CN105504015A - MHC (major histocompatibility complex) class I restrictive antitumor CTL (cytotoxic T lymphocyte) epitope peptide - Google Patents
MHC (major histocompatibility complex) class I restrictive antitumor CTL (cytotoxic T lymphocyte) epitope peptide Download PDFInfo
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Abstract
An MHC (major histocompatibility complex) class I restrictive antitumor CTL (cytotoxic T lymphocyte) epitope peptide can be bound with a binding site of human MHC class I molecules, and can activate epitope peptides of specific CTL. The two epitope peptides have amino acid sequences as follows: E1, Tyr Ile Met Phe Val Asp Pro Ser Leu; E2, Tyr Leu Val Ala Leu Ser Tyr Thr Leu. The epitope peptide bound with human MHC class I molecules is one of an episomal polypeptide, a fusion polypeptide and a mosaic polypeptide with the amino acid sequences, or one of various polymer with one monomer of the two polypeptides. The invention uses a method of combing the computer simulation technology with experiments, and improves the accuracy of epitope peptide filtering; the polypeptide matter is a short polypeptide with 9 peptides and is formed by composition in vitro easily, and can induce the antitumor immunity response, so that the epitope peptide has very great commercialized and industrialized values and is applied to the technical field of tumor immunotherapy.
Description
Technical field
The present invention relates to the restricted antitumor CTL epitope peptide of a kind of MHC-I class in immunotherapy of tumors technical field.
Background technology
In recent years, along with going deep into immunne response Study on Molecular Mechanism, now recognize that the immunocyte of body is not the overall molecule corresponding to various pathogenic agent or natural antigen gradually, but for the epitope of various antigen molecule, namely proteantigen embodies its immunologic opsonin by its epi-position.Current research shows, the target antigen that CD8+T cell identifies needs first through antigen presenting cell process, be presented on antigen presenting cell or target cells with the form of " antigen peptide-MHC-I quasi-molecule " mixture afterwards, the antigen peptide be combined with MHC-I quasi-molecule is accordingly CTL epi-position.Epitope peptide can produce Specific CTL Cells by activation-inducing, can have certain fragmentation effect to the tumour of human leucocyte antigen (HLA) distribution type coupling.Therefore, researching and developing the restricted antitumor CTL epitope peptide of a kind of MHC-I class is new problem anxious to be resolved at present.
Summary of the invention
The object of the present invention is to provide the restricted antitumor CTL epitope peptide of a kind of MHC-I class, this invention be the peptide molecule be combined with people's MHC (MHC) I quasi-molecule is predicted, screening and identification, the epitope peptide that can carry out combining, can activating specific cytotoxic T lymphocyte (CTL cell) with the binding site of people MHC-I quasi-molecule is provided, thus effective killing tumor cell, reach the object for the treatment of tumour, and described epitope peptide is for the preparation of clinical treatment and the purposes that detects in neoplastic disease vaccine.
The object of the present invention is achieved like this: the restricted antitumor CTL epitope peptide of a kind of MHC-I class, can combine with the binding site of people MHC-I quasi-molecule, can activate the epitope peptide of specific cytotoxic T lymphocyte, 2 epitope peptides have following amino acid sequences and are:
E1，TyrIleMetPheValAspProSerLeu；
E2，TyrLeuValAlaLeuSerTyrThrLeu；
The described epitope peptide be combined with people MHC-I quasi-molecule, for having the sequestered polypeptide of this aminoacid sequence, pattern of fusion polypeptide and mosaic type polypeptide; And one of the above 2 peptide species are the various forms of polymers of monomer;
Described MHC-I class restricted targeting anti-tumor CTL epitope peptide by synthetic, or is obtained by prokaryotic cell prokaryocyte or eukaryotic cell expression purifying;
The described restricted antitumor CTL epitope peptide of MHC-I class is according to epitope peptide and the interactional mechanism of MHC-I quasi-molecule, prediction obtains epitope peptide, and to be effectively combined with MHC-I quasi-molecule according to it and the CHARACTERISTICS IDENTIFICATION that can activate T lymphocyte specific is effective epitope peptide, this epitope peptide length is 9 aminoacid sequences only, external easy synthesis, facilitates clinical application;
The described epitope peptide involved by the restricted antitumor CTL epitope peptide of MHC-I class and function or the known protein of character merge or chimeric, namely these protein molecules or chimeric molecule contain the polypeptid acid sequence that the present invention relates to, and have the same or similar activity of these polypeptide.
