CN105859865B - A kind of dual antineoplastic polypeptide based on Eps8-EGFR binding domain - Google Patents
A kind of dual antineoplastic polypeptide based on Eps8-EGFR binding domain Download PDFInfo
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- CN105859865B CN105859865B CN201610293675.9A CN201610293675A CN105859865B CN 105859865 B CN105859865 B CN 105859865B CN 201610293675 A CN201610293675 A CN 201610293675A CN 105859865 B CN105859865 B CN 105859865B
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- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
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Abstract
The present invention relates to a kind of dual antineoplastic polypeptide based on Eps8-EGFR binding domain, the amino acid sequence of the polypeptide is Glu-Phe-Leu-Asp-Cys-Phe-Gln-Lys-Phe (SEQ ID No:1).Dual antineoplastic polypeptide of the present invention can either inducing cytotoxic T cell, effectively killing HLA-A*2402 positive, Eps8 positive tumors, and can directly inhibit HLA-A*2402 positive, Eps8 positive tumor cell proliferation, can be used for preparing dual anti-tumor drug.
Description
Technical field
The present invention relates to organic chemistry fileds, and in particular to the polypeptide from mammal, the polypeptide have antitumor work
Property, suitable for preparing anti-tumor drug.
Background technique
Polypeptide drugs have very important Development volue in clinical application.Part of polypeptide drug, which has, promotes body to exempt from
The effect of epidemic disease function, referred to as polypeptide vaccine.Induction is by force and the identification of the novel tumor antigen of specificity antineoplastic immunity response is protected
Exploitation and clinical application (Reche P, the et al.J Immunol Res for the polypeptide vaccine of various types tumour are demonstrate,proved
2015；2015:349049；Jazirehi AR,et al.Cancer Res 2011；71(4):1406-1417；Andersen
RS,et al.Cancer Immunol Immunother 2011；60(2):227-234；Gritzapis AD,et
al.Cancer Res 2010；70(7):2686-2696；Klepin HD,et al.Oncologist 2009；14(3):222-
232.).So far, it is induced to varying degrees there are many clinical test of practical tumor associated antigen derived peptides
Anti-tumor immune response (Walter S, et al.Nat Med2012 out；18(8):1254-1261；Bae J,et al.Clin
Cancer Res 2012；18:4850-60；Slingluff CJ,et al.Clin Cancer Res 2007；13:6386-
95；Slingluff CJ,et al.Clin Cancer Res 2009；15:7036-44；Slingluff CJ,et al.J
Clin Oncol 2011；29:2924-32.)
Since the Immune Selection for the treatment of driving will lead to the deletion, mutation or downward of tumour antigen, and then cause tumour thin
Therefore born of the same parents' immunologic escape is the ideal targets of immunotherapy to the essential tumor associated antigen of tumour cell occurrence and development,
The risk of tumor immune escape can be minimized.
Eps8, i.e. EGF-R ELISA access substrate 8 (Epidermal growth factor receptor
Pathway Substrate 8, Eps8), it is EGF-R ELISA (EGFR, Epidermal Growth Factor
Receptor) important one of kinase activity substrate.It has been confirmed that Eps8 expresses up-regulation, including palace in many tumour cells
Neck cancer (Chen YJ, et al.Mol Cancer Ther 2008；7:1376-85.), colorectal cancer (Maa MC, et al.J
Biol Chem2007；282:19399-409.), hypophysoma (Xu M, et al.Endocrinology 2009；150:2064-
71.), oral squamous cell carcinomas (Chu PY, et al.Asia Pac J Clin Oncol 2012；8:e77-81.), Pancreatic neoplasms
(Welsch T,et al.Cancer Lett 2007；255:205-18.), breast cancer (Yao J, et al.Cancer Res
2006；66:4065-78.), thyroid cancer (Griffith OL, et al.J Clin Oncol 2006；24:5043-51.),
The cancer of the esophagus (Bashir M, et al.Cell Commun Signal 2010；8:13.) and glioblastoma (Ding X, et
al.Oncol Rep 2013；29:697-703.) etc. entity tumors and Huppert's disease (Li YuhuaThe equal Shandong medicine
2011；51:9-11.), leukaemia (Li YH,et al.Clin Lab 2013；59(11-12):1261-1269；Li YH,et
al.Leuk Res 2015；39(6):575-581；Kang H,et al.Blood2012；119:1872-81.) etc. hematological systems
Tumour.Further analysis finds that Eps8 expression up-regulation promotes tumor cell proliferation and transfer, inhibits apoptosis of tumor cells, reduces
Drug susceptibility, with closely related (Welsch T, the et al.Cancer Lett 2007 of tumor patient poor prognosis；255:205-
18；Chen YJ,et al.Mol Cancer Ther 2008；7:1376-85；Ding X,et al.Oncol Rep 2013；
29:697-703；Li YH,et al.Future Oncol 2013；9(10):1587-1594.).The above research illustrates that Eps8 is
The key molecule and prognostic factor of tumor development.
