CN109371005A - HLA-0201 restrictive PADI4 epitope polypeptide and application thereof - Google Patents
HLA-0201 restrictive PADI4 epitope polypeptide and application thereof Download PDFInfo
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Abstract
The invention relates to the field of biomedicine, in particular to an HLA-0201 restriction PADI4 epitope polypeptide and application thereof, and provides an HLA-0201 restriction PADI4 epitope polypeptide, the amino acid sequence of which is selected from the following (a) to (c): (a) YLTGVEISL, SEQ ID NO. 1; (b) CLEEKVCSL, SEQ ID NO. 2; (c) ELLKRELGL, SEQ ID NO. 3. According to the invention, the gene encoding the PADI4 epitope polypeptide comprises an expression vector of a PADI4 epitope polypeptide gene. The HLA-0201 restrictive PADI4 epitope polypeptide has strong affinity with HLA-0201, and the immunogenicity of the polypeptide is evaluated, so that the polypeptide can induce specific HLA-0201 restrictive cytotoxic T lymphocytes in peripheral blood of healthy people with positive HLA-0201, and is an immunogenic polypeptide naturally processed and presented by cells. The HLA-0201 restriction PADI4 epitope polypeptide induced antigen specific cytotoxic T lymphocyte has high killing activity and high IFN-gamma secretion capability.
Description
Technical field
The present invention relates to field of biomedicine more particularly to a kind of restricted PADI4 epitope polypeptide of HLA-0201 and its answer
With.
Background technique
In mammals, peptidyl arginine goes imido grpup enzyme family one to share 5 members, is PADI1,2,3,4 respectively
With 6, they all have imido grpup enzymatic activity, can in the way of dependent on Ca2+ ion by conversion of Arginine as citrulling,
Middle PADI1,2,3 and 6 are mainly distributed in cytoplasm, and PADI4 contains nuclear localization signal in N-terminal, are distributed mainly on nucleus
In, this is also the precondition that it participates in histone modification, and PADI4 is another difference is that it can be by monomethylation
Conversion of Arginine is citrulling, and extra imido grpup and methyl are removed in the form of aminomethane (NH2CH3).PADI4 to H2A,
Tri- kinds of histones of H3, H4 have catalytic activity, the decorating site of H2A and H4 is located on the arginine of third position, and this two
A site has the sequence conservation of SGRGK；It is and more to the decorating site of H3, comprising: H3R2, R8, R17 and R26, they are simultaneously
Without the conservative in sequence.Wherein H3R8, H3R17 and H4R3 are the main function site of PADI4 in vivo.PADI4
Transcription to modification arginic on the histone H 3 meeting receptor-mediated gene of inhibitory hormone, when hormonal stimulation causes under genetic transcription
Timing, PADI4 can be raised onto the promoter of pS2 gene, and cause corresponding site on H3 goes imido grpup, this modification
CARM1 can be prevented to the arginic catalysis of H3, the latter is considered as necessary to hormone-mediated genetic transcription, and PADI4 is exactly logical
Past imido grpupization acts on antagonism CARM1, to inhibit the progress of transcription.PADI4 has in various malignant tumor tissues
Very high expression, especially in various gland cancer.Westernblot and the immunohistochemistry of citrullinated protein antibodies is resisted to also demonstrate
Expression of the PADI4 in tumor carcinoma cells.
Therefore, if body be immunized using PADI4 as target, it will body is made to generate the spy for being directed to PADI4 albumen
Specific immunological response is provided and is arranged for the prevention and treatment of related neoplasms to enable body to effectively inhibit, remove tumour cell
It applies.
Synthetic peptide vaccine is the new epidemic disease of one kind that grows up recently as molecular biology and immunologic progress
Seedling can induce body to generate the immune response of specificity, and its side effect is slight, safety is good, is current vaccine research
A new direction, be widely applied and treated with antitumor and antiviral immunity, oneself evidence suggests, synthetic peptide can directly with
MHC-I class molecule combines, and processing, processing without APC, it and natural endogenous peptide have in terms of activating immune system
There is equally valid.Oneself becomes a new strategy of current anti-malignant tumor to polypeptide vaccine, and the tumour of most study at present
Therapeutic vaccine.
