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for invention","granted":true,"earliest_filing_date":"2009-09-30","grant_date":"2012-10-31","anticipated_term_date":"2029-09-30","has_disclaimer":false,"patent_status":"ACTIVE","publication_count":3,"has_spc":false,"has_grant_event":true,"has_entry_into_national_phase":false},"abstract":{"en":[{"text":"(Problems) To provide a therapeutic agent for infections comprising certain substances together with 15K granulysin, which has characteristics different from antibiotics and no cytotoxicity, to which bacteria can hardly acquire resistance, and shows stronger bactericidal effect against Mycobacterium tuberculosis than an agent comprising 15K granulysin by itself. (Means for solving problems) The present invention provides a therapeutic agent for infections comprising as active ingredient: a combination of 15K granulysin and 15K granulysin in vivo expression vector, a combination of 15K granulysin and at least one interleukin selected from IL-6, IL-23 or IL-27, a combination of 15K granulysin in vivo expression vector and at least one interleukin selected from IL-6, IL-23 or IL-27, or a combination of 15K granulysin in vivo expression vector and HSP65DNA and IL-12DNA in vivo expression vector, which enhances killing effects on bacteria and has less side effect, and to which bacteria can hardly acquire resistance.\n","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"}]},"abstract_lang":["en"],"has_abstract":true,"claim":{"en":[{"text":"A therapeutic agent for infections comprising as active ingredients:\n 15K granulysin; and \n at least one of the following substances (a) to (c).\n (a) interleukin 6 \n (b) interleukin 23 \n (c) interleukin 27","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"A therapeutic agent for infections comprising as active ingredients:\n a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo; and \n at least one of the following substances (a) to (c).\n (a) interleukin 6 \n (b) interleukin 23 \n (c) interleukin 27","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"A therapeutic agent for infections comprising the following (a) and (b) as active ingredients:\n (a) a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo; and \n (b) vectors in which a gene encoding 65KDA heat-shock protein of Mycobacterium tuberculosis H37Rv and a gene encoding interleukin 12 are respectively incorporated to express 65KDA heat-shock protein and interleukin 12 in vivo.","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"A therapeutic agent for infections comprising as active ingredients:\n 15K granulysin; and \n a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo.","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"The therapeutic agent for infections according to claim 1 or 4, wherein the 15K granulysin is a recombinant protein.","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"The therapeutic agent for infections according to claim 1 or 2, wherein causative microorganism of the infections is Mycobacterium tuberculosis.","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"The therapeutic agent for infections according to claim 3 or 4, wherein causative microorganism of the infections is Mycobacterium tuberculosis.","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"},{"text":"The therapeutic agent for infections according to claim 5, wherein causative microorganism of the infections is Mycobacterium tuberculosis.","lang":"en","source":"EPO_FULLTEXT","data_format":"ORIGINAL"}]},"claim_lang":["en"],"has_claim":true,"description":{"en":{"text":"FIELD OF THE INVENTION The present invention relates to a therapeutic agent for treating infectious diseases such as tuberculosis. BACKGROUND OF THE INVENTION In medical care, it goes without saying that a therapeutic agent for infectious diseases is indispensable. At present, a number of therapeutic agents for infections such as antibiotics and synthetic antibacterial agents are provided to be used in medical care. However, currently, an antibacterial agent which is mainly provided as therapeutic agent for infections has in fact an unavoidable problem; appearance of drug resistant bacteria. That is, a new antibacterial agent leads to produce a new drug resistant bacterium, and such a sarcastic state continues until now. For example, tuberculosis occupies the first position of a death rate among single infectious diseases, and its increasing tendency becomes a worldwide problem. Further, a drug resistant bacterium having resistance to almost all antibiotics has been confirmed, and this problem has been obvious. Recently, it has been revealed that granulysin, which is a molecule expressed in Natural Killer cells (NK cell) or Cytotoxic T Lymphocytes (CTL), has direct ability to kill and injure bacteria such as Mycobacterium tuberculosis [ Stenger, S.et al., Science 282, 121-125 (1998 )]. Granulysin is produced as 15K and, thereafter, processed into 9K in a cytotoxic granule. 