Separately there is part of polypeptide drug and play the biological activities such as inhibition tumor proliferation, transfer, referred to as polypeptide inhibits
Agent.This kind of polypeptide drugs are for the purpose of blocking and promote tumor associated signal paths.Last decade has multiple antineoplastic polypeptide drugs and is criticized
Quasi- listing, such as be applied to prostate cancer gonadotropin-releasing hormone (GRH) (GnRH) antagonist abarelix (Abarelix:
abarelix-depot-F,abarelix-depot-M,abarelix-L,PPI 149,R 3827.Drugs R D 2003；4
) and degarelix (Frampton JE, et al.Drugs 2009 (3): 161-166.；69 (14): 1967-1976.), and answer
Proteasome inhibitor carfilzomib (McCormack PL.Drugs 2012 for Huppert's disease；72(15):
2023-2032.)。
The patent application of Publication No. CN 103694333A discloses a kind of EPS8 antitumor CTL epitope peptide, and demonstrates
It promotes the effect of CTL cell killing tumour cell.But the follow-up study of the present inventor is found, above-mentioned CTL epitope peptide swells
Tumor cell proliferation inhibitory effect is undesirable, and inhibiting rate is below 50%.
Therefore, the polypeptide of dual anti-tumor effect is developed, that is, the polypeptide not only can promote CTL cell killing tumour cell, but also
Tumor cell proliferation, Clone formation can directly be inhibited, be of great significance to the design of anti-tumor drug.
Summary of the invention
There is provided for the technical problems to be solved by the invention is a kind of dual antitumor more based on Eps8-EGFR binding domain
Peptide, which can not only cause the CTL of corresponding molecular specificity, but also can block Eps8/EGFR signal path, inhibit tumour cell
Proliferation.
Technical proposal that the invention solves the above-mentioned problems are as follows:
A kind of dual antineoplastic polypeptide based on Eps8-EGFR binding domain, the amino acid sequence of the polypeptide are Glu-Phe-
Leu-Asp-Cys-Phe-Gln-Lys-Phe (SEQ ID No:1).
Above-mentioned dual antineoplastic polypeptide can be synthesized to obtain by sequence shown in SEQ ID NO:1 using solid-phase synthesis.
Above-mentioned dual antineoplastic polypeptide is located in Eps8-EGFR binding domain, not only has immunogenicity, but also can block EGFR/
Eps8 signal path, inhibits the proliferation of tumour cell, therefore can be used for preparing tumor vaccine, can be also used for preparing antitumor
Drug.
Dual antineoplastic polypeptide of the present invention can inducing specific T cell immune response, it is special to show as stimulation
Property T cell secreting high levels IFN-γ and to Eps8 positive tumor cell generate specific killing effect.It is of the present invention double
Weight antineoplastic polypeptide can also block the signal path of EGFR/Eps8, directly inhibition tumor cell proliferation, therefore can be with conventional chemotherapy
Drug combination.
Detailed description of the invention
Fig. 1 is the mass spectrogram of dual antineoplastic polypeptide of the present invention.