Although having achieved great progress in terms of studying tumour-specific peptide vaccine, come due to having identified at present
T cell epitope extremely limit to, be concentrated mainly on HLA-A2, lack A33, A24, A11 restricted epitope.And not with ethnic group
Together, polymorphism is presented in HLA-I class molecule, and in addition to A2, A33, A24, A11 also occupy very big specific gravity.HLA-0201 is one
Kind is in population of China with a kind of MHC-I class molecule of higher distribution.Therefore, the restrictive tumour antigen of new HLA is identified
Seem extremely necessary and important.
Summary of the invention
The purpose of the present invention is to provide a kind of restricted PADI4 epitope polypeptide of HLA-0201 and its applications, on solving
State technical problem.
The present invention using following technical scheme in order to solve the above technical problems, realized:
In a first aspect, the present invention provides a kind of restricted PADI4 epitope polypeptide of HLA-0201, amino acid sequence is selected from down
State (a)-(c):
(a) YLTGVEISL, i.e. SEQ ID NO.1；
(b) CLEEKVCSL, i.e. SEQ ID NO.2；
(c) ELLKRELGL, i.e. SEQ ID NO.3.
According to the present invention, the gene of the PADI4 epitope polypeptide is encoded.
Second aspect, the present invention provide a kind of expression vector, and the expression vector includes the PADI4 epitope in first aspect
The gene of polypeptide.
The third aspect, the present invention provide a kind of incremental cell of antigen, and it is by first aspect that the antigen, which is incremented by cell,
The load of PADI4 epitope polypeptide.
Fourth aspect, the present invention provide a kind of specific immunity effector cell, and the specific immunity effector cell is directed to
PADI4 epitope polypeptide described in first aspect.
5th aspect, the present invention provide a kind of pharmaceutical composition, and described pharmaceutical composition includes PADI4 table in first aspect
Position polypeptide or the antigen of the third aspect are incremented by the specific immunity effector cell in cell or fourth aspect, the HLA-0201 limit
The pharmaceutical composition of property PADI4 epitope polypeptide processed is used to treat or prevent the tumour of HLA-0201 positive object.
According to the present invention, described pharmaceutical composition includes pharmaceutically acceptable carrier or excipient.
6th aspect, the antigen in first aspect present invention in PADI4 epitope polypeptide or the third aspect are incremented by cell or the
Specific immunity effector cell in four aspects, which treats or prevents in tumour medicine in preparation, to apply.
According to the present invention, the tumour of the treatment or prevention is to co-express the tumour of HLA-0201 and PADI4 albumen, is
Gastric cancer, colon cancer, lung cancer, the cancer of the esophagus, G. cephalantha cancer of pancreas, breast cancer, prostate cancer, non-Hodgkin lymphoma and colloid
Any one in blastoma.
The beneficial effects of the present invention are:
The restricted PADI4 epitope polypeptide of HLA-0201 of the invention and HLA-0201 have strong affinity, to its immunogene
Property evaluated, find its can be induced in HLA-0201 positive healthy human peripheral specificity, HLA-0201 limitation
The Cytotoxic T lymphocytes of property, and be one processed naturally by cell, the immunogenic polypeptide of submission.HLA-0201 limitation
Property PADI4 epitope polypeptide induction antigen-specific Cytotoxic T lymphocytes have High Fragmentation activity and high IFN-γ secretion energy
Power.
Detailed description of the invention
Fig. 1 is the external evoked HLA-0201 positive colon cancer patient periphery of Dendritic Cells (DC) of P109-117 peptide sensitization
The ELISPOT testing result of the IFN-γ secretion of blood Peptide-specific CTL cell.
Fig. 2 is the external evoked HLA-0201 positive colon cancer patient periphery of Dendritic Cells (DC) of P109-117 peptide sensitization
The flow cytomery result of the IFN-γ secretion of blood Peptide-specific CTL cell.
Specific embodiment
In order to be easy to understand the technical means, the creative features, the aims and the efficiencies achieved by the present invention, tie below
Specific embodiments and the drawings are closed, the present invention is further explained, and however, the following embodiments are merely preferred embodiments of the present invention, not
All.Based on the implementation example in the implementation mode, those skilled in the art are obtained without making creative work
Other embodiments belong to protection scope of the present invention.Experimental method in following embodiments is unless otherwise specified normal
Rule method, the materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
A kind of restricted PADI4 epitope polypeptide of HLA-0201, amino acid sequence are selected from following (a)-(c):
(a) YLTGVEISL, i.e. SEQ ID NO.1；
(b) CLEEKVCSL, i.e. SEQ ID NO.2；
(c) ELLKRELGL, i.e. SEQ ID NO.3.
