KR20220079081A - Pharmaceutical composition for preventing or treating tuberculosis - Google Patents

Abstract

The present invention relates to a fusion protein comprising a fusion polypeptide derived from Mycobacterium tuberculosis ; a polynucleotide encoding the protein; a recombinant vector comprising the polynucleotide; And it relates to a pharmaceutical composition for preventing or treating tuberculosis comprising the fusion protein, polynucleotide or recombinant vector.

Description

Pharmaceutical composition for preventing or treating tuberculosis {Pharmaceutical composition for preventing or treating tuberculosis}

The present invention relates to a fusion protein comprising a fusion polypeptide derived from Mycobacterium tuberclosis; a polynucleotide encoding the protein; a recombinant vector comprising the polynucleotide; And it relates to a pharmaceutical composition for preventing or treating tuberculosis comprising the fusion protein, polynucleotide or recombinant vector.

Tuberculosis is a disease caused by a bacterium called Mycobacterium Tuberculosis. Tuberculosis is exhaled into the air through a cough or sneeze containing Mycobacterium tuberculosis of a contagious pulmonary tuberculosis patient, and can be infected by inhaling it. Although it is generally transmitted through the respiratory tract, not all infected people become tuberculosis patients, and even if they are infected with Mycobacterium tuberculosis, they can lead a healthy life without getting sick if their immunity is normal. Therefore, it is very important to develop a prophylactic or therapeutic vaccine that protects people who are not infected with tuberculosis or who are infected with tuberculosis.

Bacillus Calmette-Gurin (BCG) is a live attenuated vaccine that attenuates the virulence of a bacterium called Mycobacterium bovis . It is the most used tuberculosis vaccine worldwide and is effective in protecting children. However, there is a problem that the duration is limited to childhood, and the preventive effect on adult pulmonary tuberculosis, the main form of tuberculosis, is unstable at 0-80%. Accordingly, countries around the world are developing new tuberculosis vaccines that can replace or supplement existing tuberculosis vaccines.

The new anti-tuberculosis vaccine is a protein subunit vaccine using a tuberculosis antigen, a DNA vaccine expressing the tuberculosis antigen inducing protective immunity in plasmid DNA or a viral vector, or a viral vector vaccine, and a tuberculosis antigen inducing protective immunity in the BCG vaccine. It is being developed in the form of a recombinant BCG vaccine to express and a recombinant tuberculosis vaccine in which the pathogenic gene of Mycobacterium tuberculosis has been removed. DNA vaccines have been tried many new vaccines against tuberculosis so far, and their efficacy has been proven in animal models. In addition, many tuberculosis antigens have been discovered using DNA vaccine techniques.

DNA vaccines have proven to be very effective in establishing cellular immune responses, including cytotoxic T lymphocytes (CTLs) and Th1 responses, which are known to be essential for acquiring effective anti-mycobacteria immunity in mice and humans (Bonato VL). et al., Infect Immun, 1998, 66: 169-175). In addition, in the introduction of an efficient immunization technique, antigen discovery is also being actively carried out due to the importance of selecting an appropriate antigen essential for tuberculosis defense efficacy.

Accordingly, the present inventors completed the present invention by developing a vaccine for the prevention or treatment of tuberculosis using an antigen having a tuberculosis protective effect.

Korean Patent No. 10-1378240

It is an object of the present invention to provide a fusion protein comprising a fusion polypeptide derived from Mycobacterium tuberclosis.

Another object of the present invention is to provide a polynucleotide encoding the fusion protein.

Another object of the present invention is to provide a recombinant vector comprising the polynucleotide.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating tuberculosis comprising the fusion protein.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating tuberculosis comprising the polynucleotide.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating tuberculosis comprising the recombinant vector.

In order to achieve the above object, the present invention provides a fusion protein comprising a fusion polypeptide derived from Mycobacterium tuberclosis.

In addition, the present invention provides a polynucleotide encoding the fusion protein.

In addition, the present invention provides a recombinant vector comprising the polynucleotide.

In addition, the present invention provides a pharmaceutical composition for preventing or treating tuberculosis comprising the fusion protein.

In addition, the present invention provides a pharmaceutical composition for preventing or treating tuberculosis comprising the polynucleotide.

In addition, the present invention provides a pharmaceutical composition for preventing or treating tuberculosis comprising the recombinant vector.

The fusion protein according to the present invention has the effect of increasing a specific immune response to a tuberculosis antigen and remarkably reducing the number of Mycobacterium tuberculosis in the lungs, and thus can be usefully used for the prevention or treatment of tuberculosis.

1 shows a gene construct for the production of a fusion protein.
Figure 2 shows the results of measuring the specific immune response to the tuberculosis antigen through the IFN-γ ELISPOT analysis after administering the DNA vaccine to the mouse animal model.
Figure 3 shows the results of measuring the number of Mycobacterium tuberculosis in the lungs and histopathological results of the lungs after administration of the DNA vaccine to the mouse animal model.
Figure 4 shows the results of measuring the number of Mycobacterium tuberculosis in the lungs and histopathological results of the lungs after administration of the DNA vaccine to the mouse animal model.
5 shows the results of measuring the number of Mycobacterium tuberculosis in the lungs after administration of a DNA vaccine to a mouse animal model and re-infection with Mycobacterium tuberculosis.

The present invention provides a fusion protein comprising a fusion polypeptide derived from Mycobacterium tuberculosis .

The fusion polypeptide may be one selected from the group consisting of Ag85A, TB10.4, Mtb32b and PstS3, and may preferably include Ag85A, TB10.4, Mtb32b and PstS3. In one embodiment of the present invention, the Ag85A consists of the amino acid sequence of SEQ ID NO: 1, the TB10.4 consists of the amino acid sequence of SEQ ID NO: 2, the Mtb32b consists of the amino acid sequence of SEQ ID NO: 3, The PstS3 may be composed of the amino acid sequence of SEQ ID NO: 4.

In addition, the fusion polypeptide may further include a polypeptide selected from the group consisting of PPE39, GlcB and RipA, and preferably further include a polypeptide including PPE39, GlcB and RipA. . In one embodiment of the present invention, the PPE39 may consist of the amino acid sequence of SEQ ID NO: 5, the GlcB may consist of the amino acid sequence of SEQ ID NO: 6, and the RipA may consist of the amino acid sequence of SEQ ID NO: 7.

The fusion polypeptide may be linked by a 2A peptide (2A self-cleaving peptide) or a GS linker, and preferably, the GS linker may include (GS)n (where n is an integer from 1 to 10). . In one embodiment of the present invention, the GS linker may consist of the amino acid sequence of SEQ ID NO: 8.

In the present invention, the fusion protein may further include a signal peptide.

As used herein, the term "signal peptide or secretory signal sequence" refers to a short, about 20 to 30 amino acid long amino acid present at the N-terminus of a newly synthesized protein defined as a secretory pathway. refers to peptides.

The signal peptide may be selected from the group consisting of a tissue plaminogen activator (tPA) signal peptide, a Herpes Simplex Virus glycoprotein Ds (HSV gDs) signal peptide, and a growth hormone signal peptide, preferably a mammal. A secretory signal sequence used in higher eukaryotic cells may be used, and more preferably, a tPa sequence may be used.

In one embodiment of the present invention, the tPA sequence may consist of the amino acid sequence of SEQ ID NO: 9. In addition, the signal sequence of the present invention can be used by substituting a codon having a high expression frequency in a host cell.

In the present invention, the fusion protein may further include an immune enhancing peptide.

As used herein, the term "immune enhancing peptide" refers to a peptide that increases the immune response by activating cells (eg, dendritic cells, etc.) involved in the immune response.

The immune enhancing peptide may be selected from the group consisting of a CD40 ligand, an fms-like tyrosine kinase-3 (Flt3) ligand, flagellin, and OX40, and may preferably be an Flt3 ligand, but is not limited thereto. it is not In one embodiment of the present invention, the Flt3 ligand may consist of the amino acid sequence of SEQ ID NO: 10.

The present invention relates to a signal peptide; an immune enhancing peptide of Flt3 ligand; and a fusion polypeptide comprising Ag85A, TB10.4, Mtb32b and PstS3.

In one embodiment of the present invention, the fusion protein may consist of the amino acid sequence of SEQ ID NO: 11.

In addition, the present invention provides a signal peptide; an immune enhancing peptide of Flt3 ligand; and a fusion polypeptide comprising PPE39, GlcB and RipA.

In one embodiment of the present invention, the fusion protein may consist of the amino acid sequence of SEQ ID NO: 12.

In addition, the present invention provides a polynucleotide encoding the fusion protein.

The polynucleotides of the present invention may be prepared by chemical synthesis or genetic engineering techniques. Chemical synthesis methods are well known to those skilled in the art, and any method may be used. In addition, it can be purchased by requesting from a commercial nucleic acid synthesis and provider. In the case of manufacturing by genetic manipulation technology, for example, a nucleic acid fragment encoding a fusion polypeptide derived from Mycobacterium tuberclosis, a signal peptide, and an immune enhancing peptide known in the prior art is obtained, respectively, and these fragments are placed in frame. It can be made by connecting them appropriately. Methods for obtaining the nucleic acid fragments are well known in the art, and those skilled in the art can easily link them using appropriate restriction enzymes. In a specific implementation of the present invention, a method for preparing by chemical synthesis is disclosed.

The polynucleotide of the present invention may include a polynucleotide encoding a fusion polypeptide comprising Ag85A, TB10.4, Mtb32b and PstS3.

The Ag85A consists of the nucleic acid sequence of SEQ ID NO: 13, the TB10.4 consists of the nucleic acid sequence of SEQ ID NO: 14, the Mtb32b consists of the nucleic acid sequence of SEQ ID NO: 15, and the PstS3 consists of the nucleic acid sequence of SEQ ID NO: 16 may be made of Ag85A, TB10.4, Mtb32b and PstS3 may be linked with a GS linker, and preferably, the GS linker may consist of a nucleic acid sequence selected from SEQ ID NOs: 20 to 23.

In addition, the polynucleotide of the present invention may include a polynucleotide encoding a fusion polypeptide comprising PPE39, GlcB and RipA.

The PPE39 may consist of the nucleic acid sequence of SEQ ID NO: 17, the GlcB may consist of the nucleic acid sequence of SEQ ID NO: 18, and the RipA may consist of the nucleic acid sequence of SEQ ID NO: 19. PPE39, GlcB and RipA may be linked by a GS linker, and preferably, the GS linker may consist of a nucleic acid sequence selected from SEQ ID NOs: 20 to 23.

In addition, the polynucleotide of the present invention may further include a polynucleotide encoding a signal peptide, the signal peptide may be a tPA sequence, and the polynucleotide encoding the tPA sequence is SEQ ID NO: 24 or 25 It may consist of a nucleic acid sequence.

In addition, the polynucleotide of the present invention may further include a polynucleotide encoding an immune enhancing peptide, the immune enhancing peptide may be an Flt3 ligand, and the polynucleotide encoding the Flt3 ligand is SEQ ID NO: 26 or 27 It may consist of a nucleic acid sequence of

In one embodiment of the present invention, the polynucleotide comprises: a polynucleotide encoding a fusion polypeptide comprising Ag85A, TB10.4, Mtb32b and PstS3; a polynucleotide encoding a signal peptide; and a polynucleotide encoding an immune enhancing peptide. Preferably, the polynucleotide may consist of the nucleic acid sequence of SEQ ID NO: 28.

In one embodiment of the present invention, the polynucleotide is a polynucleotide encoding a fusion polypeptide comprising PPE39, GlcB and RipA; a polynucleotide encoding a signal peptide; and a polynucleotide encoding an immune enhancing peptide. Preferably, the polynucleotide may consist of the nucleic acid sequence of SEQ ID NO: 29.

In addition, the present invention provides a recombinant vector comprising the polynucleotide.

As used herein, the term "vector" refers to a genetic construct comprising foreign DNA inserted into a genome encoding a polypeptide. The recombinant expression vector of the present invention is a vector in which a polynucleotide encoding a fusion protein containing a fusion polypeptide derived from Mycobacterium tuberculosis , a signal peptide and an immune enhancing peptide is inserted into the genome.

The vector may be a plasmid vector, a viral vector, a cosmid vector or an artificial chromosome vector, and the viral vector may be a bacteriophage vector, an adenoviral vector, a retroviral vector or an adeno-associated viral vector.

The recombinant vector of the present invention may contain a nucleic acid encoding the fusion protein in a form suitable for expression of the nucleic acid encoding the fusion protein of the present invention in a host cell. That is, the recombinant vector of the present invention comprises one or more regulatory sequences, selected based on the host cell to be used for expression, which are operably linked to the nucleic acid sequence to be expressed.

As used herein, the term “operably linked” means that a desired nucleotide sequence is linked to a regulatory sequence in such a way that its expression can be achieved (eg, in an in vitro transcription/translation system or in a host cell). means that it has been

As used herein, the term "regulatory sequence" refers to promoters, enhancers and other regulatory elements (eg, polyadenylation signals). Regulatory sequences include those that direct expression of a desired nucleic acid in many host cells and those that direct expression of a desired nucleic acid only in specific host cells (eg, tissue-specific regulatory sequences). It can be understood by those skilled in the art that the design of the expression vector may vary depending on factors such as the selection of a host cell to be transformed and a desired protein expression level. The expression vector of the present invention can be introduced into a host cell to express the fusion protein.

In addition, the present invention provides a pharmaceutical composition for preventing or treating tuberculosis comprising the fusion protein.

In one embodiment of the present invention, the composition may further include an adjuvant containing IL-12, IL-21 and MIP-1a proteins, preferably, the adjuvant is SEQ ID NO: It may include an amino acid sequence of 30 to 33. In the above, IL-12 p35 is composed of the amino acid sequence of SEQ ID NO: 30, IL-12 p40 is composed of the amino acid sequence of SEQ ID NO: 31, IL-21 is composed of the amino acid sequence of SEQ ID NO: 32, MIP-1a (MIP-1 alpha) is composed of the amino acid sequence of SEQ ID NO: 33.

As used herein, the term "immune adjuvant" refers to a substance added to a vaccine to stimulate the immune system's response to an antigen.

In addition, the present invention provides a pharmaceutical composition for preventing or treating tuberculosis comprising the polynucleotide or the recombinant vector.

The composition may further include a polynucleotide encoding an adjuvant containing IL-12, IL-21 and MIP-1a protein, preferably a polynucleotide encoding the amino acid sequence of SEQ ID NOs: 30 to 33 It may be one, and more preferably, it may include the nucleic acid sequence of SEQ ID NOs: 34 to 37.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable” refers to exhibiting non-toxic properties to cells or humans exposed to the composition. The carrier may be used without limitation as long as it is known in the art, such as buffers, preservatives, pain relievers, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants, and the like.

The composition of the present invention may be formulated in oral formulations such as granules, powders, liquids, tablets, capsules, or dry syrups, or parenteral formulations such as injections, preferably, the composition of the present invention is in the form of a solution or injection However, it is not limited to these formulations.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "administration" means introducing a predetermined substance to an individual by an appropriate method, and the administration route of the composition may be administered through any general route as long as it can reach a target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, may be administered intrarectally, but is not limited thereto.

