CN111116734A - Tumor-associated gene c-kit mutation-associated antigen short peptide and application thereof - Google Patents
Tumor-associated gene c-kit mutation-associated antigen short peptide and application thereof Download PDFInfo
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- CN111116734A CN111116734A CN201911336736.5A CN201911336736A CN111116734A CN 111116734 A CN111116734 A CN 111116734A CN 201911336736 A CN201911336736 A CN 201911336736A CN 111116734 A CN111116734 A CN 111116734A
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001103—Receptors for growth factors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
Abstract
The invention discloses c-kit mutation related antigen short peptide and application thereof. The sequence of the c-kit mutation related antigen short peptide is shown in any one of SEQ ID NO 1-20. The short peptide has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce the generation of specific Cytotoxic T Lymphocytes (CTLs), can be used for immune elimination of c-kit gene mutation cells, and further prevents c-kit gene mutation-related diseases, especially the c-kit gene mutation-related tumor diseases; therefore, the c-kit antigen short peptide has good potential of polypeptide vaccine and DC vaccine, and has good clinical transformation and disease prevention potential. Moreover, the c-kit antigen short peptide has short length and small chemical synthesis difficulty, can be directly synthesized to obtain a high-purity product, greatly reduces the application cost, has definite effect and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of biological medicines. More particularly, relates to a c-kit mutation associated antigen short peptide of a tumor associated gene and application thereof.
Background
The c-kit proto-oncogene maps to the 2 and 3 bands of long arm 1, region 4 of the human chromosome (4q12-13), the product of which is the type III tyrosine kinase growth factor receptor, encoding a 145kD transmembrane glycoprotein tyrosine kinase receptor. The c-kit gene has 21 exons, the activation of the c-kit is normally triggered by a Stem Cell Factor (SCF), so that the phosphorylation of substrate protein stimulates a signal transduction pathway, and important cell functions such as proliferation, apoptosis and the like are finally stimulated, while the mutated c-kit gene can be automatically phosphorylated without depending on a ligand, the cell proliferation is uncontrollable, and the occurrence and development of tumors can be finally caused. Researchers have shown that gain-of-function mutations (gain-of-function mutations) in the c-kit gene may be central events in the development and progression of tumors. Therefore, maintaining the c-kit in a normal state is very important for maintaining the normal function of cells and preventing diseases such as cancer.
Tumor antigen peptide specific CTL is induced and established by using tumor associated antigen short peptide, thereby obtaining CTL clone with specific killing tumor cells, and the activated CTL can kill corresponding target cells and play a role in immune monitoring. The key premise of the technology is to obtain related antigen short peptides which have good immunogenicity and specificity and can induce and generate specific cytotoxic T lymphocytes.
Disclosure of Invention
The invention aims to develop c-kit gene mutation related antigen short peptide aiming at tumor related gene c-kit, the c-kit gene mutation related antigen short peptide has high affinity with MHC I molecules on DC cells, can effectively stimulate and induce to generate specific Cytotoxic T Lymphocytes (CTLs), can be used for immune elimination of c-kit gene mutation cells, and has good potential of polypeptide vaccines and DC vaccines.
The invention aims to provide a c-kit mutation associated antigen short peptide of a tumor associated gene.
Another object of the present invention is to provide the use of the short peptide in the preparation of DC vaccine for c-kit mutation.
It is a further object of the present invention to provide a DC vaccine for c-kit mutations.