Fig. 2 is the testing result of the specific CTL secretion of gamma-IFN ability of dual antineoplastic polypeptide induction of the present invention
Figure, wherein figure A is induction CTL secretion of gamma-IFN microphoto；Scheme the bar chart of B induction CTL secretion of gamma-IFN spot number.
Fig. 3 is the specific CTL of dual antineoplastic polypeptide induction of the present invention to the Eps8 positive, HLA-A*2402 is positive
The curve graph of colon cancer cell SW620 Cytotoxicity in vitro ability, the abscissa in figure indicate effector cell (CTL) and target cell
(SW620) ratio (effect target ratio), ordinate indicates killing rate (%).
Fig. 4 is the specific CTL of dual antineoplastic polypeptide induction of the present invention to the Eps8 positive, HLA-A*2402 is positive
The curve graph of colon cancer cell Colo320 Cytotoxicity in vitro ability, the abscissa in figure indicate effector cell (CTL) and target cell
(Colo320) ratio (effect target ratio), ordinate indicates killing rate (%).
Fig. 5 is the specific CTL of dual antineoplastic polypeptide induction of the present invention to the Eps8 positive, HLA-A*2402 is positive
The curve graph of non-small cell lung cancer cell A549 Cytotoxicity in vitro ability, the abscissa in figure indicate that effector cell (CTL) and target are thin
The ratio (effect target ratio) of born of the same parents (A549), ordinate indicates killing rate (%).
Fig. 6 is the specific CTL of dual antineoplastic polypeptide induction of the present invention to the Eps8 positive, HLA-A*2402 is positive
The curve graph of hepatocellular carcinoma H22 Cytotoxicity in vitro ability, the abscissa in figure indicate effector cell (CTL) and target cell
(HepG2) ratio (effect target ratio), ordinate indicates killing rate (%).
Fig. 7 is that dual antineoplastic polypeptide of the present invention acts on 48h to the Eps8 positive, HLA-A*2402 positive tumor cells
The curve graph of proliferation inhibition rate, the abscissa in figure indicate that peptide concentration, ordinate indicate proliferation inhibition rate (%).
Fig. 8 is dual antineoplastic polypeptide of the present invention to the Eps8 positive, HLA-A*2402 positive tumor cells clone shape
At inhibiting rate bar chart, the abscissa in figure indicates that peptide concentration, ordinate indicate Clone formation inhibiting rate (%)."*”
Indicate P < 0.05 compared with corresponding solvent control group (0 μM)；In figure "**" indicate and corresponding solvent control group (0 μM) phase
Than P < 0.01；In figure "***" indicate P < 0.001 compared with corresponding solvent control group (0 μM).
Fig. 9 is CTL epitope peptide described in the patent application of Publication No. CN 103694333A to the Eps8 positive, HLA-A*
The curve graph of 0201 positive SW480 cell proliferation inhibition rate.
Specific embodiment
Embodiment 1 (screening of Eps8-EGFR binding domain polypeptide)
The antineoplastic polypeptide in Eps8-EGFR structural domain of the present invention source is the primary structure according to antigen, is used
Immunoinformatics means, with online biological software SYFPEITHI (http://www.syfpeithi.de/bin/
MHCServer.dll/EpitopePrediction.htm) (algorithm is recorded in Rammensee H, et
al.Immunogenetics 1999；50 (3-4): 213-219.) and BIMAS (http://www-bimas.cit.nih.gov/
Molbio/hla_bind/) (algorithm is recorded in Parker KC, et al.J Immunol 1994；152(1):163-175.)
To the HLA-A of Eps8 molecule EGFR binding domain*2402 restricted carry out forecast analysis, filtering out amino acid sequence is SEQ ID
Polypeptide shown in No:1, and it is denoted as Eps8-327.Polypeptide shown in SEQ ID No:1 by Zhongtai Bio-Chem. Co., Ltd., Hangzhou according to
Sequence provided by the present inventor is synthesized using the Fmoc solid phase method of peptide synthesis.It is synthesized using reverse-phase HPLC instrument
Target product carry out purifying and purity analysis, as the result is shown its purity > 95%, then identification and molecular weight are carried out using mass spectrography
Measurement, obtains mass spectrogram as shown in Figure 1.
