CN108218961A - A kind of Antigenic Peptide chain group for treating tumour and its application in drug - Google Patents
A kind of Antigenic Peptide chain group for treating tumour and its application in drug Download PDFInfo
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- CN108218961A CN108218961A CN201810224090.0A CN201810224090A CN108218961A CN 108218961 A CN108218961 A CN 108218961A CN 201810224090 A CN201810224090 A CN 201810224090A CN 108218961 A CN108218961 A CN 108218961A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a kind of Antigenic Peptide chain group for the treatment of tumour individuation biological immune and its application in drug, the Antigenic Peptide chain group of the treatment tumour includes SEQ ID No:The combination of any one or at least two amino acid sequences in 1 57.The Antigenic Peptide chain group of the present invention can induce the blastomogenic Dendritic Cells of production, antigenic information thus can be presented to T cell as the Dendritic Cells of antigen presenting cell, so as to interact with T cell, T cell is made to generate specific killing tumour cell, plays the role of killing tumor cell.
Description
Technical field
It is more particularly to a kind of for tumour individuation biology the invention belongs to malignant tumour biological immune technical field of pharmaceuticals
The Antigenic Peptide chain group of immunization therapy and its application in drug.
Background technology
At present, global Cancer Mortality rises increasingly, and the death rate is high, poor prognosis.National Cancer Center whole nation tumour
Study on prevention office exists《International journal of cancer》Largest In China scale cancer Survival data Macro or mass analysis data are issued to show, in
5 years survival rates of state's cancer are 30.9%, far below developed country's level;The survival rate of rural patient is only City patient's simultaneously
Half.In developed country, prostate cancer, breast cancer occupy the majority, and in China, the cancers such as lung cancer, gastric cancer, liver cancer are more common, hair
Sick rate and the highest cancer of the death rate are lung cancer.The traditional therapies therapeutic effect such as operation, chemotherapy, radiotherapy is limited, patient 5 years
Survival rate is still relatively low;Especially eliminating side effect of radiotherapy and chemotherapy to is big, and patients ' life quality is poor, and survival rate is low.
Biological immune treatment is the new treatment side of future therapeutic tumour by body immune system killing tumor cell
Method has been increasingly becoming the hot spot for the treatment of tumour.The method of the tumour of biological immune treatment at present is more, thin including common CIK
Born of the same parents' immunization therapy, DC medications treatment etc., but its therapeutic effect is not notable, and survival is not improved significantly.Separately have
With the immunocyte medication that not mutated tumour high-expression albumen stimulates, research has anti tumor immune response, but since its is non-specific
Property expression, no doubt with the presence of side reaction, including eye-blurred, Hearing, fash etc..
The essence of biological immune treatment is mainly by body immune system come killing tumor cell, is made wherein directly playing
It is killer T cell, and Dendritic Cells (DCs) is antigen presenting cell (APCs), major function is by antigenic information
Offer to T cell.It is believed that certain autoimmune responses are since microenvironment tissue damage causes local DC to activate, then
It interacts with T cell, so as to cause immune response.Therefore, the ability of DCs initiations t cell response can be used for tumour medication
In.The related high protein induced generation DCs of expression of some tumours of external use, and defeated time patient's body, it is relatively special to be used as tumour
Induced t cell in APCs.Animal model has confirmed that DC tumour medications reverse the anergy of T cell and cause to connect
The anti-tumor effect got off.However, the related height of tumour expresses the DCs of protein induced generation and without stringent specificity, swell
Histocyte other than knurl also expresses same albumen, and therefore, side reaction is a problem.
Tumour is the unlimited hyperplasia of cell as a result, and the growth of cell is by gene-determined.There are tumours in human body
Gene and the different gene group of two big function of tumor suppressor gene.Tumour is due to the up-regulation of oncogene function, tumour
The suppressed result of suppressor function.Various extraneous factors are by gene such as radioactive ray, carcinogenic chemicals, virus etc.
Change and carry out induced tumors, the change of gene includes the various DNA damages such as base mutation, base crosslinking, DNA break, DNA missings
Wound.Gene therapy is the biomedical treatment based on the inhereditary material for changing people, is by the normal gene of people or has treatment
The gene of effect imports human body target cell by certain way, directly against the root of disease --- and abnormal gene is sent out in itself
Therapeutic effect is waved, so as to achieve the purpose that treat disease;Gene therapy product enters generates target protein or more again after cell
Peptide, so as to play special biological therapy effect.Clinical experiments have proved that the effect of gene therapy, is higher than simple Radiotherapy chemotherapy curative effect
Go out several times;When treating non-small cell carcinoma, 60% patient tumors subside completely or partial remission;The effect of to breast cancer is even more height
Up to 90%.