Main points of the present invention are to provide the epitope peptide that can carry out combining, can activating specific cytotoxic T lymphocyte (CTL cell) with the binding site of people MHC-I quasi-molecule.Its ultimate principle is: the first theory and combining ability of information biology Proof-Of Principle epitope peptide and MHC-I quasi-molecule, and verifies the bonding force of epitope peptide and MHC-I quasi-molecule further by the experiment of computer simulation associating T2 avidity; Then by the synthesis of Fmoc principle, HPLC purifying epitope peptide, and its purity and molecular weight is analyzed by HPLC-MS; Finally utilize DC load epi-position inducing peptide CTL cell, and by the tumour target cell mixed culture from different MHC-I molecular phenotype, observe CTL cellular immunization and kill and wound the restricted of the MHC-I molecule of target cell.The restricted antitumor CTL epitope peptide of a kind of MHC-I class compared with prior art, have and use computer modeling technique and test the method combined, the accuracy of further raising epitope peptide screening, peptide material is only the small peptide of 9 peptides, external easy synthesis, can induce and produce remarkable anti tumor immune response, there is the advantages such as very large commercial industries value, will be widely used in immunotherapy of tumors technical field.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the present invention is described in detail.
Fig. 1 is the Space structure simulation figure of E1 epitope peptide.
Fig. 2 is the Space structure simulation figure mono-that E1 epitope peptide and MHC-I molecule combine.
Fig. 3 is the Space structure simulation figure bis-that E1 epitope peptide and MHC-I molecule combine.
Fig. 4 is the Space structure simulation figure of E2 epitope peptide.
Fig. 5 is the Space structure simulation figure mono-that E2 epitope peptide and MHC-I molecule combine.
Fig. 6 is the Space structure simulation figure bis-that E2 epitope peptide and MHC-I molecule combine.
Fig. 7 is the mass spectroscopy figure of E1 epitope peptide.
Fig. 8 is the high-efficient liquid phase chromatogram technique analysis figure of E1 epitope peptide.
Fig. 9 is the mass spectroscopy figure of E2 epitope peptide.
Figure 10 is the high-efficient liquid phase chromatogram technique analysis figure of E2 epitope peptide.
Embodiment
The restricted antitumor CTL epitope peptide of a kind of MHC-I class, can combine with the binding site of people MHC-I quasi-molecule, can activate the epitope peptide of specific cytotoxic T lymphocyte, 2 epitope peptides have following amino acid sequences and are:
E1，TyrIleMetPheValAspProSerLeu；
E2，TyrLeuValAlaLeuSerTyrThrLeu。
The described epitope peptide be combined with people MHC-I quasi-molecule, for having the sequestered polypeptide of this aminoacid sequence, pattern of fusion polypeptide and mosaic type polypeptide; And one of the above 2 peptide species are the various forms of polymers of monomer.
Described MHC-I class restricted targeting anti-tumor CTL epitope peptide by synthetic, or is obtained by prokaryotic cell prokaryocyte or eukaryotic cell expression purifying.
The described restricted antitumor CTL epitope peptide of MHC-I class is according to epitope peptide and the interactional mechanism of MHC-I quasi-molecule, prediction obtains epitope peptide, and to be effectively combined with MHC-I quasi-molecule according to it and the CHARACTERISTICS IDENTIFICATION that can activate T lymphocyte specific is effective epitope peptide, this epitope peptide length is 9 aminoacid sequences only, external easy synthesis, facilitates clinical application.
The described epitope peptide involved by the restricted antitumor CTL epitope peptide of MHC-I class and function or the known protein of character merge or chimeric, namely these protein molecules or chimeric molecule contain the polypeptid acid sequence that the present invention relates to, and have the same or similar activity of these polypeptide.