15 K and 9K granulysins are respectively incorporated into a macrophage so as to kill and injure bacteria such as Mycobacterium tuberculosis phagocytosed into the macrophage. However, 9K granulysin requires a perforin, which is a molecule derived from the same cytotoxic intragranule, to enter into the macrophage. This is because it is necessary to perforate a target cell by perforin such that 9K granulysin enters into the cell therethrough. Accordingly, 9K granulysin shows cytotoxicity. \nOn the other hand, 15K granulysin does not require perforin capable of perforating the target cell in order to enter into a macrophage, and kills and injures bacteria such as Mycobacterium tuberculosis phagocytosed into the macrophage. Accordingly, 15K granulysin shows no cytotoxicity. The present inventors produced 9K granulysin transgenic mouse and 15K granulysin transgenic mouse, then intravenously administered 5x10 5 CFU of H37Rv Mycobacterium tuberculosis through tail vein in each mouse and a wild-type control mouse respectively, and after 4 weeks, measured the numbers of Mycobacterium tuberculosis in lungs of each mouse, and confirmed that the number of Mycobacterium tuberculosis in the lung of 15K granulysin transgenic mouse is more reduced than that of 9K granulysin transgenic mouse with a statistically significant difference (p<0.05; Student's t Test). Thus, the present inventors were the first to find that 15K granulysin had significantly stronger killing effect and suppressing effect on Mycobacterium tuberculosis in vivo than 9K granulysin. In addition, the result suggested that 9K Granulysin had very weak suppressing effect on Mycobacterium tuberculosis in vivo. Based on the above result, the present inventors filed an application relating to a therapeutic agent for infections comprising 15K granulysin as an active ingredient, which has no cytotoxicity and has stronger inhibiting effect against Mycobacterium tuberculosis than 9K granulysin, and a therapeutic agent for infections comprising a vector in which a gene encoding 15 K granulysin is incorporated to express 15K granulysin in vivo as an active ingredient. The application has been patented (Japanese Patent No. 4149713 ). \nHowever, in order to prepare a stronger therapeutic agent for infections, a therapeutic agent comprising certain substances together with 15K granulysin rather than comprising 15K granulysin itself, which is effective on infections caused by bacteria such as Mycobacterium tuberculosis phagocytosed into the macrophage, is desired. SUMMARY OF INVENTION The present invention provides a therapeutic agent for infections comprising certain substances together with 15K granulysin rather than only 15K granulysin itself, to which bacteria acquire less resistance, and which has different characteristics from antibiotics and stronger effect on killing bacteria such as Mycobacterium tuberculosis (M. tuberculosis) phagocytosed into the macrophage. One embodiment of the present invention is related to a therapeutic agent for infections comprising as active ingredients: 15K granulysin; and a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo. \nAnother embodiment of the present invention is related to a therapeutic agent for infections comprising as active ingredients: 15K granulysin; and at least one of the following substances (a) to (c). (a) interleukin 6, (b) interleukin 23(c), interleukin 27 \nYet another embodiment of the present invention is related to a therapeutic agent for infections comprising as active ingredients: a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo; and at least one of the following substances (a) to (c). (a) interleukin 6, (b) interleukin 23, (c) interleukin 27 \nYet another embodiment of the present invention is related to a therapeutic agent for infections comprising the following (a) and (b) as active ingredients: (a) a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo; and(b) vectors in which a gene encoding 65KDA heat-shock protein of M. tuberculosis H37Rv and a gene encoding interleukin 12 are respectively incorporated to express 65KDA heat-shock protein and interleukin 12 in vivo. \nYet another embodiment of the present invention is related to the therapeutic agent for infections, wherein the 15K granulysin is