CN106177947A - Immunologic surveillance point blocking drugs and the united pharmaceutical applications of tumor vaccine - Google Patents

Immunologic surveillance point blocking drugs and the united pharmaceutical applications of tumor vaccine Download PDF

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CN106177947A
CN106177947A CN201610587923.0A CN201610587923A CN106177947A CN 106177947 A CN106177947 A CN 106177947A CN 201610587923 A CN201610587923 A CN 201610587923A CN 106177947 A CN106177947 A CN 106177947A
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蔡炯
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Tiannian Pharmaceutical (Harbin) Co., Ltd.
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Peking Union Medical College Hospital Chinese Academy of Medical Sciences
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
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Abstract

The invention discloses immunologic surveillance point blocking drugs and the purposes at the medicine prepared for treating cancer combined by tumor vaccine.It is prepared as new medicine by immunologic surveillance point blocking drugs and tumor vaccine being combined, realize two kinds of immunotherapies and combine the treatment to cancer, reach single therapy the most inaccessiable excellent therapeutic effect, significantly limit the growth of tumor, extend the life span of patient.

Description

Immunologic surveillance point blocking drugs and the united pharmaceutical applications of tumor vaccine
Technical field
The present invention relates to immunologic surveillance point blocking drugs and tumor vaccine is combined in preparation in the medicine treating cancer Purposes.
Background technology
The annual new cancer patient of China there are about 2,500,000, and because of cancer, the number of death is about 1,400,000.Future Air, water pollution, environmental disruption may improve sickness rate and the case fatality rate of cancer further.At present, colorectal cancer has become Being one of 3 kinds of modal cancers, circumscribed colorectal cancer can pass through operative treatment, and shift patient and only have small part permissible Acquisition multi-mode is treated.The limitation colorectal cancer patients of about 50% occurs transfer and recurrence after operative treatment.The prognosis of patient Depend on tumor grade being interacted by host's tumor to be affected, show as the T cell infiltration of focus.
Immunization therapy depends on the activation of T cell in microenvironment, and what research was more at present is immunologic surveillance point medicine, including CTLA-4 antagonist antibodies, PD-1 antagonist antibodies, TIM-3 antagonist antibodies, LAG-3 antagonist antibodies, solubility OX40L, Activated form OX40 antibody, activated form GITR antibody, activated form 4-1BB antibody, activated form CD40 antibody, activated form CD27 antibody, Antagonism type CD70 antibody etc..In the kinds of tumors such as melanoma, nonsmall-cell lung cancer, the antibody for CTLA-4, PD-1 shows Good oncotherapy effect, and it is approved as the standard treatments under specified conditions.
PD-1 is the Inhibitory receptor expressed on T cell, B cell, mononuclear cell, macrophage, and its part includes PD- L1、PD-L2.PD-L1 expresses on immunocyte, and more overexpression is on tumor cell.PD-L1/PD-1 path and immunity are escaped Ease, T cell are exhausted relevant, cause T cell propagation, cytokine to produce and cytotoxicity is impaired.Compare the T cell of lymph node, The up-regulated of the infiltrating T cells PD-1 of colorectal cancer focus, the ability producing cytokine and perforin reduces；Tumor is micro- In environment, the expression of PD-L1 is high, and prompting PD-L1/PD-1 axle plays an important role on generation immunosuppressive environment.
But, clinical trial does not finds that PD-1 immunologic surveillance point blocks the treatment that mispairing reparation is stablized colorectal cancer patients Effect, but effective in cure to the colorectal cancer patients of mis-match repair deficient.PD-1 immunologic surveillance point blocks and stably ties mispairing reparation directly The failed reason of patients with bowel cancer may be as follows: 1. the immunogenicity of this tumor is poor, the immunoreation not being pre-existing in, T cell Do not produce remarkable result, so the molecule for immunologic surveillance point does not the most play effect, but have been reported that T cell is tied at constitutional yet Rectal cancer plays remarkable result；2. the local microenvironment of metastatic tumo(u)r is in hyperimmunization inhibitory state, it is suppressed that activation The inflow of type T cell.Form T cell suppression microenvironment especially by CCL5/CCR5 axle, obtain CCR5 inhibitor The confirmation of Maraviroc clinical trial.PD-L1 monoclonal antibody (Atezolizumab) adds FOLFOX, and to add VEGF monoclonal antibody (Avastin) right Obstinate colorectal cancer has high control effect.
