CN107446938A - Selectively targeted receptor protein MAGEA and its CAR carrier Ts a kind of construction method - Google Patents
Selectively targeted receptor protein MAGEA and its CAR carrier Ts a kind of construction method Download PDFInfo
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- CN107446938A CN107446938A CN201610371950.4A CN201610371950A CN107446938A CN 107446938 A CN107446938 A CN 107446938A CN 201610371950 A CN201610371950 A CN 201610371950A CN 107446938 A CN107446938 A CN 107446938A
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Abstract
The present invention provides a kind of selectively targeted receptor protein MAGEA and its construction method of CAR carrier Ts, the construction method includes, first extract the RNA of the monoclonal hybridoma of anti-osteosarcoma, then RT PCR are carried out with the specific primer of monoclonal antibody, the variable region DNA fragmentation of heavy chain of antibody and light chain is cloned into carrier T, sequencing, obtain the receptor protein MAGEA of specific recognition tumour cell, and its expressed sequence is cloned into CAR carrier Ts, obtain selectively targeted MAGEA novel C AR carrier Ts.The present invention can be the entity tumor of CAR T cells treatment, and effective target is especially provided in the immunization therapy of osteosarcoma.
Description
Technical field
The present invention relates to immunotherapy of tumors field, and in particular to a kind of selectively targeted receptor protein MAGEA and its
The construction method of CAR-T carriers.
Background technology
Malignant tumour is one of current global major causes of death.《Global cancer report in 2014》Claim 2012 entirely
Ball cancer patient and death are all disturbingly increasing, and newly-increased cases of cancer has nearly half to appear in Asia, wherein greatly
Part is in first in China, the newly-increased cases of cancer of China.In 4 kinds of malignant tumours such as liver, esophagus, stomach and lung, China is new
Increase case and death toll occupies first place in the world.The therapeutic process of cancer is considerably complicated, and current all treatment means are all to have one
Fixed limitation, and cellular immunotherapy turns into the method for being uniquely possible to thoroughly remove cancer cell in theory：Immune response
It can be found that and destroy tumour cell, then form memory cell long-term surviving, can be under the conditions of other auxiliary treatments
The cancer cell of recurrence is removed, thus immunotherapy method is considered as most accurate, most powerful and safest prevention from suffering from the diseases and controlled
Treatment mechanism.After tumour immunotherapy in 2013 is chosen as ten big sciences breakthrough first by Science magazines, U.S. in 2014 and 2015
State authority tumour academic conference AACR（American cancer research association）And ASCO（American Society of Clinical Oncology's annual meeting）Upper tumour immunity
Therapy always is focus.
At present, in clinical trial, CAR-T cells have been used to B cell lymphoma, neuroblastoma, neuroglia mother
Cytoma, lung cancer, prostate cancer and melanoma etc..Clinical trial results show, the especially treatment to bone-marrow-derived lymphocyte leukaemia
Significant effect.Its mechanism is exactly to collect T cell from patient's self-blood, carries out genetic engineering processing to T cell, makes T cell table
Face gives expression to the specific receptor that can identify specific tumor antigen, and this acceptor is referred to as Chimeric antigen receptor（chimeric
Antigen receptor, CAR), while add in the intracellular section of acceptor and cause the signal transfer region domain of T cell activation.CAR
It is a kind of protein acceptor, the specified protein on T cell tumor cell surface can be made（Antigen）, express CAR T cell
It can recognize that and combine tumour antigen, and then attack tumour cell.This expression CAR T cell is referred to as CAR-T.By design
CAR-T cells can be grown in laboratory cultures, reach as many as billions of CAR-T cells by after amplification and be injected into patient's body
Interior, the T cell after injecting can also breed in patient's body, and kill the tumour cell with corresponding specific antigen.