As used herein, the term “individual” refers to all animals including humans, rats, mice, and livestock. Preferably, it may be a mammal including a human.

As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is dependent on the patient's sex, age, body weight, health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route, and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other fields of medicine It can be readily determined by a person skilled in the art according to well-known factors. For administration, the recommended dosage may be administered once a day, or divided into several administrations.

Hereinafter, the present invention will be described in more detail through examples. These examples are for explaining the present invention in more detail, and the scope of the present invention is not limited to these examples.

Example 1. Preparation of fusion proteins

The fusion protein of the present invention includes a fusion polypeptide derived from Mycobacterium tuberculosis , a signal peptide, and an immunity enhancer peptide. The Mycobacterium tuberculosis -derived fusion polypeptide includes Ag85A, TB10.4, Mtb32b and PstS3, and each polypeptide (antigen) is linked with a 2A peptide (2A self-cleaving peptide) was prepared. In addition, the signal peptide tPA (tissue plaminogen activator) peptide and the immune enhancing peptide Flt3L (fms-like tyrosine kinase-3) ligand were prepared to be linked to the N-terminus of the fusion polypeptide.

In addition, the Mycobacterium tuberculosis -derived fusion polypeptide was prepared by fusion to further include a polypeptide of PPE39, GlcB and / or RipA in addition to Ag85A, TB10.4, Mtb32b and PstS3. . Each polypeptide (antigen) was prepared by linking with a 2A peptide (2A self-cleaving peptide) or a GS linker, and the N-terminus of the fusion polypeptide was also prepared such that the signal peptide tPA peptide and the immune enhancing peptide Flt3L ligand were linked. did

Hereinafter, a fusion protein in which a fusion polypeptide of Ag85A, TB10.4, Mtb32b and PstS3 is linked with a 2A peptide and an HA tag is added to the C-terminus is described as “GX-70”, Ag85A, TB10.4, Mtb32b, A fusion protein in which a fusion polypeptide of PPE39 and PstS3 is linked by a 2A peptide is described as “GX-171A”, and a fusion protein in which a fusion polypeptide of Ag85A, TB10.4, Mtb32b, RipA and PstS3 is linked by a 2A peptide is referred to as “GX-” 171B", the fusion protein of Ag85A, TB10.4, Mtb32b, and PstS3 linked by a GS linker was described as "GX-170A", and the fusion polypeptide of PPE39, GlcB and RipA was linked by a GS linker The fusion protein was described as “GX-170B” ( FIG. 1 ).

The candidate fusion proteins were prepared by synthesizing the gene sequence for each corresponding fusion protein and inserting it into a high expression vector pGX27 (refer to Korean Patent No. 1442254).

Example 2. Preparation of an adjuvant

The adjuvant of the present invention includes IL-12, IL-21 and MIP-1a proteins. The N-terminus of IL-12 was prepared so that the CMV promoter (pCMV) was connected, the N-terminus of IL-21 was prepared so that the RSV promoter (pRSV) was connected, and the N-terminus of MIP-1a was the EF1a promoter (pEF1a). ) was prepared to be connected. Hereinafter, an adjuvant containing IL-12, IL-21 and MIP-1a proteins was described as "BD-121A" (FIG. 1).

A cassette for expressing each corresponding fusion protein was synthesized and inserted into a high expression vector pGX27 (refer to Korean Patent No. 1442254).

Example 3. Analysis of the immune enhancement efficacy of a composition containing a fusion protein and an adjuvant

The present inventors performed an experiment to determine whether the composition containing the fusion protein and the adjuvant exhibits an immune enhancing effect. Briefly, PBS (formulation control) or DNA vaccine was administered to the femoral muscles of C57BL/6 mice twice at 2-week intervals using an OrbiJector ^ⓡ (SL VAXiGEN, Korea) in vivo electroporator. After the final administration, the spleen was removed and the specific immune response to the tuberculosis antigen was measured by IFN-γ ELISPOT analysis. Information on the groups administered with PBS or DNA vaccine is as follows: Group 1, PBS (formulation control group); Group 2, GX-70 8 μg; Group 3, GX-70 8 μg + BD-121A 8 μg; Group 4, GX-171A 8 μg; Group 5, GX-171A 8 μg + BD-121A 8 μg; Group 6, GX-171B 8 μg; and group 7, 8 μg GX-171B + 8 μg BD-121A.

As a result, tuberculosis-specific immune responses were induced in tuberculosis candidates GX-70, GX-171A and GX-171B. In groups 3, 5 and 7, it was confirmed that the tuberculosis-specific immune response was further increased (FIG. 2).

Example 4. Tuberculosis Prevention Efficacy Analysis

The present inventors performed an experiment to determine whether the composition containing the fusion protein and the adjuvant is effective in preventing tuberculosis. Briefly, PBS (formulation control) or DNA vaccine was administered to the femoral muscles of C57BL/6 mice three times at 3-week intervals using an OrbiJector ^ⓡ (SL VAXiGEN, Korea) in vivo electroporator. The positive control group, BCG, was administered to C57BL/6 mice once every 3 weeks. After 3 weeks of final administration, Mycobacterium tuberculosis was air-infected, and the number of Mycobacterium tuberculosis was measured in the lungs 3 weeks after that to confirm the protective efficacy against Mycobacterium tuberculosis. Information on the groups administered with PBS or DNA vaccine is as follows: Group 1, PBS (formulation control group); Group 2, GX-70 4 μg; Group 3, 4 μg GX-171A + 4 μg BD-121A; Group 4, 4 μg GX-171B + 4 μg BD-121A; and group 5, BCG (positive control).

As a result, in the group administered with all vaccine candidates, a lower number of tuberculosis bacteria was confirmed compared to the formulation control group, and it was confirmed that the degree of inflammation was suppressed in the lung histopathology results (FIG. 3). However, no difference in protective potency between each vaccine candidate was identified.

Accordingly, the present inventors performed additional experiments to evaluate the efficacy of preventing tuberculosis by co-administering the additionally manufactured GX-170A and GX-170B. Briefly, PBS (formulation control) or DNA vaccine was administered to the femoral muscles of C57BL/6 mice three times at 3-week intervals using an OrbiJector ^ⓡ (SL VAXiGEN, Korea) in vivo electroporator. The positive control group, BCG, was administered to C57BL/6 mice once every 3 weeks. After 3 weeks of final administration, Mycobacterium tuberculosis was air-infected, and the number of Mycobacterium tuberculosis was measured in the lungs 3 weeks after that to confirm the preventive efficacy against Mycobacterium tuberculosis. Information on the groups administered with PBS or DNA vaccine is as follows: Group 1, PBS (formulation control group); Group 2, GX-70 8 μg; Group 3, GX-70 8 μg + BD-121A 8 μg; Group 4, GX-171A 8 μg + BD-121A 8 μg; Group 5, GX-170A 8 μg + GX-170B 8 μg + BD-121A 4 μg; and Group 6, BCG (positive control).

As a result, it was confirmed that the group administered with all vaccine candidates had a significant anti-tuberculosis efficacy compared to the formulation control group (FIG. 4). In the group administered with GX-70, tuberculosis prevention efficacy was found to be higher than that of the formulation control group regardless of the addition of an adjuvant, and the group administered with GX-171A and BD-121A was similar to the group administered with GX-70. It was confirmed to be effective (FIG. 4). In particular, it was confirmed that the group administered with GX-170A, GX-170B and BD-121A had a more significant tuberculosis prevention effect than the group administered with GX-70, and the same was observed in the lung histopathology results (Fig. 4).

Example 5. Tuberculosis treatment efficacy analysis

The present inventors performed an experiment to determine whether the composition containing the fusion protein and the adjuvant is effective in treating tuberculosis. Briefly, C57BL/6 mice were air-infected with Mycobacterium tuberculosis and 4 weeks later, tuberculosis drugs INH (isoniazid) and PZA (pyrazinamide) were treated with drinking water for 14 weeks. During the treatment period, the BCG group (positive control group) was administered once every 8 weeks, and PBS (formulation control group) or DNA vaccine was administered to the femoral muscle of C57BL/6 mice at 5, 8, 11, and 13 weeks. OrbiJector ^ⓡ (SL VAXiGEN, Korea) was administered three times using an in vivo electroporator. After confirming that the Mycobacterium tuberculosis was not detected at the end of the tuberculosis drug treatment, the number of re-infected Mycobacterium tuberculosis was observed in the lungs after secondary infection with Mycobacterium tuberculosis by air infection at 20 weeks. Information on the groups receiving the DNA vaccine is as follows: Group 1, Naive, who did not receive tuberculosis medication; Group 2, PBS (formulation control); Group 3, GX-70 8 μg; Group 4, GX-170A 8 μg; Group 5, GX-170A 8 μg + GX-170B 8 μg; Group 6, GX-70 8 μg + BD-121A 8 μg; Group 7, GX-170A 8 μg + BD-121A 8 μg; and group 8, GX-170A 8 μg + GX-170B 8 μg + BD-121A 8 μg.

As a result, it was confirmed that the number of tuberculosis re-infection after tuberculosis infection was lower in all groups than in the untreated group (FIG. 5). In the group treated with GX-170A and GX-170B, the number of Mycobacterium tuberculosis showed a tendency to decrease. sound was confirmed (FIG. 5).

From the above results, the present inventors confirmed that the tuberculosis treatment efficacy was confirmed by the combined administration of GX-170A and GX-170B, and confirmed that the tuberculosis treatment efficacy was further increased by the combined administration of an additional adjuvant.