Encode the gene of PADI4 epitope polypeptide, the expression vector comprising above-mentioned PADI4 epitope polypeptide gene.
A kind of incremental cell of antigen, antigen, which is incremented by cell, to be loaded by above-mentioned PADI4 epitope polypeptide.
A kind of specific immunity effector cell, specific immunity effector cell are directed to above-mentioned PADI4 epitope polypeptide.
A kind of pharmaceutical composition, pharmaceutical composition include above-mentioned PADI4 epitope polypeptide or above-mentioned antigen be incremented by cell or on
Specific immunity effector cell is stated, the pharmaceutical composition of the restricted PADI4 epitope polypeptide of HLA-0201 is for treating or preventing
The tumour of HLA-0201 positive object, pharmaceutical composition include pharmaceutically acceptable carrier or excipient.
Above-mentioned PADI4 epitope polypeptide or above-mentioned antigen are incremented by cell or above-mentioned specific immunity effector cell controls in preparation
It treats or prevents to apply in tumour medicine, the tumour for the treatment of or prevention is to co-express the tumour of HLA-0201 and PADI4 albumen, is
Gastric cancer, colon cancer, lung cancer, the cancer of the esophagus, G. cephalantha cancer of pancreas, breast cancer, prostate cancer, non-Hodgkin lymphoma and colloid
Any one in blastoma.
Embodiment 1
Screening for HLA-0201 high-affinity peptide
On the basis of carrying out computer simulation analysis to PADI4, selectively synthesis is possible in conjunction with HLA-0201
And the Antigenic Peptide (such as table 1) for inducing the PADI4 of body generation CTL special, it is thin by the RMA-S for stablizing expression HLA-0201 molecule
The peptide Binding experiment of born of the same parents' (TAP deficiency) filters out the epitope peptide for having strong affinity with HLA-0201.
It is screened using peptide Binding experiment specific as follows with the epitope peptide of HLA-0201 high-affinity:
(1) the T2 cell for stablizing expression HLA-0201 molecule is collected, after being washed three times with ice PBS, tune cell concentration to 1 ×
106/ml is laid in 96 orifice plates, 100 holes μ l/.(2) with the candidate polypeptide of 50uM, the β2-microglobulin of 2.5 μ g/ml in 37 DEG C,
It is incubated for 18h altogether in 5%CO2 incubator.(3) cell being incubated for is collected, is washed three times with ice PBS, 2 μ l FITC label is added
The monoclonal antibody of HLA-0201 specificity places 4 DEG C of refrigerators, is incubated for 30min.(4) PBS is washed three times, is examined with flow cytometer
Survey average fluorescent strength.
Result judgement: the combination situation of immuno-fluorescence assay peptide and HLA-0201 molecule, be based on exogenous polypeptid with
The combination of RMA-S cell surface MHC-I class molecule can be such that the expression quantity of the MHC-I class molecule on its surface increases, and the two is combined and got over
Firm, then the expression quantity of detectable MHC-I class molecule is more, using average fluorescent strength as Testing index.As a result with fluorescence
Coefficient (FI) is used as measurement index, and FI > 1 of polypeptide is considered as the epitope of high-affinity.
