with other anti-cancer agents, and monitoring for cardiovascular side effects and/or toxicity.

1 - 16 . (canceled) 
     
     
         17 . A method of detecting the development of a cardiovascular side effect and/or toxicity in a subject receiving treatment with a DLL4 antagonist, comprising:
 (a) determining the level of a natriuretic peptide in a sample from the subject; and   (b) comparing the level of the natriuretic peptide in the sample to a predetermined level of the natriuretic peptide;   
       wherein an increase in the level of the natriuretic peptide indicates development of a cardiovascular side effect and/or toxicity. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method of  claim 17 , wherein the sample is blood, serum, or plasma. 
     
     
         21 . The method of  claim 17 , wherein the cardiovascular side effect and/or toxicity is cardiotoxicity. 
     
     
         22 . The method of  claim 17 , wherein the predetermined level of the natriuretic peptide is the amount of natriuretic peptide in a sample obtained at an earlier date. 
     
     
         23 . The method of  claim 17 , wherein the predetermined level of the natriuretic peptide is the amount of natriuretic peptide in a sample obtained prior to treatment. 
     
     
         24 . The method of  claim 17 , wherein the predetermined level of the natriuretic peptide is a normal reference level. 
     
     
         25 . The method of  claim 24 , wherein the normal reference level for BNP is about 100 pg/ml or less in blood, serum, or plasma. 
     
     
         26 . The method of  claim 17 , wherein a sample is obtained approximately every 2 weeks. 
     
     
         27 . The method of  claim 26 , wherein if the natriuretic peptide level is above a predetermined level for two consecutive samples, the subject is administered a therapeutically effective amount of an ACE inhibitor and/or a β-blocker. 
     
     
         28 . The method of  claim 17 , wherein if the natriuretic peptide level is above a predetermined level for any one sample, the subject is administered a therapeutically effective amount of an ACE inhibitor and/or a β-blocker. 
     
     
         29 . The method of  claim 17 , wherein if the natriuretic peptide level is above a predetermined level for any one sample, the subject is administered a therapeutically effective amount of an ACE inhibitor and/or a β-blocker and the DLL4 antagonist is withheld. 
     
     
         30 . The method of  claim 17 , wherein the natriuretic peptide is B-type natriuretic peptide (BNP). 
     
     
         31 . The method of  claim 30 , wherein the predetermined level of BNP is about 100 pg/ml in blood, serum, or plasma. 
     
     
         32 . The method of  claim 30 , wherein the predetermined level of BNP is about 200 pg/ml in blood, serum, or plasma. 
     
     
         33 . The method of  claim 30 , wherein the predetermined level of BNP is about 300 pg/ml in blood, serum, or plasma. 
     
     
         34 . The method of  claim 29 , wherein if the BNP level decreases to below about 200 pg/ml after administration of the ACE inhibitor and/or a β-blocker, then administration of the DLL4 antagonist is resumed. 
     
     
         35 . The method of  claim 28 , wherein if the BNP level decreases after administration of the ACE inhibitor and/or a β-blocker, then administration of the DLL4 antagonist is resumed. 
     
     
         36 - 45 . (canceled) 
     
     
         46 . The method of  claim 17 , wherein the DLL4 antagonist is an antibody that specifically binds human DLL4. 
     
     
         47 . The method of  claim 17 , wherein the DLL4 antagonist is an antibody comprising:
 a heavy chain CDR1 comprising TAYYIH (SEQ ID NO: 1), a heavy chain CDR2 comprising YISSYNGATNYNQKFKG (SEQ ID NO:3), and a heavy chain CDR3 comprising RDYDYDVGMDY (SEQ ID NO:5), and a light chain CDR1 comprising RASESVDNYGISFMK (SEQ ID NO:6), a light chain CDR2 comprising AASNQGS (SEQ ID NO:7), and a light chain CDR3 comprising QQSKEVPWTFGG (SEQ ID NO:8).   
     
     
         48 . The method of  claim 17 , wherein the DLL4 antagonist is an antibody comprising:
 a heavy chain variable region comprising SEQ ID NO:10 and a light chain variable region comprising SEQ ID NO:12.   
     
     
         49 . The method of  claim 17 , wherein the DLL4 antagonist is antibody OMP-21M18. 
     
     
         50 . The method of  claim 17 , wherein the DLL4 antagonist is an anti-DLL4/anti-VEGF bispecific antibody. 
     
     
         51 . The method of  claim 28 , wherein the ACE inhibitor is selected from the group consisting of: captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril, ceronapril, casokinins, lactokinins, teprotide, alacepril, cilazapril, delapril, imidapril, moexipril, rentiapril, spirapril, temocapril, moveltipril and trandolapril. 
     
     
         52 . The method of  claim 28 , wherein the β-blocker is selected from the group consisting of: carvedilol, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol, acebutolol, bisoprolol, esmolol, labetalol, bucindolol, nebivolol, alprenolol; amosulalol, arotinolol, befunolol, betaxolol, bevantolot, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, celiprolol, cetamolol, cloranololdilevalol, epanolol, indenolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol, nipradilol, penbutolol, practolol, pronethalol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, toliprolol, and xibenolol. 
     
     
         53 . The method of  claim 28 , wherein the β-blocker is carvedilol. 
     
     
         54 . The method of  claim 17 , wherein the subject has cancer. 
     
     
         55 . The method of  claim 54 , wherein the cancer is selected from the group consisting of: lung cancer, breast cancer, colon cancer, colorectal cancer, melanoma, pancreatic cancer, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, and head and neck cancer. 
     
     
         56 . The method of  claim 54 , wherein the subject is treated with the DLL4 antagonist in combination with one or more additional anti-cancer agents. 
     
     
         57 . The method of  claim 17 , wherein the cardiovascular side effect and/or toxicity is related to the DLL4 antagonist. 
     
     
         58 . The method of  claim 17 , wherein the cardiovascular side effect and/or toxicity is left ventricular dysfunction or congestive heart failure. 
     
     
         59 . The method of  claim 50 , wherein the anti-DLL4/anti-VEGF bispecific antibody is selected from the group consisting of 219R45-MB-21M18, 219R45-MB-21R79, 219R45-MB-21R75, and 219R45-MB-21R83. 
     
     
         60 . The method of  claim 59 , wherein the antibody is 219R45-MB-21R83.