Following examples will contribute to understanding of the present invention, but these embodiments are only in order to be illustrated the present invention, and the present invention is not limited to these contents.
Embodiment one
Epitope peptide and people MHC-I quasi-molecule avidity are verified:
1, by the method that hyper-base sequence method is combined with quantitative motif method, the peptide sequence of checking the present invention design and MHC-I quasi-molecule binding characteristic.
Hyper-base sequence method is based on same human leucocyte antigen (HLA) (HLA) family, the antigen peptide of even not receiving with the HLA opposite molecule of the same race of family has the peptide motif that same or analogous anchor point residue is formed, and the anchor point residue of hyper-base sequence Main Function is positioned at peptide chain 2 (P2) amino-acid residues and C-terminal 9 (P9) amino-acid residues.When the residue of P2, P9 is A, I, L, M, V, T, and second is die aromatischen Aminosaeuren, and the 9th is hydrophobic amino acid, has higher avidity with HLA-A2 molecule.These amino acid whose particular sequences are the avtive spot that is combined with MHC-I molecule of peptide molecule or key amino acid, determine the living features with MHC-I quasi-molecule Binding peptide.
Application
http:// www.syfpeithi.de/bin/MHCServer.dll/ EpitopePrediction.htm provides analysis software to carry out the analysis of hyper-base sequence method to polypeptid acid sequence.
Quantitative motif method supposes based on IBS, namely, in the combination of antigen peptide and HLA-A2 molecule, the side chain effect (grappling, suppression or neutrality) of antigen peptide mainly relies on the position residing in peptide with corresponding amino-acid residue to be affected less by adjacent amino-acid residue.This can suppose in a peptide sequence in certain scope, and each amino-acid residue is separate and affect the combination of whole peptide and MHC-I quasi-molecule, and the combination of this antigen peptide to be exactly each position amino-acid residue combine can comprehensive.On the basis of this assumption, Parker in 1993 etc. analyze the avidity of 154 nonapeptides and HLA-A2 molecule with peptide Binding experiment, and obtain the associate(d) matrix that comprises 180 coefficients, wherein each coefficient has reacted corresponding to energy when this position of corresponding amino-acid residue.In conjunction with can be larger, epitope peptide be combined tightr with HLA-A2 molecule.The corresponding amino-acid residue attachment coefficient of certain mensuration polypeptide each position is multiplied and takes advantage of typical coefficient 0.151 again, be the bonding force of this peptide and HLA-A2, when attachment coefficient is more than or equal to 5, can be defined as being combined with HLA-A2 molecule and stablize, otherwise it is unstable to regard as combination.According to above-mentioned principle, the analysis software that application http://www.bimas.com provides carries out the analysis of quantitative motif method to polypeptid acid sequence.
Although hyper-base sequence method prediction CTL epi-position overcomes the false negative result adopting Simple motif method easily to produce in the past, but because this prediction procedure has identical weakness with motif method, namely in prediction, only consider the impact of two, nine residues and have ignored the residue in other site in conjunction with situation, easily there is false positive results, therefore the accuracy (table 1) that quantitative motif method improves CTI. Antigen Epitope Prediction should be combined.Table 1 shows, and hyper-base sequence method and quantitative motif method all show that two epitope peptide E1 and E2 and HLA-A2 molecules have good binding ability; Table 2 is amino acid whose abbreviation table in 20.