Another immunotherapy method is inoculated tumour vaccine, and its principle is to utilize tumor cell or tumor antigen material Induction body produces specific cellular immunity and humoral immune reaction, i.e. activates the immune system of patient self, carrys out enhancing body Anti-cancer ability, and then stop the growth of tumor, spread and recur, be finally reached control and even remove the purpose of tumor.
Tumor is not external, but what autogenous cell occurred, therefore it is reacted not as to antibacterial, virus by body Reacting the strongest, so that early symptom is inconspicuous, the when of discovery, tumor has reached an advanced stage the stage, and tumor cell is sent out Having given birth to transfer, all of Therapeutic Method is also unable to reach the purpose of healing.Inoculated tumour vaccine then can be tumorigenic Just can remove tumor efficiently, specifically in early days, and untoward reaction is little.
Additionally, tumor vaccine therapy also can combine with operative treatment, radiotherapy and chemotherapy, occupy in Comprehensive Treatment tumor Critical role.A kind of method is exactly to be injected together with adjuvant by the tumor associated antigen of purification or restructuring, induces humoral immunization And cellular immunization.Research shows, has a kind of molecule MUC1 and relation between tumor close, has become as the target spot of immunotherapy of tumors.
External peptide based on the VNTR of MUC1 combines or mixes the epidemic disease of intrinsic stimulus object of multiple inherent immunity system Seedling has carried out I clinical trial phase.Adjuvant includes SB-AS2, incomplete Freund's adjuvant and keyhole limpet hemocyanin (KLH) etc..Two Individual nonglycosylated VNTR dosage form enters III clinical trial phase the most like a bomb.
First is Stimuvax (Merck, NJ, USA), and it is that the VNTR MUC1 peptide of 25 aggressiveness is by fat Plastid parcel associating and a Toll-like receptor-4 agonist (lipid A), the most carrying out three III clinical trial phases: two Individual in nonsmall-cell lung cancer (NSCLC), a breast carcinoma associating hormone therapy at estrogen receptor positive.These tests are bases In the challenging result that the IIB phase is studied, i.e. demonstrate and be in IIIB stage NSCLC(and be limited to the disease of local) one Group patient, the median survival interval accepting Stimuvax and highest standard nursing is 30.6 months, and only accepts highest standard nursing The median survival interval of patient be 13.3 months.The lung cancer therapy test of nearest people more than 1,000 shows cancer vaccine, overall therapeutic Effect is the most inconspicuous, may with enter group be that Patients with Advanced Lung Cancer has relation.By the packet following rule of discovery: smoking patients (n =762) therapeutic effect is better than the patient of non-smoking, and median life span extended to 32.1 months (p=from 20.6 months 0.0058)；The median life span of female patient (n=269) extended to from 20.6 months 36.8 months (p=0.0370), non- The median life span of adenocarcinoma patients (n=496) extended to 29.6 months (p=0.0435) from 19.6 months；Merging simultaneously Patient (n=806) the median life span treated extended to the research of 30.8 months (p=0.0175) and shows from 20.6 months, phase Patient for using the patient of vaccine, only chemotherapy and vaccine to use after chemotherapy simultaneously is benefited.
