Anti-her2 combinations for treating tumors

Abstract

The present invention relates to therapeutic combinations and methods for treating cancers using combination therapy.

1 . A method for treating cancer in a subject that is in need of such treatment, comprising systemically administering to said subject the combination comprising:
 (i) an effective amount of a Her2/Neu binding antagonist antibody; and   (ii) an effective amount of an immunotherapeutic is a compound having a structure of Formula (I):   
       
         
           
           
               
               
           
         
       
       wherein dashed line represents bond or absence of bond; 
       X is S or —NR 1 , R 1  is —W 0 —W 1 —W 2 —W 3 —W 4 , 
       W 0  is a bond, alkyl, alkenyl, alkynyl, alkoxy, or -alkyl-S-alkyl-, 
       W 1  is a bond, —O—, or —NR 2 —, wherein R 2  is hydrogen, alkyl or alkenyl, 
       W 2  is a bond, —O—, —C(O)—, —C(S)—, or —S(O) 2 —, 
       W 3  is a bond, —NR 3 —, wherein R 3  is hydrogen, alkyl or alkenyl, 
       W 4  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, or heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R 4 , —O-alkyl-R 4 , -alkyl-O—R 4 , —C(O)—R 4 , -alkyl-C(O)—R 4 , -alkyl-C(O)—O—R 4 , —C(O)—O—R 4 , —S—R 4 , —S(O) 2 —R 4 , —NH—S(O) 2 —R 4 , -alkyl-S—R 4 , -alkyl-S(O) 2 —R 4 , —NHR 4 , —NR 4 R 4 , —NH-alkyl-R 4 , halogen, —CN, —NO 2 , and —SH, wherein R 4  is independently hydrogen, alkyl, alkenyl, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl; 
       Z is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, haloalkyl, heteroaryl, heterocyclyl, each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, —N(R 5 ) 2 , -alkoxy-alkyl, -alkoxy-alkenyl, —C(O)-alkyl, —C(O)—O-alkyl, —O—C(O)-alkyl, —C(O)—N(R 5 ) 2 , aryl, heteroaryl, —CO-aryl, and —CO-heteroaryl, wherein each R 5  is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl; 
       R is hydrogen, alkyl, alkoxy, haloalkyl, halogen, aryl, heteroaryl, heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH 2 , nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R 4 , —O-alkyl-R 4 , -alkyl-O—R 4 , —C(O)—R 4 , —C(O)—NH—R 4 , —C(O)—NR 4 R 4 , -alkyl-C(O)—R 4 , -alkyl-C(O)—O—R 4 , —C(O)—O—R 4 , —O—C(O)—R 4 , —S—R 4 , —C(O)—S—R 4 , —S—C(O)—R 4 , —S(O) 2 —R 4 , —NH—S(O) 2 —R 4 , -alkyl-S—R 4 , -alkyl-S(O) 2 —R 4 , —NHR 4 , —NR 4 R 4 , —NH-alkyl-R 4 , halogen, —CN, and —SH, wherein R 4  is independently hydrogen, alkyl, alkenyl, alkoxy, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl; 
       n is 0, 1, 2, 3, or 4; 
       Y is —NR 6 R 7 , —CR 6 R 7 R 8 , or -alkyl-NH 2 , each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, —NH 2 , halogen, —N(R 5 ) 2 , -alkoxy-alkyl, -alkoxy-alkenyl, —C(O)-alkyl, —C(O)—O-alkyl, —C(O)—N(R 5 ) 2 , aryl, heteroaryl, —CO-aryl, and —CO-heteroaryl, 
       wherein R 6 , R 7  and R 8  are independently hydrogen, alkyl, alkenyl, alkoxy, alkylamino, dialkylamino, alkylthio, arylthio, -alkyl-hydroxyl, -alkyl-C(O)—O—R 9 , -alkyl-C(O)—R 9 , or -alkyl-O—C(O)—R 9 , wherein each R 5  is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl, wherein R 9  is hydrogen, alkyl, alkenyl, halogen, or haloalkyl;
 X and Z taken together may optionally form a (5-9)-membered ring, 
 
       or a pharmaceutically acceptable salt or solvate thereof, that is capable of activating a human plasmacytoid dendritic cell, myeloid dendritic cell, or NK cell, or a combination thereof. 
     
     
         2 . The method of  claim 1 , wherein said Her2/Neu binding antagonist is trastuzumab. 
     
