CN106279391B - Tumor associated antigen XAGE-1b small peptide and application - Google Patents

Tumor associated antigen XAGE-1b small peptide and application Download PDF

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CN106279391B
CN106279391B CN201610669169.5A CN201610669169A CN106279391B CN 106279391 B CN106279391 B CN 106279391B CN 201610669169 A CN201610669169 A CN 201610669169A CN 106279391 B CN106279391 B CN 106279391B
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张蓓
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Guangzhou, Biological Technology Co. Ltd.
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Abstract

The invention discloses tumor associated antigen XAGE-1b small peptide and application, the sequence of small peptide is SEQ ID NO：2~SEQ ID NO：One in 15.The CTL that XAGE-1b antigen inducing peptide of the invention is established will not generate immune response to testicular cell, killing tumor cell.Induce obtained ctl clone that there is good tumor cell specific lethal effect.Simultaneously during establishing CTL, the XAGE-1b Antigenic Peptide that filters out of inventor's discovery has and HLA affinity appropriate on DC cell and can effectively stimulate, inducing producing specificity CTLs, illustrates that it has the potentiality of good polypeptide vaccine and DC vaccine.By cloning XAGE-1b Antigenic Peptide specificity TCR gene, viral vectors is constructed, peripheral circulation CD8+T cell of transduceing obtains the T cell of tcr gene modification（TCR-T）Clone equally has tumor cell specific lethal effect similar with parental generation CTL, prompts it with good clinical conversion and actual application prospect.

Description

Tumor associated antigen XAGE-1b small peptide and application
Technical field
The present invention relates to tumor associated antigen peptide and its application, in particular to tumor associated antigen XAGE-1b small peptide and its Using.
Background technique
It is well known that T cell is adopted, to treat tumour be that the technology that most attracts people's attention, especially receptor engineering T are thin at present The application of born of the same parents just becomes soul-stirring cancer treatment method, equally has to virus infection and autoimmune disease extensive Application prospect.
Human immunity monitoring system is resisting the important function in Tumor Growth, and immune surveillance system is each by coordinating Para-immunity cell is achieved the purpose for inhibiting tumour growth, wherein cytotoxic T cell (cytotoxic T Lymphocyte, CTLs) play the part of extremely important role, it is the lethal effect cell of most critical.Specific for tumour antigen CD8+T Cell can be with specific recognition and direct killing tumour cell is without damaging normal cell.Therefore T cell treatment becomes Optimal ideas of cancer therapy.U.S. NIH once foretold that cell therapy, which may become, " can thoroughly cure the unique of tumour Means ".Therefore, obtain can specific recognition, killing tumor cell CTL be treat tumour core.Utilize tumour correlation Antigen (Tumor-associated antigen, TAA) polypeptid induction establishes tumor antigen peptide specific CTL, can be obtained tool There is the ctl clone of specific killing tumour cell, and for exploitation in next step there is the T cell of clinical practice application value to adopt and control It treats tumour and has established important foundation, while inventor can also obtain following achievement：
1) these pass through the tumor associated antigen peptide amino acid sequence that evaluation and screening goes out, and it is effective anti-will to can be used for building Tumour peptide vaccine, DC vaccine；
2) inventor can be made to obtain the explicitly TCR with specific recognition tumour antigen by molecule clone technology to compile Code gene, the foundation for tcr gene modification T cell.
3) by the fluorescence probe of synthesis and small peptide specific binding, molecular probe with independent intellectual property rights can be developed Kit, early diagnosis and treatment for non-small cell lung cancer.
Currently, T cell receptor (T cell receptor, TCR) gene modification T cell (TCR-T), such as chimeric antigen Receptor (chimeric antigen receptor, CAR) modification T cell (CAR-T) technology equally receives much attention.CAR-T application The curative effect to attract people's attention has been obtained in neoplastic hematologic disorder treatment.CAR merges CD3 signal element by scFv, and functional activity relies on In the sensibility of signal element, signal element is made of costimulatory molecules and (or) cell factor.However, there is studies have shown that table It is not so good as the T cell of express alpha β TCR heterodimer to the sensibility of polypeptide up to the T cell of CAR.TCR-T is repaired by tcr gene T cell technology is adornd, by the acquired TCR encoding gene transduction circulation CD8 with specific recognition tumor-antigen peptide+T is thin Born of the same parents, can be obtained in a very short period of time by this method largely stablize high expression specificity TCR, have and parental generation CTL The gene modification T cell of same tumour-specific identification and lethal effect, to meet needed for practical clinical.