Invention content
The object of the present invention is to provide a kind of Antigenic Peptide chain group for the treatment of tumour individuation biological immune and its in medicine
Application in object, Antigenic Peptide chain group of the invention can induce the blastomogenic Dendritic Cells of production, thus as antigen presenting cell
Dendritic Cells antigenic information can be presented to T cell, so as to T cell interact, make T cell generate specific killing
Tumour cell plays the role of killing tumor cell.
For this purpose, technical solution of the present invention is as follows:
In a first aspect, the present invention provides a kind of Antigenic Peptide chain group for treating tumour, the Antigenic Peptide chain group of the treatment tumour
Including SEQ ID No:The combination of any one or at least two amino acid sequences in 1-57, such as can be SEQ ID No:
Any one in 1-57, it is two arbitrary, three arbitrary, four arbitrary, it is arbitrary five until arbitrary 56 or all 57
Combination, since the limitation of length is no longer all enumerated herein.
Particular sequence is as follows:
SEQ ID No:1 --- QLMPFGS, SEQ ID No:2 --- LMPFGSL,
SEQ ID No:3 --- MPFGSLL, SEQ ID No:4 --- PFGSLLD,
SEQ ID No:5 --- FGSLLDY, SEQ ID No:6 --- GSLLDYV,
SEQ ID No:7 --- SLLDYVR, SEQ ID No:8 --- VQLMPFGS,
SEQ ID No:9 --- QLMPFGSL, SEQ ID No:10 --- LMPFGSLL,
SEQ ID No:11 --- MPFGSLLD, SEQ ID No:12 --- PFGSLLDY,
SEQ ID No:13 --- FGSLLDYV, SEQ ID No:14 --- GSLLDYVR,
SEQ ID No:15 --- SLLDYVRE, SEQ ID No:16 --- TVQLMPFGS,
SEQ ID No:17 --- VQLMPFGSL, SEQ ID No:18 --- QLMPFGSLL,
SEQ ID No:19 --- LMPFGSLLD, SEQ ID No:20 --- MPFGSLLDY,
SEQ ID No:21 --- PFGSLLDYV, SEQ ID No:22 --- FGSLLDYVR,
SEQ ID No:23 --- GSLLDYVRE, SEQ ID No:24 --- SLLDYVREH,
SEQ ID No:25 --- STVQLMPFGS, SEQ ID No:26 --- TVQLMPFGSL,
SEQ ID No:27 --- VQLMPFGSLL, SEQ ID No:28 --- QLMPFGSLLD,
SEQ ID No:29 --- LMPFGSLLDY, SEQ ID No:30 --- MPFGSLLDYV,
SEQ ID No:31 --- PFGSLLDYVR, SEQ ID No:32 --- FGSLLDYVRE,
SEQ ID No:33 --- GSLLDYVREH, SEQ ID No:34 --- SLLDYVREHK,
SEQ ID No:35 --- TSTVQLMPFGS, SEQ ID No:36 --- STVQLMPFGSL,
SEQ ID No:37 --- TVQLMPFGSLL, SEQ ID No:38 --- VQLMPFGSLLD,
SEQ ID No:39 --- QLMPFGSLLDY, SEQ ID No:40 --- LMPFGSLLDYV,
SEQ ID No:41 --- MPFGSLLDYVR, SEQ ID No:42 --- PFGSLLDYVRE,
SEQ ID No:43 --- FGSLLDYVREH, SEQ ID No:44 --- GSLLDYVREHK,
SEQ ID No:45 --- SLLDYVREHKD, SEQ ID No:46 --- LTSTVQLMPFGS,
SEQ ID No:47 --- TSTVQLMPFGSL, SEQ ID No:48 --- STVQLMPFGSLL,
SEQ ID No:49 --- TVQLMPFGSLLD, SEQ ID No:50——VQLMPFGSLLDY,
SEQ ID No:51——QLMPFGSLLDYV,SEQ ID No:52——LMPFGSLLDYVR,
SEQ ID No:53——MPFGSLLDYVRE,SEQ ID No:54——PFGSLLDYVREH,
SEQ ID No:55——FGSLLDYVREHK,SEQ ID No:56——GSLLDYVREHKD,
SEQ ID No:57——SLLDYVREHKDN.
Second aspect, the present invention provide a kind of pharmaceutical composition, and described pharmaceutical composition is included as described in relation to the first aspect
SEQ ID No:Any one in 1-57 or at least two amino acid sequences.
Preferably, described pharmaceutical composition is aqueous suspension, solution or solid state.
Preferably, the solid state is uncoated or coated tablet form, such as pill, gel capsule, capsule or powder
End etc..