     
         3 . The method of  claim 1 , wherein said immunotherapeutic is a compound selected from the group consisting of: 
       2-propylthiazolo[4,5-c]quinolin-4-amine, 
       1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, 
       4-amino-2-(ethoxymethyl)-a,a-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 
       1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, 
       N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl-]methanesulfonamide, 
       4-amino-2-ethoxymethyl-aa-dimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol, 
       4-amino-aa-dimethyl-2-methoxyethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, 
       1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, 
       N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea, 
       1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, 
       1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine, 
       N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-cyclohexylurea, 
       N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-(3-cyanophenyl)thiourea, 
       N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropyl]benzamide, 
       2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine, 
       N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-2-ethoxyacetamide, 
       1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, 1-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl]phenyl}methanesulfonamide, 
       1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, 
       3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol, 
       1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-propylurea, 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-3-cyclopentylurea, 
       1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-7-(4-hydroxymethylphenyl)-1H-imidazo[4,5-c]quinolin-4-amine, 
       4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N-methoxy-N-methylbenzamide, 
       2-ethoxymethyl-N1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine, 
       1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, and 
       N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide. 
     
     
         4 . The method of  claim 1 , wherein said combination is capable of providing a systemic effect against cancer or tumor recurrence. 
     
     
         5 . The method of  claim 1 , further comprising administering an effective amount of an additional therapeutic agent. 
     
     
         6 . The method of  claim 5 , wherein said additional therapeutic agent is an anticancer agent. 
     
     
         7 . The method of  claim 6 , wherein said anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor, an antiandrogen agent, a GNRh modulator or mixtures thereof. 
     
     
         8 . The method of  claim 5 , wherein said additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, imatanib, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, cytarabine, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristine, vinblastine, nocodazole, teniposide etoposide, gemcitabine, epothilone, vinorelbine, camptothecin, daunorubicin, actinomycin D, mitoxantrone, acridine, doxorubicin, epirubicin, or idarubicin. 
     
     
         9 . The method of  claim 1 , wherein said immunotherapeutic is of an amount that is capable of:
 (1) inducing IFN-α in an enriched human blood DCs;   (2) inducing TNF-α in an enriched human blood DCs;   (3) inducing IL-12-α in an enriched human blood DCs;   (4) activating CD45 +  immune cells in tumor microenvironment;   (5) activating CD4 +  and CD8 +  T cells in tumor microenvironment;   (6) activating NK cells in tumor microenvironment;   (7) activating plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDc) in tumor microenvironment;   (8) activating macrophages and Monocytes in tumor microenvironment; and/or   (9) increasing migratory DCs in draining lymph nodes.   
     
     
         10 . The method of  claim 1  wherein said effective amount of the immunotherapeutic is from about 0.0005 mg/kg, 0.0006 mg/kg, 0.0007 mg/kg, 0.0008 mg/kg, 0.0009 mg/kg, 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.05 mg/kg, 0.075 mg/kg, 0.1 mg/kg, 0.125 mg/kg, 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.215 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2 mg/kg, or 2.25 mg/kg, to about 2.5 mg/kg, all inclusive, twice daily, once daily, once every two, three, four, five or six days, or once, twice, or three times per week. 
     
     
         11 . The method of  claim 1  wherein said effective amount of the immunotherapeutic is from about 0.0005 mg/kg, to about 0.0006 mg/kg, 0.0007 mg/kg, 0.0008 mg/kg, 0.0009 mg/kg, 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.05 mg/kg, 0.075 mg/kg, 0.1 mg/kg, 0.125 mg/kg, 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.215 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2 mg/kg, 2.25 mg/kg, or 2.5 mg/kg, all inclusive, twice daily, once daily, once every two, three, four, five or six days, or once, twice, or three times per week. 
     
     
         12 . The method of  claim 1  wherein said effective amount of the immunotherapeutic is from about 0.0008 mg/kg to about 0.0067 mg/kg, weekly in a human. 
     
     
         13 . The method of  claim 1 , wherein said administration is orally, sublingually, intravenously, intramuscularly, or subcutaneously. 
     
     
         14 . The method of  claim 1 , wherein said immunotherapeutic in said subject has a local concentration that is between about 0.005 μg/ml to about 12 μg/ml. 
     
     
         15 . The method of  claim 1 , wherein said immunotherapeutic in said subject has a local concentration that is between about 0.05 μg/ml, 0.1 μg/ml, 0.15 μg/ml, 0.2 μg/ml, 0.3 μg/ml, or 0.4 μg/ml, to about 0.5 μg/ml. 
     
     
         16 . The method of  claim 1 , wherein said cancer is selected from the group consisting of: breast cancer, colorectal cancer, diffuse large B-cell lymphoma, endometrial cancer, follicular lymphoma, gastric cancer, glioblastoma, head and neck cancer, hepatocellular cancer, lung cancer, melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.