<110> Genexine, Inc. Korea Disease Control and Prevention Agency <120> Pharmaceutical composition for preventing or treating tuberculosis <130> 1068294 <160> 37 <170> KoPatentIn 3.0 <210> 1 <211> 295 <212> PRT <213> Artificial Sequence <220> < 223> amino acid sequence of Ag85A <400> 1 Phe Ser Arg Pro Gly Leu Pro Val Glu Tyr Leu Gln Val Pro Ser Pro 1 5 10 15 Ser Met Gly Arg Asp Ile Lys Val Gln Phe Gln Ser Gly Gly Ala Asn 20 25 30 Ser Pro Ala Leu Tyr Leu Leu Asp Gly Leu Arg Ala Gln Asp Asp Phe 35 40 45 Ser Gly Trp Asp Ile Asn Thr Pro Ala Phe Glu Trp Tyr Asp Gln Ser 50 55 60 Gly Leu Ser Val Val Val Met Pro Val Gly Gly Gln Ser Ser Phe Tyr Ser 65 70 75 80 Asp Trp Tyr Gln Pro Ala Cys Gly Lys Ala Gly Cys Gln Thr Tyr Lys 85 90 95 Trp Glu Thr Phe Leu Thr Ser Glu Leu Pro Gly Trp Leu Gln Ala Asn 100 105 110 Arg His Val Lys Pro Thr Gly Ser Ala Val Val Gly Leu Ser Met Ala 115 120 125 Ala Ser Ser Ala Leu Thr Leu Ala Ile Tyr His Pro Gln Gln Phe Val 130 135 140 Tyr Ala Gly Ala Met Ser Gly Leu Leu Asp Pro Ser Gln Ala Met Gly 145 150 155 160 Pro Thr Leu Ile Gly Leu Ala Met Gly Asp Ala Gly Gly Tyr Lys Ala 165 170 175 Ser Asp Met Trp Gly Pro Lys Glu Asp Pro Ala Trp Gln Arg Asn Asp 180 185 190 Pro Leu Leu Asn Val Gly Lys Leu Ile Ala Asn Asn Thr Arg Val Trp 195 200 205 Val Tyr Cys Gly Asn Gly Lys Pro Ser Asp Leu Gly Gly Asn Asn Leu 210 215 220 Pro Ala Lys Phe Leu Glu Gly Phe Val Arg Thr Ser Asn Ile Lys Phe 225 230 235 240 Gln Asp Ala Tyr Asn Ala Gly Gly Gly His Asn Gly Val Phe Asp Phe 245 250 255 Pro Asp Ser Gly Thr His Ser Trp Glu Tyr Trp Gly Ala Gln Leu Asn 260 265 270 Ala Met Lys Pro Asp Leu Gln Arg Ala Leu Gly Ala Thr Pro Asn Thr 275 280 285 Gly Pro Ala Pro Gln Gly Ala 290 295 <210> 2 <211> 95 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of TB10.4 <400> 2 Ser Gln Ile Met Tyr Asn Tyr Pro Ala Met Leu Gly His Ala Gly Asp 1 5 10 15 Met Ala Gly Tyr Ala Gly Thr Leu Gln Ser Leu Gly Ala Glu Ile Ala 20 25 30 Val Glu Gln Ala Ala Leu Gln Ser Ala Trp Gln Gly Asp Thr Gly Ile 35 40 45 Thr Tyr Gln Ala Trp Gln Ala Gln Trp Asn Gln Ala Met Glu Asp Leu 50 55 60 Val Arg Ala Tyr His Ala Met Ser Ser Thr His Glu Ala Asn Thr Met 65 70 75 80 Ala Met Met Ala Arg Asp Thr Ala Glu Ala Ala Lys Trp Gly Gly 85 90 95 < 210> 3 <211> 323 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of Mtb32d <400> 3 Ala Pro Pro Ala Leu Ser Gln Asp Arg Phe Ala Asp Phe Pro Ala Leu 1 5 10 15 Pro Leu Asp Pro Ser Ala Met Val Ala Gln Val Gly Pro Gln Val Val 20 25 30 Asn Ile Asn Thr Lys Leu Gly Tyr Asn Asn Ala Val Gly Ala Gly Thr 35 40 45 Gly Ile Val Ile Asp Pro Asn Gly Val Val Leu Thr Asn Asn Ala Val 50 55 60 Ile Ala Gly Ala Thr Asp Ile Asn Ala Phe Ser Val Gly Ser Gly Gln 65 70 75 80 Thr Tyr Gly Val Asp Val Val Gly Tyr Asp Arg Thr Gln Asn Val Ala 85 90 95 Val Leu Gln Leu Arg Gly Ala Gly Gly Leu Pro Ser Ala Ala Ile Gly 100 105 110 Gly Gly Val Ala Val Gly Glu Pro Val Val Ala Met Gly Asn Ser Gly 115 120 125 Gly Gln Gly Gly Thr Pro Arg Ala Val Pro Gly Arg Val Val Ala Leu 130 135 140 Gly Gln Thr Val Gln Ala Ser Asp Ser Leu Thr Gly Ala Glu Glu Thr 145 150 155 160 Leu Asn Gly Leu Ile Gln Phe Asp Ala Ala Ile Gln Pro Gly Asp Ala 165 170 175 Gly Gly Pro Val Val Asn Gly Leu Gly Gln Val Val Gly Met Asn Thr 180 185 190 Ala Ala Ser Asp Asn Phe Gln Leu Ser Gln Gly Gly Gln Gly Phe Ala 195 200 205 Ile Pro Ile Gly Gln Ala Met Ala Ile Ala Gly Gln Ile Arg Ser Gly 210 215 220 Gly Gly Ser Pro Thr Val His Ile Gly Pro Thr Ala Phe Leu Gly Leu 225 230 235 240 Gly Val Val Asp Asn Asn Gly Asn Gly Ala Arg Val Gln Arg Val Val 245 250 255 Gly Ser Ala Pro Ala Ala Ser Leu Gly Ile Ser Thr Gly Asp Val Ile 260 265 270 Thr Ala Val Asp Gly Ala Pro Ile Asn Ser Ala Thr Ala Met Ala Asp 275 280 285 Ala Leu Asn Gly His His Pro Gly Asp Val Ile Ser Val Thr Trp Gln 290 295 300 Thr Lys Ser Gly Gly Thr Arg Thr Gly Asn Val Thr Leu Ala Glu Gly 305 310 315 320 Pro Pro Ala <210> 4 <211> 347 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of PstS3 <400> 4 Cys Gly Asn Asp Asp Asn Val Thr Gly Gly Gly Ala Thr Thr Gly Gln 1 5 10 15 Ala Ser Ala Lys Val Asp Cys Gly Gly Lys Lys Thr Leu Lys Ala Ser 20 25 30 Gly Ser Thr Ala Gln Ala Asn Ala Met Thr Arg Phe Val Asn Val Phe 35 40 45 Glu Gln Ala Cys Pro Gly Gln Thr Leu Asn Tyr Thr Ala Asn Gly Ser 50 55 60 Gly Ala Gly Ile Ser Glu Phe Asn Gly Asn Gln Thr Asp Phe Gl y Gly 65 70 75 80 Ser Asp Val Pro Leu Ser Lys Asp Glu Pro Ser Gly Ala Ala Arg Cys 85 90 95 Gly Ser Pro Ala Trp Asn Leu Pro Val Val Phe Gly Pro Ile Ala Val 100 105 110 Thr Tyr Asn Leu Asn Ser Val Ser Ser Leu Asn Leu Asp Gly Pro Thr 115 120 125 Leu Ala Lys Ile Phe Asn Gly Ser Ile Thr Gln Trp Asn Asn Pro Ala 130 135 140 Ile Gln Ala Leu Asn Arg Asp Phe Thr Leu Pro Gly Glu Arg Ile His 145 150 155 160 Val Val Phe Arg Ser Asp Glu Ser Gly Thr Thr Asp Asn Phe Gln Arg 165 170 175 Tyr Leu Gln Ala Ala Ser Asn Gly Ala Trp Gly Lys Gly Ala Gly Lys 180 185 190 Ser Phe Gln Gly Gly Val Gly Glu Gly Ala Arg Gly Asn Asp Gly Thr 195 200 205 Ser Ala Ala Ala Lys Asn Thr Pro Gly Ser Ile Thr Tyr Asn Glu Trp 210 215 220 Ser Phe Ala Gln Ala His A sp Leu Thr Met Ala Asn Ile Val Thr Ser 225 230 235 240 Ala Gly Gly Asp Pro Val Ala Ile Thr Ile Asp Ser Val Gly Gln Thr 245 250 255 Ile Ala Gly Ala Thr Ile Ser Gly Val Gly Asn Asp Leu Val Leu Asp 260 265 270 Thr Asp Ser Phe Tyr Arg Pro Lys Arg Pro Gly Ser Tyr Pro Ile Val 275 280 285 Leu Ala Thr Tyr Glu Ile Val Cys Ser Lys Tyr Pro Asp Ser Gln Val 290 295 300 Gly Thr Ala Val Lys Ala Phe Leu Gln Ser Thr Ile Gly Ala Gly Gln 305 310 315 320 Ser Gly Leu Gly Asp Asn Gly Tyr Ile Pro Ile Pro Asp Glu Phe Lys 325 330 335 Ser Arg Leu Ser Thr Ala Val Asn Ala Ile Ala 340 345 <210> 5 <211> 621 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of PPE39 <400> 5 Val Asn Phe Ser Val Leu Pro Glu Ile Asn Ser Gly Arg Me t Phe 1 5 10 15 Phe Gly Ala Gly Ser Gly Pro Met Leu Ala Ala Ala Ala Ala Trp Asp 20 25 30 Gly Leu Ala Ala Glu Leu Gly Leu Ala Ala Glu Ser Phe Gly Leu Val 35 40 45 Thr Ser Gly Leu Ala Gly Gly Ser Gly Gln Ala Trp Gln Gly Ala Ala 50 55 60 Ala Ala Ala Met Val Val Ala Ala Ala Pro Tyr Ala Gly Trp Leu Ala 65 70 75 80 Ala Ala Ala Ala Arg Ala Gly Gly Ala Ala Val Gln Ala Lys Ala Val 85 90 95 Ala Gly Ala Phe Glu Ala Ala Arg Ala Ala Met Val Asp Pro Val Val 100 105 110 Val Ala Ala Asn Arg Ser Ala Phe Val Gln Leu Val Leu Ser Asn Val 115 120 125 Phe Gly Gln Asn Ala Pro Ala Ile Ala Ala Ala Glu Ala Thr Tyr Glu 130 135 140 Gln Met Trp Ala Ala Asp Val Ala Ala Met Val Gly Tyr His Gly Gly 145 150 155 160 Ala Ser Ala Ala Ala Ala Ala Leu Ala Pro Trp Gln Gln Ala Val Pro 165 170 175 Gly Leu Ser Gly Leu Leu Asp Ser Ala Gln Se r Ser Ala Gln Ala Val 180 185 190 Thr Ala Gln Ala Val Gly Ser Thr Val Pro Gly Pro Leu Gln Gly Ile 195 200 205 Asn Phe Gly Phe Gly Asn Ile Gly Ser Leu Asn Leu Gly Ser Gly Asn 210 215 220 Thr Gly Asp Thr Asn Val Gly Ser Gly Asn Ile Gly Asn Thr Asn Leu 225 230 235 240 Gly Gly Gly Asn Ile Gly Ser Phe Asn Leu Gly Ser Gly Asn Gln Gly 245 250 255 Asp Ile Asn Leu Gly Ile Gly Asn Val Gly Asn Leu Asn Leu Gly Ser 260 265 270 Gly Asn Phe Gly Ser Gln Asn Leu Gly Ser Gly Asn Ile Gly Ser Thr 275 280 285 Asn Val Gly Ser Gly Asn Ile Gly Ser Thr Asn Val Gly Ser Gly Asn 290 295 300 Ile Gly Asp Thr Asn Phe Gly Asn Gly Asn Asn Gly Asn Phe Asn Phe 305 310 315 320 Gly Ser Gly Asn Thr Gly Ser As n Asn Ile Gly Phe Gly Asn Thr Gly 325 330 335 Ser Gly Asn Phe Gly Phe Gly Asn Thr Gly Asn Asn Asn Ile Gly Ile 340 345 350 Gly Leu Thr Gly Asp Gly Gln Ile Gly Ile Gly Gly Leu Asn Ser Gly 355 360 365 Ser Gly Asn Ile Gly Phe Gly Asn Ser Gly Thr Gly Asn Val Gly Leu 370 375 380 Phe Asn Ser Gly Thr Gly Asn Val Gly Phe Gly Asn Ser Gly Thr Ala 385 390 395 400 Asn Thr Gly Phe Gly Asn Ala Gly Asn Val Asn Thr Gly Phe Trp Asn 405 410 415 Gly Gly Ser Thr Asn Thr Gly Leu Ala Asn Ala Gly Ala Gly Asn Thr 420 425 430 Gly Phe Phe Asp Ala Gly Asn Tyr Asn Phe Gly Ser Leu Asn Ala Gly 435 440 445 Asn Ile Asn Ser Ser Phe Gly Asn Ser Gly Asp Gly Asn Ser Gly Phe 450 455 460 Leu Asn Ala Gly Asp Val Asn Ser Gly Va l Gly Asn Ala Gly Asp Val 465 470 475 480 Asn Thr Gly Leu Gly Asn Ser Gly Asn Ile Asn Thr Gly Gly Phe Asn 485 490 495 Pro Gly Thr Leu Asn Thr Gly Phe Phe Ser Ala Met Thr Gln Ala Gly 500 505 510 Pro Asn Ser Gly Phe Phe Asn Ala Gly Thr Gly Asn Ser Gly Phe Gly 515 520 525 His Asn Asp Pro Ala Gly Ser Gly Asn Ser Gly Ile Gln Asn Ser Gly 530 535 540 Phe Gly Asn Ser Gly Tyr Val Asn Thr Ser Thr Thr Ser Met Phe Gly 545 550 555 560 Gly Asn Ser Gly Val Leu Asn Thr Gly Tyr Gly Asn Ser Gly Phe Tyr 565 570 575 Asn Ala Ala Val Asn Asn Thr Gly Ile Phe Val Thr Gly Val Met Ser 580 585 590 Ser Gly Phe Phe Asn Phe Gly Thr Gly Asn Ser Gly Leu Leu Val Ser 595 600 605 Gly Asn Gly Leu Ser Gly Ph e Phe Lys Asn Leu Phe Gly 610 615 620 <210> 6 <211> 740 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of GlcB <400> 6 Thr Asp Arg Val Ser Val Gly Asn Leu Arg Ile Ala Arg Val Leu Tyr 1 5 10 15 Asp Phe Val Asn Asn Glu Ala Leu Pro Gly Thr Asp Ile Asp Pro Asp 20 25 30 Ser Phe Trp Ala Gly Val Asp Lys Val Val Ala Asp Leu Thr Pro Gln 35 40 45 Asn Gln Ala Leu Leu Asn Ala Arg Asp Glu Leu Gln Ala Gln Ile Asp 50 55 60 Lys Trp His Arg Arg Arg Val Ile Glu Pro Ile Asp Met Asp Ala Tyr 65 70 75 80 Arg Gln Phe Leu Thr Glu Ile Gly Tyr Leu Leu Pro Glu Pro Asp Asp 85 90 95 Phe Thr Ile Thr Thr Ser Gly Val Asp Ala Glu Ile Thr Thr Thr Ala 100 105 110 Gly Pro Gln Leu Val Val Pro Val Leu Asn Ala Arg Phe Ala Leu Asn 115 120 125 Ala Ala Asn Ala Arg Trp Gly Ser Leu Tyr Asp Ala Leu Tyr Gly Thr 130 135 140 Asp Val Ile Pro Glu Thr Asp Gly Ala Glu Lys Gly Pro Thr Tyr Asn 145 150 155 160 Lys Val Arg Gly Asp Lys Val Ile Ala Tyr Ala Arg Lys Phe Leu Asp 165 170 175 Asp Ser Val Pro Leu Ser Ser Gly Ser Phe Gly Asp Ala Thr Gly Phe 180 185 190 Thr Val Gln Asp Gly Gln Leu Val Val Ala Leu Pro Asp Lys Ser Thr 195 200 205 Gly Leu Ala Asn Pro Gly Gln Phe Ala Gly Tyr Thr Gly Ala Ala Glu 210 215 220 Ser Pro Thr Ser Val Leu Leu Ile Asn His Gly Leu His Ile Glu Ile 225 230 235 240 Leu Ile Asp Pro Glu Ser Gln Val Gly Thr Thr Asp Arg Ala Gly Val 245 250 255 Lys Asp Val Ile Leu Glu Ser Ala Ile Thr Thr Ile Met Asp Phe Glu 260 265 270 Asp Ser Val Ala Ala Val Asp Ala Ala Asp Lys Val Leu Gly Tyr Arg 275 280 285 Asn Trp Leu Gly Leu Asn Lys Gly Asp Leu Ala Ala Ala Val Asp Lys 290 295 300 Asp Gly Thr Ala Phe Leu Arg Val Leu Asn Arg Asp Arg Asn Tyr Thr 305 310 315 320 Ala Pro Gly Gly Gly Gln Phe Thr Leu Pro Gly Arg Ser Leu Met Phe 325 330 335 Val Arg Asn Val Gly His Leu Met Thr Asn Asp Ala Ile Val Asp Thr 340 345 350 Asp Gly Ser Glu Val Phe Glu Gly Ile Met Asp Ala Leu Phe Thr Gly 355 360 365 Leu Ile Ala Ile His Gly Leu Lys Ala Ser Asp Val Asn Gly Pro Leu 370 375 380 Ile Asn Ser Arg Thr Gly Ser Ile Tyr Ile Val Lys Pro Lys Met His 385 390 395 400 Gly Pro Ala Glu Val Ala Phe Thr Cys Glu Leu Phe Ser Arg Val Glu 405 410 415 Asp Val Leu Gly Leu Pro Gln Asn Thr Met Lys Ile Gly Ile Met Asp 420 425 430 Glu Glu Arg Arg Thr Thr Val Asn Leu Lys Ala Cys Ile Lys Ala Ala 435 440 445 Ala Asp Arg Val Val Phe Ile Asn Thr Gly Phe Leu Asp Arg Thr Gly 450 455 460 Asp Glu Ile His Thr Ser Met Glu Ala Gly Pro Met Val Arg Lys Gly 465 470 475 480 Thr Met Lys Ser Gln Pro Trp Ile Leu Ala Tyr Glu Asp His Asn Val 485 490 495 Asp Ala Gly Leu Ala Ala Gly Phe Ser Gly Arg Ala Gln Val Gly Lys 500 505 510 Gly Met Trp Thr Met Thr Glu Leu Met Ala Asp Met Val Glu Thr Lys 515 520 525 Ile Ala Gln Pro Arg Ala Gly Ala Ser Thr Ala Trp Val Pro Ser Pro 530 535 540 Thr Ala Ala Thr Leu His Ala Leu His Tyr His Gln Val Asp Val Ala 545 550 555 560 Ala Val Gln Gln Gly Leu Ala Gly Lys Arg Arg Ala Thr Ile Glu Gln 565 570 575 Leu Leu Thr Ile Pro Leu Ala Lys Glu Leu Ala Trp Ala Pro Asp Glu 580 585 590 Ile Arg Glu Glu Val Asp Asn Asn Cys Gln Ser Ile Leu Gly Tyr Val 595 600 605 Val Arg Trp Val Asp Gln Gly Val Gly Cys Ser Lys Val Pro Asp Ile 610 615 620 His Asp Val Ala Leu Met Glu Asp Arg Ala Thr Leu Arg Ile Ser Ser 625 630 635 640 Gln Leu Leu Ala Asn Trp Leu Arg His Gly Val Ile Thr Ser Ala Asp 645 650 655 Val Arg Ala Ser Leu Glu Arg Met Ala Pro Leu Val Asp Arg Gln Asn 660 665 670 Ala Gly Asp Val Ala Tyr Arg Pro Met Ala Pro Asn Phe Asp Asp Ser 675 680 685 Ile Ala Phe Leu Ala Ala Gln Glu Leu Ile Leu Ser Gly Ala Gln Gln 690 695 700 Pro Asn Gly Tyr Thr Glu Pro Ile Leu His Arg Arg Arg Arg Arg Glu Phe 705 710 715 720 Lys Ala Arg Ala Ala Glu Lys Pro Ala Pro Ser Asp Arg Ala Gly Asp 725 730 735 Asp Ala Ala Arg 740 <210> 7 <211> 433 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of RipA <400> 7 Asp Pro Gln Thr Asp Thr Ile Ala Ala Leu Ile Ala Asp Val Ala Lys 1 5 10 15 Ala Asn Gln Arg Leu Gln Asp Leu Ser Asp Glu Val Gln Ala