If described pharmaceutical composition is in drying regime, it can for example form sediment with one or more inert diluents
The mixing such as powder, cellulose, sucrose, lactose or silica.It can also include other substances in the dry state, such as a kind of
Or a variety of lubricants such as magnesium stearate or talcum powder, colorant, coating (sugar coated tablet) or varnish.If the drug of the present invention
Composition is liquid form, then it can include containing inert diluent such as water, ethyl alcohol, glycerine, vegetable oil or atoleine
Pharmaceutical solution, suspension, emulsion, syrup and elixir.Described pharmaceutical composition can also be included in addition to diluent
Other liquid substances, such as wetting agent, sweetener, thickener, flavoring agent or stabilizer product.
Preferably, the auxiliary material pharmaceutically received is further included.
Preferably, the auxiliary material is any one in excipient, diluent, carrier, flavoring agent, adhesive and filler
Or at least two combination, such as can be excipient, carrier and diluent, flavoring agent, adhesive and filler or dilution
Agent, the combination of carrier, flavoring agent, adhesive and filler, due to the limitation of length, the form of all combinations no longer arranges one by one
It lifts.
The third aspect, the Antigenic Peptide chain group that the present invention provides treatment tumour as described in relation to the first aspect are preparing treating cancer
Pharmaceutical composition in application.The cancer is the cancer (i.e. entity malignant tumour) of any kind, because the present invention
Antigenic Peptide chain group can induce the Dendritic Cells for generating tumour-specific, thus as the Dendritic Cells energy of antigen presenting cell
Antigenic information is presented to T cell, so as to interact with T cell, T cell is made to generate specific killing tumour cell, so as to
Play the role of killing tumor cell.
In the present invention, the cancer is preferably lung cancer, breast cancer, oophoroma, prostate cancer, melanoma, brain tumor, food
Pipe cancer, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer, kidney, cutaneum carcinoma, spongioblastoma, neuroblastoma, sarcoma,
Embryonal-cell lipoma, osteochondroma, osteoma, osteosarcoma, seminoma, orchioncus, uterine cancer, H/N tumors, multiple marrow
Knurl, malignant lymphoma, polycythemia vera, leukaemia, thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer,
In cholangiocarcinoma, chorioepithelioma or pediatric tumors any one or at least two combination.In addition, described pharmaceutical composition
It can also be with another or at least two anti-cancer agent in conjunction applications, such as arimedex (Letrozole and/or Anastrozole)
Deng.
Described pharmaceutical composition may be utilized independently or is used in combination in given treatment with other drugs or with putting
Penetrate therapy or operation joint.Specifically used method is:
(1) internal stimulus method:
The Antigenic Peptide chain group of the treatment tumour is dissolved in pH value as in 7.4PBS (Hyclone) solution, concentration is adjusted to
Covering 5%Aldara cream (iNova Pharmaceuticals after 200ug are subcutaneously injected in 2.5mg/ml, each upper arm
Australia Pty Ltd.), once a week, 12 weeks are a cycle.
(2) stimulated in vitro method:
(1) the 0th day
Monocyte separation is carried out using COBE Spectra blood analysis systems (Caridian BCT, Inc.) to acquire
Hemofiltration amount 2500-3500ml;Prepare the sterile samples of 2ml, 1ml is divided to carry out cell count, and carry out Activity determination (streaming/7-
ADD);Calculate the volume of separation DC cell samples:Total karyocyte 7 × 109/ calculating concentration;Cell is transferred to the transfer of 300ml
In bag, it is transferred to GMP laboratories;Prepare 1L DC-CM culture solutions, 500ml × 2 part;With the syringe holder sample of 60ml from transfer
Bag removes, and is divided in the centrifuge tube of 4 200ml;Often pipe adds in 100-150ml HBSS, closes lid, and gently mixing;Drop
Speed centrifugation, 15min, 800rpm (137Xg), room temperature;With the sterile pipette tips transfer supernatants of 2ml, cell is resuspended in 100-150ml
HBSS, capping, mixing;Low-speed centrifugal 10min, 1000rpm (214Xg), room temperature;With the sterile pipette tips transfer supernatants of 2ml, it is resuspended
Cell is in 30ml DC-CM culture solutions;Cell is transferred to from 4 centrifuge tubes in 500ml centrifuge tubes, and with 10ml DC-CM
Former centrifuge tube is rinsed, and is transferred to 500ml centrifuge tubes, is covered, mixing;0.5ml is shifted to 12 × 75mm tubules with 3ml syringes