Second is MUC1(100 aggressiveness) combine oxidized mannan, it is used a lot of years, in clinic Before, I phase and the II phase tests and the III phase tests research demonstrate effectiveness.31 postclimacteric breast carcinoma altogether II phase patient by immunity mannan-MUC1 9 times, and combined tamoxifen in 36 weeks.15 diseases of placebo group People has 4 recurrences, and 16 patients with oxidation mannan-MUC1 treatment do not recur (p=0.0292). 9 antibody MUC1 being detected in 13 patients accepting vaccine, in 10 patients accepting vaccine, 4 detect that MUC1 is special Property t cell responses.There is not MUC1 specific immune response in placebo group.2012-2015 follows up a case by regular visits to III phase clinical research table Bright: the breast cancer relapse rate of placebo group is 60%(6/15), the patient's breast cancer relapse rate using cancer vaccine is 12.5%(2/ 16), the life-span significantly extends, and after overall use cancer vaccine, the percentage ratio pole without cancer patient dramatically increases；Never there is epidemic disease in patient Toxicity that Seedling causes and autoimmune disease, vaccine injection ensure these patient with breast cancers in 7 years without cancer return.
Clinical trial also shows that cancer vaccine is all safety to cancer of pancreas, carcinoma of prostate, ovarian cancer and renal cell carcinoma patients Effectively.According to hepatocarcinoma, colorectal cancer, the antigen presentation situation of thyroid carcinoma, cancer vaccine may be suitable for this Partial tumors and suffer from The treatment of person.1 example inoperable recurrence patients with gastric cancer uses the treatment of antigen induction DC cell local, does not occurs multiple in 30 months Send out.I/II clinical trial phase research to 15 multiple myeloma patients shows, most of disease of application cancer vaccine Feelings are stable (at least 17.5 ~ 41.3 months), the specific immunity of T cell and B cell occur.The research of I clinical trial phase shows, liver Dirty transfer colorectal cancer patients uses the xenogenesis cancer cell vaccine of expression of GM-CSF after undergoing hepatectomy for liver metastases, and vein is low simultaneously Dosage gives cyclophosphamide, and patient produces the antibody of anti-MUC1, and in 9 patients, 6 time-to-live were more than 3 years, and 4 again without multiple Send out.II phase clinical research finds, 74 patients use DC cell therapy and vaccine therapy, and 2 years of colorectal cancer patients are without recurrence Survival rate close (respectively 47% and 55%), is all better than nonimmune group.39 adenoma of colon in late period (Precancerous Lesion of Colon) inoculations After cancer vaccine, 17 produce the antibody of anti-MUC1 and long term immune memory, and remain do not produce 22 patients of antibody be because of Suppress cell quantity more relevant for the medullary system in blood before vaccination.
Summary of the invention
For the problems referred to above existed in terms for the treatment of colorectal cancer at present, the invention provides immunologic surveillance point blocking agent Thing and tumor vaccine are combined and are being prepared the purposes in the medicine treating cancer, reach single therapy method and are all beyond one's reach Therapeutic effect, effectively extends the survival of patients time.
As one of them preferred scheme, in above-mentioned application, described cancer is colorectal cancer.Colorectal cancer includes colon Cancer and rectal cancer, colon cancer and rectal cancer are only that disease sites is different, and focus cancerous cell kind is the same.Immunologic surveillance point The medicine that preparation combined by blocking drugs and tumor vaccine is the most effective for the treatment of colorectal cancer.
As one of them preferred scheme, in above-mentioned application, described immunologic surveillance point includes CTLA-4, PD-1, TIM-3 With at least one in LAG-3.
As one of them preferred scheme, in above-mentioned application, described immunologic surveillance point blocking drugs is PD-1 antagonism type Antibody.
As one of them preferred scheme, in above-mentioned application, described tumor vaccine is the lung with MUC1 albumen as target spot Theratope.
It is highly preferred that in above-mentioned application, described lung cancer vaccine is as antigen preparation by any one protein following Become:
(1) aminoacid sequence is as shown in SEQ ID NO.1；
(2) through replacing, lacking or add one or several aminoacid on the basis of aminoacid sequence shown in SEQ ID NO.1 And there is the derived protein of identical function；
(3) containing the required sequence shown in SEQ ID NO.2 in aminoacid sequence；
(4) 30% and the aminoacid sequence of above homology is had with the required sequence shown in SEQ ID NO.2.
