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 . (canceled) 
     
     
         2 . A method of detecting the development of a cardiovascular side effect and/or toxicity in a subject receiving treatment with an antibody that specifically binds human delta-like protein 4 (DLL4), comprising:
 (a) determining the level of B-type natriuretic peptide (BNP) in a sample from the subject;   (b) comparing the level of BNP in the sample to a predetermined level of BNP; and   (c) administering to the subject a therapeutically effective amount of an ACE inhibitor and/or a β-blocker if the level of BNP is above the predetermined level of BNP;   wherein the antibody comprises 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).   
     
     
         3 . The method of  claim 2 , wherein the sample is blood, serum, or plasma. 
     
     
         4 . The method of  claim 2 , wherein a sample is obtained approximately every 2 weeks. 
     
     
         5 . The method of  claim 2 , wherein the predetermined level of BNP is:
 (a) the amount of BNP in a sample obtained at an earlier date;   (b) the amount of BNP in a sample obtained prior to treatment; or   (c) a normal reference level.   
     
     
         6 . The method of  claim 5 , wherein the normal reference level for BNP is about 100 pg/ml or less in blood, serum, or plasma. 
     
     
         7 . The method of  claim 2 , wherein the predetermined level of BNP is about 100 pg/ml or less, about 150 pg/ml or less, about 200 pg/ml or less, or about 300 pg/ml or less. 
     
     
         8 . The method of  claim 2 , wherein the predetermined level of BNP is about 100 pg/ml or less. 
     
     
         9 . The method of  claim 2 , wherein the subject has cancer. 
     
     
         10 . The method of  claim 9 , wherein the cancer is non-small cell lung cancer or pancreatic cancer. 
     
     
         11 . The method of  claim 2 , wherein the β-blocker is carvedilol. 
     
     
         12 . The method of  claim 2 , wherein the subject is treated with the antibody in combination with one or more additional therapeutic agents. 
     
     
         13 . The method of  claim 12 , wherein the additional therapeutic agent is a chemotherapeutic agent. 
     
     
         14 . The method of  claim 12 , wherein the additional therapeutic agent(s) is:
 (a) carboplatin and pemetrexed, or   (b) gemcitabine.   
     
     
         15 . The method of  claim 2 , wherein the cardiovascular side effect and/or toxicity is related to the antibody. 
     
     
         16 . The method of  claim 2 , wherein the cardiovascular side effect and/or toxicity is left ventricular dysfunction or congestive heart failure. 
     
     
         17 . The method of  claim 2 , further comprising withholding treatment with the antibody if the level of BNP is above the predetermined level of BNP. 
     
     
         18 . The method of  claim 17 , wherein if the level of BNP decreases after administration of the ACE inhibitor and/or the β-blocker, then treatment with the antibody is resumed. 
     
     
         19 . A method of identifying a subject as eligible for treatment with an antibody that specifically binds human delta-like protein 4 (DLL4), comprising:
 (a) determining the level of B-type natriuretic peptide (BNP) in a sample from the subject prior to treatment;   (b) identifying the subject as eligible for treatment with the antibody if the level of BNP is below a predetermined level; and   (c) administering the antibody that specifically binds DLL4 to the subject,   wherein the antibody comprises 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).   
     
     
         20 . A method for reducing a cardiovascular side effect and/or toxicity in a subject receiving treatment with an antibody that specifically binds human delta-like protein 4 (DLL4), comprising:
 (a) determining the level of B-type natriuretic peptide (BNP) in a sample from the subject;   (b) comparing the level of BNP in the sample to a predetermined level of BNP; and   (c) administering to the subject a therapeutically effective amount of an ACE inhibitor and/or a β-blocker if the level of BNP in the sample is higher than the predetermined level of BNP,   and wherein the antibody comprises 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).   
     
     
         21 . A method of preventing or attenuating the development of a cardiovascular side effect and/or toxicity in subject receiving treatment with an antibody that specifically binds human delta-like protein 4 (DLL4), comprising:
 (a) determining the level of B-type natriuretic peptide (BNP) in a sample from the subject prior to treatment;   (b) comparing the level of BNP in the sample to a predetermined level of BNP;   (c) administering to the subject a therapeutically effective amount of an ACE inhibitor and/or a β-blocker, if the level of BNP in the sample is higher than the predetermined level of BNP; and   (d) administering to the subject the antibody that specifically binds DLL4,   wherein the antibody comprises 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).   
     
     
         22 . A method of screening a subject for the risk of a cardiovascular side effect and/or toxicity from treatment with an antibody that specifically binds human delta-like protein 4 (DLL4), comprising:
 (a) determining the level of B-type natriuretic peptide (BNP) in a sample from the subject;   (b) comparing the level of BNP in the sample to a predetermined level of BNP, wherein if the level of BNP in the sample is higher than the predetermined level of BNP then the subject is at risk for a cardiovascular side effect and/or toxicity; and   (c) administering a therapeutically effective amount of an ACE inhibitor and/or a β-blocker prior to treatment with the antibody if the subject is at risk for a cardiovascular side effect and/or toxicity;   and wherein the antibody comprises 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).