CN102973950B - PRAME and WT1 bivalent tumor DNA vaccine - Google Patents
PRAME and WT1 bivalent tumor DNA vaccine Download PDFInfo
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- CN102973950B CN102973950B CN201110261931.3A CN201110261931A CN102973950B CN 102973950 B CN102973950 B CN 102973950B CN 201110261931 A CN201110261931 A CN 201110261931A CN 102973950 B CN102973950 B CN 102973950B
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Abstract
The invention discloses a PRAME and WT1 bivalent tumor DNA vaccine. A nucleic acid sequence of the vaccine is represented by SEQ ID NO.1. The DNA vaccine provided by the invention has the advantages of ingenious idea, high expression in human bodies, and widely applicable population. Through enhancing body specific humoral and cellular immune responses upon PRAME and WT1 antigen proteins, PRAME and WT1 antigen-positive tumors are killed, such that various cancers can be treated. Because PRAME and WT1 have specific highly expression in tumor cells of various cancers and have no expression in human body normal cells, the DNA tumor vaccine can be used for treating various cancers.
Description
Technical field
The present invention relates to PRAME, WT1 bivalent tumor DNA vaccine.
Background technology
Operation, radiation and chemotherapy are three kinds of conventional meanses for the treatment of of cancer, and in recent years, along with the research and development of new chemotherapeutic drugs are gone on the market, the continuous renewal of operation and radiotherapy technology, the long-term surviving rate of tumor patient increases.But because the early diagnosis technology of tumor is also perfect not to the utmost, quite a few patients with solid tumor has transfer in various degree when performing the operation.Although radiation and chemotherapy can pre-non-proliferation and transfer to a certain extent, still have quite a few patient can not avoid recurrence.Secondly, modern science proves that tumor stem cell and circulating tumor cell cause shifting the root with recurrence, and three large routine treatments are very little to this two classes tumor cell effect.
Tumor immunology (tumor Immunology) utilizes immunologic Theories and methods, the mutual relation of the research antigenicity of tumor, the immunologic function of body and tumorigenesis, body is to the science of the immunne response of tumor and the mechanism of antineoplastic immune thereof, the immunologic diagnosis of tumor and immune protection.
There are the progress of advancing by leaps and bounds tumor immunology more than ten years in the past.First, prove now that tumor patient exists the specific immune response to tumor, the Partial tumors patient that operation, chemotherapy, radiotherapy are cured, be not because these means can kill whole tumor cell, but due to when tumor cell burden significantly reduces, the immunologic function of body is recovered to some extent, removes the propagation of MRD or suppression remaining tumor cells.Secondly, the clinical trial certificate of adoptive immunotherapy, when patient is injected into TS effector lymphocyte (LAK or TIL) of q.s, not only can extend total survival period, in some patients, also can observe mass reduction.In conjunction with the result of these two aspects, therapeutic tumor vaccine receives increasing concern.The mechanism of action of this type of vaccine uses the immunogenic method strengthening tumor specific antigen, brings out the anti-tumor immune response of body, reach the object reducing and eliminate tumor.
Tumor vaccine at present in clinical trial has various ways, has cellular type (dendritic cell, the tumor cell of deactivation), cell homogenates type, synthesising biological macromole type (polypeptide, albumen, DNA/RNA), and viral vector type.Wherein, DNA vaccination has many-sided superiority.The first, it can induce the immunne response producing and have long term immune memory.The second, naked DNA is not containing the antigen component of inducing antibodies reaction, and the antibody of these anti-vaccines can weaken tiring of vaccine.3rd, produce with preparation cost low, technique is simple.Although DNA vaccination is with the obvious advantage, due to the reason such as its expression efficiency in human body is low, so that clinical effectiveness is not satisfactory.
Summary of the invention
The object of this invention is to provide PRAME, WT1 bivalent tumor DNA vaccine.This DNA vaccination is skillfully constructed, and the expression rate in human body is high, is suitable for crowd wide.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
PRAME, WT1 bivalent tumor DNA vaccine, the nucleotide sequence of this vaccine is as shown in SEQ ID NO:1.