The induction that inventor began to be engaged in from 2005 tumor associated antigen peptide specific CTL is established, TCR correlative study (Int J Hematol.2011,93:176-185) and tcr gene modification T cell research, successfully tumour correlation is resisted respectively Former WT1 and Aurora kinase A specificity TCR transduction circulation CD8+T cell (Blood, 2011,118:1495-1503； Blood, 2012,119:368-376), TCR-T clone is obtained, through external, internal identification, it was confirmed that its anti-lung cancer or leukaemia The validity of cell.
Tcr gene modification T cell technology increasingly show its important value in immunotherapy of tumors and it is fine before Scape, and the key precondition for generating TCR-T is to obtain the TCR with specific recognition tumour antigen, establishes tumour by external evoked Associated antigen polypeptide specific CTL is an important channel for realizing this target.
XAGE-1 (X antigen family member 1) be Cancer-testis antigen (Cancer-Testis antigen, CTA) one of family member, CTA are also known as tumour-hair tonic system (Tumor-Germline, TG) antigen.Such antigen, is only expressed in Testicle spermatogonia, without being expressed in normal tissue cell, meanwhile, research finds that CTA is expressed in a variety of histological types Tumour, thus also known as tomour specific shares antigen (tumor-specific shared antigens, TSSA).Due to testis Spermatogonium does not express major histocompatibility antigen compound (major histocompatibility complex, MHC) I Class molecule, therefore the immune response of the CTL of CTA induction is to testicular cell fanout free region, killing tumor cell.Exactly because this Characteristic makes ideal antigen of the CTA as immunotherapy of tumors.Mankind XAGE-1 belongs to GAGE/PAGE family, XAGE-1 gene It is positioned at Xp11.21-Xp11.22, including tetra- kinds of spliceosomes of XAGE-1a, XAGE-1b, XAGE-1c, XAGE-1d, XAGE-1b (X Antigen family, member 1b) full length gene 622bp, encode the amyloid protein precursor being made of 81 amino acid.
XAGE-1b includes breast cancer, prostate cancer, various types of lung cancer (gland cancer, squamous carcinoma and cellule in kinds of tumors Lung cancer etc.), oophoroma, melanoma, glioblastoma, have expression in lymthoma and leukaemia etc..The gene has XAGE- 1a, XAGE-1b, XAGE-1c and XAGE-1d4 kind transcribe isomers, wherein XAGE-1b be can by immunocyte identify it is excellent Gesture antigen, immunogenicity is very strong, high expression in adenocarcinoma of lung is especially in NSCLC, it has also become one of lung cancer immunization therapy is new Target spot.However, there has been no the reports that XAGE-1b Antigenic Peptide specific CTL has been established at present.Although some CTA polypeptid specificities CTL has built up and passes through identification, such as：NY-ESO-1(New York esophageal squamous cell carcinoma 1) Peptide-specific CTL, MAGE antigen (melanoma-associated antigens), MAGE-1 specific CTL etc..But by Individual difference between the heterogeneity and tumor patient of tumour, obtaining enough tumor antigen peptide specific CTL clones is It is very necessary.
It is generally acknowledged that the length of polypeptide is shorter, the specific immunity ability that can induce is weaker, or even can not induce completely Provide the ctl clone of therapeutic value；Conversely, polypeptide length is longer, specific CTL clone more can induce out.However polypeptide Length is longer, and synthesis difficulty is bigger, is more difficult to obtain pure polypeptide, there are unpredictable for formation of the presence of impurity peptide to clone Influence, and the purifying cost of polypeptide is high but is still difficult to avoid that the presence of impurity peptide, and the cost of this scheme is extremely high It is high.Accordingly it is desirable to shorten the length of polypeptide in the case where retaining polypeptide antigen as far as possible.CN102428102A is disclosed Technical solution in a part for attempting in interception XAGE-1b antigen induce humoral immunity or cellular immunity to tumour, but It is that its result is not satisfactory, the length of polypeptide is not shorter than 16AA still.