It is interior, it is counted;Calculate the culture bottle number needed:TNC/1.75×108=culture bottle the number needed;Calculate the volume of DC-CM
Requirement:(it is added to the volume 1.75 × 10 of diluting cells7/ml):What the quantity that culture bottle needs × 10ml DC-CM=needed
DC-CM volumes;With 25ml suction pipes, add 15ml DC-CM to each culture bottle;With 10ml or 25ml suction pipes, 10ml is added to be resuspended
Sample (1.75 × 107/ ml) to each culture bottle, it is tamping with lid;Culture bottle is shaken up, liquid is made to be paved with entire bottom of bottle;
Culture bottle be put into incubator (37 DEG C, 5%CO2;± 10 DEG C, ± 0.5%CO2), 2 hours 30min ±, make cell adherent;
IMDM be put into incubator (37 DEG C, 5%CO2;± 10 DEG C, ± 0.5%CO2), rinse culture bottle 2 times with 35ml IMDM;It needs
IMDM volumes=culture bottle quantity × 70ml IMDM;It rinses after culture bottle, adds the DC-CM of 50ml cell factors:It needs
IMDM=culture bottles quantity × 50ml;The concentration for adding in IL-4 and GM-CSF is all 1000IU/ml;IL-4 is diluted, uses 1%HAS
To 1000IU/ml inside PBS;5-10 culture bottle is operated every time to reduce the time being exposed in air;Culture bottle from
It is taken out in incubator, jiggles culture bottle;Blow adherent cell off with 2ml suction pipes;35ml temperature IMDM to each culture bottle,
Pay attention to:Add from the acellular side of bottle wall.A loose lower bottle cap, gently precious jade culture bottle, makes still adherent cell get off.Gently precious jade
Culture bottle avoids cell from being attached on wall.It is laid flat culture bottle.With 2ml suction pipes, IMDM is shifted, pays attention to tilting culture bottle.Use 35ml
IMDM is rinsed once again.Add the DC-CM that 50ml contains cell factor to each culture bottle, capping.Culture bottle is gently laid flat, is made
Liquid covers bottom of bottle.Culture bottle be put into incubator (37 DEG C, 5%CO2;± 10 DEG C, ± 0.5%CO2)。
(2) the 6th days:The ripe mixed liquor of addition
With 1%HSA-PBS dilutions IL-1 β, INF- α, IL-6 to 25ug/ml;If culture bottle quantity is less than 50,50 are prepared
The cell factor of a culture bottle;Final concentration:IL-1β10ng/ml、INF-α10ng/ml、IL-615ng/ml.The diluting cells factor
In 44mlDC-CM, until last volume 50ml.1ml, which is inhaled, with aseptic straw contains the DC-CM of cell factor to each culture bottle.
Liquid in mixing culture bottle (after adding in cell factor).Culture bottle be put into incubator (37 DEG C, 5%CO2;± 10 DEG C, ±
0.5%CO2)。
(3) the 7-8 days:Prepare peptide chain pulse culture solution (PPM)
Calculate the amount of the PPM needed:The amount for the PPM that culture bottle quantity X30ml+300ml=needs;By culture bottle from culture
Case takes out, and bottle inner cell is transferred to 500ml sterile centrifugation tubes.It (pours into 25ml suction pipes or directly, 3 culture bottles are transferred to one
A 500ml centrifuge tubes).It is counted with suction pipe suction 1ml to 12 × 75mm pipes, and carries out mycoplasma, Chlamydia detection.Reduction of speed from
Heart 1200rpm (309Xg), 7min, room temperature (if multiple pipes, centrifuge) simultaneously.Culture bottle is rinsed, and flushing with 30ml PPM
Liquid is transferred to 500ml centrifuge tubes.Reduction of speed centrifugal elutriation liquid, 1200rpm (309Xg), 7min, room temperature.Flushing liquor is removed with 2ml suction pipes
With the supernatant of harvest pipe, cell is resuspended with 10ml PPM.Transfer harvests pipe DC cells to a new 200ml centrifuge tube.Turn
Flush pipe DC cells are moved to a new 200ml centrifuge tube.Reduction of speed centrifuges, 1200rpm (309Xg), 7min, room temperature;It is inhaled with 2ml
Pipe shifts all supernatants, and cell is resuspended with 25ml PPM, and the harvest pipe DC cells of harvest and flush pipe DC cells are merged
Enter same pipe, indicate:DC cell pipes.Capping centrifuges simultaneously mixing.One group of individuation specific mutations peptide chain that 1 pipe freezes is taken out,
Peptide chain is dissolved with DC-PPM.Add peptide chain to DC pipes, a concentration of 5ug/ml.Pine lid after be put into incubator (37 DEG C, 5%CO2;±10
DEG C, ± 0.5%CO2), incubator, mixing, 1.5 hours total times are taken out per 30min.The DC cells that 0.2ml is taken to be resuspended, transfer
Into 12 × 75mm pipes, endotoxin check and evaluation is carried out.Reduction of speed centrifuges, 1200rpm (309Xg), 7min, room temperature.With 2ml suction pipes
Remove supernatant.Individuation specificity DC cells are harvested, counts and is dissolved in 1ml PBS solutions.Tumor-draining lymphode or
It is injected in other.