Osteosarcoma is the primary malignant bone tumor of most common teenager, can with the complex treatment performed the operation with reference to new adjuvant chemotherapy
To cure about 60% patient, the patient's Endodontic failure for still having 40%, especially osteosarcoma DISTANT METASTASES IN, Lung metastases are that osteosarcoma causes
The main reason for dead.It was found that after clinical Lung metastases, the five year survival rate of patient is only 10-20%.In the last thirty years, for bone and flesh
The adjustment of the dose intensity of the Clinical Trials of knurl Lung metastases and original medicine does not make decided progress, and understands bone and flesh in depth
The metastasis of knurl, targetedly formulating new therapeutic strategy turns into an urgent demand for improving prognosis in osteosarcoma.Although CAR-T swells
Knurl immunotherapy method obtains immense success on B cell lymphoma and leukaemia, but is imitated for entity tumors such as osteosarcoma
Fruit is undesirable always.
It is the anti-CD19-CAR built using CD19 as target antigen that CAR technologies, which are applied to clinical successful examples,.Due to
CAR-T cells have powerful attack, therefore screen target antigen to improve the Therapeutic safety and effect effect based on CAR
It can seem particularly critical.The perfect condition of CAR-T cell therapies is that T cell can understand the mesh for distinguishing tumour cell and normal structure
Molecule is marked, unfortunately current CAR-T cell therapies entity tumor, especially lack effective target in osteosarcoma immunity treatment
Mark.
The content of the invention
For overcome the deficiencies in the prior art, the present invention provides structure of the species specificity for MAGEA CAR-T carriers
Method.Solve osteosarcoma immunity and treat no this important clinical problem of suitable target spot, it is powerful so as to utilize
CAR-T immunotherapy techniques, specific removing tumour cell.
The technical scheme is that：A kind of selectively targeted receptor protein MAGEA and its CAR-T carriers structure side
Method, the construction method include, and first extract the RNA of the monoclonal hybridoma of anti-osteosarcoma, then with monoclonal antibody
Specific primer carries out RT-PCR, and the variable region DNA fragmentation of heavy chain of antibody and light chain is cloned into carrier T, is sequenced, and obtains
The receptor protein MAGEA of specific recognition tumour cell, and its expressed sequence is cloned on CAR-T carriers, obtain specificity
Target MAGEA novel C AR-T carriers.
Further, the receptor protein MAGEA of the specific recognition tumour cell, its nucleotide sequence NCBI codes are
NM_005362.3。
Further, the amino acid sequence NCBI codes of the receptor protein MAGEA are NP_005353.1.
Further, the preparation method of the monoclonal hybridoma comprises the following steps：Using MAGEA albumen conducts
Mouse is immunized immunogene, then takes the mouse spleen after immune processing, obtains bone-marrow-derived lymphocyte, then to choose myeloma thin
Born of the same parents, bone-marrow-derived lymphocyte is realized with myeloma cell by chaotropic agent to be merged, and carrying out preliminary screening by HAT culture mediums completes fusion
Heterocaryon hybridoma, and pass through ELISA antibody analysis screening obtain monoclonal hybridoma.
Further, by receptor protein monoclonal antibody gene structure on CAR-T expression vector, slow disease is passed through
Malicious packaging system, prepares pseudovirion, and a kind of T lymphocytes of specially recognizing tumor cells can be obtained by carrying out transfection.
The present invention has found cancer-testis antigen by the screening of protein science（Cancer Testis Antigens,
CTAs it is) high in osteosarcoma tissue to express, and be proportionate with shifting risk for Patients with Osteosarcoma, indicate poor prognosis.And
CTAs is expressed apparently higher than non-tumor stem cell in osteosarcoma stem cell.Largely repeating experimental studies have found that osteosarcoma is special
The MAGEA of one of the cancer-testis antigen molecule of opposite sex expression, by monoclonal antibody technique and molecule clone technology, is constructed
MAGEA CAR-T carriers.This targeting MAGEA CAR-T carriers first will expand the treatment for osteosarcoma, later stage
To other treatment of solid tumor fields.
The innovative point of the present invention is, on the basis of largely repeatable experiment, it was found that the specific antigen of osteosarcoma
MAGEA, on the one hand it on the other hand can also use other immunization therapies such as TCR-T etc. as the target spot of CAR-T immunization therapies
The target spot of method.The present invention have found specific recognition MAGEA by monoclonal antibody hybridoma technology and molecule clone technology
Monoclonal antibody sequences, and successfully obtain the method for constructing the CAR-T carriers that can identify MAGEA.For CAR-T cell therapies
Entity tumor, especially osteosarcoma immunity treatment on provide effective target.