It is highly preferred that in above-mentioned application, the preparation method of described lung cancer vaccine is: expand the volume of the protein as antigen Code gene, is connected to expression vector, converts bacillus coli DH 5 alpha, obtains after the product of IPTG abduction delivering is purified Antigen protein, adds aluminum hydroxide adjuvant and mixes.
It is highly preferred that in above-mentioned application, described expression vector is pMAL-p5X plasmid, described purification includes filtering through inner pressed Membrane filtration is degerming, and filtrate concentrates through external-compression type filter membrane again；Concentrated solution through 10K filter membrane dialyse 2 times to Tris buffer, centrifugal after Upper Amylose is affine, and resin purification obtains vaccine key component protein, reaches standard < 0.5EU/ μ g through endotoxin removal. PMAL-p5X plasmid is the coli expression carrier of commercialization, has more significant height for expressing the antigen protein of the present invention Efficiency.
As one of them preferred scheme, in above-mentioned application, described immunologic surveillance is selected blocking drugs and is used venous transfusion Being administered, intravenously administrable beneficially immunologic surveillance point blocking drugs rapidly enters blood circulation, through cancer location；Tumor vaccine is adopted Being administered by the mode of intramuscular injection, intramuscular delivery is beneficial to the slow release of medicine, stimulating immune system in a long time, produces The immunocyte of target tumor.
As one of them preferred scheme, in above-mentioned application, described immunologic surveillance point blocking drugs and tumor vaccine minute The most individually dosed, when the dosage of combination medicine is used alone with medicine, dosage is identical.Tumor vaccine does not increase the resistance of immunologic surveillance point Disconnected side effects of pharmaceutical drugs, tumor vaccine itself has no side effect.
Compared with prior art, there is advantages that
The present invention is prepared as new medicine by immunologic surveillance point blocking drugs and tumor vaccine being combined, it is achieved two kinds of immunity are treated Method combines the treatment to colorectal cancer, reaches single therapy the most inaccessiable excellent therapeutic effect, significantly limit tumor Growth, extends the life span of patient.
Accompanying drawing explanation
Fig. 1 is the protein electrophorese figure that in embodiment 1, DH5 α-pMAL-p5X-MNR expresses；
Fig. 2 is each experimental group Growth of Human Colon Cancer situation testing result in embodiment 2；
Fig. 3 is the testing result of each experimental group colon cancer mouse life in embodiment 2.
Detailed description of the invention
In order to make those skilled in the art be more fully understood that the present invention program, below in conjunction with the accompanying drawings and detailed description of the invention The present invention is described in further detail.The biomaterial used in embodiment if no special instructions, both from commercially available business Product.
The preparation of the embodiment 1 lung cancer vaccine with MUCI albumen as target spot
The synthesis of antigen protein
According to the aminoacid sequence shown in SEQ ID NO.1, use Gene Designer software that its encoding gene is carried out password Son optimizes, and introduces at upstream region of geneNdeI restriction enzyme site, downstream introducesNcoI restriction enzyme site, synthetic gene is cloned into PUC57 carrier, ammonia benzyl resistance.Use after gene chemical synthesisNdeI andNcoI enzymes double zyme cutting, connects into through same enzyme action PMAL-p5X plasmid, and connect with DNA ligase, it is transformed into competence DH5 α antibacterial, cultivates with the agar containing ammonia benzyl (AMP) Screen on plate, select monoclonal LB-AMP culture medium culturing, extract plasmid enzyme restriction and identify, then carry out order-checking and identify.To contain The DH5 α antibacterial having the pMAL-p5X plasmid (for convenience of describing, by named for this plasmid pMAL-p5X-MNR) of encoding gene is used LB-AMP cultivates, and treats that OD600nm reaches the IPTG, abduction delivering 12h of the 0.5 final concentration of 1mM of addition.Same abduction delivering with The DH5 α antibacterial of pMAL-p5X is as comparison.Taking the bacterium solution before and after induction and carry out protein electrophorese, coomassie brilliant blue R250 dyes. DH5 α-pMAL-p5X-MNR gives expression to the protein (shown in finger arrow as right in Fig. 1) of about 65KD, and compares antibacterial DH5 α-pMAL- P5X gives expression to the protein (shown in finger arrow as left in Fig. 1) of about 48KD.