Following embodiment 2-7 polypeptide Eps8-327 (SEQ ID No:1) obtained to this example respectively it is dual antitumor
Effect is verified.
Embodiment 2 [induction of external primed antigen presenting cells (APC)]
Use Dendritic Cells derived from peripheral blood mononuclear cells (DC) as the APC, (Nakahara with reference to described in other places
S, et al.Cancer Res 2003Jul 155,63 (14): 4112-8) DC is induced in vitro.Specifically, utilizing
Ficoll-Plaque density gradient method separating health volunteer (HLA-A*2402 is positive) mononuclearcell is separated in peripheral blood
(PBMCs), original DC is separated by adherent method, in PRMI-1640,1000U/ml granulocytes-macrophages containing 10%FBS
It is cultivated in colony stimulating factor (GM-CSF) and the culture solution of 1000U/ml IL-4 (IL-4).In culture the 7th day, containing 3 μ
It is small through the DC 3 of cytokine induction using each synthetic peptide (20 μ g/ml) impulse in the culture medium of g/ml β2-microglobulin
When.Cell generated expresses DC relevant molecule in cell surface, as (data are not shown II molecule of CD80, CD83, CD86 and HLA-
Show).
Embodiment 3 (induction of external CTL)
The above-mentioned DC through polypeptide impulse inactivates (30 μ g/ml, 30min) with mitomycin C (MMC), with 1:20 ratio and certainly
Body CD8+T cell (being obtained by CD8 positive separating kit by positive selection) mixes, in the culture medium of Yu Han IL-7 10ng/ml
Culture.3rd day, IL-2 to final concentration of 20U/ml is added in the medium.The 7th day and the 14th day, with it is through peptide impulse, go out
Self DC living further stimulates T cell.21st day collection cell detection CTL function (Olson BM, et al.Cancer
Immunol Immunother 2011；60(6):781-792；Andersen RS,et al.Cancer Immunol
Immunother 2011；60(2):227-234.).
Embodiment 4 (CTL secretion of gamma-IFN function)
Above-mentioned CTL activity is detected using IFN-γ-ELISPOT.Specifically, kit operating instruction is pressed, in 96 hole nitre
Acid cellulose Membrance cuiture plate preincubate captures antisera overnight, and next day counts and adjusts above-mentioned effector cell to 1 × 106/ ml, inoculation
In culture plate, every 100 μ l of hole is incubated for for 24 hours, board-washing, is incubated for primary antibody, secondary antibody respectively, and ELISPOT plate reader pair is finally used in colour developing
Spot is counted.Grouping includes: positive control group: effector cell+10 μ l PHA, 1~4 μ g/ml of final concentration；Experimental group: effect
Cell；Background negative control group: the Lympho-Spot serum free medium of 100 μ l.
As a result: as shown in Fig. 2, the T cell secretion of gamma-IFN digital display of Eps8-327 induction, which writes, to be increased compared with solvent control group
Add, P < 0.001.
Embodiment 5 (CTL killing tumor cell function)
Utilize the ability of lactic dehydrogenase (LDH) method for releasing detection CTL killing tumor cell.Specifically, according to CytoNon-Radioactive Cytotoxicity Assay kit operating instruction, is effector cell with above-mentioned CTL,
With each tumour cell (SW620, Colo320, A549 and HepG2) for target cell, detection specific T-cells kill tumour cell
Hurt ability.Experimental group, the spontaneous release group of effector cell, the spontaneous release group of target cell, target cell maximum release group, background pair are set
According to group and volume correction group.Effector cell and target cell are incubated for altogether, substrate colour developing 30min is added after reacting 4h, terminates reaction
Afterwards, absorbance (A) value of microplate reader measurement wavelength 490nm calculates CTL to the killing rate of tumour cell.Killing rate (%)=
[(the opposite A value of the opposite spontaneous release group of A value-effector cell of the opposite spontaneous release group of A value-target cell of experimental group)/(target
The opposite A value of the opposite spontaneous release group of A value-target cell of cell maximum release group)] × 100%.Wherein, experimental group, target cell
Spontaneous release group and the spontaneous release group of effector cell are individually subtracted medium controls A value and obtain its corresponding opposite A value；Target is thin
Born of the same parents' maximum release group subtracts fixing fabric structure group and obtains its corresponding opposite A value.