Fluorescence coefficient (FI)=(sample mean fluorescence intensity-background average fluorescent strength)/background average fluorescent strength
Wherein epitope peptide P109-117 and HLA-0201 has high-affinity, and sequence is YLTGVEISL (such as table 1)
The result of the affinity of PADI4 polypeptide of the table 1 in conjunction with T2-HLA-0201-
| Start position | Sequence | FI | |
| 1 | 109 | YLTGVEISL | 1.67 |
| 2 | 611 | CLEEKVCSL | 0.86 |
| 3 | 551 | ELLKRELGL | 0.67 |
Embodiment 2
As shown in Figs. 1-2, the restricted polypeptide antigen of HLA-0201 in the source colon cancer patient peripheral blood lymphocytes PADI4
Specific CTL it is external evoked
The anticoagulant periphery whole blood of HLA-0201+/PADI4+ colon cancer patient, passes through lymphocyte separation medium (Ficoll-
Histopaque 1.077) density gradient centrifugation (room temperature, 400 × g, 30 minutes), Interphase cells are taken, 50ml centrifuge tube is placed in
In, it is washed cell 3 times, is obtained peripheral blood mononuclear cells (PBMC) with no calcium and magnesium PBS (pH7.2)-EDTA (2mM).It is obtained
Mononuclearcell complete medium (RPMI1640 containing 10% fetal calf serum) suspension PBMC, is laid on 6 by 1 × 107 cells/well
Orifice plate, 37 DEG C, after 5%CO2 is incubated for 2 hours, gently shakes plank, non-adherent cell is sucked out, freezes spare.
The attached cell DC serum-free that rhGM-CSF (500U/ml) and people's recombination rhIL-4 (10ng/ml) are recombinated containing people
Liquid medium is cultivated in 37 DEG C, 5%CO2 incubator.It cultivates by the 7th day, with peptide P109-117 sensitization 4 hours.Together
The non-adherent cell (being rich in lymphocyte) that Shi Fusu freezes, is suspended in the RPMI1640 culture medium of 10% fetal calf serum, adjusts
Whole cell concentration is 4 × 106 cells/ml, and 0.5ml is taken to be added into the above-mentioned self DCs through peptide P109-117 sensitization respectively, in
37 DEG C, co-culture (T:DCs=10:1) under 5% carbon dioxide conditions, this is the stimulation of the first round.Later in the 5th of co-cultivation the
20U/ml rhIL-2 is added in it, and culture collected above-mentioned lymphocyte after 7 days, equally with the ratio of 10:1 again with freshly prepared 2
The androgynous DCs of × 105/ml peptide sensitization co-cultures the stimulation for carrying out the second wheel with 10% fetal calf serum RPMI1640 culture solution.Together
The stimulation of sample costimulation once a week is three times.A 20U/ml rhIL-2 was added in incubation every 3 days, measures within 2-3 days half
Fresh culture is replaced, and is expanded according to point hole for needing to carry out cell, post-stimulatory 7 days collection cells of last, using immune
Magnetic bead positive selection sorting CD8+T cell, method are strictly carried out according to the specification that manufacturer provides.
The CD8+T effector cell sub-elected:
(1) (result is as shown in Figure 1, the longitudinal axis indicates IFN-γ+spot formation in 106 CD8+T cells for ELISPOT detection
Units, horizontal axis indicate stimulation cell；RAM-S-P109-117 indicates the target cell loaded with P109-117 peptide；RAM-S is indicated
The target cell of peptide is not loaded)
The CD8+T cell gone out through immunological magnetic bead sorting is suspended in the RPMI1640 culture medium of 10% fetal calf serum as anti-
Cell is answered, adjustment cell concentration is 5 × 106/ml, and cell suspension is directly transferred to the ELISPOT inspection for being coated with anti-IFN-γ antibody
Drafting board, 100 holes μ l/.RMA-S cell use the irradiation of 4000rad Co 60 to go proliferation after as cell is stimulated, in conjunction with PADI4 Antigenic Peptide,
Adjustment cell concentration is 5 × 106/ml, then cell suspension is separately added into the detection hole containing reacting cells, 100 μ l/
Hole.Referring to the T cell colony of the method detection secretion of gamma-IFN of IFN-γ ELISPOT detection kit specification.Figure 1A is magnetic
The special CD8+T cell of the P109-117 peptide that pearl sub-elects has the reacting cells RMA-S-P109- of P109-117 peptide with load
117 and control reacting cells stimulation after, the T of the secretion of gamma-IFN detected is counted accurately；Figure 1B is the P611-619 that magnetic bead sorting goes out
The special CD8+T cell of peptide has the reacting cells RMA-S-P611-619 and control reacting cells thorn of P611-619 peptide with load
After swashing, the T of the secretion of gamma-IFN detected is counted accurately；Fig. 1 is the special CD8+T cell of the P551-559 peptide of magnetic bead sorting out, is used
After load has reacting cells RMA-S-P551-559 and the control reacting cells stimulation of P551-559 peptide, the secretion IFN- that detects
The T of γ is counted accurately.