a recombinant protein. \nYet another embodiment of the present invention is related to the therapeutic agent for infections, wherein causative microorganism of the infections is Mycobacterium tuberculosis. According to one embodiment of the present invention, a therapeutic agent for infections comprising as active ingredients: 15K granulysin; and a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo (Hereinafter, referred to as \"15K granulysin in vivo expression vector\")is disclosed. The administration of the therapeutic agent shows no cytotoxicity and shows stronger killing effect on bacteria such as M. tuberculosis phagocytosed into the macrophage than that of 15K granulysin itself or of 15K granulysin in vivo expression vector itself. According to another embodiment of the present invention, a therapeutic agent for infections comprising as active ingredients: 15K granulysin; and at least one of interleukin 6 (hereinafter referred to as \"IL-6\"), interleukin 23 (hereinafter referred to as \"IL-23\") or interleukin 27 (hereinafter referred to as \"IL-27\") is disclosed. The administration of the therapeutic agent shows no cytotoxicity and shows stronger killing effect on bacteria such as M. tuberculosis than that of 15K granulysin itself or of at least one of IL-6, IL-23 or IL-27 itself. According to yet another embodiment of the present invention, a therapeutic agent for infections comprising as active ingredients: 15K granulysin in vivo expression vector; and at least one of IL-6, IL-23, or IL-27 is disclosed. The administration of the therapeutic agent shows stronger killing effects on bacteria such as M. tuberculosis than that of 15K granulysin in vivo expression vector itself or of at least one of IL-6, IL-23 or IL-27 itself. According to yet another embodiment of the present invention, a therapeutic agent for infections comprising as active ingredients: 15K granulysin in vivo expression vector; and HVJ-envelope HSP65DNA and IL-12 DNAin vivo expression vectors against M. tuberculosis created by the present inventors (Hereinafter, referred to as \"HSP65DNA and IL-12DNA in vivo expression vectors\") is disclosed. These HSP65 DNA and IL-12DNA in vivo expression vectors show strong treatment effects on not only mouse family but also Macaca fascicularis family which is considered as the closest model to human in terms of tuberculosis infection. The administration of the therapeutic agent shows stronger killing effects on bacteria such as M. tuberculosis than that of 15K granulysin in vivo expression vector itself or of HSP65 DNA and IL-12 DNA in vivo expression vector itself. \nIn addition, HSP65DNA and IL-12DNA in vivo expression vectors are prepared by incorporating 65KDa heat-shock protein DNA (HSP65DNA) of M. tuberculosis H37Rv and IL-12 DNA into an envelope of Sendai virus (HVJ) , and known to show a strong treatment effect on M. tuberculosis. ( Okada et al, Jpn.J.Clin.Immunol.,31 (5) 356-368 (2008 )) According to yet another embodiment of the present invention, 15K granulysin recombinant protein is stably provided in great quantities. According to yet another embodiment of the present invention, an agent for infections which is effective to Mycobacterium tuberculosis is provided. The present invention provides a therapeutic agent for infections comprising a combination of 15K granulysin and 15K granulysin in vivo expression vector, a combination of 15K granulysin and at least one interleukin selected from IL-6, IL-23 or IL-27, a combination of 15K granulysin in vivo expression vector and at least one interleukin selected from IL-6, IL-23 or IL-27, or a combination of 15K granulysin in vivo expression vector and HSP65DNA and IL-12DNA in vivo expression vectors, which has no side effect and shows killing effect on bacteria such as M. tuberculosis. BRIEF DESCRIPTION OF THE DRAWINGS \n FIG. 1 is a view showing treatment effects of 15K granulysin recombinant protein and 15K granulysin in vivo expression vector in liver of mice (DBA/1) intraperitoneally-infected with M. tuberculosis. FIG.2 is a view showing treatment effects of 15K granulysin recombinant protein and IL-6 in spleen of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.3 is a view showing treatment effects of 15K granulysin in vivo expression vector and IL-6 in spleen of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.4 is a view showing treatment effects of 15K granulysin recombinant protein and IL-6 in liver of mice (BALB/c) infected with M. tuberculosis by aerosol. FIG.5 is a view showing treatment effects of 15K granulysin recombinant protein and IL-6 in lung of mice (BALB/c) infected