Aminoacid sequence corresponding to described nucleotide sequence is as shown in SEQ ID NO:2.
Above-mentioned PRAME, WT1 bivalent tumor DNA vaccine is for the preparation of the purposes in anti-tumor medicine or vaccine.
Described tumor is WT1 positive tumor and/or PRAME positive tumor.
Described tumor comprises: cancer of pancreas, ovarian cancer, melanoma, renal carcinoma, carcinoma of prostate, intestinal cancer, carcinoma of endometrium, cervical cancer, carcinoma of testis, thyroid carcinoma, small cell lung cancer, mesothelioma, breast carcinoma, esophageal carcinoma, gastric cancer, neuroendocrine carcinoma, hepatocarcinoma, carcinoma of gallbladder, osteocarcinoma, soft tissue cancer, esophageal carcinoma, lymphoma etc.
Above-mentioned PRAME, WT1 tumor DNA vaccine can be obtained by the method for following key step:
Carry out antigen gene synthesis according to the nucleotide sequence shown in SEQ ID NO:1, this sequence comprises: multistage PRAME and WT1 genetic fragment, fragment catenation sequence, HindIII, EcoR I restriction endonuclease recognition sequence and KozaK translation initiation sequence.By HindIII and EcoR I restricted enzyme, antigen gene and pVAX1 plasmid are sheared respectively afterwards, make it expose sticky end.With DNA ligase, antigen gene is connected by sticky end with pVAX1 plasmid again, becomes recombiant plasmid.By Transfected Recombinant Plasmid escherichia coli, make it copy in Bacillus coli cells, increase.Through extracting and the purification of plasmid, be met PRAME, WT1 bivalent tumor DNA vaccine of requirement.
The present invention selects multistage PRAME and WT-1 gene fragment order, and these fragments are connected in beading mode, add that restricted enzyme and Kozak translation initiation sequence carry out full genome synthesis, and be connected to commodity carrier pVAX1 (Invitrogen) to complete vaccine construction.Coding region is connected to colibacillus expression plasmid simultaneously, is used as evaluating the reagent of vaccine valence for preparing protein polypeptide on a small quantity.
The present invention is in order to reach reasonable therapeutic effect, prevent tumor because antigen run off and protected from immune attack, inventor devises a bivalent vaccine through repeatedly repetition test and comprises two kinds of different tumor antigens, PRAME (Melanoma antigen preferentially expressed in tumors) and WT-1 (Wilms tumorprotein).These two kinds of antigens play a part different in the propagation of cancerous cell, transfer and diffusion.PRAME participates in the relevant signal transduction of retinoic acid receptors, is considered to relevant with the function of anti-apoptotic to the growth of tumor cell.WT-1 is then considered to a transcription factor, participates in the multiple biological function of tumor cell.The expression rate of these two kinds of antigens in cancer of pancreas specimen all higher (> 75%), except except, their expression rates in other solid tumors and blood cancer are also quite high.
The present invention by tumor associated antigen PRAME and WT1 Partial Fragment gene order and the restructuring of other correlated serieses, and is building up in eukaryotic expression DNA plasmid vector, with this plasmid for main component makes injection medicine, is used for the treatment of Several Kinds of Malignancy.Its principle is: this vaccine, after being injected into human body, can entering human body cell and express recombinant antigen protein, and then exciting human is for the specific immune response of PRAME and WT1 antigen.The specificity humoral produced and cellular immunization will kill PRAME and WT1 antigen positive tumor, reach treatment of cancer object.
In sum, owing to have employed technique scheme, the invention has the beneficial effects as follows:
Tumor DNA vaccine of the present invention is skillfully constructed, and the expression rate in human body is high, is suitable for crowd wide.By enhancing body for the specificity humoral of PRAME and WT1 antigen protein and cell immune response, PRAME and WT1 antigen positive tumor is killed and wounded, thus reach treatment kinds cancer object.Because PRAME and WT1 has specificity a large amount to express in the tumor cell of kinds cancer, and do not express in human normal cell, so this DNA tumor vaccine will can be used in treating kinds cancer.