(2) peptide specific CTL IFN-γ dyeing intracellular
20 μM of corresponding peptides are added in the effector cell induced, after 48 hours, conventional dyeing (result such as Fig. 2 institute intracellular
Show, the DC that wherein effector cell of left figure loads from nonreactive former peptide external evoked Cytotoxic T lymphocytes；The effect of right figure
DC of the cell from P109-117 peptide sensitization external evoked Cytotoxic T lymphocytes).We are from tumour phase in this embodiment
Antigen PADI4 is closed to filter out the epitope peptide P109-117 of the restrictive high immunogenicity of a HLA-0201 (its sequence is
YLTGVEISL), there is High Fragmentation activity and high IFN-γ secretion ability by the cytotoxic cell of the antigen-specific of the inducing peptide.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
For personnel it should be appreciated that the present invention is not limited to the above embodiments, described in the above embodiment and specification is only the present invention
Preference, be not intended to limit the invention, without departing from the spirit and scope of the present invention, the present invention also has various
Changes and improvements, these changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention is by institute
Attached claims and its equivalent thereof.
Claims (9)
1. a kind of restricted PADI4 epitope polypeptide of HLA-0201, amino acid sequence is selected from following (a)-(c):
(a) YLTGVEISL, i.e. SEQ ID NO.1；
(b) CLEEKVCSL, i.e. SEQ ID NO.2；
(c) ELLKRELGL, i.e. SEQ ID NO.3.
2. the restricted PADI4 epitope polypeptide of a kind of HLA-0201 according to claim 1, it is characterised in that: described in coding
The gene of PADI4 epitope polypeptide.
3. a kind of expression vector, it is characterised in that: the expression vector includes PADI4 epitope polypeptide as stated in claim 2
Gene.
4. a kind of antigen is incremented by cell, it is characterised in that: it is by the PADI4 described in claim 1 that the antigen, which is incremented by cell,
Epitope polypeptide load.
5. a kind of specific immunity effector cell, it is characterised in that: the specific immunity effector cell is in claim 1
The PADI4 epitope polypeptide.
6. a kind of pharmaceutical composition, it is characterised in that: described pharmaceutical composition include in claim 1 PADI4 epitope polypeptide or
Antigen in claim 4 is incremented by the specific immunity effector cell in cell or claim 5, and the HLA-0201 is restricted
The pharmaceutical composition of PADI4 epitope polypeptide is used to treat or prevent the tumour of HLA-0201 positive object.
7. a kind of pharmaceutical composition according to claim 6, it is characterised in that: described pharmaceutical composition includes pharmaceutically may be used
The carrier or excipient of receiving.
8. PADI4 epitope polypeptide or the incremental cell of antigen or special in claim 5 in claim 4 in claim 1
Property immune effector cell preparation treat or prevent tumour medicine in apply.
9. treatment or prevention tumour medicine according to claim 8, it is characterised in that: the tumour of the treatment or prevention is
Co-express HLA-0201 and PADI4 albumen tumour, be gastric cancer, colon cancer, lung cancer, the cancer of the esophagus, G. cephalantha cancer of pancreas,
Any one in breast cancer, prostate cancer, non-Hodgkin lymphoma and glioblastoma.
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Cited By (2)
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| CN111735948A (en) * | 2020-07-13 | 2020-10-02 | 山东新创生物科技有限公司 | Application of PADI4 in preparation of tumor diagnosis kit |
| CN111748017A (en) * | 2019-03-26 | 2020-10-09 | 上海瑞可新生物科技有限公司 | Antigen polypeptide, expression vector, combined drug, kit and application thereof |
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| CN101101290A (en) * | 2006-11-30 | 2008-01-09 | 山东省医药生物技术研究中心 | Tumour serum mark and its uses |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111748017A (en) * | 2019-03-26 | 2020-10-09 | 上海瑞可新生物科技有限公司 | Antigen polypeptide, expression vector, combined drug, kit and application thereof |
| CN111735948A (en) * | 2020-07-13 | 2020-10-02 | 山东新创生物科技有限公司 | Application of PADI4 in preparation of tumor diagnosis kit |
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