with M. tuberculosis by aerosol. FIG.6 is a view showing treatment effects of 15K granulysin recombinant protein and 15K granulysin in vivo expression vector in liver of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.7 is a view showing treatment effects of 15K granulysin recombinant protein and 15K granulysin in vivo expression vector in spleen of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.8 is a view showing treatment effects of 15K granulysin recombinant protein and IL-23 in spleen of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.9 is a view showing treatment effects of 15K granulysin recombinant protein and IL-23 in liver of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.10 is a view showing treatment effects of 15K granulysin recombinant protein and IL-23 in lung of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.11 is a view showing treatment effects of 15K granulysin in vivo expression vector and IL-23 in spleen of mice (DBA/1) infected with M. tuberculosis by aerosol. FIG.12 is a view showing treatment effects of 15K granulysin recombinant protein and IL-27 in lung of mice (BALB/c) infected with M. tuberculosis by aerosol. FIG.13 is a view showing treatment effects of 15K granulysin in vivo expression vector and HSP65DNA and IL-12DNA in vivo expression vectors in liver of mice (DBA/1) infected with M. tuberculosis by aerosol. DETAILED DESCRIPTION OF THE INVENTION Embodiments of the present invention will be explained below. \n15K granulysin used as an active ingredient of the present therapeutic agent may be obtained by being separated from a living body. However, since 15K granulysin is a trace component in a living body, it is preferable to be used as a recombinant protein obtained by expressing a gene encoding 15K granulysin. Alternatively, it is also a suitable means to produce 15K granulysin in a living body, utilizing 15K granulysin in vivo expression vector in which a gene encoding 15K granulysin is incorporated, as an active ingredient. (Preparation of 15K Granulysin Recombinant Protein) A sequence of a gene encoding 15K granulysin has been already reported. Based on this, a gene encoding 15K granulysin is effectively prepared to express this gene, which results in preparing a recombinant protein of 15K granulysin. Specifically, the nucleotide chains that are complementary to both ends of a sequence of a gene encoding 15K granulysin are used as amplification primers, and a gene amplification method such as a PCR method is used to prepare a gene amplification product of the gene encoding 15K granulysin. \nThis is incorporated into a suitable gene expression vector, and suitable host such as Escherichia coli, Bacillus subtilis, yeast and insect cell is transformed with such the recombinant vector so as to produce a desired 15K granulysin. It is preferable that, as a gene expression vector used herein, a vector having a promoter and an enhancer at a region upstream of a gene to be expressed, and a transcription termination sequence at a region downstream of the gene is used. In addition, an expression of a 15K granulysin gene is not limited to a direct expression system. For example, a fused protein expression system utilizing a β-galactosidase gene, a glutathione-S-transferase gene or a thioredoxin gene may be used. As a gene expression vector using Escherichia coli as a host, there are exemplified pQE, pGEX, pT7-7, pMAL, pTrxFus, pET, and pNT26CII. As a gene expression vector using Bacillus subtilis as a host, there are exemplified pPL608, pNC3, pSM23, and pKH80. In addition, as a gene expression vector using yeast as a host, there are exemplified pGT5, pDB248X, pART1, pREP1, YEp13, YRp7, and YCp50. In addition, as a gene expression vector using a mammal cell or an insect cell as a host, there are exemplified p91023, pCDM8, pcDL-SRa296, pBCMGSNeo, pSV2dhfr, pSVdhfr, pAc373, pAcYM1, pRc/CMV, pREP4, and pcDNAI. These gene expression vectors may be selected depending on the purpose of expression of 15K granulysin. For example, when 15K granulysin is expressed, it is preferable to select a gene expression vector for which Escherichia coli, Bacillus subtilis or yeast may be selected as a host. When 15K granulysin is expressed to show an assuredly activity even at a small amount, it is preferable to select a gene expression vector for which a mammal cell or an insect cell may be selected as a host. In addition, it is possible to select the existing gene expression vector as described above, but a gene expression vector may be appropriately produced depending on a purpose, and this may be of course used. Transfection