Glu Gln 20 25 30 Glu Ser Val Asn Lys Ala Met Val Asp Val Glu Thr Ala Arg Asp Asn 35 40 45 Ala Ala Ala Ala Glu Asp Asp Leu Glu Val Ser Gln Arg Ala Val Lys 50 55 60 Asp Ala Asn Ala Ala Ile Ala Ala Ala Gln His Arg Phe Asp Thr Phe 65 70 75 80 Ala Ala Ala Thr Tyr Met Asn Gly Pro Ser Val Ser Tyr Leu Ser Ala 85 90 95 Ser Ser Pro Asp Glu Ile Ile Ala Thr Val Thr Ala Ala Lys Thr Leu 100 105 110 Ser Ala Ser Ser Gln Ala Val Met Ala Asn Leu Gln Arg Ala Arg Thr 115 120 125 Glu Arg Val Asn Thr Glu Ser Ala Ala Arg Leu Ala Lys Gln Lys Ala 130 135 140 Asp Lys Ala Ala Ala Asp Ala Lys Ala Ser Gln Asp Ala Ala Val Ala 145 150 155 160 Ala Leu Thr Glu Thr Arg Arg Lys Phe Asp Glu Gln Arg Glu Glu Val 165 170 175 Gln Arg Leu Ala Ala Glu Arg Asp Ala Ala Gln Ala Arg Leu Gln Ala 180 185 190 Ala Arg Leu Val Ala Trp Ser Ser Glu Gly Gly Gln Gly Ala Pro Pro 195 200 205 Phe Arg Met Trp Asp Pro Gly Ser Gly Pro Ala Gly Gly Arg Ala Trp 210 215 220 Asp Gly Leu Trp Asp Pro Thr Leu Pro Met Ile Pro Ser Ala Asn Ile 225 230 235 240 Pro Gly Asp Pro Ile Ala Val Val Asn Gln Val Leu Gly Ile Ser Ala 245 250 255 Thr Ser Ala Gln Val Thr Ala Asn Met Gly Arg Lys Phe Leu Glu Gln 260 265 270 Leu Gly Ile Leu Gln Pro Thr Asp Thr Gly Ile Thr Asn Ala Pro Ala 275 28 0 285 Gly Ser Ala Gln Gly Arg Ile Pro Arg Val Tyr Gly Arg Gln Ala Ser 290 295 300 Glu Tyr Val Ile Arg Arg Gly Met Ser Gln Ile Gly Val Pro Tyr Ser 305 310 315 320 Trp Gly Gly Gly Asn Ala Ala Gly Pro Ser Lys Gly Ile Asp Ser Gly 325 330 335 Ala Gly Thr Val Gly Phe Asp Cys Ser Gly Leu Val Leu Tyr Ser Phe 340 345 350 Ala Gly Val Gly Ile Lys Leu Pro His Tyr Ser Gly Ser Gln Tyr Asn 355 360 365 Leu Gly Arg Lys Ile Pro Ser Ser Gln Met Arg Arg Gly Asp Val Ile 370 375 380 Phe Tyr Gly Pro Asn Gly Ser Gln His Val Thr Ile Tyr Leu Gly Asn 385 390 395 400 Gly Gln Met Leu Glu Ala Pro Asp Val Gly Leu Lys Val Arg Val Ala 405 410 415 Pro Val Arg Thr Ala Gly Met Thr Pro Tyr Val Val Arg Tyr Ile Glu 420 425 430 Tyr <210> 8 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of GS linker <400> 8 Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 1 5 10 < 210> 9 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of tPA <400> 9 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser 20 <210> 10 <211> 156 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of Flt3L <400> 10 Thr Gln Asp Cys Ser Phe Gln His Ser Pro Ile Ser Ser Asp Phe Ala 1 5 10 15 Val Lys Ile Arg Glu Leu Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val 20 25 30 Thr Val Ala Ser Asn Leu Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp 35 40 45 Arg Leu Val Leu Ala Gln Arg Trp Met Glu Arg Leu Lys Thr Val Ala 50 55 60 Gly Ser Lys Met Gln Gly Leu Leu Glu Arg Val Asn Thr Glu Ile His 65 70 75 80 Phe Val Thr Lys Cys Ala Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe 85 90 95 Val Gln Thr Asn Ile Ser Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu 100 105 110 Val Ala Leu Lys Pro Trp Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu 115 120 125 Glu Leu Gln Cys Gln Pro Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser 130 135 140 Pro Arg Pro Leu Glu Ala Thr Ala Pro Thr Ala Pro 145 150 155 <210> 11 <211> 1281 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of GX-170A <400 > 11 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala Thr Gln Asp Cys Ser Phe Gln 20 25 30 His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser 35 40 45 Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln 50 55 60 Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg 65 70 75 80 Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu 85 90 95 Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe 100 105 110 Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg 115 120 125 Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile 130 135 140 Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp 145 150 155 160 Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr 165 170 175 Ala Pro Thr Ala Pro Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Phe 180 185 190 Ser Arg Pro Gly Leu Pro Val Glu Tyr Leu Gln Val Pro Ser Pro Ser 195 200 205 Met Gly Arg Asp Ile Lys Val Gln Phe Gln Ser Gly Gly Ala Asn Ser 210 215 220 Pro Ala Leu Tyr Leu Leu Asp Gly Leu Arg Ala Gln Asp Asp Phe Ser 225 230 235 240 Gly Trp Asp Ile Asn Thr Pro Ala Phe Glu Trp Tyr Asp Gln Ser Gly 245 250 255 Leu Ser Val Val Met Pro Val Gly Gly Gln Ser Ser Phe Tyr Ser Asp 260 265 270 Trp Tyr Gln Pro Ala Cys Gly Lys Ala Gly Cys Gln Thr Tyr Lys Trp 275 280 285 Glu Thr Phe Leu Thr Ser Glu Leu Pro Gly Trp Leu Gln Ala Asn Arg 290 295 300 His Val Lys Pro Thr Gly Ser Ala Val Val Gly Leu Ser Met Ala Ala 305 310 315 320 Ser Ser Ala Leu Thr Leu Ala Ile Tyr His Pro Gln Gln Phe Val Tyr 325 330 335 Ala Gly Ala Met Ser Gly Leu Leu Asp Pro Ser Gln Ala Met Gly Pro 340 345 350 Thr Leu Ile Gly Leu Ala Met Gly Asp Ala Gly Gly Tyr Lys Ala Ser 355 360 365 Asp Met Trp Gly Pro Lys Glu Asp Pro Ala Trp Gln Arg Asn Asp Pro 370 375 380 Leu Leu Asn Val Gly Lys Leu Ile Ala Asn Asn Thr Arg Val Trp Val 385 390 395 400 Tyr Cys Gly Asn Gly Lys Pro Ser Asp Leu Gly Gly Asn Asn Leu Pro 405 410 415 Ala Lys Phe Leu Glu Gly Phe Val Arg Thr Ser Asn Ile Lys Phe Gln 420 425 430 Asp Ala Tyr Asn Ala Gly Gly Gly His Asn Gly Val Phe Asp Phe Pro 435 440 445 Asp Ser Gly Thr His Ser Trp Glu Tyr Trp Gly Ala Gln Leu Asn Ala 450 455 460 Met Lys Pro Asp Leu Gln Arg Ala Leu Gly Ala Thr Pro Asn Thr Gly 465 470 475 480 Pro Ala Pro Gln Gly Ala Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 485 490 495 Ser Gln Ile Met Tyr Asn Tyr Pro Ala Met Leu Gly His Ala Gly Asp 500 505 510 Met Ala Gly Tyr Ala Gly Thr Leu Gln Ser Leu Gly Ala Glu Ile Ala 515 520 525 Val Glu Gln Ala Ala Leu Gln Ser Ala Trp Gln Gly Asp Thr Gly Ile 530 535 540 Thr Tyr Gln Ala Trp Gln Ala Gln Trp Asn Gln Ala Met Glu Asp Leu 545 550 555 560 Val Arg Ala Tyr His Ala Met Ser Ser Thr His Glu Ala Asn Thr Met 565 570 575 Ala Met Met Ala Arg Asp Thr Ala Glu Ala Ala Lys Trp Gly Gly Gly 580 585 590 Ser Gly Ser Gly Ser Gly Ser Gly Ser Ala Pro Pro Ala Leu Ser Gln 595 600 605 Asp Arg Phe Ala Asp Phe Pro Ala Leu Pro Leu Asp Pro Ser Ala Met 610 615 620 Val Ala Gln Val Gly Pro Gln Val Val Asn Ile Asn Thr Lys Leu Gly 625 630 635 640 Tyr Asn Asn Ala Val Gly Ala Gly Thr Gly Ile Val Ile Asp Pro Asn 645 650 655 Gly Val Val Leu Thr Asn Asn Ala Val Ile Ala Gly Ala Thr Asp Ile 660 665 670 Asn Ala Phe Ser Val Gly Ser Gly Gln Thr Tyr Gly Val Asp Val Val 675 680 685 Gly Tyr Asp Arg Thr Gln Asn Val Ala Val Leu Gln Leu Arg Gly Ala 690 695 700 Gly Gly Leu Pro Ser Ala Ala Ile Gly Gly Gly Val Ala Val Gly Glu 705 710 715 720 Pro Val Val Ala Met Gly Asn Ser Gly Gly Gln Gly Gly Thr Pro Arg 725 730 735 Ala Val Pro Gly Arg Val Val Ala Leu Gly Gln Thr Val Gln Ala Ser 740 745 750 Asp Ser Leu Thr Gly Ala Glu Glu Thr Leu Asn Gly Leu Ile Gln Phe 755 760 765 Asp Ala Ala Ile Gln Pro Gly Asp Ala Gly Gly Pro Val Val Asn Gly 770 775 780 Leu Gly Gln Val Val Gly Met Asn Thr Ala Ala Ser Asp Asn Phe Gln 785 790 795 800 Leu Ser Gln Gly Gly Gln Gly Phe Ala Ile Pro Ile Gly Gln Ala Met 805 810 815 Ala Ile Ala Gly Gln Ile Arg Ser Gly Gly Gly Ser Pro Thr Val His 820 825 830 Ile Gly Pro Thr Ala Phe Leu Gly Leu Gly Val Val Asp Asn Asn Gly 835 840 845 Asn Gly Ala Arg Val Gln Arg Val Val Gly Ser Ala Pro Ala Ala Ser 850 855 860 Leu Gly Ile Ser Thr Gly Asp Val Ile Thr Ala Val Asp Gly Ala Pro 865 870 875 880 Ile Asn Ser Ala Thr Ala Met Ala Asp Ala Leu Asn Gly His His Pro 885 890 895 Gly Asp Val Ile Ser Val Thr Trp Gln Thr Lys Ser Gly Gly Thr Arg 900 905 910 Thr Gly Asn Val Thr Leu Ala Glu Gly Pro Pro Ala Gly Ser Gly Ser 915 920 925 Gly Ser Gly Ser Gly Ser Cys Gly Asn Asp Asp Asn Val Thr Gly Gly 930 935 940 Gly Ala Thr Thr Gly Gln Ala Ser Ala Lys Val Asp Cys Gly Gly Lys 945 950 955 960 Lys Thr Leu Lys Ala Ser Gly Ser Thr Ala Gln Ala Asn Ala Met Thr 965 970 975 Arg Phe Val Asn Val Phe Glu Gln Ala Cys Pro Gly Gln Thr Leu Asn 980 985 990 Tyr Thr Ala Asn Gly Ser Gly Ala Gly Ile Ser Glu Phe Asn Gly Asn 995 1000 1005 Gln Thr Asp Phe Gly Gly Ser Asp Val Pro Leu Ser Lys Asp Glu Pro 1010 1015 1020 Ser Gly Ala Ala Arg Cys Gly Ser Pro Ala Trp Asn Leu Pro Val Val 1025 1030 1035 1040 Phe Gly Pro Ile Ala Val Thr Tyr Asn Leu Asn Ser Val Ser Ser Leu 1045 1050 1055 Asn Leu Asp Gly Pro Thr Leu Ala Lys Ile Phe Asn Gly Ser Ile Thr 1060 1065 1070 Gln Trp Asn Asn Pro Ala Ile Gln Ala Leu Asn Arg Asp Phe Thr Leu 1075 1080 1085 Pro Gly Glu Arg Ile His Val Val Phe Arg Ser Asp Glu Ser Gly Thr 1090 1095 1100 Thr Asp Asn Phe Gln Arg Tyr Leu Gln Ala Ala Ser Asn Gly Ala Trp 1105 1110 1115 1120 Gly Lys Gly Ala Gly Lys Ser Phe Gln Gly Gly Val Gly Glu Gly Ala 1125 1130 1135 Arg Gly Asn Asp Gly Thr Ser Ala Ala Ala Lys Asn Thr Pro Gly Ser 1140 1145 1150 Ile Thr Tyr Asn Glu Trp Ser Phe Ala Gln Ala His Asp Leu Thr Met 1155 1160 1165 Ala Asn Ile Val Thr Ser Ala Gly Gly Asp Pro Val Ala Ile Thr Ile 1170 1175 1180 Asp Ser Val Gly Gln Thr Ile Ala Gly Ala Thr Ile Ser Gly Val Gly 1185 1190 1195 1200 Asn Asp Leu Val Leu Asp Thr Asp Ser Phe Tyr Arg Pro Lys Arg Pro 1205 1210 1215 Gly Ser Tyr Pro Ile Val Leu Ala Thr Tyr Glu Ile Val Cys Ser Lys 1220 1225 1230 Tyr Pro Asp Ser Gln Val Gly Thr Ala Val Lys Ala Phe Leu Gln Ser 1235 1240 1245 Thr Ile Gly Ala Gly Gln Ser Gly Leu Gly Asp Asn Gly Tyr Ile Pro 1250 1255 1260 Ile Pro Asp Glu Phe Lys Ser Arg Leu Ser Thr Ala Val Asn Ala Ile 1265 1270 1275 1280 Ala <210> 12 <211> 2005 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of GX-170B <400> 12 Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala Thr Gln Asp Cys Ser Phe Gln 20 25 30 His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg G lu Leu Ser 35 40 45 Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln 50 55 60 Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg 65 70 75 80 Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu 85 90 95 Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe 100 105 110 Gln Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg 115 120 125 Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile 130 135 140 Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp 145 150 155 160 Ser Ser Thr Leu Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr 165 170 175 Ala Pro Thr Ala Pro Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Val 180 185 190 Asn Phe Ser Val Leu Pro Pro Glu Ile Asn Ser Gly Arg Met Phe Phe 195 200 205 Gly Ala Gly Ser Gly Pro Met Leu Ala Ala Ala Ala Ala Trp Asp Gly 210 215 220 Leu Ala Ala Glu Leu Gly Leu Ala Ala Glu Ser Phe Gly Leu Val Thr 225 230 235 240 Ser Gly Leu Ala Gly Gly Ser Gly Gln Ala Trp Gln Gly Ala Ala Ala 245 250 255 Ala Ala Met Val Val Ala Ala Ala Pro Tyr Ala Gly Trp Leu Ala Ala 260 265 270 Ala Ala Ala Arg Ala Gly Gly Ala Ala Val Gln Ala Lys Ala Val Ala 275 280 285 Gly Ala Phe Glu Ala Ala Arg Ala Ala Met Val Asp Pro Val Val Val 290 295 300 Ala Ala Asn Arg Ser Ala Phe Val Gln Leu Val Leu Ser Asn Val Phe 305 310 315 320 Gly Gln Asn Ala Pro Ala Ile Ala Ala Ala Glu Ala Thr Tyr Glu Gln 325 330 335 Met Trp Ala Ala Asp Val Ala Ala Met Val Gly Tyr His Gly Gly Ala 340 345 350 Ser Ala Ala Ala Ala Ala Leu Ala Pro Trp Gln Gln Ala Val Pro Gly 355 360 365 Leu Ser Gly Leu Leu Leu Asp Ser Ala Gln Ser Ser Ala Gln Ala Val Thr 370 375 380 Ala Gln Ala Val Gly Ser Thr Val Pro Gly Pro Leu Gln Gly Ile Asn 385 390 395 400 Phe Gly Phe Gly Asn Ile Gly Ser Leu Asn Leu Gly Ser Gly Asn Thr 405 410 415 Gly Asp Thr Asn Val Gly Ser Gly Asn Ile Gly Asn Thr Asn Leu Gly 420 425 430 Gly Gly Asn Ile Gly Ser Phe Asn Leu Gly Ser Gly Asn Gln Gly Asp 435 440 445 Ile Asn Leu Gly Ile Gly Asn Val Gly Asn Leu Asn Leu Gly Ser Gly 450 455 460 Asn Phe Gly Ser Gln Asn Leu Gly Ser Gly Asn Ile Gly Ser Thr Asn 465 470 475 480 Val Gly Ser Gly Asn Ile Gly Ser Thr Asn Val Gly Ser Gly Asn Ile 48 5 490 495 Gly Asp Thr Asn Phe Gly Asn Gly Asn Asn Gly Asn Phe Asn Phe Gly 500 505 510 Ser Gly Asn Thr Gly Ser Asn Asn Ile Gly Phe Gly Asn Thr Gly Ser 515 520 525 Gly Asn Phe Gly Phe Gly Asn Thr Gly Asn Asn Asn Ile Gly Ile Gly 530 535 540 Leu Thr Gly Asp Gly Gln Ile Gly Ile Gly Gly Leu Asn Ser Gly Ser 545 550 555 560 Gly Asn Ile Gly Phe Gly Asn Ser Gly Thr Gly Asn Val Gly Leu Phe 565 570 575 Asn Ser Gly Thr Gly Asn Val Gly Phe Gly Asn Ser Gly Thr Ala Asn 580 585 590 Thr Gly Phe Gly Asn Ala Gly Asn Val Asn Thr Gly Phe Trp Asn Gly 595 600 605 Gly Ser Thr Asn Thr Gly Leu Ala Asn Ala Gly Ala Gly Asn Thr Gly 610 615 620 Phe Phe Asp Ala Gly Asn Tyr Asn Phe Gly Ser Leu Asn Ala Gly Asn 625 630 635 640 Ile Asn Ser Ser Phe Gly Asn Ser Gly Asp Gly Asn Ser Gly Phe Leu 645 650 655 Asn Ala Gly Asp Val Asn