Compared with prior art, provided by the present invention for the Antigenic Peptide chain group of tumour individuation biological immune treatment at least
It has the advantages that:
The present invention provides a kind of Antigenic Peptide chain group for treating tumour and its application in drug, the treatment tumour
Antigenic Peptide chain group includes SEQ ID No:The combination of any one or at least two amino acid sequences in 1-57.The present invention's is anti-
Former peptide chain group can induce the blastomogenic Dendritic Cells of production, thus the Dendritic Cells as antigen presenting cell can believe antigen
Breath is presented to T cell, so as to interact with T cell, T cell is made to generate specific killing tumour cell, plays killing tumour
The effect of cell.After medication at least 6 weeks, it can significantly observe that tumour largely disappears by instrument, density is thin out, and variation is apparent;
Incidence of side effects is small, less to the injury of patient.
Description of the drawings
Fig. 1 is HLA*A3101-HVKITDFGR Tetramer colored graphs before and after 1 medication of embodiment;
For embodiment 1, the lung tumors before and after medication change CT figures to Fig. 2;
For embodiment 2, the lung tumors before and after medication change CT figures to Fig. 3.
Specific embodiment
Below in conjunction with the accompanying drawings and specific embodiment the present invention is described further, but following embodiments are absolutely not to this hair
It is bright to have any restrictions.
Embodiment 1
Patient A, man, 63 years old.Adenocarcinoma of lung, clinical IV phases are in progress after vinorelbine plus cisplatin chemotherapy 5 times, and intrapulmonary is multiple
Transfer.Pulmonary lesions tissue biopsy is taken, carries out 488 tumor development related gene Panel and HLA typing chip detections
Afterwards, patient carries EGFR C797S mutation, and HLA partings are HLA-A:A*1002A*3102;HLA-B:B*3101B*4013;HLA-
C:C*0303C*0801;HLA-DQB1:DQB1*0402DQB1*0101;HLA-DRB1:DRB1*0405DRB1*1301.
Treatment (hereinafter referred to as " medication ") is combined using the Antigenic Peptide chain group of the treatment tumour of the present invention, 1 times a week, altogether
10 weeks.Before Flow detection medications, after 3 weeks, specific IFN-γ secretion after 10 weeks, and same time point imaging observation tumour
Size variation (see figure one and figure two).The peptide chain of specific choice is as follows:
A) MPFGSLL, b) LMPFGSLL, c) FGSLLDYV, d) TVQLMPFGS, e) PFGSLLDYV, f) VQLMPFGSLL,
G) GSLLDYVREH, h) VQLMPFGSLLD, i) FGSLLDYVREH, j) VQLMPFGSLLDY, k) GSLLDYVREHKD.
As shown in Figure 1, HLA*A3101-HVKITDFGR Tetramer colored graphs, wherein, Fig. 1-A is dye before medication
Figure, CD8+Tetramer+T a concentration of 2.76%;Fig. 1-B are 3 weeks after stain chromatic graphs of medication, and CD8+Tetramer+T is a concentration of
3.52%;Fig. 1-C be 6 weeks after stain chromatic graphs of medication, CD8+Tetramer+T a concentration of 4.8%;As can be seen that spot from three group pictures
The variation tendency that point quantity is increased significantly, illustrates that the ratio (concentration) of tumor-killing cell CD8+Tetramer+T in blood is bright
It is aobvious to improve.
Fig. 2 is lung tumors size variation situation before and after medication, as shown in Figure 2, before medication treatment (Fig. 2-A), left hilus pulumonis
Tumor size is 4cm × 5cm.After medication is treated 10 weeks (Fig. 2-B), left hilus pulumonis tumour disappears substantially, and front and rear variation is apparent.Explanation
The Antigenic Peptide chain group of the present invention can induce the blastomogenic Dendritic Cells of production, and the Dendritic Cells as antigen presenting cell can incite somebody to action
Antigenic information is presented to T cell, interacts with T cell, and T cell is made to generate specific killing tumour cell, and it is swollen to play killing
The effect of oncocyte, and it is with obvious effects.