of the above-mentioned gene expression vector in which a 15K granulysin gene is incorporated, into a host cell, and a transformation method therewith may be performed by the general method, for example, a calcium chloride method, and an electroporation method are used in the case of using Escherichia coli and Bacillus subtilis as a host cell, and a calcium phosphate method, an electroporation method and a liposome method are used in the case of using a mammal cell and an insect cell as a host. The obtained transformant is cultured according to the conventional methods so as to accumulate a desired 15K granulysin. Medium used in such the culture may be appropriately selected depending on the characteristics of a host. For example, LB medium and TB medium may be appropriately used in the case of using Escherichia coli as a host, and RPMI1640 medium may be appropriately used in the case of using mammal cells as a host. 15K granulysin may be isolated and purified from the obtained culture according to the conventional method. For example, various treating operations utilizing physical and/or chemical nature of 15K granulysin may be used. Specifically, treatment with a protein precipitating agent, ultrafiltration, gel filtration, high performance liquid chromatography, centrifugation, electrophoresis, affinity chromatography using a specific antibody, and dialysis method can be used alone or by combining these methods. (Preparation of 15K Granulysin In Vivo Expression Vector) An active ingredient of the present therapeutic agent is a recombinant vector, which is an in vivo expression vector in which a gene encoding 15K granulysin used for expressing the aforementioned recombinant protein is incorporated. Examples of the in vivo expression vector are not limited to, but include an adenovirus vector and a retrovirus vector. For an in vivo expression vector, for example, the aforementioned virus gene is incorporated into a cosmid vector, and a gene capable of expressing 15K granulysin is further incorporated into the cosmid vector and then, this cosmid vector and a parent virus DNA-TP which has been treated with a restriction enzyme are transfected into 293 cells, whereby, homologous recombination occurs in the 293 cells, thus, a desired in vivo expression vector is produced. (Present Therapeutic Agent Comprising 15K granulsin Recombinant Protein and 15K Granulysin In Vivo Expression Vector as Active Ingredient) \nThe combined use of 15K granulsin recombinant protein and 15K granulysin in vivo expression vector shows stronger killing effect on bacteria such as M. tuberculosis phagocytosed into the macrophage than independent use of the above. 15K granulysin may be formed to a preparation composition by blending an appropriate pharmaceutical preparation thereinto (of course, only 15K glanulysin is possible). As a pharmaceutical preparation carrier, for example, excipients and diluents such as fillers, bulking agents, binders, wetting agents, stabilizers, solubilizers, disintegrating agents and surface active agents which are conventionally used as a pharmaceutical preparation carrier may be freely selected depending on a specific dosage form. A form of a preparation composition is not particularly limited as far as 15K granulysin is effectively used in treatments of infectious diseases. For example, solid agents such as tablets, powders, granules and pills, and also injectable forms such as solutions, suspensions and emulsions may be used. An appropriate carrier to 15K granulysin may be added to produce a dried agent, which is formulated to be liquid upon use. The 15K granulysin in vivo expression vector prepared as described above is isolated and purified, and thereafter administered into a living body, so as to produce 15K granulysin in vivo and exhibit pharmacological effects of 15K granulysin. A dose amount may be appropriately selected depending on an administration method and an administration form of an agent, and symptom of a patient. It is preferable to administer 10,000µg/50kg of the 15K granulysin recombinant protein once per day or by dividing into a few times per day and 6 times at a few dates interval, while it is preferable to administer 2,000µg/50kg of the 15K granulysin in vivo expression vector once per day and 6 times at a few dates interval, but it is not limited thereto. A dosage form of the 15K granulysin in vivo expression vector is generally an injectable form. Also, 15K granulysin in vivo expression vector may be prepared in an injectable form by adding an appropriate carrier thereto. Then, the 15K granulysin recombinant protein and the 15K granulysin in vivo expression vector in the injectable forms may be administered by intravenous, intramuscular, intraosseous, intra-articular, subcutaneous, intracutaneous, or intraperitoneal administration at the same time or alternately at a given interval. (Present Therapeutic Agent Comprising 15K Granulsin Recombinant Protein and at least one Interleukin Selected from IL-6, IL-23 or IL-27 as Active Ingredient) \nCombined use of the 15K granulysin recombinant protein and at least one interleukin selected from IL-6, IL-23 or IL-27 shows killing effects on bacteria such as M. tuberculosis phagocytosed into the macrophage than independent use of the above materials. 