Composition and method for treating cancer using herpes virus

Abstract

The present invention provides a herpes virus in which a non-essential gene for replication is inactivated. More particularly, the present invention provides a herpes virus in which a non-essential gene for replication present in a UL or US region is inactivated. More preferably, the non-essential gene for replication contains US3 or UL56. The herpes virus may be preferably a herpes simplex virus, and more preferably herpes simplex virus 1 or herpes simplex virus 2. The present invention provides a method, composition and use for treating various diseases or disorders including tumor and infectious diseases. The present invention also provides a method, composition and use for activating a prodrug.

1 . A herpes virus, wherein at least one non-essential gene for replication thereof is inactivated.  
     
     
         2 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         3 . A herpes virus according to  claim 1 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, US1, US2, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         4 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         5 . A herpes virus according to  claim 4 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         6 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication contains UL56 or US3.  
     
     
         7 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication contains UL39 and UL40.  
     
     
         8 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication contains UL39 and UL56.  
     
     
         9 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication contains UL2 and US3.  
     
     
         10 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication contains UL56.  
     
     
         11 . A herpes virus according to  claim 1 , wherein the non-essential gene for replication contains US3.  
     
     
         12 . A herpes virus according to  claim 1 , wherein at least two non-essential genes for replication are inactivated.  
     
     
         13 . A herpes virus according to  claim 10 , wherein the second non-essential gene for replication and thereafter are selected from the group consisting of RL1, RL2, ORFP, ORFO, RL3, UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL16, UL20, UL20.5, UL21, UL24, UL39, UL40, UL41, UL43, UL43.5, UL44, UL45, UL46, UL47, UL50, UL51, UL55, UL56, US1, US1.5, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         14 . A herpes virus according to  claim 1 , further comprising an exogenous suicide gene.  
     
     
         15 . A herpes virus according to  claim 1 , further comprising a carboxyesterase gene.  
     
     
         16 . A herpes virus according to  claim 1 , wherein the virus has ability to select cancer cells.  
     
     
         17 . A herpes virus according to  claim 1 , wherein the inactivation includes at least one nucleotide substitution, addition, deletion or modification in the sequence of the non-essential gene for replication.  
     
     
         18 . A herpes virus according to  claim 1 , wherein the virus is a modified herpes simplex virus.  
     
     
         19 . A herpes virus according to  claim 1 , wherein the virus is a modified HSV-1 or HSV-2.  
     
     
         20 . A pharmaceutical composition, comprising: 
 a herpes virus wherein at least one non-essential gene for replication thereof is inactivated; and    a pharmaceutically acceptable carrier.    
     
     
         21 . A pharmaceutical composition according to  claim 20 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         22 . A pharmaceutical composition according to  claim 20 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, US1, US2, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         23 . A pharmaceutical composition according to  claim 20 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         24 . A pharmaceutical composition according to  claim 23 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         25 . A pharmaceutical composition according to  claim 20 , wherein the non-essential gene for replication contains UL56 or US3.  
     
     
         26 . A pharmaceutical composition according to  claim 20 , wherein the inactivation includes at least one nucleotide substitution, addition, deletion or modification in the sequence of the non-essential gene for replication.  
     
     
         27 . A pharmaceutical composition according to  claim 20 , wherein a signal for stopping translation is inserted into the sequence of the non-essential gene for replication.  
     
     
         28 . A pharmaceutical composition according to  claim 25 , wherein the signal for stopping translation is a polyadenylation signal.  
     
     
         29 . A pharmaceutical composition according to  claim 20 , wherein the virus is a modified herpes simplex virus.  
     
     
         30 . A pharmaceutical composition according to  claim 20 , wherein the virus is a modified HSV-1 or HSV-2.  
     
     
         31 . A pharmaceutical composition according to  claim 20 , further comprising a prodrug capable of converting the attenuated herpes virus into an active form.  
     
     
         32 . A pharmaceutical composition according to  claim 31 , wherein the prodrug is selected from the group consisting of ganciclovir, acyclovir, taxol, and camptothecin.  
     
     
         33 . A pharmaceutical composition according to  claim 20 , wherein the composition is used for treatment of tumor.  
     