Embodiment 2
Patient B, female, 51 years old, left adenocarcinoma of lung after 5 periods of chemotherapy, was in progress after taking orally molecular targeted medicine Gefitinib.Row
Lung neoplasm aspiration biopsy after carrying out 488 tumor development related gene Panel and HLA typing chip detections, is as a result shown
Patient, which carries, carries EGFR C797S mutation.HLA partings are HLA-A:A*0302A*3305;HLA-B:B*1801B*
4002;HLA-C:C*0301C*0401:;HLA-DQB1:DQB1*0102DQB1*0203;HLA-DRB1:DRB1*0301DRB1*
1004。
Treatment is combined using the Antigenic Peptide chain group of the treatment tumour of the present invention, 1 times a week, totally 12 weeks.Specific choice
Peptide chain it is as follows:
A) PFGSLLD, b) LMPFGSLL, c) GSLLDYVR, d) QLMPFGSLL, e) GSLLDYVRE, f) TVQLMPFGSL,
G) FGSLLDYVRE, h) VQLMPFGSLLD, i) LTSTVQLMPFGS, j) GSLLDYVREHKD.
Pretherapy and post-treatment lung tumors size variation situation is as shown in figure 3, as seen from Figure 3, before medication treatment, left lung neoplasm is big
Small 2 × 3cm (Fig. 3-A);6 weeks after medication treatment, left lung neoplasm disappears substantially, and left lung function restores (Fig. 3-B), considers at this time special
Specific T cell enters caused by tumour;This example demonstrates that the Antigenic Peptide chain group of the present invention can induce the blastomogenic dendron shape of production
Antigenic information can be presented to T cell by cell, the Dendritic Cells as antigen presenting cell, interacted with T cell, made T
Cell generates specific killing tumour cell, plays the role of killing tumor cell, and with obvious effects.
Embodiment 3-60
Embodiment 3-60 takes variety classes, and different degrees of cancer patient carries out 488 tumor development related genes
After the detection of Panel and HLA typing chips, all patients carry EGFR p.C797S mutation, respectively using different Antigenic Peptides
The combining form of chain group is treated, once a week, totally 12 weeks.HLA*A3101-HVKITDFGR of embodiment 3-60
Tetramer coloration results and pretherapy and post-treatment lung tumors size variation situation are similar with embodiment 1-2, due to the limitation of length,
It is no longer repeated herein.It is thin that the Antigenic Peptide chain group of the explainable present invention of result above can induce the blastomogenic dendron shape of production
Antigenic information can be presented to T cell by born of the same parents, the Dendritic Cells as antigen presenting cell, interacted with T cell, made T thin
Born of the same parents generate specific killing tumour cell, play the role of killing tumor cell, and with obvious effects.
During being treated to embodiment 1-60, with before ELISA detections antigen peptide chain, medication 3 weeks, 7 weeks, 11 weeks
Specific IFN-γ secretion situation, concrete outcome are as shown in table 1.
Comparative example 1-10
Variety classes, different degrees of cancer patient are taken, carries out 488 tumor development related genes Panel and HLA
After typing chip detection, all patients carry EGFR p.C797S mutation, during being treated to comparative example 1-10, use
Before ELISA detection medications, medication 3 weeks, 7 weeks, the specific IFN-γ secretion situation of 12 weeks, concrete outcome is as shown in table 1, medication
Amount is identical with embodiment 1-60;Wherein, comparative example 1-5 is added without peptide chain.
As it can be seen from table 1 embodiment 1-60,12 weeks after medication, the specific IFN-γ level of T cell secretion has
Significantly raised trend, illustrate to have used any one in the Antigenic Peptide chain group of the present invention or its arbitrarily combine and can increase cancer
The tumor-killing ability of disease peripheral blood in patients further demonstrates the effect of the present invention.And in comparative example 1-10, IFN-γ is horizontal
Change less before and after medication, illustrate that it does not increase the tumor-killing ability of peripheral blood in patients.
Table 1IFN- γ secretion statistics lists
Then, the rate of side effects of embodiment 1-60 is counted, the results are shown in Table 2, can from table 2
Go out, used the present invention Antigenic Peptide chain group after, the incidence (i.e. positive rate) of side reaction is relatively low, illustrate its side effect compared with
Small, the influence and injury to patient are relatively low.
2 rate of side effects statistical result of table
It should be noted that and understand, the feelings of the spirit and scope of the present invention required by appended claims are not departed from
Under condition, various modifications and improvements can be made to the present invention of foregoing detailed description.It is therefore desirable to the model of the technical solution of protection
It encloses and is not limited by given any specific exemplary teachings.
Applicant states, made for the present invention further specifically the above content is specific preferred embodiment is combined
It is bright, it is impossible to assert that the specific implementation of the present invention is confined to these explanations.For the ordinary skill of the technical field of the invention
For personnel, without departing from the inventive concept of the premise, several simple deduction or replace can also be made, should all be considered as category
In protection scope of the present invention.