Above-mentioned identical method, amplification is used to give expression to the protein shown in SEQ ID NO.2 ~ 4.
The preparation of lung cancer vaccine MNRVax
The preparation of lung cancer vaccine is described in detail as a example by the antigen protein that DH5 α-pMAL-p5X-MNR expresses.
First cultivate the DH5 α bacterial strain containing pMAL-p5X-MNR plasmid, treat OD600nmReach the 0.5 final concentration of 1mM's of addition IPTG, abduction delivering 12h.Centrifugal collection culture medium.Degerming through inner pressed membrane filtration, filtrate concentrates through external-compression type filter membrane again. Concentrated solution through 10K filter membrane dialyse 2 times to Tris buffer, centrifugal after the upper affine resin purification of Amylose to obtain vaccine main Component protein matter, reaches standard < 0.5EU/ μ g through endotoxin removal.Prepare aseptic aluminium hydroxide adjuvant, 0.22 μm membrane filtration Latter 4 DEG C save backup.Taking 0.5ml aluminum hydroxide adjuvant and add 0.5mg (0.5ml) vaccine protein matter, mix homogeneously becomes lung Theratope, named MNRVax1.
Use above-mentioned identical method, be that antigen prepares lung cancer vaccine, sequentially with the protein shown in SEQ ID NO.2 ~ 4 Named MNRVax2 ~ 4.
Combination immunization therapy zoopery
Take 36 6-8 week old female C57BL/6J mices, oxter injection MC38 colon cancer cell 1 × 106Individual/100 μ l, treat tumor Length is divided into following six groups to the most tangible detecting, often group 6.Administering drug combinations 2 times weekly, totally 6 times.
Packet situation:
Double saline control groups: abdominal cavity and muscle injecting normal saline 100 μ l respectively；
Muscle matched group: intramuscular injection normal saline 100 μ l；
Abdominal cavity compares: intraperitoneal injection of saline 100 μ l；
Muscle MNRVax1 group: intramuscular injection MNRVax1 vaccine 100 μ l, includes 50 μ g protein；
Abdominal cavity PD-1 antibody group: lumbar injection PD-1 antibody, injects 100 μ l, containing antibody 150 μ g；
MNRVax1+PD-1 antibody group: intramuscular injection MNRVax1 vaccine (injecting 100 μ l, containing 50 μ g protein) adds lumbar injection PD-1 antibody (injects 100 μ l, containing 150 μ g).
Measure weekly tumor size 3 times, measure 4 weeks continuously, according to length × wide2/ 2 calculate gross tumor volume, and observe muscle Matched group, muscle MNRVax1 group, abdominal cavity PD-1 antibody group, the survival rate of MNRVax1+PD-1 antibody group mice.