     
         34 . A pharmaceutical composition according to  claim 33 , further comprising at least one drug for treatment of tumor.  
     
     
         35 . A pharmaceutical composition according to  claim 20 , wherein the composition is used to enhance an anticancer action of the prodrug which is converted into an active form by the herpes virus.  
     
     
         36 . A pharmaceutical composition according to  claim 20 , wherein the composition is used for treatment of an infectious disease.  
     
     
         37 . A pharmaceutical composition according to  claim 36 , wherein the infectious disease is caused by a herpes virus.  
     
     
         38 . A pharmaceutical composition according to  claim 36 , comprising a gene derived from a pathogen of the infectious disease.  
     
     
         39 . A pharmaceutical composition according to  claim 20 , comprising L1BR1.  
     
     
         40 . A pharmaceutical composition according to  claim 20 , wherein the composition is in the form of a vaccine.  
     
     
         41 . A pharmaceutical composition according to  claim 20 , wherein the composition is an agent for treating or preventing a disease or disorder caused by infection of a herpes virus.  
     
     
         42 . A pharmaceutical composition according to  claim 41 , wherein the disease caused by the infection of a herpes virus is a sexually transmitted disease.  
     
     
         43 . A pharmaceutical composition according to  claim 40 , wherein the composition is used for treatment or prevention of an infectious disease.  
     
     
         44 . A pharmaceutical composition according to  claim 43 , further comprising a pathogen of the infectious disease.  
     
     
         45 . A pharmaceutical composition according to  claim 43 , wherein the pathogen of the infectious disease is a virus or bacterium.  
     
     
         46 . A pharmaceutical composition according to  claim 43 , wherein the pathogen of the infectious disease is selected from the group consisting of HIV, influenza virus, and rotavirus.  
     
     
         47 . A method for treating or preventing an infectious disease or tumor, comprising the step of: 
 administering a pharmaceutical composition comprising a herpes virus, at least one non-essential gene for replication thereof being inactivated, and a pharmaceutically acceptable carrier, to a subject requiring the treatment or prevention.    
     
     
         48 . A method according to  claim 47 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         49 . A method according to  claim 47 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, US1, US2, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         50 . A method according to  claim 47 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         51 . A method according to  claim 50 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         52 . A method according to  claim 47 , wherein the non-essential gene for replication contains US3 or UL56.  
     
     
         53 . A method according to  claim 47 , wherein the inactivation includes at least one nucleotide substitution, addition, deletion or modification.  
     
     
         54 . A method according to  claim 47 , wherein the herpes virus is a modified herpes simplex virus.  
     
     
         55 . A method according to  claim 47 , wherein the herpes virus is a modified HSV-1 or HSV-2.  
     
     
         56 . A method according to  claim 47 , further comprising the step of administering a prodrug which is converted into an active form by a herpes virus.  
     
     
         57 . A method according to  claim 56 , wherein the prodrug is selected from the group consisting of ganciclovir, acyclovir, taxol, and camptothecin.  
     
     
         58 . A method according to  claim 47 , comprising the step of administering at least one drug for treatment of tumor.  
     
     
         59 . A method according to  claim 47 , further comprising the step of administering at least one drug for treatment of an infectious disease.  
     
     
         60 . A method according to  claim 47 , wherein the tumor is selected from the group consisting of ovarian cancer, liver cancer, pancreatic cancer, bladder cancer, urethra cancer, large intestine cancer, skin cancer, malignant melanoma, osteosarcoma, head and neck squamous cell carcinoma, and stomach cancer.  
     
     
         61 . A method for enhancing an anticancer action of a prodrug which is converted into an active form by a herpes virus, the method comprising the step of: 
 administering a pharmaceutical composition comprising a herpes virus, at least one non-essential gene for replication thereof being inactivated, and a pharmaceutically acceptable carrier to a subject requiring the enhancement of an anticancer action.    
     
     
         62 . A method according to  claim 61 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         63 . A method according to  claim 61 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11, and US12.  
     
     
         64 . A method according to  claim 61 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         65 . A method according to  claim 64 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         66 . A method according to  claim 61 , wherein the non-essential gene for replication contains US3 or UL56.  
     
     
         67 . A method according to  claim 61 , wherein the prodrug is selected from the group consisting of ganciclovir, acyclovir, taxol, and camptothecin.  
     