Sequence table
<110>Tianjin Heng Jia biotechnologies Development Co., Ltd
<120>A kind of Antigenic Peptide chain group for treating tumour and its application in drug
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<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 6
Gly Ser Leu Leu Asp Tyr Val
1 5
<210> 7
<211> 7
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 7
Ser Leu Leu Asp Tyr Val Arg
1 5
<210> 8
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 8
Val Gln Leu Met Pro Phe Gly Ser
1 5
<210> 9
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 9
Gln Leu Met Pro Phe Gly Ser Leu
1 5
<210> 10
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 10
Leu Met Pro Phe Gly Ser Leu Leu
1 5
<210> 11
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 11
Met Pro Phe Gly Ser Leu Leu Asp
1 5
<210> 12
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 12
Pro Phe Gly Ser Leu Leu Asp Tyr
1 5
<210> 13
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 13
Phe Gly Ser Leu Leu Asp Tyr Val
1 5
<210> 14
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 14
Gly Ser Leu Leu Asp Tyr Val Arg
1 5
<210> 15
<211> 8
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 15
Ser Leu Leu Asp Tyr Val Arg Glu
1 5
<210> 16
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 16
Thr Val Gln Leu Met Pro Phe Gly Ser
1 5
<210> 17
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 17
Val Gln Leu Met Pro Phe Gly Ser Leu
1 5
<210> 18
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 18
Gln Leu Met Pro Phe Gly Ser Leu Leu
1 5
<210> 19
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 19
Leu Met Pro Phe Gly Ser Leu Leu Asp
1 5
<210> 20
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 20
Met Pro Phe Gly Ser Leu Leu Asp Tyr
1 5
<210> 21
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 21
Pro Phe Gly Ser Leu Leu Asp Tyr Val
1 5
<210> 22
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 22
Phe Gly Ser Leu Leu Asp Tyr Val Arg
1 5
<210> 23
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 23
Gly Ser Leu Leu Asp Tyr Val Arg Glu
1 5
<210> 24
<211> 9
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 24
Ser Leu Leu Asp Tyr Val Arg Glu His
1 5
<210> 25
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 25
Ser Thr Val Gln Leu Met Pro Phe Gly Ser
1 5 10
<210> 26
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 26
Thr Val Gln Leu Met Pro Phe Gly Ser Leu
1 5 10
<210> 27
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 27
Val Gln Leu Met Pro Phe Gly Ser Leu Leu
1 5 10
<210> 28
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 28
Gln Leu Met Pro Phe Gly Ser Leu Leu Asp
1 5 10
<210> 29
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 29
Leu Met Pro Phe Gly Ser Leu Leu Asp Tyr
1 5 10
<210> 30
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 30
Met Pro Phe Gly Ser Leu Leu Asp Tyr Val
1 5 10
<210> 31
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 31
Pro Phe Gly Ser Leu Leu Asp Tyr Val Arg
1 5 10
<210> 32
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 32
Phe Gly Ser Leu Leu Asp Tyr Val Arg Glu
1 5 10
<210> 33
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 33
Gly Ser Leu Leu Asp Tyr Val Arg Glu His
1 5 10
<210> 34
<211> 10
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 34
Ser Leu Leu Asp Tyr Val Arg Glu His Lys
1 5 10
<210> 35
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 35
Thr Ser Thr Val Gln Leu Met Pro Phe Gly Ser
1 5 10
<210> 36
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 36
Ser Thr Val Gln Leu Met Pro Phe Gly Ser Leu
1 5 10
<210> 37
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 37
Thr Val Gln Leu Met Pro Phe Gly Ser Leu Leu
1 5 10
<210> 38
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 38
Val Gln Leu Met Pro Phe Gly Ser Leu Leu Asp
1 5 10
<210> 39
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 39
Gln Leu Met Pro Phe Gly Ser Leu Leu Asp Tyr
1 5 10
<210> 40
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 40
Leu Met Pro Phe Gly Ser Leu Leu Asp Tyr Val
1 5 10
<210> 41
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 41
Met Pro Phe Gly Ser Leu Leu Asp Tyr Val Arg
1 5 10
<210> 42
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 42
Pro Phe Gly Ser Leu Leu Asp Tyr Val Arg Glu
1 5 10
<210> 43
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 43
Phe Gly Ser Leu Leu Asp Tyr Val Arg Glu His
1 5 10
<210> 44
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 44
Gly Ser Leu Leu Asp Tyr Val Arg Glu His Lys
1 5 10
<210> 45
<211> 11
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 45
Ser Leu Leu Asp Tyr Val Arg Glu His Lys Asp
1 5 10
<210> 46
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 46
Leu Thr Ser Thr Val Gln Leu Met Pro Phe Gly Ser
1 5 10
<210> 47
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 47
Thr Ser Thr Val Gln Leu Met Pro Phe Gly Ser Leu
1 5 10
<210> 48
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 48
Ser Thr Val Gln Leu Met Pro Phe Gly Ser Leu Leu
1 5 10
<210> 49
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 49