Small peptide the problem of there is likely to be poor specificities, it is good and short with good immunogenicity how to obtain specificity Peptide is an extremely challenging job.
Summary of the invention
The purpose of the present invention is to provide tumor associated antigen XAGE-1b small peptide and its applications.
The technical solution adopted by the present invention is that：
XAGE-1b small peptide, sequence are SEQ ID NO：2~SEQ ID NO：One in 15.
Such as SEQ ID NO：2~SEQ ID NO：XAGE-1b small peptide shown in 15 can induce tumor-specific cytotoxicity T The generation of cell.
The abductive approach of tumor-specific cytotoxicity T cell uses SEQ ID NO：2~SEQ ID NO：15 At least one in XAGE-1b small peptide offers and CD8 through Dendritic Cells+T cell co-cultures, and induction screening obtains tomour specific Property cytotoxic T cell.
A kind of tumour polypeptide vaccine is made of active antigens ingredient and adjuvant, and active antigens ingredient is such as SEQ ID NO：2 ~SEQ ID NO：At least one in 15XAGE-1b small peptide.
A kind of DC vaccine for oncotherapy, mainly by SEQ ID NO：2~SEQ ID NO：15 XAGE-1b small peptide In at least one and Dendritic Cells load to obtain.
High degree of specificity expression of the small peptide as selected by the present invention in non-small cell lung cancer, passes through synthesis and SEQ ID NO：2~SEQ ID NO：The fluorescence probe of the specific binding of XAGE-1b small peptide shown in 15, can develop with independent intellectual property right The kit of molecular probe for the early diagnosis and treatment of non-small cell lung cancer, and establishes relevant research platform.
The beneficial effects of the invention are as follows：
The CTL that XAGE-1b antigen inducing peptide of the invention is established will not generate immune response to testicular cell, only kill swollen Oncocyte.Induce obtained ctl clone that there is good tumor cell specific lethal effect.Simultaneously during establishing CTL, The XAGE-1b Antigenic Peptide that filters out of inventor's discovery has and HLA affinity appropriate on DC cell and can effectively stimulate, lures Specific CTL s is given birth in artificial delivery, illustrates that it has the potentiality of good polypeptide vaccine and DC vaccine.By cloning XAGE-1b Antigenic Peptide Specificity TCR gene constructs viral vectors, and peripheral circulation CD8+T cell of transduceing obtains the T cell (TCR- of tcr gene modification T it) clones, equally there is tumor cell specific lethal effect similar with parental generation CTL, prompt it with good clinical conversion And actual application prospect.
Detailed description of the invention
Fig. 1 is expression of the XAGE-1b in lung adenocarcinoma cell；
Fig. 2 is XAGE-1b (46-54) specific CTL IFN-γ release test；
Fig. 3 is XAGE-1b (31-39) specific CTL IFN-γ release test.
Specific embodiment
Tumour antigen selects XAGE-1b antigen, and XAGE-1b gene is located at X chromosome (Xp11.21-Xp11.22), overall length 622bp encodes the amyloid protein precursor being made of 81 amino acid.Amino acid sequence is following (to be originated from GenBank:NM_ 001097594.2)：
MESPKKKNQQLKVGILHLGSRQKKIRIQLRSQCATWKVICKSCISQTPGINLDLGSGVKVKIIPKEEHCKMPEAGEE QPQV(SEQ ID NO：1)
Below with reference to experiment, technical solution of the present invention is further illustrated.
Expression of the XAGE-1b in non-small cell lung cancer
XAGE-1 is important member in CTA family, in addition to having wide expression in non-small cell lung cancer, in a variety of evils There is expression in property tumour, establishes XAGE-1b Antigenic Peptide specific CTL clone and be extremely important.It is sent out in early-stage study Bright people randomly selects surgical resection lung cancer specimen (make a definite diagnosis through pathologic finding and obtain patient's agreement), conventional line RT-PCR Detect expression (PCR primer of the XAGE-1b mRNA in NSCLC：F：5'-TTTCTCCGCTACTGAGACAC-3'(SEQ ID NO：16), R：5'-CAGGTGCTGGGAAGGGAAAT-3'(SEQ ID NO：17)).As a result as Fig. 1, display XAGE-1b exist There is wide expression in lung adenocarcinoma cell.