Result be administered after the 4th day, the tumor size of MNRVax1+PD-1 antibody group (hereinafter referred to as therapeutic alliance group) is 0.308 ±0.056cm3, substantially less than antibody group (0.575 ± 0.208 cm3), vaccine group (0.575 ± 0.154 cm3) and double saline pair According to group (0.561 ± 0.206 cm3)。
After therapeutic alliance the 8th day, the tumor size of therapeutic alliance group is 0.302 ± 0.101 cm3, pole is substantially less than anti- Tumor size 0.516 ± 0.199 cm of body group3, 0.832 ± 0.301 cm of vaccine group3, the 0.983 of double saline control groups ± 0.512 cm3.I.e. Antybody therapy reduces the tumor burden of 47.5%, and therapeutic alliance reduces the tumor burden of 69.3%.Anti- The tumor size of body treatment group is less than abdominal cavity saline control group (0.996 ± 0.155 cm3, p < 0.01), show to combine and control It is better than single Antybody therapy to treat, the inhibitory action onset morning to tumor.Therapeutic alliance group responsiveness is 100%, Antybody therapy group Responsiveness is 67%.
After therapeutic alliance 13 days, tumor was from the 0.308 ± 0.056cm of the 4th day3It is reduced into 0.224 ± 0.154cm3, and Antybody therapy group 0.575 ± 0.208 cm3From increasing to 0.890 ± 0.419 cm3.I.e. Antybody therapy reduces the tumor of 29.9% Load, and therapeutic alliance reduces the tumor burden of 82.3%.Therapeutic alliance group responsiveness is 100%, Antybody therapy group responsiveness It is 50%.
Until the treatment tumor growth curve of 25 days is shown in Fig. 2.It can be seen that combined immunization is treated from survival curve In antibody group and vaccine group, and antibody group and vaccine group be better than matched group, antibody and vaccine can work in coordination with prolongation rectal cancer move The life span of thing, is shown in Fig. 3.In a word, the therapeutic effect to colorectal cancer, vaccine adds the therapeutic alliance not only onset time of antibody Early, and, the persistent period is long.This Therapeutic Method not only can suppress the growth of tumor, it is also possible to when extending the existence of animal Between.
Experiment effect and MNRVax1 difference that MNRVax2, MNRVax3 and MNRVax4 are antibody combined with PD-1 are little, all Being better than being used alone vaccine or being used alone PD-1 antibody, detailed process repeats the most one by one at this.
Colorectal cancer patients purposes
PD-1 antibody consumption about 3mg/Kg body weight, intravenous administration, Per-Hop behavior is once；Cancer vaccine consumption about 7 μ g/Kg Body weight, upper arm muscle injection is administered, and Per-Hop behavior is once.Persistently using 1-12 month, effect is better than being used alone vaccine or list Solely use PD-1 antibody.
Patients with lung cancer purposes
PD-1 antibody consumption about 3mg/Kg body weight, intravenous administration, Per-Hop behavior is once；Cancer vaccine consumption about 7 μ g/Kg Body weight, upper arm muscle injection is administered, and Per-Hop behavior is once.Persistently using 1-12 month, effect is better than being used alone vaccine or list Solely use PD-1 antibody.
The explanation of above example is only intended to help to understand the core concept of the present invention.It should be pointed out that, for this technology For the those of ordinary skill in field, under the premise without departing from the principles of the invention, it is also possible to the present invention is carried out some improvement And modification, these improve and modify in the protection domain also falling into the claims in the present invention.