Accompanying drawing explanation
Examples of the present invention will be described by way of reference to the accompanying drawings, wherein:
Fig. 1 is that the embodiment of the present invention 1 transgenic animal humoral immunization is tired evaluation result figure;
Fig. 2 is the embodiment of the present invention 1 transgenetic animal cell immunizing potency evaluation result figure;
Fig. 3 is the evaluation result figure that tires of the embodiment of the present invention 1 transgenic animal immunocyte Cytotoxicity in vitro tumor cell;
Fig. 4 is the embodiment of the present invention 1 transgenic animal interior tumor cell killing experiments evaluation result figure;
Fig. 5 is the embodiment of the present invention 2 human peripheral cell in vitro immunizing potency evaluation result figure;
Fig. 6 is the evaluation result figure that tires of the embodiment of the present invention 2 human peripheral blood immune cells Cytotoxicity in vitro tumor cell.
Detailed description of the invention
All features disclosed in this description, or the step in disclosed all methods or process, except mutually exclusive feature and/or step, all can combine by any way.
Arbitrary feature disclosed in this description, unless specifically stated otherwise, all can be replaced by other equivalences or the alternative features with similar object.That is, unless specifically stated otherwise, each feature is an example in a series of equivalence or similar characteristics.
Embodiment 1: immunizing transgenic mice detects Immunel response intensity and antitumor cell effect experimental
Experimental program is as follows:
1, animal subject:
10-12 HLA-A2.1 transgenic female mice in age in week.
2, animal subject grouping:
HLA-A2.1 transgenic mice is divided into two large group at random, and each large component is three groups, and every group is denoted as
1) 1-1: animal experiment in vitro experimental group
2) 1-2: animal experiment in vitro matched group
3) 1-3: animal experiment in vitro observation group
4) 2-1: experiments experiment group in animal body
5) 2-2: experiment contrast group in animal body
6) 2-3: laboratory observation group in animal body
Each 15 transgenic mices of every group, totally 90.
3, lymph node inoculation (observation group does not inject):
Method:
1) plasmid is diluted: get 2mg recombiant plasmid and empty plasmid (pVAX1) respectively, be diluted to 0.4mg/ml with 1X PBS buffer, use in order to subsequent experimental.
2) anesthetized animal: use isoflurane trachea inhalation anesthesia.
3), before carrying out lymph node inoculation, blood 0.1mL is got, as the negative control that follow-up ELISA tests at 1-1 and 1-2 group mouse orbit venous plexus respectively.
4) lymph node injection: experimental group and matched group aseptically expose inguinal lymph nodes, with micro-syringe injection tested material plasmid in lymph node, inject 4 times altogether, the time is respectively the 1st, 4,15 and 18 day.
As follows to every treated animal injection system:
Experimental group: 1-1,2-1 (injection 25uL, 0.4mg/ml recombiant plasmid)
Matched group: 1-2,2-2 (injection 25uL, 0.4mg/ml pVAX1 empty plasmid)
Observation group: 1-3,2-3 (not injecting)
4, immunne response evaluation:
Adopt its peripheral blood and spleen cell the 28th natural gift other places dead 1-1,1-2 and 1-3 group mice, carry out the evaluation of immunne response.
1) humoral immunization is tired evaluation:
Evaluate object and method: ELISA method.Whether evaluate object is measure in peripheral blood to have specific antibody to produce and the tiring of antibody.Method is buffered liquid with 0.05M PH9.6 carbonate bag target antigen albumen is diluted to protein content is 5 μ g/ml, and the every hole of ELISA Plate adds 100ul and is placed in 4 DEG C and spends the night; After 0.15MPH7.4PBS cleaning, add 200ul 1%BSA/PBS at room temperature with ELISA Plate non-specific binding 60min with sealase target, add after cleaning 100ul dilution after Peripheral Blood and antigen at room temperature hatch in conjunction with 60min, after cleaning non-binding antibody, add 100ul debita spissitudo anti-mouse two antienzyme len antibody incubated at room temperature 60min, the substrate at room temperature labelling colour developing 30min of 100ul debita spissitudo is added after cleaning, survey absorbance by microplate reader, produce density with serum-dilution titre express antibody.