Ser Gly Val Gly Asn Ala Gly Asp Val Asn 660 665 670 Thr Gly Leu Gly Asn Ser Gly Asn Ile Asn Thr Gly Gly Phe Asn Pro 675 680 685 Gly Thr Leu Asn Thr Gly Phe Phe Ser Ala Met Thr Gln Ala Gly Pro 690 695 700 Asn Ser Gly Phe Phe Asn Ala Gly Thr Gly Asn Ser Gly Phe Gly His 705 710 715 720 Asn Asp Pro Ala Gly Ser Gly Asn Ser Gly Ile Gln Asn Ser Gly Phe 725 730 735 Gly Asn Ser Gly Tyr Val Asn Thr Ser Thr Thr Ser Met Phe Gly Gly 740 745 750 Asn Ser Gly Val Leu Asn Thr Gly Tyr Gly Asn Ser Gly Phe Tyr Asn 755 760 765 Ala Ala Val Asn Asn Thr Gly Ile Phe Val Thr Gly Val Met Ser Ser 770 775 780 Gly Phe Phe Asn Phe Gly Thr Gly Asn Ser Gly Leu Leu Val Ser Gly 785 790 795 800 Asn Gly Leu Ser Gly Phe Phe Lys Asn Leu Phe Gly Gly Ser Gly Ser 805 810 815 Gly Ser Gly Ser Gly Ser Thr Asp Arg Val Ser Val Gly Asn Leu Arg 820 825 830 Ile Ala Arg Val Leu Tyr Asp Phe Val Asn Asn Glu Ala Leu Pro Gly 835 840 845 Thr Asp Ile Asp Pro Asp Ser Phe Trp Ala Gly Val Asp Lys Val Val 850 855 860 Ala Asp Leu Thr Pro Gln Asn Gln Ala Leu Leu Asn Ala Arg Asp Glu 865 870 875 880 Leu Gln Ala Gln Ile Asp Lys Trp His Arg Arg Arg Val Ile Glu Pro 885 890 895 Ile Asp Met Asp Ala Tyr Arg Gln Phe Leu Thr Glu Ile Gly Tyr Leu 900 905 910 Leu Pro Glu Pro Asp Asp Phe Thr Ile Thr Thr Ser Gly Val Asp Ala 915 920 925 Glu Ile Thr Thr Thr Ala Gly Pro Gln Leu Val Val Pro Val Leu Asn 930 935 940 Ala Arg Phe Ala Leu Asn Ala Ala Asn Ala Arg Trp Gly Ser Leu Tyr 945 950 955 960 Asp Ala Leu Tyr Gly Thr Asp Val Ile Pro Glu Thr Asp Gly Ala Glu 965 970 975 Lys Gly Pro Thr Tyr Asn Lys Val Arg Gly Asp Lys Val Ile Ala Tyr 980 985 990 Ala Arg Lys Phe Leu Asp Asp Ser Val Pro Leu Ser Ser Gly Ser Phe 995 1000 1005 Gly Asp Ala Thr Gly Phe Thr Val Gln Asp Gly Gln Leu Val Val Ala 1010 1015 1020 Leu Pro Asp Lys Ser Thr Gly Leu Ala Asn Pro Gly Gln Phe Ala Gly 1025 1030 1035 1040 Tyr Thr Gly Ala Ala Glu Ser Pro Thr Ser Val Leu Leu Ile Asn His 1045 1050 1055 Gly Leu His Ile Glu Ile Leu Ile Asp Pro Glu Ser Gln Val Gly Thr 1060 1065 1070 Thr Asp Arg Ala Gly Val Lys Asp Val Ile Leu Glu Ser Ala Ile Thr 1075 1080 1085 Thr Ile Met Asp Phe Glu Asp Ser Val Ala Ala Val Asp Ala Ala Asp 1090 1095 1100 Lys Val Leu Gly Tyr Arg Asn Trp Leu Gly Leu Asn Lys Gly Asp Leu 1105 1110 1115 1120 Ala Ala Ala Val Asp Lys Asp Gly Thr Ala Phe Leu Arg Val Leu Asn 1125 1130 1135 Arg Asp Arg Asn Tyr Thr Ala Pro Gly Gly Gly Gln Phe Thr Leu Pro 1140 1145 1150 Gly Arg Ser Leu Met Phe Val Arg Asn Val Gly His Leu Met Thr Asn 1155 1160 1165 Asp Ala Ile Val Asp Thr Asp Gly Ser Glu Val Phe Glu Gly Ile Met 1170 1175 1180 Asp Ala Leu Phe Thr Gly Leu Ile Ala Ile His Gly Leu Lys Ala Ser 1185 1190 1195 1200 Asp Val Asn Gly Pro Leu Ile Asn Ser Arg Thr Gly Ser Ile Tyr Ile 1205 1210 1215 Val Lys Pro Lys Met His Gly Pro Ala Glu Val Ala Phe Thr Cys Glu 1220 1225 1230 Leu Phe Ser Arg Val Glu Asp Val Leu Gly Leu Pro Gln Asn Thr Met 1235 1240 1245 Lys Ile Gly Ile Met Asp Glu Glu Arg Arg Arg Thr Thr Val Asn Leu Lys 1250 1255 1260 Ala Cys Ile Lys Ala Ala Ala Asp Arg Val Val Phe Ile Asn Thr Gly 1265 1270 1275 1280 Phe Leu Asp Arg Thr Gly Asp Glu Ile His Thr Ser Met Glu Ala Gly 1285 1290 1295 Pro Met Val Arg Lys Gly Thr Met Lys Ser Gln Pro Trp Ile Leu Ala 1300 1305 1310 Tyr Glu Asp His Asn Val Asp Ala Gly Leu Ala Ala Gly Phe Ser Gly 1315 1320 1325 Arg Ala Gln Val Gly Lys Gly Met Trp Thr Met Thr Glu Leu Met Ala 1330 1 335 1340 Asp Met Val Glu Thr Lys Ile Ala Gln Pro Arg Ala Gly Ala Ser Thr 1345 1350 1355 1360 Ala Trp Val Pro Ser Pro Thr Ala Ala Thr Leu His Ala Leu His Tyr 1365 1370 1375 His Gln Val Asp Val Ala Ala Val Gln Gln Gly Leu Ala Gly Lys Arg 1380 1385 1390 Arg Ala Thr Ile Glu Gln Leu Leu Thr Ile Pro Leu Ala Lys Glu Leu 1395 1400 1405 Ala Trp Ala Pro Asp Glu Ile Arg Glu Glu Val Asp Asn Asn Cys Gln 1410 1415 1420 Ser Ile Leu Gly Tyr Val Val Arg Trp Val Asp Gln Gly Val Gly Cys 1425 1430 1435 1440 Ser Lys Val Pro Asp Ile His Asp Val Ala Leu Met Glu Asp Arg Ala 1445 1450 1455 Thr Leu Arg Ile Ser Gln Leu Leu Ala Asn Trp Leu Arg His Gly 1460 1465 1470 Val Ile Thr Ser Ala Asp Val Arg Ala Ser Leu Glu Arg Met Ala Pro 1475 1480 1485 Leu Val Asp Arg Gln Asn Ala Gly Asp Val Ala Tyr Arg Pro Met Ala 1490 1495 1500 Pro Asn Phe Asp Asp Ser Ile Ala Phe Leu Ala Ala Gln Glu Leu Ile 1505 1510 1515 1520 Leu Ser Gly Ala Gln Gln Pro Asn Gly Tyr Thr Glu Pro Ile Leu His 1525 1530 1535 Arg Arg Arg Arg Glu Phe Lys Ala Arg Ala Ala Glu Lys Pro Ala Pro 1540 1545 1550 Ser Asp Arg Ala Gly Asp Asp Ala Ala Arg Gly Ser Gly Ser Gly Ser 1555 1560 1565 Gly Ser Gly Ser Asp Pro Gln Thr Asp Thr Ile Ala Ala Leu Ile Ala 1570 1575 1580 Asp Val Ala Lys Ala Asn Gln Arg Leu Gln Asp Leu Ser Asp Glu Val 1585 1590 1595 1600 Gln Ala Glu Gln Glu Ser Val Asn Lys Ala Met Val Asp Val Glu Thr 1605 1610 1615 Ala Arg Asp Asn Ala Ala Ala Ala Glu Asp Asp Leu Glu Val Ser Gln 1620 1625 1630 Arg Ala Val Lys Asp Ala Asn Ala Ala Ile Ala Ala Ala Gln His Arg 1635 1640 1645 Phe Asp Thr Phe Ala Ala Ala Thr Tyr Met Asn Gly Pro Ser Val Ser 1650 1655 1660 Tyr Leu Ser Ala Ser Ser Pro Asp Glu Ile Ile Ala Thr Val Thr Ala 1665 1670 1675 1680 Ala Lys Thr Leu Ser Ala Ser Ser Gln Ala Val Met Ala Asn Leu Gln 1685 1690 1695 Arg Ala Arg Thr Glu Arg Val Asn Thr Glu Ser Ala Ala Arg Leu Ala 1700 1705 1710 Lys Gln Lys Ala Asp Lys Ala Ala Ala Asp Ala Lys Ala Ser Gln Asp 1715 1720 1725 Ala Ala Val Ala Ala Leu Thr Glu Thr Arg Arg Lys Phe Asp Glu Gln 1730 1 735 1740 Arg Glu Glu Val Gln Arg Leu Ala Ala Glu Arg Asp Ala Ala Gln Ala 1745 1750 1755 1760 Arg Leu Gln Ala Ala Arg Leu Val Ala Trp Ser Ser Glu Gly Gly Gly Gln 1765 1770 1775 Gly Ala Pro Pro Phe Arg Met Trp Asp Pro Gly Ser Gly Pro Ala Gly 1780 1785 1790 Gly Arg Ala Trp Asp Gly Leu Trp Asp Pro Thr Leu Pro Met Ile Pro 1795 1800 1805 Ser Ala Asn Ile Pro Gly Asp Pro Ile Ala Val Val Asn Gln Val Leu 1810 1815 1820 Gly Ile Ser Ala Thr Ser Ala Gln Val Thr Ala Asn Met Gly Arg Lys 1825 1830 1835 1840 Phe Leu Glu Gln Leu Gly Ile Leu Gln Pro Thr Asp Thr Gly Ile Thr 1845 1850 1855 Asn Ala Pro Ala Gly Ser Ala Gln Gly Arg Ile Pro Arg Val Tyr Gly 1860 1865 1870 Arg Gln Ala Ser Glu Tyr Val Ile Arg Arg Gly Met Ser Gln Ile Gly 1875 1880 1885 Val Pro Tyr Ser Trp Gly Gly Gly Asn Ala Ala Gly Pro Ser Lys Gly 1890 1895 1900 Ile Asp Ser Gly Ala Gly Thr Val Gly Phe Asp Cys Ser Gly Leu Val 1905 1910 1915 1920 Leu Tyr Ser Phe Ala Gly Val Gly Ile Lys Leu Pro His Tyr Ser Gly 1925 1930 1935 Ser Gln Tyr Asn Leu Gly Arg Lys Ile Pro Ser Ser Gln Met Arg Arg 1940 1945 1950 Gly Asp Val Ile Phe Tyr Gly Pro Asn Gly Ser Gln His Val Thr Ile 1955 1960 1965 Tyr Leu Gly Asn Gly Gln Met Leu Glu Ala Pro Asp Val Gly Leu Lys 1970 1975 1980 Val Arg Val Ala Pro Val Arg Thr Ala Gly Met Thr Pro Tyr Val Val 1985 1990 1995 2000 Arg Tyr Ile Glu Tyr 2005 <210> 13 <211> 885 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of Ag85A <400> 13 tttagcaggc caggcctgcc cgtggagtat ctgcaggtgc cctccccttc tatgggccgc 60 gacatcaagg tgcagttcca gtccggagga gccaactctc cagccctgta tctgctggac 120 ggcctgagag cccaggacga tttcagcggc tgggacatca atacacccgc ctttgagtgg 180 tacgaccaga gcggactgtc cgtggtcatg ccagtgggag gacagtcctc tttttactcc 240 gactggtatc agcctgcatg cggcaaggca ggatgtcaga cctacaagtg ggagaccttc 300 ctgacaagcg agctgcctgg ctggctgcag gccaacaggc acgtgaagcc aacaggctcc 360 gccgtggtgg gactgtctat ggcagccagc tccgccctga ccctggcaat ctaccaccct 420 cagcagttcg tgtacgcagg agcaatgagc ggactgctgg acccctccca ggcaatggga 480 ccaaccctga tcgga ctggc aatgggcgac gcaggaggat ataaggcaag cgacatgtgg 540 ggaccaaagg aggaccccgc atggcagagg aacgacccac tgctgaatgt gggcaagctg 600 atcgccaaca ataccagagt gtgggtgtac tgtggaaacg gcaagccatc cgatctggga 660 ggaaacaatc tgcctgccaa gttcctggag ggctttgtgc ggacatctaa tatcaagttc 720 caggacgcat ataacgcagg aggaggacac aatggcgtgt tcgactttcc cgattccggc 780 acccactctt gggagtactg gggagcacag ctgaacgcaa tgaagcccga cctgcagaga 840 gccctgggag caacccccaa tacaggacca gcaccacagg gagca 885 <210> 14 <211> 285 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of TB10.4 <400> 14 agccagatca tgtacaacta tcctgccatg ctgggacacg caggcgacat ggcaggatac 60 gcaggcaggcaccc tgcaggc caggcaggcaccc tgcaggc tgcagtctct gggcaggt agcagtctt gggcaggt agcagtctc gaaccaggca 180 atggaggacc tggtgcgggc ctaccacgcc atgtcctcta cccacgaggc caatacaatg 240 gccatgatgg ccagagatac cgcagaggca gcaaagtggg gagga 285 <210> 15 <211> 969 <212> DNA <223> Artificial Sequence <220> 00> 15 gccccccctg ccctgtccca ggaccggttc gccgattttc ctgccctgcc actggacccc 60 tctgccatgg tggcacaagt gggacctcag gtggtgaaca tcaatacaaa gctgggctac 120 aacaatgcag tgggagcagg caccggaatc gtgatcgacc caaacggcgt ggtgctgaca 180 aacaatgccg tgatcgccgg cgccaccgac atcaatgcct tttctgtggg cagcggccag 240 acatacggcg tggacgtggt gggctatgat aggacccaga atgtggccgt gctgcagctg 300 aggggagcag gaggcctgcc ttccgccgcc atcggcggcg gcgtggccgt gggcgagcca 360 gtggtggcaa tgggcaacag cggaggacag ggaggcacac cacgggccgt gcccggcaga 420 gtggtggccc tgggacagac cgtgcaggca agcgattccc tgaccggagc cgaggagaca 480 ctgaacggcc tgatccagtt tgatgcagca atccagccag gcgacgcagg aggacctgtg 540 gtgaatggcc tgggacaggt ggtgggaatg aacaccgcag cctctgacaa tttccagctg 600 agccagggag gacagggatt tgcaatccca atcggacagg caatggcaat cgcaggacag 660 atcaggagcg gaggaggctc cccaaccgtg cacatcggac caacagcctt cctgggactg 720 ggagtggtgg acaacaatgg caacggcgcc cgggtgcaga gagtggtggg ctccgcccca 780 gcagcatctc tgggcatcag caccggcgac gtgatcacag ccgtggatgg cgcccctatc 840 aacagcgcca ccg ccatggc cgatgccctg aatggccacc acccaggcga cgtgatcagc 900 gtgacctggc agacaaagtc cggaggcacc aggacaggaa acgtgacact ggcagaggga 960 ccaccagca 969 nucleic acid sequence of ac ac gata 16 <211> 1044 <212> tg3 <213> Artificial Sequence <210> 16 <211> 1044 <212> DNA <213> Artificial Sequence < ggagcaacca caggacaggc ctccgccaag 60 gtggattgtg gcggcaagaa gaccctgaag gcatccggct ctacagcaca ggcaaacgcc 120 atgaccaggt tcgtgaacgt gttcgagcag gcatgcccag gacagaccct gaactataca 180 gcaaatggca gcggagcagg catctccgag ttcaacggca atcagacaga ctttggcggc 240 tctgatgtgc ctctgagcaa ggacgagcca tccggagcag caagatgtgg cagccctgcc 300 tggaatctgc cagtggtgtt tggccccatc gccgtgacct acaacctgaa tagcgtgagc 360 tccctgaacc tggatggccc cacactggcc aagattttca acggctccat cacccagtgg 420 aacaatcccg ccatccaggc cctgaaccgg gacttcaccc tgcctggcga gagaatccac 480 gtggtgtttc gctccgacga gtctggcacc acagataact tccagagata cctgcaggca 540 gcatctaatg gagcatgggg caagggagca ggcaagagct ttcagggagg agtgcggagag gaccagagcca gaccagggagag 600 accagccca g ctctatcaca 660 tacaatgagt ggagcttcgc ccaggcccac gacctgacca tggccaatat cgtgacaagc 720 gccggaggcg atcctgtggc aatcaccatc gactccgtgg gacagaccat cgcaggagcc 780 acaatctctg gcgtgggcaa cgatctggtg ctggacacag atagcttcta taggcctaag 840 cgcccaggct cctacccaat cgtgctggcc acctatgaga tcgtgtgctc taagtacccc 900 gacagccaag tgggcacagc cgtgaaggcc tttctgcagt ccaccatcgg agcaggacag 960 tctggactgg gcgataacgg ctacatccct atcccagacg agttcaagag cagactgtcc 1020 accgccgtga atgccatcgc ctaa 1044 < 210> 17 <211> 1863 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of PPE39 <400> 17 gtgaatttca gcgtgctgcc ccctgagatc aactccggcc ggatgttctt tggagcaggc 60 tccggaccta tgctggctgc cgccgccgcc tgggacggac tggcagcaga gctgggcctg 120 gccgccgaga gctttggcct ggtgacaagc ggcctggccg gcggctctgg ccaggcctgg 180 cagggcgctg ccgccgccgc catggtggtg gctgccgccc catacgccgg ctggctggcc 240 gccgccgccg ccagagccgg aggagccgcc gtgcaggcca aggccgtggc cggcgccttc cggcgtgttc ggacc c cagctgg tgctgagcaa cgtgttcgga cagaacgcac cagcaatcgc tgccgccgag 420 gcaacctacg agcagatgtg ggcagcagat gtggcagcaa tggtgggcta tcacggagga 480 gcaagcgccg ccgccgccgc cctggcccca tggcagcagg ccgtgcccgg cctgagcgga 540 ctgctggact ccgcccagtc ctctgcccag gccgtgaccg cacaggcagt gggctccaca 600 gtgcccggcc ctctgcaggg catcaatttc ggctttggca acatcggctc tctgaatctg 660 ggcagcggca acacaggcga taccaatgtg ggcagcggca acatcggcaa taccaacctg 720 ggcggcggca atatcggctc cttcaacctg ggctctggca atcagggcga catcaacctg 780 ggcatcggca atgtgggcaa tctgaacctg ggcagcggca actttggctc ccagaatctg 840 ggctctggca acatcggcag caccaatgtg ggctccggca acatcggctc tacaaatgtg 900 ggcagcggaa atatcggcga taccaatttc ggcaacggca acaatggcaa tttcaacttt 960 ggctccggca acacaggctc taacaatatc ggctttggca ataccggcag cggcaacttc 1020 ggctttggca atacaggcaa caataacatc ggcatcggcc tgaccggcga cggacagatc 1080 ggaatcggag gcctgaactc tggcagcggc aatatcggct tcggcaactc tggcacaggc 1140 aatgtgggcc tgttcaacag cggcaccggc aatgtgggct ttggcaactc cggcacagcc 1200 aataccggct tcggcaac gc cggcaatgtg aacacaggct tttggaatgg cggctccaca 1260 aacaccggac tggcaaatgc aggagcagga aacaccggct tctttgacgc cggcaattac 1320 aactttggct ctctgaacgc cggcaatatc aacagctcct tcggcaatag cggcgacggc 1380 aactccggct ttctgaatgc cggcgatgtg aactctggcg tgggcaatgc cggcgacgtg 1440 aacacaggcc tgggcaatag cggcaatatc aacaccggcg