Oncolytic vaccinia virus
Provided is an oncolytic virus having both improved safety and productivity. Provided are: a conditionally replicating vaccinia virus which lacks the functions of a vaccinia virus growth factor (VGF), an extracellular signal-regulated kinase (ERK) activation protein, and a ribonucleotide reductase (RNR), is not replicated in a normal cell, is selectively replicable in a proliferative cell, and has improved safety; and a conditionally replicating vaccinia virus which lacks the functions of a VGF, an ERK activation protein, and an RNR, is not replicated in a normal cell, is selectively replicable in a proliferative cell, and has improved safety and productivity, and in which a gene encoding an extracellular enveloped virus (EEV)-related protein is substituted with a gene corresponding to another vaccinia virus strain having a high EEV-producing ability.
1 . A vaccinia virus deficient in functions of vaccinia virus growth factor (VGF), extracellular signal-regulated kinase (ERK)-activating protein, and ribonucleotide reductase (RNR), wherein all or part of regions of each of C11R, O1L, and F4L genes have been deleted or modified, and the functions of these gene products have been inactivated;
wherein genes encoding extracellular enveloped virus (EEV)-related proteins are replaced by a corresponding genes of another vaccinia virus strain having a high EEV productivity;
wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A36R, A56R, B5R, F12L, and F13L, and have been replaced by corresponding genes of another vaccinia virus strain having a high EEV productivity, wherein the corresponding genes of another vaccinia virus strain having a high EEV productivity are genes encoding the same amino acid sequence as those of EEV-related proteins selected from the group consisting of A33R, A36R, A56R, B5R, F12L, and F13L being present in vaccinia virus IHD-J strain or IHD-W strain; or
wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A34R, A36R, A56R, B5R, F12L, and F13L, and have been replaced by corresponding genes of another vaccinia virus strain having a high EEV productivity, wherein the corresponding genes of another vaccinia virus strain having a high EEV productivity are genes encoding the same amino acid sequence as those of EEV-related proteins selected from the group consisting of A33R, A34R, A36R, A56R, B5R, F12L, and F13L being present in vaccinia virus IHD-J strain or IHD-W strain.
2 . The virus according to claim 1 , which is a growth-restricted virus having improved safety, wherein the virus does not replicate in a normal cell and can selectively replicate in a proliferating cell.
3 . The virus according to claim 1 , wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A36R, A56R, B5R, F12L, and F13L, and have been replaced by corresponding genes of another vaccinia virus strain having a high EEV productivity, wherein the corresponding genes of another vaccinia virus strain having a high EEV productivity are genes encoding the same amino acid sequence as those of EEV-related proteins selected from the group consisting of A33R, A36R, A56R, B5R, F12L, and F13L being present in vaccinia virus IHD-J strain or IHD-W strain.
4 . The virus according to claim 1 , wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A34R, A36R, A56R, B5R, F12L, and F13L, and have been replaced by corresponding genes of another vaccinia virus strain having a high EEV productivity, wherein the corresponding genes of another vaccinia virus strain having a high EEV productivity are genes encoding the same amino acid sequence as those of EEV-related proteins selected from the group consisting of A33R, A34R, A36R, A56R, B5R, F12L, and F13L being present in vaccinia virus IHD-J strain or IHD-W strain.
5 . A pharmaceutical composition for treating a cancer, comprising the virus according to claim 1 .
6 . The pharmaceutical composition according to claim 5 , which is for intravenous administration, intraperitoneal administration, or intratumoral administration.
7 . A growth-restricted vaccinia virus vector, which is the virus according to claim 1 into which a foreign DNA has been introduced.
8 . The vector according to claim 7 , wherein the foreign DNA is a gene encoding a cancer-specific antigen, an immune response regulator, or a protein with affinity for a cancer cell surface antigen.
9 . A method of improving productivity of a growth-restricted vaccinia virus, comprising: replacing DNA sequences of genes encoding extracellular enveloped virus (EEV)-related proteins of the growth-restricted vaccinia virus by DNA sequences of corresponding genes of another vaccinia virus strain having a high EEV productivity, wherein the growth-restricted vaccinia virus does not replicate in a normal cell, and can selectively replicate in a proliferating cell, the growth-restricted vaccinia virus deficient in functions of vaccinia virus growth factor (VGF), extracellular signal- regulated kinase (ERK)-activating protein, and ribonucleotide reductase (RNR),
wherein all or part of regions of each of C11R, O1L, and F4L genes have been deleted or modified, and the functions of these gene products have been inactivated-,
wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A36R, A56R, B5R, F12L, and F13L genes or
wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A34R, A36R, A56R, B5R, F12L, and F13L genes and have been replaced by corresponding genes of another vaccinia virus strain having a high EEV productivity, and
wherein the corresponding genes of another vaccinia virus strain having a high EEV productivity are genes encoding the same amino acid sequence as those of EEV-related proteins selected from the group consisting of A33R, A34R, A36R, A56R, B5R, F12L, and F13L being present in vaccinia virus IHD-J strain or IHD-W strain.
10 . The method according to claim 9 , wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A36R, A56R, B5R, F12L, and F13L genes.
11 . The method according to claim 9 , wherein the genes encoding the extracellular enveloped virus (EEV)-related proteins are A33R, A34R, A36R, A56R, B5R, F12L, and F13L genes.