Thr Val Gln Leu Met Pro Phe Gly Ser Leu Leu Asp
1 5 10
<210> 50
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 50
Val Gln Leu Met Pro Phe Gly Ser Leu Leu Asp Tyr
1 5 10
<210> 51
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 51
Gln Leu Met Pro Phe Gly Ser Leu Leu Asp Tyr Val
1 5 10
<210> 52
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 52
Leu Met Pro Phe Gly Ser Leu Leu Asp Tyr Val Arg
1 5 10
<210> 53
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 53
Met Pro Phe Gly Ser Leu Leu Asp Tyr Val Arg Glu
1 5 10
<210> 54
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 54
Pro Phe Gly Ser Leu Leu Asp Tyr Val Arg Glu His
1 5 10
<210> 55
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 55
Phe Gly Ser Leu Leu Asp Tyr Val Arg Glu His Lys
1 5 10
<210> 56
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 56
Gly Ser Leu Leu Asp Tyr Val Arg Glu His Lys Asp
1 5 10
<210> 57
<211> 12
<212> PRT
<213>Artificial sequence (artificial sequences)
<400> 57
Ser Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn
1 5 10
Claims (7)
1. a kind of Antigenic Peptide chain group for treating tumour, which is characterized in that the Antigenic Peptide chain group of the treatment tumour includes SEQ ID
No:The combination of any one or at least two amino acid sequences in 1-57.
2. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes SEQ ID No described in claim 1:1-
Any one in 57 or at least two amino acid sequences.
3. pharmaceutical composition according to claim 2, which is characterized in that described pharmaceutical composition is aqueous suspension, solution
Or solid state.
4. pharmaceutical composition according to claim 3, which is characterized in that the solid state is uncoated or coated tablet
Form.
5. according to the pharmaceutical composition described in any one of claim 2-4, which is characterized in that further include pharmaceutically receive it is auxiliary
Material.
6. pharmaceutical composition according to claim 5, which is characterized in that the auxiliary material for excipient, diluent, carrier,
In flavoring agent, adhesive and filler any one or at least two combination.
7. Antigenic Peptide chain group the answering in the pharmaceutical composition for preparing treating cancer for the treatment of tumour according to claim 1
With.
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CN201810224090.0A CN108218961A (en) | 2018-03-19 | 2018-03-19 | A kind of Antigenic Peptide chain group for treating tumour and its application in drug |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810224090.0A CN108218961A (en) | 2018-03-19 | 2018-03-19 | A kind of Antigenic Peptide chain group for treating tumour and its application in drug |
Publications (1)
Publication Number | Publication Date |
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Family
ID=62659747
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CN201810224090.0A Withdrawn CN108218961A (en) | 2018-03-19 | 2018-03-19 | A kind of Antigenic Peptide chain group for treating tumour and its application in drug |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020210202A1 (en) * | 2019-04-11 | 2020-10-15 | The Board Of Trustees Of The Leland Stanford Junior University | Cytotoxic t lymphocytes specific for mutated forms of epidermal growth factor receptor for use in treating cancer |
CN113292642A (en) * | 2020-04-13 | 2021-08-24 | 倍而达药业(苏州)有限公司 | Third-generation epidermal growth factor receptor inhibitor drug-resistant mutation neoantigen and application thereof |
Citations (2)
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CN101208354A (en) * | 2005-02-24 | 2008-06-25 | 安姆根有限公司 | Epidermal growth factor receptor mutations |
WO2016202963A2 (en) * | 2015-06-19 | 2016-12-22 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer and other cancers |
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2018
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CN101208354A (en) * | 2005-02-24 | 2008-06-25 | 安姆根有限公司 | Epidermal growth factor receptor mutations |
WO2016202963A2 (en) * | 2015-06-19 | 2016-12-22 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer and other cancers |
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WANG 等: "Human tumor antigens for cancer vaccine development", 《IMMUNOLOGICAL REVIEWS》 * |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020210202A1 (en) * | 2019-04-11 | 2020-10-15 | The Board Of Trustees Of The Leland Stanford Junior University | Cytotoxic t lymphocytes specific for mutated forms of epidermal growth factor receptor for use in treating cancer |
CN113292642A (en) * | 2020-04-13 | 2021-08-24 | 倍而达药业(苏州)有限公司 | Third-generation epidermal growth factor receptor inhibitor drug-resistant mutation neoantigen and application thereof |
CN113292642B (en) * | 2020-04-13 | 2023-02-28 | 倍而达药业(苏州)有限公司 | Third-generation epidermal growth factor receptor inhibitor drug-resistant mutation neoantigen and application thereof |
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