gcttcaaccc aggcacactg 1500 aataccggct tcttttccgc catgacacag gccggcccca actctggctt ctttaatgca 1560 ggcaccggca acagcggatt tggacacaac gacccagcag gcagcggcaa ttccggcatc 1620 cagaactctg gcttcggcaa tagcggctac gtgaacacat ctaccacaag catgtttggc 1680 ggcaattctg gcgtgctgaa caccggctac ggcaatagcg gcttctataa cgccgccgtg 1740 aataacacag gcatctttgt gaccggcgtg atgtctagcg gcttctttaa tttcggcaca 1800 ggcaactccg gcctgctggt gtctggcaat ggcctgagcg gcttctttaa gaacctgttt 1860 gga 1863 <210> 18 <211> 2220 <212> DNA <213> Artificial Sequence <220> <223 > nucleic acid sequence of GlcB <400> 18 accgaccgcg tgtccgtggg caacctgaga atcgccaggg tgctgtatga tttcgtgaat 60 aacgaggccc tgcctggcac agacatcgac ccagacagct tttgggcag g agtggataag 120 gtggtggccg acctgacccc tcagaatcag gccctgctga acgccagaga cgagctgcag 180 gcccagatcg acaagtggca ccggcggaga gtgatcgagc caatcgacat ggacgcctac 240 aggcagttcc tgacagagat cggctatctg ctgccagagc ccgacgactt caccatcacc 300 acatccggcg tggatgccga gatcaccaca accgcaggac ctcagctggt ggtgccagtg 360 ctgaacgcaa ggttcgccct gaatgcagca aacgccagat ggggcagcct gtacgatgcc 420 ctgtatggca cagacgtgat cccagagacc gatggagcag agaagggacc tacatacaat 480 aaggtgaggg gcgacaaagt gatcgcctat gcccgcaagt tcctggacga ttctgtgccc 540 ctgtcctctg gcagcttcgg cgacgccaca ggctttaccg tgcaggatgg acagctggtg 600 gtggccctgc ctgataagtc caccggactg gcaaacccag gacagtttgc aggatacacc 660 ggagcagcag agtcccccac atctgtgctg ctgatcaatc acggcctgca catcgagatc 720 ctgatcgacc ctgagagcca agtgggcaca accgacagag caggagtgaa ggatgtgatc 780 ctggagtccg ccatcacaac catcatggat ttcgaggact ctgtggcagc agtggatgca 840 gcagacaagg tgctgggcta cagaaattgg ctgggcctga acaagggcga tctggctgcc 900 gccgtggata aggacggcac cgcctttctg agggtgctga atagagacag gaactatacc 960 gcc ccaggag gaggacagtt cacactgcca ggccggtctc tgatgtttgt gagaaatgtg 1020 ggccacctga tgaccaacga cgccatcgtg gatacagacg gcagcgaggt gttcgagggc 1080 atcatggatg ccctgtttac aggcctgatc gccatccacg gcctgaaggc ctccgacgtg 1140 aatggccccc tgatcaactc ccgcaccggc tctatctaca tcgtgaagcc aaagatgcac 1200 ggacctgcag aggtggcctt cacatgcgag ctgtttagcc gggtggagga cgtgctgggc 1260 ctgcctcaga ataccatgaa gatcggcatc atggatgagg agcgccggac aaccgtgaac 1320 ctgaaggcct gtatcaaggc tgccgccgac agggtggtgt tcatcaatac aggctttctg 1380 gatcgcaccg gcgacgagat ccacacatcc atggaggccg gcccaatggt gagaaagggc 1440 accatgaagt ctcagccctg gattctggcc tatgaggatc acaacgtgga cgcaggactg 1500 gcagcaggct tcagcggcag agcccaagtg ggcaagggca tgtggacaat gaccgagctg 1560 atggccgata tggtggagac aaagatcgca cagcctaggg ccggagccag caccgcatgg 1620 gtgccttccc caacagcagc caccctgcac gcactgcact accaccaggt ggacgtggca 1680 gcagtgcagc agggactggc aggcaagaga agggccacca tcgagcagct gctgacaatc 1740 cctctggcaa aggagctggc atgggcacca gacgagatca gggaggaggt ggataataac 1800 tgccagtcca tcctgggcta tgtggtgcgg tgggtggatc agggagtggg atgttctaag 1860 gtgccagaca tccacgacgt ggccctgatg gaggacaggg ccacactgcg gatcagctcc 1920 cagctgctgg ccaactggct gaggcacggc gtgatcacct ctgccgacgt gcgcgcaagc 1980 ctggagagga tggcaccact ggtggacagg cagaatgcag gcgatgtggc ctacagacct 2040 atggcc ccaa acttcgacga tagcatcgcc tttctggcag cacaggagct gatcctgtcc 2100 ggagcacagc agccaaacgg atataccgag cctatcctgc accgccggag aagggagttc 2160 aaggccagag ccgcagagaa gccagcacct tccgataggg caggcgacga tgcagcccgc 2220 2220 <210> 19 <211> 1302 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of RipA <400> 19 gatccccaga cagacaccat cgccgccctg atcgcagacg tggcaaaggc caaccagagg 60 ctgcaggatc tgagcgacga ggtgcaggca gagcaggagt ccgtgaataa ggcaatggtg 120 gacgtggaga ccgcccggga taacgctgcc gccgccgagg acgatctgga ggtgagccag 180 agagccgtga aggatgcaaa cgcagcaatc gctgccgccc agcacaggtt cgacaccttc 240 gccgccgcca cctacatgaa tggcccctct gtgagctatc tgagcgcctc tagccctgac 300 gagatcatcg ccacagtgac cgcagcaaag accctgtccg cctcctctca ggccgtgatg 360 gcaaatctgc agagggcacg gacagagagg gtgaacaccg agtccgccgc ccgcctggca 420 aagcagaagg cagataaggc tgccgccgac gcaaaggcat ctcaggatgc agcagtggcc 480 gccctgacag agaccaggcg gaagttcgac gagcagagag aggaggtgca 540gactg caggccggg at gagcagagag aggaggtgca gactgcaaaggcat ctcaggatgc gc atggagctcc 600 gagggaggac agggcgcccc accctttcgg atgtgggacc ccggcagcgg accagcaggc 660 ggcagagcct gggatggact gtgggacccc accctgccta tgatcccatc cgccaatatc 720 cccggcgacc ctatcgccgt ggtgaaccag gtgctgggca tcagcgccac atccgcccag 780 gtgacagcca acatgggcag aaagttcctg gagcagctgg gcatcctgca gcccacagac 840 accggaatca ccaatgcacc tgcaggcagc gcccagggac gcatcccacg ggtgtacggc 900 aggcaggcat ccgagtatgt gatcagaagg ggcatgtccc agatcggcgt gccttactct 960 tggggaggag gaaacgcagc aggaccatcc aagggaatcg actctggagc aggcaccgtg 1020 ggattcgatt gttccggcct ggtgctgtat tcttttgccg gcgtgggcat caagctgcca 1080 cactactccg gctctcagta taatctgggc cgcaagatcc cctctagcca gatgcgccgg 1140 ggcgatgtga tcttctacgg ccctaatggc agccagcacg tgaccatcta tctgggaaac 1200 ggacagatgc tggaggcacc agacgtgggc ctgaaggtga gggtggcacc tgtgcgcaca 1260 gcaggcatga ccccatacgt ggtgcggtac atcgagtatt aa 1302 <210> 20 <211> 30 <212> DNA <213 > Artificial Sequence <220> <223> nucleic acid sequence of GS linker <400> 20 ggcagcggct ccggctctgg cagcggctct 30 <210> 21 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of GS linker <400> 21 ggctccggct ctggcagcgg ctccggctct 30 <210> 22 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of GS linker <400> 22 ggctctggca gcggctccgg ctctggcagc 30 <210> 23 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of GS linker < 400> 23 ggcagcggct ccggctctgg cagcggctcc 30 <210> 24 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of tPA <400> 24 atggatgcca tgaagagggg actgtgctgc gtgctgctgc tcaagctgctgc taggtccggagg 210 cgtgt > 25 <211> 69 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of tPA <400> 25 atggatgcca tgaagagggg actgtgctgc gtgctgctgc tgtgcggagc cgtgttcgtg 60 tccccatct 69 <210> 26 <211> 474 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of Flt3L <400> 26 acccaggatt gttctttcca gcacagcccc atcagctccg actttgccgt gaagatccgc 60 gagctgagcg actacctgct g caggattat cccgtgacag tggcctccaa tctgcaggac 120 gaggagctgt gcggaggact gtggaggctg gtgctggcac agcggtggat ggagagactg 180 aagaccgtgg caggctccaa gatgcaggga ctgctggagc gcgtgaacac cgagatccac 240 ttcgtgacaa agtgcgcctt tcagccccct ccaagctgtc tgcggtttgt gcagacaaac 300 atctccagac tgctgcagga gacctctgag cagctggtgg ccctgaagcc ctggatcaca 360 aggcagaatt tctctcgctg cctggagctg cagtgtcagc ctgactctag caccctgcca 420 cctccatgga gccctcggcc actggaggca accgcaccaa cagcacctgg ctcc 474 <210> 27 <211> 474 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of Flt3L <400> 27 cacgccaccc aggattgttc tttccagcac agccctatca gctccgactt tgccgtgaag 60 atccgggagc tgtctgatta cctgctgcag gactatcccg tgacagtggc cagcaacctg 120 caggacgagg agctgtgcgg aggactgtgg aggctggtgc tggcacagag atggatggag 180 aggctgaaga ccgtggcagg ctccaagatg cagggactgc tggagcgggt gaatacagag 240 atccacttcg tgaccaagtg cgcctttcag ccccctccaa gctgtctgcg gttcgtgcagcag 300 accaacatca gcagagaca tggc g aatttttc taggtgcctg gagctgcagt gtcagccaga ttctagcacc 420 ctgccacctc catggagccc tcgcccactg gaggccacag caccaaccgc acca 474 <210> 28 <211> 3846 <212> DNA <213> Artificial Sequence cg cgat <223> nucleic acid sequence at c gtgctgctgc tgtgcggagc cgtgttcgtg 60 tctccaagcc acgccaccca ggattgttct ttccagcaca gccccatcag ctccgacttt 120 gccgtgaaga tccgcgagct gagcgactac ctgctgcagg attatcccgt gacagtggcc 180 tccaatctgc aggacgagga gctgtgcgga ggactgtgga ggctggtgct ggcacagcgg 240 tggatggaga gactgaagac cgtggcaggc tccaagatgc agggactgct ggagcgcgtg 300 aacaccgaga tccacttcgt gacaaagtgc gcctttcagc cccctccaag ctgtctgcgg 360 tttgtgcaga caaacatctc cagactgctg caggagacct ctgagcagct ggtggccctg 420 aagccctgga tcacaaggca gaatttctct cgctgcctgg agctgcagtg tcagcctgac 480 tctagcaccc tgccacctcc atggagccct cggccactgg aggcaaccgc accaacagca 540 cctggctccg gctctggcag cggctccggc tgaggcttttagctca ggcctgcct aggcct cggcctagt aggcct cggccactg aggcct cggcaggtg 600g ggagccaact ctccagccct gtatctgctg gacggcctga gagcccagga cgatttcagc 720 ggctgggaca tcaatacacc cgcctttgag tggtacgacc agagcggact gtccgtggtc 780 atgccagtgg gaggacagtc ctctttttac tccgactggt atcagcctgc atgcggcaag 840 gcaggatgtc agacctacaa gtgggagacc ttcctgacaa gcgagctgcc tggctggctg 900 caggccaaca ggcacgtgaa gccaacaggc tccgccgtgg tgggactgtc tatggcagcc 960 agctccgccc tgaccctggc aatctaccac cctcagcagt tcgtgtacgc aggagcaatg 1020 agcggactgc tggacccctc ccaggcaatg ggaccaaccc tgatcggact ggcaatgggc 1080 gacgcaggag gatataaggc aagcgacatg tggggaccaa aggaggaccc cgcatggcag 1140 aggaacgacc cactgctgaa tgtgggcaag ctgatcgcca acaataccag agtgtgggtg 1200 tactgtggaa acggcaagcc atccgatctg ggaggaaaca atctgcctgc caagttcctg 1260 gagggctttg tgcggacatc taatatcaag ttccaggacg catataacgc aggaggagga 1320 cacaatggcg tgttcgactt tcccgattcc ggcacccact cttgggagta ctggggagca 1380 cagctgaacg caatgaagcc cgacctgcag agagccctgg gagcaacccc caatacagga 1440 ccagcaccac agggagcagg cagcggctcc ggctctggca gcggctctag ccagatcatg 1500 tacaactatc ctgccatgct gggacacgca ggcgacatgg caggatacgc aggcaccctg 1560 cagtctctgg gagcagagat cgcagtggag caggccgccc tgcagagcgc ctggcagggc 1620 gataccggca tcacatatca ggcatggcag gcacagtgga accaggcaat ggaggacctg 1680 gtgcgggcct accacgccat gtcctctacc cacgaggcca atacaatggc catgatggcc 1740 agagataccg cagaggcagc aaagtgggga ggaggctccg gctctggcag cggctccggc 1800 tctgcccccc ctgccctgtc ccaggaccgg ttcgccgatt ttcctgccct gccactggac 1860 ccctctgcca tggtggcaca agtgggacct caggtggtga acatcaatac aaagctgggc 1920 tacaacaatg cagtgggagc aggcaccgga atcgtgatcg acccaaacgg cgtggtgctg 1980 acaaacaatg ccgtgatcgc cggcgccacc gacatcaatg ccttttctgt gggcagcggc 2040 cagacatacg gcgtggacgt ggtgggctat gataggaccc agaatgtggc cgtgctgcag 2100 ctgaggggag caggaggcct gccttccgcc gccatcggcg gcggcgtggc cgtgggcgag 2160 ccagtggtgg caatgggcaa cagcggagga cagggaggca caccacgggc cgtgcccggc 2220 agagtggtgg ccctgggaca gaccgtgcag gcaagcgatt ccctgaccgg agccgaggag 2280 acactgaacg gcctgatcca gtttgatgca gcaatccagc caggcgacgc aggaggacct 2340 gtggtgaatg gcctgg gaca ggtggtggga atgaacaccg cagcctctga caatttccag 2400 ctgagccagg gaggacaggg atttgcaatc ccaatcggac aggcaatggc aatcgcagga 2460 cagatcagga gcggaggagg ctccccaacc gtgcacatcg gaccaacagc cttcctggga 2520 ctgggagtgg tggacaacaa tggcaacggc gcccgggtgc agagagtggt gggctccgcc 2580 ccagcagcat ctctgggcat cagcaccggc gacgtgatca cagccgtgga tggcgcccct 2640 atcaacagcg ccaccgccat ggccgatgcc ctgaatggcc accacccagg cgacgtgatc 2700 agcgtgacct ggcagacaaa gtccggaggc accaggacag gaaacgtgac actggcagag 2760 ggaccaccag caggctctgg cagcggctcc ggctctggca gctgcggcaa cgacgataat 2820 gtgaccggag gaggagcaac cacaggacag gcctccgcca aggtggattg tggcggcaag 2880 aagaccctga aggcatccgg ctctacagca caggcaaacg ccatgaccag gttcgtgaac 2940 gtgttcgagc aggcatgccc aggacagacc ctgaactata cagcaaatgg cagcggagca 3000 ggcatctccg agttcaacgg caatcagaca gactttggcg gctctgatgt gcctctgagc 3060 aaggacgagc catccggagc agcaagatgt ggcagccctg cctggaatct gccagtggtg 3120 tttggcccca tcgccgtgac ctacaacctg aatagcgtga gctccctgaa cctggatggc 3180 cccacactgg ccaagatttt c aacggctcc atcacccagt ggaacaatcc cgccatccag 3240 gccctgaacc gggacttcac cctgcctggc gagagaatcc acgtggtgtt tcgctccgac 3300 gagtctggca ccacagataa cttccagaga tacctgcagg cagcatctaa tggagcatgg 3360 ggcaagggag caggcaagag ctttcaggga ggagtgggag agggagccag aggcaacgat 3420 ggcaccagcg ccgccgccaa gaacacccca ggctctatca catacaatga gtggagcttc 3480 gcccaggccc acgacctgac catggccaat atcgtgacaa gcgccggagg cgatcctgtg 3540 gcaatcacca tcgactccgt gggacagacc atcgcaggag ccacaatctc tggcgtgggc 3600 aacgatctgg tgctggacac agatagcttc tataggccta agcgcccagg ctcctaccca 3660 atcgtgctgg ccacctatga gatcgtgtgc tctaagtacc ccgacagcca agtgggcaca 3720 gccgtgaagg cctttctgca gtccaccatc ggagcaggac agtctggact gggcgataac 3780 ggctacatcc ctatcccaga cgagttcaag agcagactgt ccaccgccgt gaatgccatc 3840 gcctaa 3846 <210> 29 <211> 6018 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of GX-170B <400> 29 atggatgcca tgaagagggg actgtgctgc gtgctgctgc tgtgcggagc cgtgttcgtg 60 tccccatctc acgccaccca ggattgttct ttccagcaca gccctat cag ctccgacttt 120 gccgtgaaga tccgggagct gtctgattac ctgctgcagg actatcccgt gacagtggcc 180 agcaacctgc aggacgagga gctgtgcgga ggactgtgga ggctggtgct ggcacagaga 240 tggatggaga ggctgaagac cgtggcaggc tccaagatgc agggactgct ggagcgggtg 300 aatacagaga tccacttcgt gaccaagtgc gcctttcagc cccctccaag ctgtctgcgg 360 ttcgtgcaga ccaacatcag cagactgctg caggagacat ccgagcagct ggtggccctg 420 aagccttgga tcacaagaca gaatttttct aggtgcctgg agctgcagtg tcagccagat 480 tctagcaccc tgccacctcc atggagccct cgcccactgg aggccacagc accaaccgca 540 ccaggcagcg gctccggctc tggcagcggc tccgtgaatt tcagcgtgct gccccctgag 600 atcaactccg gccggatgtt ctttggagca ggctccggac ctatgctggc tgccgccgcc 660 gcctgggacg gactggcagc agagctgggc ctggccgccg agagctttgg cctggtgaca 720 agcggcctgg ccggcggctc tggccaggcc tggcagggcg ctgccgccgc cgccatggtg 780 gtggctgccg