Experimental result: as shown in Figure 1,1-1 (experimental group) OD value is far away higher than 1-2 group (matched group) and 1-3 group (observation group), show that experimental mice Serum Antibody content is far away higher than matched group and observation group, prove that PRAME, WT1 bivalent DNA vaccine can excite the specific humoral immunity of transgenic mice to react.
2) cellular immunization is tired evaluation:
Evaluate object and method:
A.ELISPOT tests.
Whether object evaluates to have specific CTL (cytotoxic T cell) to produce.Method is as follows:
Spleen is separated from the animal of putting to death, is separated after density gradient centrifugation and obtains mononuclear cell, and be resuspended in HL-1 culture medium for subsequent use.The antibody of the little mouse-anti IFN-γ after the every hole of enzyme mark version adds 100ul dilution is spent the night at 4 DEG C of bags, adds 200ul confining liquid, incubated at room 2h after cleaning; By mouse boosting cell (every hole 4X10
5individual) and the target antigen albumen of 10uL 100ug/ml at 37 DEG C, 5%CO
2hatch in conjunction with 36h with under 100% humidity with ELISA Plate, the IFN-γ that the specific T-cells for target antigen is produced is fixed in ELISA Plate by antibody; After cleaning cell, the detection antibody adding the little mouse-anti IFN-γ after 100ul dilution at room temperature hatches 2h altogether, then adds substrate colour developing 30min; By dry for ELISA Plate lucifuge 2h, carry out analyzing by ELISPOT enzyme connection spot-analysis system the CTL response detected in immune animal to speckle;
Experimental result: as shown in Figure 2, the speckle number obtained with 1-1 group (experimental group) splenocyte is far away higher than 1-2 group (matched group) and 1-3 group (observation group), show in experimental mice body, to create a large amount of CTL for PRAME, WT1, and almost do not create the CTL for PRAME, WT1 in matched group and observation group's Mice Body.
B. the tiring of immunocyte killing tumor cell.Method is as follows:
Get the spleen cell (2X10 of immune mouse
6individual/hole) with PRAME/WT1 antigen positive, HLA-A2.1 leukocyte phenotype tumor cell (10
5individual/hole) at 37 DEG C, hatch 4h altogether under 5%CO2 and 100% humidity, add chromogenic substrate after centrifugal and hatch 30min altogether, evaluate the effect of its killing tumor cell by LDH method.
Experimental result: as shown in Figure 3,1-1 group (experimental group) degree of colour developing is far away higher than 1-2 group (matched group) and 1-3 group (observation group), show in experimental mice body, to create a large amount of CTL for PRAME, WT1, and almost do not create the CTL for PRAME, WT1 in matched group and observation group's Mice Body.
5. interior tumor cell killing experiments:
After lymph node injecting immune (the 28th day), to cell quantities (10 such as the transgenic mice tail vein injections of 2-1,2-2 group
7individual) PRAME, WT1 antigen positive of 5uM CFSE labelling, the tumor cell of HLA-A2.1 leukocyte phenotype and 0.5uM antigen negative, HLA-A2.1 leukocyte phenotype tumor cell, get peripheral blood flow cytometer (FACS) after 18 hours and detect through the content of two kinds of cells of labelling.
Experimental result: as shown in Figure 4, in 2-1 group, by the PRAME/WT1 antigen positive of 5uM CFSE labelling, the tumor cell amount of HLA-A2.1 leukocyte phenotype well below the tumor cell by 0.5uM antigen negative, HLA-A2.1 leukocyte phenotype.And two kinds of cell contents are almost identical in 2-2 group.Result shows to create a large amount of CTL for PRAME/WT1 antigen positive, HLA-A2.1 leukocyte phenotype in 2-1 group Mice Body.
Embodiment 2: human peripheral experiment detects Immunel response intensity and antitumor cell effect experimental
Experiment purpose simulates human body endoantigen in vitro to express submission, immunne response and the fragmentation effect to tumor cell.