The above purpose of the invention is realized by the following technical scheme:
the inventor discovers that mutant polypeptides of COSM1290, COSM1311, COSM1310 and COSM1314 can be combined with MHC-I molecules through on-line analysis of a T cell epitope prediction comprehensive platform NetCTL database (http:// www.cbs.dtu.dk/services/NetCTL) and bioinformatics prediction (the several mutant sites of c-kit are detected in solid tumors such as lung cancer, malignant melanoma, intestinal cancer and the like). The site is shown to be an important target point for immune clearance of C-KIT gene mutant cells. The immunological research proves that the principle that CD8 positive T lymphocyte CTL plays cellular immunity is as follows: CTL cells are activated by recognizing antigen peptides bound to MHC-I molecules, and the activated CTL can kill corresponding target cells to exert an immune surveillance effect. Therefore, the invention predicts the binding capacity of the c-kit mutation sequence with T lymphocyte receptor (TCR) and MHC class I molecules through the bioinformatics technology, simultaneously analyzes the expression and locates outside a cell membrane, designs and optimizes the c-kit mutation related antigen short peptide aiming at tumor related genes, the polypeptide sequence of the c-kit antigen short peptide obtained by screening of the invention is preferably shown in any one of SEQ ID NO 1-20, the obtained c-kit antigen short peptide has high affinity with the MHC class I molecules on DC cells, can effectively stimulate and induce the generation of specific Cytotoxic T Lymphocytes (CTLs), inhibits the growth of the tumor cells, shows that the c-kit antigen short peptide has good potential of the polypeptide vaccine and the DC vaccine, and has good clinical transformation and disease prevention prospects.
Therefore, the following products and applications should be considered within the scope of the present invention:
the c-kit mutation related antigen short peptide of the tumor related gene has a sequence shown in any one of SEQ ID NO 1-20. The c-kit mutant short peptide product can be prepared by taking the short peptide as an active antigen component and an auxiliary agent.
The application of the short peptide in preparing products capable of inducing the generation of specific cytotoxic T lymphocytes. Specifically, the induction method of the specific cytotoxic T lymphocyte comprises the following steps: 1-20 c-kit mutant short peptides are co-cultured with CD8+ T cells by using antigen presenting cells, and c-kit mutant specific cytotoxic T cells can be induced.
The short peptide is applied to preparing a human body immunological activity regulator, and particularly is used as an active antigen component for regulating the human body immunological activity. The short peptide antigen is processed in cells to form specific fragments, namely, the antigen peptide is completely matched with MHC 1 molecules and then presented on the cell surface to be recognized by a corresponding T Cell Receptor (TCR) to form an antigen peptide-MHC-TCR complex, so that Cytotoxic T Lymphocytes (CTL) are activated.
The short peptide is applied to the preparation of products for preventing c-kit gene mutation and related diseases, in particular to c-kit gene mutation related tumors. The product comprises vaccines, such as DC vaccines or monocyte vaccines and the like.
Antigenic peptide-MHC-TCR complex, activating cytotoxic T lymphocytes, the activated specific T lymphocytes capable of killing abnormal cells carrying the c-kit mutation. Induction method of specific cytotoxic T lymphocytes: at least one of c-kit mutant short peptides shown in SEQ ID NO. 1-20 is used to react with CD8 by antigen presenting cells+TAnd co-culturing the cells, and inducing to obtain the c-kit mutation specific cytotoxic T cells.
Based on the above, the invention also provides a DC vaccine or monocyte vaccine for preventing c-kit gene mutation and related diseases, which is prepared by loading the short peptide shown by any one of SEQ ID NO. 1-20 and dendritic cells or monocytes.
The c-kit short peptide shown in any one of SEQ ID NO 1-20 and Dendritic Cells (DC) are loaded and returned, can be used as a DC vaccine for disease prevention, stimulates an organism to generate polypeptide specific anti-cytotoxic T cells, and further realizes the prevention of c-kit gene mutation related diseases, especially the prevention of c-kit gene mutation related tumors.
In particular, the vaccine is an intravenous infusion vaccine.