ccccatacgc cggctggctg gccgccgccg ccgccagagc cggaggagcc 840 gccgtgcagg ccaaggccgt ggccggcgcc ttcgaggccg ccagggccgc aatggtggac 900 ccagtggtgg tggcagcaaa ccgctctgcc ttcgtgcagc tggtgctgag caacgtgttc 960 g gacagaacg caccagcaat cgctgccgcc gaggcaacct acgagcagat gtgggcagca 1020 gatgtggcag caatggtggg ctatcacgga ggagcaagcg ccgccgccgc cgccctggcc 1080 ccatggcagc aggccgtgcc cggcctgagc ggactgctgg actccgccca gtcctctgcc 1140 caggccgtga ccgcacaggc agtgggctcc acagtgcccg gccctctgca gggcatcaat 1200 ttcggctttg gcaacatcgg ctctctgaat ctgggcagcg gcaacacagg cgataccaat 1260 gtgggcagcg gcaacatcgg caataccaac ctgggcggcg gcaatatcgg ctccttcaac 1320 ctgggctctg gcaatcaggg cgacatcaac ctgggcatcg gcaatgtggg caatctgaac 1380 ctgggcagcg gcaactttgg ctcccagaat ctgggctctg gcaacatcgg cagcaccaat 1440 gtgggctccg gcaacatcgg ctctacaaat gtgggcagcg gaaatatcgg cgataccaat 1500 ttcggcaacg gcaacaatgg caatttcaac tttggctccg gcaacacagg ctctaacaat 1560 atcggctttg gcaataccgg cagcggcaac ttcggctttg gcaatacagg caacaataac 1620 atcggcatcg gcctgaccgg cgacggacag atcggaatcg gaggcctgaa ctctggcagc 1680 ggcaatatcg gcttcggcaa ctctggcaca ggcaatgtgg gcctgttcaa cagcggcacc 1740 ggcaatgtgg gctttggcaa ctccggcaca gccaataccg gcttcggcaa cgccggcaat 1800 gtgaaca cag gcttttggaa tggcggctcc acaaacaccg gactggcaaa tgcaggagca 1860 ggaaacaccg gcttctttga cgccggcaat tacaactttg gctctctgaa cgccggcaat 1920 atcaacagct ccttcggcaa tagcggcgac ggcaactccg gctttctgaa tgccggcgat 1980 gtgaactctg gcgtgggcaa tgccggcgac gtgaacacag gcctgggcaa tagcggcaat 2040 atcaacaccg gcggcttcaa cccaggcaca ctgaataccg gcttcttttc cgccatgaca 2100 caggccggcc ccaactctgg cttctttaat gcaggcaccg gcaacagcgg atttggacac 2160 aacgacccag caggcagcgg caattccggc atccagaact ctggcttcgg caatagcggc 2220 tacgtgaaca catctaccac aagcatgttt ggcggcaatt ctggcgtgct gaacaccggc 2280 tacggcaata gcggcttcta taacgccgcc gtgaataaca caggcatctt tgtgaccggc 2340 gtgatgtcta gcggcttctt taatttcggc acaggcaact ccggcctgct ggtgtctggc 2400 aatggcctga gcggcttctt taagaacctg tttggaggct ccggctctgg cagcggctcc 2460 ggctctaccg accgcgtgtc cgtgggcaac ctgagaatcg ccagggtgct gtatgatttc 2520 gtgaataacg aggccctgcc tggcacagac atcgacccag acagcttttg ggcaggagtg 2580 gataaggtgg tggccgacct gacccctcag aatcaggccc tgctgaacgc cagagacgag 2640 ctgcaggccc ag atcgacaa gtggcaccgg cggagagtga tcgagccaat cgacatggac 2700 gcctacaggc agttcctgac agagatcggc tatctgctgc cagagcccga cgacttcacc 2760 atcaccacat ccggcgtgga tgccgagatc accacaaccg caggacctca gctggtggtg 2820 ccagtgctga acgcaaggtt cgccctgaat gcagcaaacg ccagatgggg cagcctgtac 2880 gatgccctgt atggcacaga cgtgatccca gagaccgatg gagcagagaa gggacctaca 2940 tacaataagg tgaggggcga caaagtgatc gcctatgccc gcaagttcct ggacgattct 3000 gtgcccctgt cctctggcag cttcggcgac gccacaggct ttaccgtgca ggatggacag 3060 ctggtggtgg ccctgcctga taagtccacc ggactggcaa acccaggaca gtttgcagga 3120 tacaccggag cagcagagtc ccccacatct gtgctgctga tcaatcacgg cctgcacatc 3180 gagatcctga tcgaccctga gagccaagtg ggcacaaccg acagagcagg agtgaaggat 3240 gtgatcctgg agtccgccat cacaaccatc atggatttcg aggactctgt ggcagcagtg 3300 gatgcagcag acaaggtgct gggctacaga aattggctgg gcctgaacaa gggcgatctg 3360 gctgccgccg tggataagga cggcaccgcc tttctgaggg tgctgaatag agacaggaac 3420 tataccgccc caggaggagg acagttcaca ctgccaggcc ggtctctgat gtttgtgaga 3480 aatgtgggcc acctgatg ac caacgacgcc atcgtggata cagacggcag cgaggtgttc 3540 gagggcatca tggatgccct gtttacaggc ctgatcgcca tccacggcct gaaggcctcc 3600 gacgtgaatg gccccctgat caactcccgc accggctcta tctacatcgt gaagccaaag 3660 atgcacggac ctgcagaggt ggccttcaca tgcgagctgt ttagccgggt ggaggacgtg 3720 ctgggcctgc ctcagaatac catgaagatc ggcatcatgg atgaggagcg ccggacaacc 3780 gtgaacctga aggcctgtat caaggctgcc gccgacaggg tggtgttcat caatacaggc 3840 tttctggatc gcaccggcga cgagatccac acatccatgg aggccggccc aatggtgaga 3900 aagggcacca tgaagtctca gccctggatt ctggcctatg aggatcacaa cgtggacgca 3960 ggactggcag caggcttcag cggcagagcc caagtgggca agggcatgtg gacaatgacc 4020 gagctgatgg ccgatatggt ggagacaaag atcgcacagc ctagggccgg agccagcacc 4080 gcatgggtgc cttccccaac agcagccacc ctgcacgcac tgcactacca ccaggtggac 4140 gtggcagcag tgcagcaggg actggcaggc aagagaaggg ccaccatcga gcagctgctg 4200 acaatccctc tggcaaagga gctggcatgg gcaccagacg agatcaggga ggaggtggat 4260 aataactgcc agtccatcct gggctatgtg gtgcggtggg tggatcaggg agtgggatgt 4320 tctaaggtgc cagacatcca cga cgtggcc ctgatggagg acagggccac actgcggatc 4380 agctcccagc tgctggccaa ctggctgagg cacggcgtga tcacctctgc cgacgtgcgc 4440 gcaagcctgg agaggatggc accactggtg gacaggcaga atgcaggcga tgtggcctac 4500 agacctatgg ccccaaactt cgacgatagc atcgcctttc tggcagcaca ggagctgatc 4560 ctgtccggag cacagcagcc aaacggatat accgagccta tcctgcaccg ccggagaagg 4620 gagttcaagg ccagagccgc agagaagcca gcaccttccg atagggcagg cgacgatgca 4680 gcccgcggca gcggctccgg ctctggcagc ggctccgatc cccagacaga caccatcgcc 4740 gccctgatcg cagacgtggc aaaggccaac cagaggctgc aggatctgag cgacgaggtg 4800 caggcagagc aggagtccgt gaataaggca atggtggacg tggagaccgc ccgggataac 4860 gctgccgccg ccgaggacga tctggaggtg agccagagag ccgtgaagga tgcaaacgca 4920 gcaatcgctg ccgcccagca caggttcgac accttcgccg ccgccaccta catgaatggc 4980 ccctctgtga gctatctgag cgcctctagc cctgacgaga tcatcgccac agtgaccgca 5040 gcaaagaccc tgtccgcctc ctctcaggcc gtgatggcaa atctgcagag ggcacggaca 5100 gagagggtga acaccgagtc cgccgcccgc ctggcaaagc agaaggcaga taaggctgcc 5160 gccgacgcaa aggcatctca ggatgcagc a gtggccgccc tgacagagac caggcggaag 5220 ttcgacgagc agagagagga ggtgcagagg ctggcagcag agagggatgc agcacaggcc 5280 cggctgcagg ccgccgccagact ggtggcggcatgg agctggaccc gaccccaccc tgcctatgat cccatccgcc aatatccccg gcgaccctat cgccgtggtg 5460 aaccaggtgc tgggcatcag cgccacatcc gcccaggtga cagccaacat gggcagaaag 5520 ttcctggagc agctgggcat cctgcagccc acagacaccg gaatcaccaa tgcacctgca 5580 ggcagcgccc agggacgcat cccacgggtg tacggcaggc aggcatccga gtatgtgatc 5640 agaaggggca tgtcccagat cggcgtgcct tactcttggg gaggaggaaa cgcagcagga 5700 ccatccaagg gaatcgactc tggagcaggc accgtgggat tcgattgttc cggcctggtg 5760 ctgtattctt ttgccggcgt gggcatcaag ctgccacact actccggctc tcagtataat 5820 ctgggccgca agatcccctc tagccagatg cgccggggcg atgtgatctt ctacggccct 5880 aatggcagcc agcacgtgac catctatctg ggaaacggac agatgctgga ggcaccagac 5940 gtgggcctga aggtgagggt ggcacctgtg cgcacagcag gcatgacccc atacgtggtg 6000 cggtacatcg agtattaa 6018 <210> 30 <211> 253 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of IL-12p35 <400> 30 Met Trp Pro Pro Gly Ser Ala Ser Gln Pro Pro Pro Ser Pro Ala Ala 1 5 10 15 Ala Thr Gly Leu His Pro Ala Ala Arg Pro Val Ser Leu Gln Cys Arg 20 25 30 Leu Ser Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val 35 40 45 Leu Leu Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro 50 55 60 Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg 65 70 75 80 Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr 85 90 95 Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys 100 105 110 Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu 115 120 125 Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys 130 135 140 Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser 145 150 155 160 Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn 165 170 175 Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn 180 185 190 Met Leu Ala Val Ile Asp Glu Leu M et Gln Ala Leu Asn Phe Asn Ser 195 200 205 Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys 210 215 220 Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala 225 230 235 240 Val Thr Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 245 250 <210> 31 <211> 328 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of IL-12p40 <400> 31 Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu A sp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe 115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gin Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu 180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile 195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr 210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser A rg Gln Val Glu Val Ser Trp 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr 260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg 275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala 290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser 325 <210> 32 <211> 155 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of IL-21 <400> 32 Met Glu Arg Ile Val Ile Cys Leu Met Val Ile Phe Leu Gly Thr Leu 1 5 10 15 Val His Lys Ser Ser Ser Gln Gly Gln Asp Arg His Met Ile Arg Met 20 25 30 Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp 35 40 45 Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys 50 55 60 Glu Trp Ser Ala Phe Ser Cys P he Gln Lys Ala Gln Leu Lys Ser Ala 65 70 75 80 Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu 85 90 95 Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg 100 105 110 Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu 115 120 125 Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His 130 135 140 Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser 145 150 155 <210> 33 <211> 92 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of MIP-1 alpha <400> 33 Met Gln Val Ser Thr Ala Ala Leu Ala Val Leu Leu Cys Thr Met Ala 1 5 10 15 Leu Cys Asn Gln Phe Ser Ala Ser Leu Ala Ala Asp Thr Pro Thr Ala 20 25 30 Cys Cys Phe Ser Tyr Thr Ser Arg Gln Ile Pro Gln Asn Phe Ile Ala 35 40 45 Asp Tyr Phe Glu Thr Ser Ser Gln Cys Ser Lys Pro Gly Val Ile Phe 50 55 60 Leu Thr Lys Arg Ser Arg Gln Val Cys Ala Asp Pro Ser Glu Glu Trp 65 70 75 80 Val Gln Lys Tyr Val Ser Asp Leu Glu Leu Ser Ala 85 90 <210> 34 <211> 712 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of IL- 12p35 <400> 34 atgtggcccc ctgggtcagc ctcccagcca ccgccctcac ctgccgcggc cacaggtctg 60 catccagcgg ctcgccctgt gtccctgcag tgccggctca gcatgtgtcc agcgcgcagc 120 ctcctccttg tggctaccct ggtcctcctg aatgttccca tgccttcacc actcccaaaa 180 cctgctgagg gccgtcagca acatgctcca gaaggccaga caaactctgg aattttaccc 240 ttgcacttct gaagagattg atcatgaaga tatcacaaaa gataaaacga gcacagtgga 300 ggcctgttta ccattggaat taaccaagaa tgagagttgc ctaaattcca gagagacctc 360 tttcataact aatgggagtt gcctggcctc cagaaagacc tcttttatga tggccctgtg 420 ccttagtagt atttatgaag acttgaagat gtaccaggtg gagttcaaga ccatgaatgc 480 aaagcttctg atggatccta agaggcagat ctttctggat caaaacatgc tggcagttat 540 tgatgagctg atgcaggccc tgaatttcaa cagtgagact gtgccacaaa aatcctccct 600 tgaagaaccg gatttttata aaactaaaat caagctctgc atacttcttc atgctttcag 660 gattcgggca gtgactattg atagagtgat gagctatct g aatgcttcct aa 712 <210> 35 <211> 937 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of IL-12p40 <400> 35 atgtgccacc agcagctggt catcagctgg ttctccctgg ttctttctggc ttctcctctgc ttctcctgt gtg gtatccagat 120 gcccccggag agatggtggt cctgacctgc gacacaccag aggaagatgg catcacttgg 180 accctggacc agagctccga ggtcctggga agcggcaaga cactgactat tcaggtgaaa 240 gaattcgggg atgctggaca gtacacatgt cataagggcg gggaggtgct gtcccactct 300 ctgctgctgc tgcataagaa agaagatggc atctggtcta ctgacattct gaaggatcag 360 aaagagccca agaacaaaac cttcctgaga tgcgaagcca agaattatag cgggaggttt 420 acctgttggt ggctgaccac aatctctact agtgacctgc ggagcagcta cactgagcgc 480 agagcgggtc agaggagaca acaaggagta cgaatattcc gtggagtgcc aggaagattc 540 tgcatgtccc gcagccgagg aatccctgcc tatcgaagtg atggtggacg ccgtgcacaa 600 gctgaaatac gaaaactaca catcctcttt ctttatccgg gacatcatta agccagatcc 660 ccctaaaac ctgatta aggattc 660 ccctaaaaac ctgcaggtaga ag c ttatttcagt ctgacttttt gcgtgcaggt 780 ccagggcaag agtaaacgag agaagaaaga ccgggtcttc accgataaga catccgctac 840 tgtgatctgt cggaaaaacg ccagtatttc agtgagggct caggaccgct actatagttc 900 aagctggtca gagtgggcaa gcgtgccctg ttcctag 937 <210> 36 <211> 468 <212> DNA <213> Artificial Sequence <220> <223> nucleic acid sequence of IL-21 <400> 36 atggaacgga ttgtcatttg cctgatggtc atttttctgg gaaccctggt ccacaagtca 60 agcagtcagg gccaggatag gcacatgatt aggatgcgcc agctgatcga cattgtggat 120 cagctgaaga actacgtgaa tgacctggtc cctgagtttc tgcctgcacc agaggatgtc 180 gaaacaaact gcgaatggag cgccttctcc tgttttcaga aggcccagct gaaatccgct 240 aacaccggca acaatgagcg aatcatcaac gtgagcatca agaagctgaa gcggaaaccc 300 cctagcacta atgctgggcg gagacagaaa catagactga cctgcccctc ttgtgacagt 360 tatgaaaaga aaccacccaa ggagttcctg gaacgcttta aaagtctgct gcagaaaatg 420 attcaccagc acctgtcctc cagaactcac gggtccgaag attcctaa 468 <210> 37 <211> 279 <212> nucleic acid <213> t alpha gt 37 att Artificial Sequence <220> <223> caaccgccgc cctggctgtc ctgctgtgca ctatggctct gtgcaatcag 60 ttttccgcaa gtctggccgc tgatactccc accgcctgct gtttctctta cacaagtagg 120 cagatccctc agaacttcat tgctgactat tttgagacta gctcccagtg cagcaagccc 180 ggcgtgatct ttctgaccaa gcggagccgg caggtctgtg ccgatccctc cgaagaatgg 240gtgcagaagt atgtctccga cctggaactg tcagcataa 279