The comprehensive hyper-base sequence method of table 1 and quantitative motif method obtain the scoring that polypeptid acid sequence is combined with HLA-A2
Table 2 amino acid abbreviations table
2, the combination of computer simulation epitope peptide and people MHC-I quasi-molecule:
ChemDrawUltra, ChemDraw3DUltra in above-mentioned gained epitope peptide ChemOffice software package is set up respectively to the 2 and 3 dimensional organization of epitope peptide; With MOE software to epitope peptide and and the energy of HLA-A2.1 and structure modify, the three-dimensional structure that both simulations combine, carry out molecular dynamics and combine estimating of simulation and physiologically active and applying value, mainly comprise following methods: (1) epitope peptide molecular model structure.The ChemDrawUltra in ChemOffice software package is used to build epitope peptide molecule two-dirnentional structure, again the two-dirnentional structure of epitope peptide is imported ChemDraw3DUltra obtain three-dimensional model and save as Mol2 form, in docking simulation link, three-dimensional structure is imported in MOE software, select drop-down menu Compute-Minimize-Molecule successively, occur that Minimize dialog box carries out the energy level optimization of peptide molecule, make it energy level and reach the most applicable minimum energy and structural state of carrying out molecular docking with the mixture of HLA-A2.1, then the epitope peptide after optimization is exported as MOL2 form, in order to carrying out three-dimensional docking with the engagement groove groove of HLA-A2.1.(2) mixture of HLA-A2.1 prepares before carrying out molecular dynamics simulation.The initial coordinate of HLA-A2.1 comes from the exclusive website of protein structures
http:// www.rcsb.org/pdb/the HLA-A2.1 structured data obtained is imported in MOE software, select drop-down menu Applications-DockingSuite-DockingLigands successively, there is Docking dialog box, select on the right on Filename hurdle Define to carry out docking pre-structure to HLA-A2.1 structure and modify (reparation side chain, dehydration hydrogenation), structural modification completes the engagement groove groove three-dimensional information that post analysis obtains HLA-A2.1, preserves in order to docking with epitope peptide.(3) structure of model is docked.Applications-DockingSuite-DockingLigands is opened successively in MOE software, there is Docking dialog box, the engagement groove groove three-dimensional information of the HLA-A2.1 obtained is selected on DockingMode and Filename hurdle, in LigandSourse hurdle, select Mole2File and select MOL2 form each optimized and be in the minimum epitope peptide data of energy level, carry out respectively docking the scoring also finally obtaining docking simulation, estimated by the bonding force of score value to epi-position peptide molecule and HLA-A2.1 of docking simulation, due between antigen peptide and MHC molecule mainly through hydrophobic interaction, H key, the weak interactions such as sat linkage carry out intermolecular identification, these secondary key effects are stronger, in conjunction with then tightr.Computer simulation results shows, and E1, E22 bar epitope peptide all can well be combined with HLA-A2.1 (as Fig. 2,4).
3, the experiment of T2 avidity detects the combination of epitope peptide and people MHC-I quasi-molecule:
The present embodiment utilizes the feature of T2 clone, detects the avidity of epitope peptide and people MHC-I quasi-molecule.T2 cell can express MHC-class Ⅰmolecule, but because its endogenous antigen presents antigenic peptide translocator (TAP) defect required in approach, therefore can not endogenous antigen be transported, can only by the HLA-A2 molecular presentation of zero load at cell surface, and the HLA-A2 molecule of zero load is unstable at cell surface, degrades very soon or return cell interior.But external source give with antigenic peptide and HLA-A2 molecular juction synthesising complex after, the stability of cell surface HLA-A2 molecule can be strengthened, and stay cell surface.The bonding force of antigen peptide and HLA-A2 is stronger, then the expression amount of T2 cell surface HLA-A2 molecule is higher.So the increase of the T2 cell surface HLA-A2 developed by molecule amount of detectable antigens polypeptide process, the bonding force of foreign antigenic polypeptide and HLA-A2 molecule and the stability of combination can be reflected intuitively, the validity of polypeptide of the present invention can be proved further.
In embodiment, T2 cell washs 2 times through PBS, after resuspended with serum-free IMDM substratum, by 1 × 10 on 6 well culture plates
6the density plantation in/hole, after each antigenic peptide dissolves with dimethyl sulfoxide (DMSO) (DMSO), join in the nutrient solution of T2 cell with the concentration of 50 μ g/ml, and arrange blank group and positive controls, positive controls adds 30 μ g/ml Influenza matrix protein polypeptides.Each Kong Jun adds 3 μ g/ml people β
2microglobulin.T2 cell at 37 DEG C, 5%CO
2, cultivate 24h under saturated humidity condition after.After hatching end, T2 cell is with the centrifugal 5min of 1000rpm, sedimentation cell washs 3 times with ice PBS, then resuspended with 100 μ l ice PBS, add 5 μ l mouse-anti people HLA-A2.1-FITC monoclonal antibodies, hatch 15min for 4 DEG C, centrifugal abandon supernatant after resuspended with 300 μ l ice PBS, flow cytometer detects average fluorescent strength (MFI).The avidity experimental result of epitope peptide and MHC-I molecule is shown in table 3.