15K granulysin recombinant protein and at least one interleukin selected from IL-6, IL-23 or IL-27 may be formed in a preparation composition by blending an appropriate pharmaceutical preparation carrier thereinto. As for a pharmaceutical preparation carrier, for example, excipients and diluents such as fillers, bulking agents, binders, wetting agents, stabilizers, solubilizers, disintegrating agents and surface active agents which are conventionally used as a pharmaceutical preparation carrier may be freely selected depending on a specific dosage form. A form of a preparation composition is not particularly limited as far as both the 15K granulysin recombinant protein and the at least one interleukin selected from IL-6, IL-23 or IL-27 are effectively used in treatments of infectious diseases. For example, solid agents such as tablets, powders, granules and pills, and also injectable forms such as solutions, suspensions and emulsions may be used. An appropriate carrier to the 15K granulysin recombinant protein and the at least one interleukin selected from interleukin 6, interleukin 23 or interleukin 27 may be added to produce a dried agent, which is formulated to be liquid upon use. A dose amount of such the therapeutic agent may be appropriately selected depending on an administration method and an administration form of an agent, and symptom of a patient. It is preferable to administer 10,000µg/50kg of 15K granulysin recombinant protein and 2,500µg/50kg in the case of IL-6, 5,000µg/50kg in the case of IL-23, or 2,500µg/50kg in the case of IL-27, which are active ingredients, once per day or by dividing into a few times per day, and 6 times at a few dates to more than 1 week interval, but not limited thereto. The administrations of the two materials may be performed at the same time or alternately at a given interval. Because a combination of 15K granulysin protein and interleukin exhibits strong killing effects on bacteria such as M. tuberculosis phagocytosed into the macrophage, it is possible to reduce the treatment times to 3 times. Such the various forms of pharmaceutical preparations may be administered by an appropriate administration route depending on its form, for example, by intravenous, intramuscular, intraosseous, intra-articular, subcutaneous, intracutaneous, or intraperitoneal administration in the case of an injectable form, or by oral or enteral administration in the case of a solid agent form. (Present Therapeutic Agent Comprising 15K Granulsin In Vivo Expression Vector and at least one Interleukin Selected from IL-6, IL-23 or IL-27 as Active ingredient) \nCombined use of the 15K granulysin in vivo expression vector and the at least one interleukin selected from interleukin 6, interleukin 23 or interleukin 27 as active ingredients enables to show killing effects on bacteria such as M. tuberculosis phagocytosed into the macrophage than independent use of the above materials. 15K granulysin in vivo expression vector and the at least one interleukin selected from IL-6, IL-23 or IL-27 are formed to a preparation composition by blending an appropriate pharmaceutical preparation carrier thereinto. A dose amount of such the therapeutic agent may be appropriately decided depending on an administration method and an administration form of an agent, and symptom of a patient. It is preferable to administer 2,000µg/50kg of the 15K granulysin in vivo expression vector once per day and 6 times at a few dates to more than 1 week interval, while it is preferable to administer 2,500µg/50kg in the case of IL-6, 5,000µg/50kg in the case of IL-23, and 2,500µg/50kg in the case of IL-27, once per day or by dividing into a few times per day and 6 times at a few dates to more than 1 week interval, but it is not limited thereto. A dosage form of the 15K granulysin in vivo expression vector is generally an injectable form. Also, the at least one interleukin selected from IL-6, IL-23, or IL-27 may be