Claims (20)

A fusion protein comprising a fusion polypeptide derived from Mycobacterium tuberculosis . The method of claim 1,
The fusion polypeptide is selected from the group consisting of Ag85A, TB10.4, Mtb32b and PstS3. 3. The method of claim 2,
The Ag85A is composed of the amino acid sequence of SEQ ID NO: 1, the TB10.4 is composed of the amino acid sequence of SEQ ID NO: 2, the Mtb32b is composed of the amino acid sequence of SEQ ID NO: 3, and the PstS3 is the amino acid sequence of SEQ ID NO: 4 A fusion protein consisting of. The method of claim 1,
The fusion polypeptide further comprises a polypeptide selected from the group consisting of PPE39, GlcB and RipA. 5. The method of claim 4,
The PPE39 is composed of the amino acid sequence of SEQ ID NO: 5, the GlcB is composed of the amino acid sequence of SEQ ID NO: 6, the RipA is a fusion protein consisting of the amino acid sequence of SEQ ID NO: 7. 5. The method according to claim 2 or 4,
Wherein the fusion polypeptide is linked by a GS linker. 7. The method of claim 6,
The GS linker is a fusion protein consisting of the amino acid sequence of SEQ ID NO: 8. The method of claim 1,
The fusion protein further comprises a signal peptide. 9. The method of claim 8,
Wherein the signal peptide is selected from the group consisting of a tissue plaminogen activator (tPA) signal peptide, a Herpes Simplex Virus glycoprotein Ds (HSV gDs) signal peptide, and a growth hormone signal peptide. The method of claim 1,
The fusion protein further comprises an immune enhancing peptide. 11. The method of claim 10,
The immune enhancing peptide is a fusion protein selected from the group consisting of CD40 ligand, Flt3 (fms-like tyrosine kinase-3) ligand, flagellin and OX40. 12. A polynucleotide encoding a fusion protein according to any one of claims 1 to 11. A recombinant vector comprising the polynucleotide according to claim 12 . 14. The method of claim 13,
The recombinant vector is a plasmid vector or a viral vector. A pharmaceutical composition for preventing or treating tuberculosis comprising the fusion protein according to any one of claims 1 to 11. 16. The method of claim 15,
The composition further comprises an adjuvant containing IL-12, IL-21 and MIP-1a protein. 17. The method of claim 16,
The composition of the adjuvant comprising the amino acid sequence of SEQ ID NOs: 30 to 33. A pharmaceutical composition for preventing or treating tuberculosis comprising the polynucleotide according to claim 12. 19. The method of claim 18,
The composition further comprises a polynucleotide encoding an adjuvant containing IL-12, IL-21 and MIP-1a proteins. A pharmaceutical composition for preventing or treating tuberculosis comprising the recombinant vector according to claim 13.

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