Result is using fluorescence coefficient (FI) as measurement index, and calculation formula is: fluorescence coefficient (FI)=(polypeptide average fluorescent strength-β
2microglobulin average fluorescent strength)/β
2microglobulin average fluorescent strength, judging criterion: FI>1.5 is that polypeptide and HLA-A2.1 molecular binding affinities are high, 1.0<FI<1.5 is medium bonding force, and FI>0.5 is low bonding force.
The avidity experimental result of table 3 epitope peptide and MHC-I molecule
Experimental result shows: two epitope peptide E1 and E2 and MHC-I quasi-molecules all have very high bonding force.
Embodiment two
The synthesis of epitope peptide, purifying and molecular weight determination:
Employing standard Fmoc scheme, the ABI43IA type Peptide synthesizer that PE company of the application U.S. produces carries out the synthesis of polypeptide, be summarized as follows: according to peptide sequence, peptide chain is extended to aminoterminal from carboxyl terminal, after synthesis, select TFA/DCM to cut, epitope peptide collection liquid at normal temperatures drying under reduced pressure, to 1-2mL, then uses at least 50mL precooling ether sedimentation, then suction filtration, the thick product of the polypeptide obtained.After being dissolved with a small amount of DMSO by the epitope peptide crude product obtained, be diluted with water to volume required, concentration is 10mg/mL, and after 0.22 μm of Fibrous membrane filtration, purifying on Waters, US product Delta600 type HPLC also carries out purity check.Moving phase is selected containing the 0.1%TFA aqueous solution with containing 0.1%TFA second cyanogen solution.The purifying of each peptide selects C18 preparative column (Waters, US, 7.0 μm, 100A, 7.8mm × 150mm), and the purity check of each peptide selects C18 analytical column (Waters, US, 5.0 μm, 100A, 3.9mm × 150mm).After each purifying, the Measuring Molecule Weight of polypeptide is pacified ordinary method and is carried out on API2000 type (Waters, US) mass spectrograph.Figure is see Fig. 5, Fig. 7 in its mass spectroscopy, and HPLC analysis chart, see Fig. 6, Fig. 8, can find out that the molecular weight theoretical value of 2 polypeptide is all close with measured value, within permissible error scope, and purity is all more than 95%, illustrate that synthetic effect is good, can be used for next step experiment.Aforementioned polypeptides is put in-70 DEG C of preservations, for subsequent use after frozen dried.
Embodiment three
Calcium flavin (Calcein-AM) release experiment epitope peptide is to the target immunologic cytotoxicity effect of tumour cell:
1, the preparation of effector cell
The people DC cell of induced maturation, after PBS cleaning, serum-free IMDM substratum is resuspended, adds 50 μ g/ml epitope peptides, 37 DEG C of overnight incubation.DC cell, through PBS cleaning, counting, adds ametycin by the concentration of 30 μ g/ml, hatches 30min for 37 DEG C.DC cell cleans through ice PBS, after counting, with nursery stage T cell in 1:20 ratio Dual culture, and add the IL-2 of 50U/ml, to stimulate T cell.Within 1 week, stimulate 1 time, totally 3 times, induced t cell is become cytotoxic T cell (CTL), i.e. effector cell.
2, the preparation of target cell
Recovery breast cancer cell MCF7, MBA-MD-231 and OS-732 cells MG-63, U-2OS, normally cultivate, go down to posterity.Wherein MCF7, MG-63 two cell strain be that HLA-A2.1 is negative, MBA-MD-231, U-2OS two cell strain be that HLA-A2.1 is positive.
3, calcium flavin release experiment
With the Calcein-AM labels targets cell of 10mM concentration, cleaning, resuspended; Tumour cell after effector cell and mark according to the effect target ratio of 1:1,10:1,20:1,40:1,80:1,37 DEG C of Dual culture 4h; Then collect nutrient solution, the centrifugal 5min of 1000rpm, get 100 μ l supernatant liquors and measure average fluorescent strength, using simple target cell as spontaneous release, add washing agent as maximum burst size using simple target cell.