SEQUENCE LISTING
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Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
420 425 430
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
435 440 445
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
450 455 460
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
465 470 475 480
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
485 490 495
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
500 505 510
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
515 520 525
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
530 535 540
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
545 550 555 560
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
565 570 575
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
580 585 590
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
595 600 605
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
610 615 620
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
625 630 635 640
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
645 650 655
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
660 665 670
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
675 680 685
Gly Ser Thr Ala Pro Pro Ala His Ser Met Gly Gly Arg Asp Ile Val
690 695 700
Asp Gly Ser Glu Phe Pro Ala Gly Asn
705 710
<210> 4
<211> 853
<212> PRT
<213>artificial sequence
<400> 4
Met Lys Ile Lys Thr Gly Ala Arg Ile Leu Ala Leu Ser Ala Leu Thr
1 5 10 15
Thr Met Met Phe Ser Ala Ser Ala Leu Ala Lys Ile Glu Glu Gly Lys
20 25 30
Leu Val Ile Trp Ile Asn Gly Asp Lys Gly Tyr Asn Gly Leu Ala Glu
35 40 45
Val Gly Lys Lys Phe Glu Lys Asp Thr Gly Ile Lys Val Thr Val Glu
50 55 60
His Pro Asp Lys Leu Glu Glu Lys Phe Pro Gln Val Ala Ala Thr Gly
65 70 75 80
Asp Gly Pro Asp Ile Ile Phe Trp Ala His Asp Arg Phe Gly Gly Tyr
85 90 95
Ala Gln Ser Gly Leu Leu Ala Glu Ile Thr Pro Asp Lys Ala Phe Gln
100 105 110
Asp Lys Leu Tyr Pro Phe Thr Trp Asp Ala Val Arg Tyr Asn Gly Lys
115 120 125
Leu Ile Ala Tyr Pro Ile Ala Val Glu Ala Leu Ser Leu Ile Tyr Asn
130 135 140
Lys Asp Leu Leu Pro Asn Pro Pro Lys Thr Trp Glu Glu Ile Pro Ala
145 150 155 160
Leu Asp Lys Glu Leu Lys Ala Lys Gly Lys Ser Ala Leu Met Phe Asn
165 170 175
Leu Gln Glu Pro Tyr Phe Thr Trp Pro Leu Ile Ala Ala Asp Gly Gly
180 185 190
Tyr Ala Phe Lys Tyr Glu Asn Gly Lys Tyr Asp Ile Lys Asp Val Gly
195 200 205
Val Asp Asn Ala Gly Ala Lys Ala Gly Leu Thr Phe Leu Val Asp Leu
210 215 220
Ile Lys Asn Lys His Met Asn Ala Asp Thr Asp Tyr Ser Ile Ala Glu
225 230 235 240
Ala Ala Phe Asn Lys Gly Glu Thr Ala Met Thr Ile Asn Gly Pro Trp
245 250 255
Ala Trp Ser Asn Ile Asp Thr Ser Lys Val Asn Tyr Gly Val Thr Val
260 265 270
Leu Pro Thr Phe Lys Gly Gln Pro Ser Lys Pro Phe Val Gly Val Leu
275 280 285
Ser Ala Gly Ile Asn Ala Ala Ser Pro Asn Lys Glu Leu Ala Lys Glu
290 295 300
Phe Leu Glu Asn Tyr Leu Leu Thr Asp Glu Gly Leu Glu Ala Val Asn
305 310 315 320
Lys Asp Lys Pro Leu Gly Ala Val Ala Leu Lys Ser Tyr Glu Glu Glu
325 330 335
Leu Val Lys Asp Pro Arg Ile Ala Ala Thr Met Glu Asn Ala Gln Lys
340 345 350
Gly Glu Ile Met Pro Asn Ile Pro Gln Met Ser Ala Phe Trp Tyr Ala
355 360 365
Val Arg Thr Ala Val Ile Asn Ala Ala Ser Gly Arg Gln Thr Val Asp
370 375 380
Glu Ala Leu Lys Asp Ala Gln Thr Asn Ser Ser Ser Asn Asn Asn Asn
385 390 395 400
Asn Asn Asn Asn Asn Asn Leu Gly Ile Glu Gly Arg Ile Ser His Met
405 410 415
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
420 425 430
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
435 440 445
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
450 455 460
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
465 470 475 480
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
485 490 495
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
500 505 510
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
515 520 525
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
530 535 540
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
545 550 555 560
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
565 570 575
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
580 585 590
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
595 600 605
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
610 615 620
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
625 630 635 640
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
645 650 655
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
660 665 670
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
675 680 685
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
690 695 700
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
705 710 715 720
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
725 730 735
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
740 745 750
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
755 760 765
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
770 775 780
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
785 790 795 800
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
805 810 815
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
820 825 830
Pro Pro Ala His Ser Met Gly Gly Arg Asp Ile Val Asp Gly Ser Glu
835 840 845
Phe Pro Ala Gly Asn
850

Claims (10)

1. immunologic surveillance point blocking drugs and tumor vaccine are combined and are being prepared the purposes in the medicine treating cancer.