     
         68 . A method according to  claim 61 , wherein the herpes virus is a modified herpes simplex virus.  
     
     
         69 . A method according to  claim 61 , wherein the herpes virus is a modified HSV-1 or HSV-2.  
     
     
         70 . A method for reducing the severity or infection rate of a herpes virus, comprising the step of: 
 administering a vaccine comprising a herpes virus, at least one non-essential gene for replication thereof is inactivated, to a subject requiring the treatment or prevention.    
     
     
         71 . A method according to  claim 70 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         72 . A method according to  claim 71 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11, and US12.  
     
     
         73 . A method according to  claim 70 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         74 . A method according to  claim 73 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         75 . A method according to  claim 70 , wherein the non-essential gene for replication contains US3 or UL56.  
     
     
         76 . A method according to  claim 70 , wherein the herpes virus is a modified herpes simplex virus.  
     
     
         77 . A method according to  claim 70 , wherein the herpes virus is a modified HSV-1 or HSV-2.  
     
     
         78 . Use of a herpes virus for producing a pharmaceutical composition for treating or preventing tumor, wherein at least one non-essential gene for replication of the herpes virus is inactivated.  
     
     
         79 . Use according to  claim 78 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         80 . Use according to  claim 78 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11, and US12.  
     
     
         81 . A method according to  claim 78 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         82 . A method according to  claim 81 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         83 . Use according to  claim 78 , wherein the non-essential gene for replication contains US3 or UL56.  
     
     
         84 . A method according to  claim 78 , wherein the herpes virus is a modified herpes simplex virus.  
     
     
         85 . A method according to  claim 78 , wherein the herpes virus is a modified HSV-1 or HSV-2.  
     
     
         86 . Use of a herpes virus for producing a pharmaceutical composition for enhancing an anticancer action of a prodrug which is converted into an active form by the herpes virus, wherein at least one non-essential gene for replication of the herpes virus is inactivated.  
     
     
         87 . Use according to  claim 86 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         88 . Use according to  claim 86 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11, and US12.  
     
     
         89 . Use according to  claim 86 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         90 . Use according to  claim 89 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         91 . Use according to  claim 86 , wherein the non-essential gene for replication contains US3 or UL56.  
     
     
         92 . Use according to  claim 86 , wherein the herpes virus is a modified herpes simplex virus.  
     
     
         93 . Use according to  claim 86 , wherein the herpes virus is a modified HSV-1 or HSV-2.  
     
     
         94 . Use of a herpes virus for producing a pharmaceutical composition for reducing the severity and/or infection rate of a herpes virus, wherein at least one non-essential gene for replication of the herpes virus is inactivated.  
     
     
         95 . Use according to  claim 94 , wherein the non-essential gene for replication is present in a UL region or a US region.  
     
     
         96 . Use according to  claim 94 , wherein the herpes virus is herpes simplex virus, and the non-essential gene for replication is selected from the group consisting of UL2, UL3, UL4, UL7, UL10, UL11, UL12, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL39, UL40, UL41, UL43, UL44, UL45, UL46, UL47, UL50, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11, and US12.  
     
     
         97 . Use according to  claim 94 , wherein the non-essential gene for replication is a gene not involved in DNA and deoxyribonucleotide metabolism.  
     
     
         98 . Use according to  claim 97 , wherein the gene not involved in DNA and deoxyribonucleotide metabolism is selected from the group consisting of UL3, UL4, UL7, UL10, UL11, UL13, UL14, UL16, UL20, UL21, UL24, UL35, UL41, UL43, UL44, UL45, UL46, UL47, UL51, UL55, UL56, US1, US2, US3, US4, US5, US7, US8, US8.5, US9, US10, US11 and US12.  
     
     
         99 . Use according to  claim 94 , wherein the non-essential gene for replication contains US3 or UL56.  
     
     
         100 . Use according to  claim 94 , wherein the pharmaceutical composition is a vaccine.  
     
     
         101 . Use according to  claim 94 , wherein the herpes virus is a modified herpes simplex virus.  
     
     
         102 . Use according to  claim 94 , wherein the herpes virus is a modified HSV-1 or HSV-2.