As a result: as shown in figures 3 to 6, compared with solvent control group, from the polypeptide of Eps8-EGFR binding domain
The specific T-cells of Eps8-327 induction significantly kill the Eps8 positive, HLA-A*2402 positive tumour cell SW620,
Colo320 (colon cancer), A549 (non-small cell lung cancer) and HepG2 (liver cancer)
Embodiment 6 [inhibits tumor cell proliferation (CCK-8 method)]
Logarithmic growth phase cells rinsed with PBS is resuspended in containing 10% fetal calf serum RPMI 1640 of volume fraction after counting
In culture medium to density be 5 × 104/ ml is inoculated in 96 orifice plates with 100 holes μ l/, is placed in incubator and stays overnight, changes after cell is adherent
4h Nature enemy is carried out at serum free medium, culture solution is abandoned, is washed twice with PBS, prepared respective concentration is then added
The polypeptide solution of (25,50,75,100,125,150,175 μM), 10 μ l CCK-8 solution, training is added in every hole after cultivating 48h respectively
It supports and continues to cultivate 3h in case.It is placed in microplate reader, reads absorbance value at 450nm wavelength.Experiment in triplicate, is all provided with 3 again
Hole is averaged as final result.
As a result: as shown in fig. 7, the polypeptide Eps8-327 for being originated from Eps8-EGFR binding domain significantly inhibits HLA-A*2402 Hes
The proliferation of colon cancer cell SW620, Colo320, HT-29 of the Eps8 positive.Half-inhibitory concentration of the Eps8-327 to SW620
(IC50) it is 26.79 μM (95%CI:17.34-41.38), to the IC of Colo320 cell50For 108.3 μM of (95%CI:101.8-
115.2), to the IC of HT-29 cell50For 149.3 μM (95%CI:129.7-171.9).
Embodiment 7 [inhibits tumor cell clone to form (plate clone experiment)]
Each tumour cell of logarithmic growth phase, the complete culture solution containing 10%FBS are resuspended, and candidate polypeptide is added to final concentration
For 100 μM, 200 μM, 6 orifice plates are inoculated in 500 cells/wells, set 37 DEG C, 5%CO2It is cultivated 7-14 days in incubator, forms meat
It is primary with PBS buffer solution rinsing cell after the visible clone of eye (more than 50 cells), exhaust residual liquid.4% poly is added
Formaldehyde room temperature fixes 20min, abandons fixer, and PBS buffer solution rinsing cell is primary, and 0.5% crystal violet dye liquor, room temperature dyeing is added
10-20min abandons dyeing liquor, dries after distilled water flushing, and calculating Cell colonies assay=(clone's number/inoculating cell number) ×
100%.
As a result: as shown in figure 8, be originated from Eps8-EGFR binding domain polypeptide Eps8-327 inhibit tumour cell HT-29,
SW620, Colo320 and HepG2 Clone formation.
Embodiment 8 (comparative experiments)
This example uses CCK-8 method four CTL epitope peptides described in the patent application of Publication No. CN 103694333A
EPS8-101, EPS8-276, EPS8-360 and EPS8-455 inhibit the ability of tumor cell proliferation to be verified, and specific steps are such as
Under: logarithmic growth phase SW480 cells rinsed with PBS is resuspended in containing 10% fetal calf serum RPMI 640 of volume fraction after counting
In culture medium to density be 5 × 104/ ml is inoculated in 96 orifice plates with 100 holes μ l/, is placed in incubator and stays overnight, changes after cell is adherent
4h Nature enemy is carried out at serum free medium, culture solution is abandoned, is washed twice with PBS, prepared respective concentration is then added
Polypeptide solution, 10 μ l CCK-8 solution are added in every hole after cultivating 48h respectively, continue to cultivate 3h in incubator.It is placed in microplate reader,
Read absorbance value at 450nm wavelength.Experiment in triplicate, is all provided with 3 multiple holes, is averaged as final result.