Effector cell represents with cytolysis rate the kill rate of target cell: cytolysis rate=(experimental release-spontaneous release)/(maximum burst size-spontaneous release).Table 4 is the effector cell of epitope peptide induction to the target killing result of tumour cell.
The effector cell of table 4 epitope peptide induction is to the target killing percentage (%) of tumour cell
Note: lethal effect represents with kill rate (% omits).
Experimental result shows: E1, E2 two polypeptide all have lethal effect to the human breast cancer cell MBA-MD-231 of the HLA-A2 positive and human osteosarcoma cell U-2OS; E1, E2 to the human breast cancer cell line Bcap-37 of HLA-A2 feminine gender and human osteosarcoma cell MG-63 lethal effect not obvious, kill and wound and there is the restricted of MHC-I molecule.
Claims (5)
1. the restricted antitumor CTL epitope peptide of MHC-I class, is characterized in that: can combine with the binding site of people MHC-I quasi-molecule, can activate the epitope peptide of specific cytotoxic T lymphocyte, and 2 epitope peptides have following amino acid sequences and are:
E1，TyrIleMetPheValAspProSerLeu；
E2，TyrLeuValAlaLeuSerTyrThrLeu。
2. the restricted antitumor CTL epitope peptide of a kind of MHC-I class according to claim 1, is characterized in that: the described epitope peptide be combined with people MHC-I quasi-molecule, for having the sequestered polypeptide of this aminoacid sequence, pattern of fusion polypeptide and mosaic type polypeptide; And one of the above 2 peptide species are the various forms of polymers of monomer.
3. the restricted antitumor CTL epitope peptide of a kind of MHC-I class according to claim 1, is characterized in that: described MHC-I class restricted targeting anti-tumor CTL epitope peptide by synthetic, or is obtained by prokaryotic cell prokaryocyte or eukaryotic cell expression purifying.
4. the restricted antitumor CTL epitope peptide of a kind of MHC-I class according to claim 1, it is characterized in that: the described restricted antitumor CTL epitope peptide of MHC-I class is according to epitope peptide and the interactional mechanism of MHC-I quasi-molecule, prediction obtains epitope peptide, and to be effectively combined with MHC-I quasi-molecule according to it and the CHARACTERISTICS IDENTIFICATION that can activate T lymphocyte specific is effective epitope peptide, this epitope peptide length is 9 aminoacid sequences only, external easy synthesis, facilitates clinical application.
5. the restricted antitumor CTL epitope peptide of a kind of MHC-I class according to claim 1, it is characterized in that: the described epitope peptide involved by the restricted antitumor CTL epitope peptide of MHC-I class and function or the known protein of character merge or chimeric, namely these protein molecules or chimeric molecule contain the polypeptid acid sequence that the present invention relates to, and have the same or similar activity of these polypeptide.
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| CN106589105A (en) * | 2017-01-23 | 2017-04-26 | 中国医科大学 | HLA-A2-restricted ECM1-specific CTL epitope peptide and applications thereof |
| CN110305209A (en) * | 2019-07-09 | 2019-10-08 | 福建医科大学附属第一医院 | For treating the polypeptide of malignant tumour and its as the purposes of vaccine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110305209A (en) * | 2019-07-09 | 2019-10-08 | 福建医科大学附属第一医院 | For treating the polypeptide of malignant tumour and its as the purposes of vaccine |
| CN110305209B (en) * | 2019-07-09 | 2022-09-13 | 福建医科大学附属第一医院 | Polypeptide for treating malignant tumor and application thereof as vaccine |
| CN113105527A (en) * | 2020-01-13 | 2021-07-13 | 辽宁中健医药科技有限公司 | Anti-tumor dominant CTL epitope peptide of HLA-A2 restricted tumor associated antigen E protein and application thereof |
| CN113105527B (en) * | 2020-01-13 | 2024-04-26 | 沈阳医健生命科技有限责任公司 | Anti-tumor dominant CTL epitope peptide of HLA-A2 restrictive tumor associated antigen E protein and application |
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