Purposes the most according to claim 1, it is characterised in that described cancer is colorectal cancer.
Purposes the most according to claim 1, it is characterised in that described immunologic surveillance point includes CTLA-4, PD-1, TIM-3 With at least one in LAG-3.
Purposes the most according to claim 1, it is characterised in that described immunologic surveillance point blocking drugs is that PD-1 antagonism type resists Body.
Purposes the most according to claim 1, it is characterised in that described tumor vaccine is the pulmonary carcinoma with MUC1 albumen as target spot Vaccine.
Purposes the most according to claim 5, it is characterised in that described lung cancer vaccine is to be made by any one protein following It is prepared from for antigen:
(1) aminoacid sequence is as shown in SEQ ID NO.1；
(2) through replacing, lacking or add one or several aminoacid on the basis of aminoacid sequence shown in SEQ ID NO.1 And there is the derived protein of identical function；
(3) containing the required sequence shown in SEQ ID NO.2 in aminoacid sequence；
(4) 30% and the aminoacid sequence of above homology is had with the required sequence shown in SEQ ID NO.2.
Purposes the most according to claim 6, it is characterised in that the preparation method of described lung cancer vaccine is: amplification is as anti- The encoding gene of former protein, is connected to expression vector, converts bacillus coli DH 5 alpha, and the product through IPTG abduction delivering enters The antigen protein that row obtains after purification, adds aluminum hydroxide adjuvant and mixes.
Purposes the most according to claim 7, it is characterised in that described expression vector is pMAL-p5X plasmid, described purification Including degerming through inner pressed membrane filtration, filtrate concentrates through external-compression type filter membrane again；Concentrated solution dialyses 2 times extremely through 10K filter membrane Tris buffer, after being centrifuged, the upper affine resin purification of Amylose obtains vaccine key component protein, reaches through endotoxin removal Standard < 0.5EU/ μ g.
Purposes the most according to claim 1, it is characterised in that described immunologic surveillance is selected blocking drugs and used venous transfusion to give Medicine, tumor vaccine uses the mode of intramuscular injection to be administered.
Purposes the most according to claim 1, it is characterised in that described immunologic surveillance point blocking drugs and tumor vaccine minute The most individually dosed, when the dosage of combination medicine is used alone with medicine, dosage is identical.
CN201610587923.0A 2016-07-25 2016-07-25 Immunologic surveillance point blocking drugs and the united pharmaceutical applications of tumor vaccine Pending CN106177947A (en)

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Cited By (3)

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CN107012212A (en) * 2017-03-24 2017-08-04 刘长胜 Early diagnosis of cancer kit and its application based on Cell-free DNA
CN114316066A (en) * 2021-11-11 2022-04-12 元本(珠海横琴)生物科技有限公司 MNR2 protein purification method
CN116059339A (en) * 2021-11-04 2023-05-05 元本(珠海横琴)生物科技有限公司 Medicine for treating and preventing cancer and application thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107012212A (en) * 2017-03-24 2017-08-04 刘长胜 Early diagnosis of cancer kit and its application based on Cell-free DNA
CN116059339A (en) * 2021-11-04 2023-05-05 元本(珠海横琴)生物科技有限公司 Medicine for treating and preventing cancer and application thereof
CN116059339B (en) * 2021-11-04 2023-09-22 元本(珠海横琴)生物科技有限公司 Medicine for treating and preventing cancer and application thereof
CN114316066A (en) * 2021-11-11 2022-04-12 元本(珠海横琴)生物科技有限公司 MNR2 protein purification method
CN114316066B (en) * 2021-11-11 2023-07-14 元本(珠海横琴)生物科技有限公司 Purification method of MNR2 protein

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