In the preparation method of the DC vaccine for preventing c-kit gene mutation and related diseases, a vitrogen factor is selected as an adjuvant to increase the activity of DC cells, and specific antigen peptide is used for sensitizing dendritic cells in vitro to obtain an autologous dendritic cell preparation which is used as a vaccine for preventing and treating chronic diseases related to the venous return type chlamydia pneumoniae. The preparation method comprises the following steps: the maturation promoting factor and the Vitrogen factor are used as adjuvants to promote the maturation of DC cells; and then adding the short peptide of the invention into a DC cell culture system for inducing maturation, collecting DC cells loaded with the short peptide fragments, washing with physiological saline, and then resuspending with the physiological saline to obtain the DC vaccine.
More specifically, as an alternative, the DC vaccine is prepared by the following steps:
s1, extracting and inducing DC cells:
s11, obtaining immature DC cells
Collecting peripheral blood of healthy donor, separating mononuclear cells by lymphocyte separation, culturing at 37 deg.C in culture medium with 5% CO2After culturing for 3 hours under the conventional condition, the adherent cells are immature DC cells;
s12, amplification culture of immature DC cells
37℃、5％CO2Culturing for 5 days under the condition, and changing the culture solution every other day to complete the amplification culture of immature DC cells (imDC cells);
S13.Induction of DC cells
Adding a maturation promoting factor, and simultaneously taking a Vitrogen factor as an adjuvant to promote the maturation of the DC cells;
s2, loading of polypeptide:
after inducing DC cells to mature for 5 days, adding the short peptide into a culture system;
s3, preparing a DC vaccine:
and (3) centrifuging to collect the DC cells loaded with the short peptide fragments, washing the cells for 3 times by using physiological saline, and finally, resuspending the DC cells loaded with the short peptide fragments by using the physiological saline to obtain the DC vaccine.
The invention selects specific epitope polypeptide, sensitizes autologous DC cells in vitro, prepares DC cell preparation, can carry out venous return transfusion on patients, rebuilds the whole body immune balance of organisms, starts immune system and carries out specific treatment on gene mutation tumor cells. The DC technology is adopted, and a plurality of specific antigen peptides are used for jointly activating dendritic cells, have extremely strong specificity, induce dendritic cells with higher activity to carry a plurality of antigen information, can stimulate the immunity of an organism after being infused back into a human body, and can achieve the aim of inducing the human body to generate specific antibodies and specific CTL cells, thereby effectively preventing the generation and development of c-kit gene mutation and related diseases.
The invention has the following beneficial effects:
the c-kit antigen short peptide has high affinity with MHC I molecules on DC cells, and can effectively stimulate and induce the generation of specific Cytotoxic T Lymphocytes (CTLs); the generated specific cytotoxic T lymphocyte can be used for immune elimination of c-kit gene mutation cells, so that diseases related to c-kit gene mutation are prevented, and particularly, tumor diseases are prevented.
The c-kit antigen short peptide can be used for preparing polypeptide vaccines and DC vaccines, and has good clinical transformation and disease prevention prospects.
In addition, the c-kit antigen short peptide has short length, incomparable application advantages, small chemical synthesis difficulty, capability of directly synthesizing to obtain a high-purity product, greatly reduced application cost, definite effect and good application potential.
Drawings
FIG. 1 shows the results of the c-kit mutation-associated antigen short peptide-specific CTL IFN-. gamma.release assay.
FIG. 2 is a comparison of the killing activity of c-kit mutation-associated antigen short peptides against target cells.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
Example 1 prediction of T cell epitopes of mutant peptides of c-kit Gene and design of c-kit short peptides
1. The peptide sequence with high affinity to T cell epitope receptor (TCR) and MHC class I molecules is analyzed and predicted by a T cell epitope prediction data comprehensive platform (http:// www.cbs.dtu.dk/services/NetCTL) and a bioinformatics technology. The research obtains a series of c-kit mutation related antigen short peptides.