As a result: as shown in figure 9, four CTL epitope peptides EPS8-101, EPS8-276, EPS8-360 and EPS8-455 are in 0-
100 μM of concentration ranges do not have inhibiting effect to SW480 cell Proliferation, only show to inhibit to make in 150-200 μM of section of high concentration
With, but its inhibiting rate is still below 50%.By Fig. 9 compared with Fig. 7 as it can be seen that four CTL epitope peptide EPS8-101, EPS8-276,
EPS8-360 and EPS8-455 inhibits the ability of SW480 cell Proliferation to be markedly less than polypeptide Eps8-327 (SEQ of the present invention
ID No:1).
In short, the present invention identifies the novel polypeptide from Eps8-EGFR binding domain, on the one hand these polypeptides can induce
On the other hand CTL killing tumor cell can significantly inhibit tumor proliferation, Clone formation, have dual anti-tumor effect, be applicable in
In tumour immunotherapy and cancer target therapy.
Above-described embodiment 2-8 explanation, polypeptide polypeptide Eps8-327 of the present invention (SEQ ID No:1) of the present invention with
Four CTL epitope peptides EPS8-101, EPS8-276, EPS8-360 described in the patent application of Publication No. CN 103694333A
Have following differences with the function of EPS8-455 and effect: 1, polypeptide of the present invention is HLA-A*2402 restricted polypeptides are fitted
For HLA-A*2402 Positive Populations；Four CTL epitope peptides described in the patent application of Publication No. CN 103694333A are
HLA-A*0201 restricted polypeptide is suitable for HLA-A*0201 Positive Populations；2, polypeptide of the present invention is in addition to activating antitumor exempt from
Epidemic disease reaction is outer, also has the function of directly inhibiting the biological activities such as tumor cell proliferation, Clone formation, and Publication No. CN
Four CTL epitope peptides described in the patent application of 103694333A are only capable of activation anti tumor immune response.
Claims (3)
1. a kind of dual antineoplastic polypeptide based on Eps8-EGFR binding domain, the amino acid sequence of the polypeptide is Glu-Phe-
Leu-Asp-Cys-Phe-Gln-Lys-Phe (SEQ ID No:1).
2. a kind of dual antineoplastic polypeptide based on Eps8-EGFR binding domain according to claim 1, which is characterized in that
The dual antineoplastic polypeptide is synthesized using solid-phase synthesis.
3. polypeptide described in claim 1 promotes anti-tumor immune response in preparation and inhibits cellular biology of tumor active double
Application in weight anti-tumor drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005116051A3 (en) * | 2004-05-25 | 2006-03-02 | Immatics Biotechnologies Gmbh | Tumor-associated peptides that bind to mhc-molecules |
| CN1883709A (en) * | 2005-06-21 | 2006-12-27 | 南京大学 | Bi-functional targeting antineoplastic polypeptide and application thereof |
| CN103992382A (en) * | 2014-05-14 | 2014-08-20 | 南方医科大学 | Oligopeptide formed by combining targeted EPS8 (Epidermal Growth Factor Receptor pathway substrate No.8) with EGFR (Epidermal Growth Factor Receptor) and application of oligopeptide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005116051A3 (en) * | 2004-05-25 | 2006-03-02 | Immatics Biotechnologies Gmbh | Tumor-associated peptides that bind to mhc-molecules |
| CN1883709A (en) * | 2005-06-21 | 2006-12-27 | 南京大学 | Bi-functional targeting antineoplastic polypeptide and application thereof |
| CN103992382A (en) * | 2014-05-14 | 2014-08-20 | 南方医科大学 | Oligopeptide formed by combining targeted EPS8 (Epidermal Growth Factor Receptor pathway substrate No.8) with EGFR (Epidermal Growth Factor Receptor) and application of oligopeptide |
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