prepared in an injectable form by adding an appropriate carrier thereto. Then, the both materials in the injectable forms may be administered at the same time or alternately at a given interval. (Present Therapeutic Agent Comprising 15K Granulsin In Vivo Expression Vector and HSP65DNA and IL-12DNA In Vivo Expression Vectors as Active Ingredient) \nA dosage form of the 15K granulsin in vivo expression vector and an HSP65DNA and IL-12DNA in vivo expression vectors is generally an injectable form, and it may be administered by intravenous, intramuscular, intraosseous, intra-articular, subcutaneous, intracutaneous or intraperitoneal administration. A dose of such the present therapeutic agent may be appropriately selected depending on an administration method and an administration form of an agent, and symptom of a patient, but being not limited. Generally, it is preferable to administer 2,000µg/50kg of 15K granulysin in vivo expression vector and 2,000µg/50kg of the HSP65DNA and IL-12DNA in vivo expression vectors, which are active ingredients, once per day, and 6 times at a few dates interval. Because a combination of 15K granulysin in vivo expression vector and HSP65DNA and IL-12DNA in vivo expression vectors exhibits strong killing effects on bacteria such as M. tuberculosis phagocytosed into the macrophage, it is possible to reduce the treatment times to 3 times. [Example] Examples of the present invention will be described below. Improvements of killing effect on bacteria by using (1) 15K granulysin recombinant protein and 15K granulysin in vivo expression vector, (2) 15K granulysin recombinant protein and at least one interleukin selected from IL-6, IL-23 or IL-27, (3) 15K granulysin in vivo expression vector and at least one interleukin selected from IL-6, IL-23 or IL-27, and (4) 15K granulysin in vivo expression vector and HSP65DNA and IL-12 DNA in vivo expression vectors. \"Synergetic effect\" used herein means effect when a combined use of more than two materials improves killing effect on bacteria compared to an independent use of the materials. G1 to G10 groups used in the examples are shown in TABLE.1. \n TABLE-tabl0001
15K granulysin; and
at least one of the following substances (a) to (c)."],"number":1,"annotation":false,"title":false,"claim":true},{"lines":["A therapeutic agent for infections comprising as active ingredients:(a) interleukin 6(b) interleukin 23(c) interleukin 27
a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo; and
at least one of the following substances (a) to (c)."],"number":2,"annotation":false,"title":false,"claim":true},{"lines":["A therapeutic agent for infections comprising the following (a) and (b) as active ingredients:(a) interleukin 6(b) interleukin 23(c) interleukin 27
(a) a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo; and
(b) vectors in which a gene encoding 65KDA heat-shock protein of Mycobacterium tuberculosis H37Rv and a gene encoding interleukin 12 are respectively incorporated to express 65KDA heat-shock protein and interleukin 12 in vivo."],"number":3,"annotation":false,"title":false,"claim":true},{"lines":["A therapeutic agent for infections comprising as active ingredients:
15K granulysin; and
a vector in which a gene encoding 15K granulysin is incorporated to express 15K granulysin in vivo."],"number":4,"annotation":false,"title":false,"claim":true},{"lines":["The therapeutic agent for infections according to claim 1 or 4, wherein the 15K granulysin is a recombinant protein."],"number":5,"annotation":false,"title":false,"claim":true},{"lines":["The therapeutic agent for infections according to claim 1 or 2, wherein causative microorganism of the infections is Mycobacterium tuberculosis."],"number":6,"annotation":false,"title":false,"claim":true},{"lines":["The therapeutic agent for infections according to claim 3 or 4, wherein causative microorganism of the infections is Mycobacterium tuberculosis."],"number":7,"annotation":false,"title":false,"claim":true},{"lines":["The therapeutic agent for infections according to claim 5, wherein causative microorganism of the infections is Mycobacterium tuberculosis."],"number":8,"annotation":false,"title":false,"claim":true}]}},"filters":{"npl":[],"notNpl":[],"applicant":[],"notApplicant":[],"inventor":[],"notInventor":[],"owner":[],"notOwner":[],"tags":[],"dates":[],"types":[],"notTypes":[],"j":[],"notJ":[],"fj":[],"notFj":[],"classIpcr":[],"notClassIpcr":[],"classNat":[],"notClassNat":[],"classCpc":[],"notClassCpc":[],"so":[],"notSo":[],"sat":[]},"sequenceFilters":{"s":"SEQIDNO","d":"ASCENDING","p":0,"n":10,"sp":[],"si":[],"len":[],"t":[],"loc":[]}}