2. From the above polypeptides, 50 polypeptide fragments with high predictive score and less predictive toxicity were selected and further studied. The specific experiment is as follows:
the c-kit mutant short peptide specific CTL clone establishment method comprises the following steps:
sorting healthy donors by flow 105An individual CD8+T cells, Mo-DCs10 loaded with c-kit mutant short peptide42 stimulations at 1 week intervals, and autologous Peripheral Blood Mononuclear Cells (PBMC)10 loaded with C-kit short peptides and treated with mitomycin C5Each was stimulated 1 time, thereby obtaining CTL cells.
The method for establishing the c-kit gene mutation short peptide specific CTL cell by adopting in vitro induction is adopted, cell culture supernatant is sucked, and the IFN-gamma content in the supernatant is detected.
The results showed that 20 polypeptides shown in Table 1 have specific immune response effect, can activate T lymphocytes, and induce secretion of IFN-gamma (shown in FIG. 1). Meanwhile, the results also show that the corresponding relation between the 20 polypeptides and the predicted prediction scores of the 50 polypeptides is not obviously related, and the reference of the prediction results is poor.
TABLE 1
Example 2 inhibition of tumor growth assay
Example 120 c-kit mutant short peptides with specific immune response effect and capable of activating T lymphocytes are obtained. From these 5 short peptides were randomly selected and the experiment was continued for further validation.
Cell culture supernatants induced by 5 short peptides were cultured for colorectal cancer cells CaCo-2, respectively. The control group is divided into two groups of short peptide loading-free and nonsense short peptide loading groups.
The results show that 5 short peptides induced supernatant can significantly inhibit tumor growth and significantly reduce tumor survival rate compared with the control group (as shown in fig. 2).
Experimental results show that the CTL epitope established by the invention is extremely effective. The c-kit mutant short peptide shown in any one of SEQ ID NO 1-20 is subjected to dendritic cell presentation and is co-cultured with cytotoxic T lymphocyte, so that the c-kit mutant specific cytotoxic T lymphocyte can be obtained through induced screening. The c-kit mutant antigen specific cytotoxic T lymphocyte can be used for immune elimination of c-kit gene mutant cells, so as to prevent diseases related to c-kit gene mutation, especially prevent tumor diseases. Therefore, the c-kit short peptide shown in any one of SEQ ID NO 1-20 and Dendritic Cells (DC) are loaded and back-transfused, and can be used as a DC vaccine for disease prevention to stimulate an organism to generate polypeptide specific anti-cytotoxic T cells, so that the prevention of c-kit gene mutation related diseases, especially the prevention of tumors is realized.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
SEQUENCE LISTING
<110> Wittaen (Guangzhou) pharmaceutical Co., Ltd
<120> tumor-associated gene c-kit mutation-associated antigen short peptide and application thereof
<130>
<160>20
<170>PatentIn version 3.3
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Claims (10)
1. The c-kit mutation related antigen short peptide of the tumor related gene is characterized in that the sequence is shown as any one of SEQ ID NO 1-20.
2. Use of a short peptide according to claim 1 for the preparation of a product inducing the production of specific cytotoxic T lymphocytes.
3. Use of the short peptide of claim 1 for the preparation of a modulator of human immune activity.
4. The use according to claim 3, wherein the short peptide is an active antigenic component for modulating the immune activity of humans.
5. Use of the short peptide of claim 1 for the preparation of a product for preventing c-kit gene mutation.
6. Use of the short peptide of claim 1 for the preparation of a product for preventing diseases associated with c-kit gene mutation.
7. Use of the short peptide of claim 1 for the preparation of a DC vaccine or monocyte vaccine for the prevention of c-kit gene mutations.
8. Use of the short peptide of claim 1 for the preparation of a DC vaccine or a monocyte vaccine for the prevention of diseases associated with c-kit gene mutations.
9. The use according to claim 6 or 8, wherein the c-kit gene mutation related disease is a c-kit gene mutation related tumor.
10. A vaccine for preventing c-kit gene mutation, which is prepared by loading the short peptide of claim 1 with dendritic cells or monocytes.
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Application publication date: 20200508 |