Be separating peripheral blood mononuclear cells (PBMCs) the human peripheral of HLA-A2.1 by the centrifugal method of Ficoll Concentraton gradient from leukocyte phenotype.Dendritic cell (DCs) is obtained by CD14+ Beads enrichment from PBMCs; CTL is obtained by CD8+ Beads enrichment.After DCs and a certain amount of recombiant plasmid are hatched certain hour altogether, again DCs and CTL mixed by 1: 3 and add after stimulating factor hatches a period of time altogether, carry out ELISPOT test with detection specificity CTL production and tire, the outer tumor cytotoxicity of detection bodies is tired simultaneously.
Concrete grammar is as follows:
1. the antibody of the anti-human IFN-γ after the every hole of enzyme mark version adds 100ul dilution is spent the night at 4 DEG C of bags, adds 200ul confining liquid, incubated at room 2h after cleaning; By CTL cell (every hole 4X10
5individual) and the target antigen albumen of 10uL100ug/ml at 37 DEG C, 5%CO
2hatch in conjunction with 36h with under 100% humidity with ELISA Plate, the IFN-γ that the specific T-cells for target antigen is produced is fixed in ELISA Plate by antibody; After cleaning cell, the detection antibody adding the anti-human IFN-γ after 100ul dilution at room temperature hatches 2h altogether, then adds substrate colour developing 30min; By dry for ELISA Plate lucifuge 2h, carry out analyzing by ELISPOT enzyme connection spot-analysis system the CTL response detected in immune animal to speckle; ;
Experimental result: as shown in Figure 5, experimental group has a large amount of enzyme connection speckles to occur, and the DCs matched group not adding recombiant plasmid does not almost have enzyme to join speckle appearance, shows that experimental group creates in a large number for the CTL of PRAME, WT1.
2. get CTL (2X10
6individual/hole) with PRAME/WT1 antigen positive, HLA-A2.1 leukocyte phenotype tumor cell (10
5individual/hole) at 37 DEG C, hatch 4h altogether under 5%CO2 and 100% humidity, add chromogenic substrate after centrifugal and hatch 30min altogether, evaluate the effect of its killing tumor cell by LDH method.
Experimental result: experimental group colour developing degree is far away higher than matched group (PRAME/WT1 negative tumor cells) as shown in Figure 6, shows to create a large amount of CTL for PRAME/WT1.
The present invention is not limited to aforesaid detailed description of the invention.The present invention expands to any new feature of disclosing in this manual or any combination newly, and the step of the arbitrary new method disclosed or process or any combination newly.
Claims (4)
1.PRAME, WT1 bivalent tumor DNA vaccine, is characterized in that this vaccine comprises nucleotide sequence shown in SEQ ID NO:1, and nucleotide sequence shown in SEQ ID NO:1 is connected to pVAX1 plasmid.
2. PRAME, WT1 bivalent tumor DNA vaccine according to claim 1 is for the preparation of the purposes in anti-tumor medicine or vaccine.
3. PRAME, WT1 bivalent tumor DNA vaccine according to claim 2 is for the preparation of the purposes in anti-tumor medicine or vaccine, it is characterized in that: described tumor is WT1 positive tumor.
4. PRAME, WT1 bivalent tumor DNA vaccine according to claim 2 is for the preparation of the purposes in anti-tumor medicine or vaccine, it is characterized in that: described tumor is PRAME positive tumor.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110261931.3A CN102973950B (en) | 2011-09-06 | 2011-09-06 | PRAME and WT1 bivalent tumor DNA vaccine |
| PCT/CN2011/084048 WO2013033961A1 (en) | 2011-09-06 | 2011-12-15 | Bivalent vaccine of tumor dna of prame and wt1 |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110261931.3A CN102973950B (en) | 2011-09-06 | 2011-09-06 | PRAME and WT1 bivalent tumor DNA vaccine |
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| CN102973950B true CN102973950B (en) | 2015-05-27 |
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- 2011-12-15 WO PCT/CN2011/084048 patent/WO2013033961A1/en active Application Filing
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