Inventor carries out comprehensive score by having method by oneself, to the CTL epitope of XAGE-1b antigen, with two different numbers According to library (US National Institutes of Health Research Institute BIMAS, https://www-bimas.cit.nih.gov/molbio/hla_bind/ and Heidelberg, Germany biomedical information center SYFPEITHI, https://www.syfpeithi.de/) product of scoring is that this is pre- The overall score for surveying epitope, the epitope of its CTL is predicted according to overall score.Gained candidate peptide is synthesized by specialized company.Specific polypeptide sequence Basis and different HLA hypotype combining classifications are arranged, it is specific as follows：
HLA-A*2402 group：
Based on prediction result, inventor randomly chooses 2 progress result verification therein, and specific experiment is as follows.
The operation that XAGE-1b small peptide specific CTL clone is established is as follows：
The 10 of same health donor5A CD8+T cell passes through the 10 of load XAGE-1b (57-65) peptide4Between a Mo-DCs After stimulation in 1 week 2 times, then pass through self 105The PBMC of a processed load XAGE-1b small peptide of mitomycin C is stimulated 1 time Afterwards, it is obtained through standard cell poison experiment sieving.
T2 cell loads 5uM XAGE-1b small peptide as target cell, and the XAGE-1b small peptide specific cytotoxicity of CTL is logical Crossing LDH release test is confirmed.
Using the above external evoked method for establishing XAGE-1b small peptide specific CTL clone, inventor has also set up HLA- The restricted XAGE-1b of A*2402 (46-54) (SEQ ID NO：And XAGE-1b (31-39) (SEQ ID NO 3)：13) specific Ctl clone confirms its polypeptid specificity immune response effect (such as Fig. 2,3) by IFN-γ release test.
Above-mentioned experimental data shows that the CTL epitope that inventor establishes is extremely effective, prediction result and experimental result symbol Conjunction property is very good.
As it can be seen that by by least one (SEQ ID NO in above-mentioned XAGE-1b small peptide：2~15) it is mentioned through Dendritic Cells It is co-cultured in cytotoxicity T lymphocytes, inducible screening obtains specific for tumour antigen cytotoxic T lymphocyte.This Kind specific for tumour antigen cytotoxic T lymphocyte can be used for the treatment of tumour.
By at least one (SEQ ID NO in above-mentioned XAGE-1b small peptide：2~15) with Dendritic Cells (dendritic Cell, DC) load feedback, it can be used as DC vaccine for tumour immunity, stimulate body to generate the antitumor T of polypeptid specificity thin Born of the same parents, and then realize the treatment of tumour.
At least one (SEQ ID NO in above-mentioned XAGE-1b small peptide：2~15) can be used for measuring in subject sample For the antibody level of polypeptide, and then it is used for the diagnosis of non-small cell lung cancer.
XAGE-1b small peptide length of the invention is only 9 amino acid, and chemical synthesis difficulty is small, can directly synthesize to obtain High-purity product, application cost substantially reduce, while definite effect, have good application potential.
<110>Peace, army
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<120>Tumor associated antigen XAGE-1b small peptide and application
<130> XAGE-1b*2402
<160> 17
<170> PatentIn version 3.5
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Claims (6)

1.XAGE-1b small peptide, sequence QTPGINLDL.
2.XAGE-1b small peptide prepares the application in tumor-specific cytotoxicity T cell clone in induction, wherein XAGE-1b is short Peptide is as described in claim 1.
3. the abductive approach of tumor-specific cytotoxicity T cell, it is characterised in that：Use XAGE-1b described in claim 1 Small peptide is offered through Dendritic Cells and CD8+T cell co-cultures, and induction screening obtains tumor-specific cytotoxicity T cell.
4. a kind of tumour polypeptide vaccine is made of active antigens ingredient and adjuvant, it is characterised in that：Active antigens ingredient is as weighed Benefit requires the 1 XAGE-1b small peptide.
5. a kind of DC vaccine for oncotherapy, is mainly added by XAGE-1b small peptide described in claim 1 and Dendritic Cells Load obtains.
6.XAGE-1b small peptide is preparing the application in Diagnosis of Non-Small Cell Lung kit, wherein XAGE-1b small peptide such as right It is required that described in 1.
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