The present invention can clinically promote application of the immunotherapy of tumors on the entity tumors such as osteosarcoma.CAR-T cells
The treatment cellular immunotherapy best as current targeting highest, curative effect, after being developed by four generation techniques, CAR-T is
It is more long to become sensitiveer, immune continuation, there is special effect to neoplastic hematologic disorders such as lymthomas.But because the target spot lacked makes
The solid tumor patients such as osteosarcoma can not benefit from it.The present invention screens a species specificity by largely repeatable experiment
The antigen MAGEA of osteosarcoma is identified, does not have the problem of target spot so as to solve original CAR-T treatments osteosarcoma.And this is resisted
Original structure obtains specific recognition MAGEA CAR-T lymphocyte cells on CAR-T expression vector.
Embodiment
For the ease of it will be appreciated by those skilled in the art that being described in further detail below in conjunction with embodiment to the present invention：
A kind of selectively targeted receptor protein MAGEA and its CAR-T carriers construction method, the construction method include, first carried
The RNA of the monoclonal hybridoma of anti-osteosarcoma is taken, then carries out RT-PCR with the specific primer of monoclonal antibody, will
The variable region DNA fragmentation of heavy chain of antibody and light chain is cloned into carrier T, sequencing, obtains the acceptor of specific recognition tumour cell
Albumen MAGEA, and its expressed sequence is cloned on CAR-T carriers, the novel C AR-T for obtaining selectively targeted MAGEA is carried
Body.
The receptor protein MAGEA of the specific recognition tumour cell, its nucleotide sequence NCBI code are NM_
005362.3。
The amino acid sequence NCBI codes of the receptor protein MAGEA are NP_005353.1.
The preparation method of the monoclonal hybridoma comprises the following steps：Using MAGEA albumen as immunogene pair
Mouse is immunized, and is then taken the mouse spleen after immune processing, is obtained bone-marrow-derived lymphocyte, then chooses myeloma cell, B lymphs
Cell is realized with myeloma cell by chaotropic agent to be merged, and the heterocaryon of preliminary screening completion fusion is carried out by HAT culture mediums
Hybridoma, and screened by ELISA antibody analysis and obtain monoclonal hybridoma.Specifically, the Monoclonal hybridomas is thin
The preparation method of born of the same parents is：S1. mouse is immunized as immunogene using the MAGEA albumen of Bacillus coli expression.Wherein, it is right
Mouse carries out segmentation and is immunized, and because soluble antigen immunogenicity is weak, typically to add Split completely.Specifically immunologic process is：
1) initial immunity：The subcutaneous multi-point injection 2 of 50ug antigen Freund Freund's complete adjuvants) after 3 weeks：Second immune, and dosage is same as above, and adds good fortune
The subcutaneous multi-point injection of family name's Freund's incomplete adjuvant；3) after 3 weeks, third time is immune, and dosage is same as above, and is not added with the subcutaneous multiple spot note of adjuvant
Penetrate；4) then after 2-3 weeks, booster immunization, increasing injection dosage 50-500ug is advisable, and is not added with the subcutaneous multi-point injection 5 of adjuvant) passing through
After crossing 3 days of the 4) step operation, mouse spleen is taken, obtains bone-marrow-derived lymphocyte.
S2. myeloma cell is chosen again, and bone-marrow-derived lymphocyte is realized with myeloma cell by chaotropic agent to be merged, the dissolution
Agent is the polyethylene glycol of concentration 40% (W/V).The heterocaryon hybridoma of preliminary screening completion fusion is carried out by HAT culture mediums,
And screened by ELISA antibody analysis and obtain monoclonal hybridoma.
Particularly, receptor protein monoclonal antibody gene structure is passed through into slow virus on CAR-T expression vector
Packaging system, pseudovirion is prepared, a kind of T lymphocytes of specially recognizing tumor cells can be obtained by carrying out transfection.
The present embodiment can clinically promote application of the immunotherapy of tumors on the entity tumors such as osteosarcoma.CAR-T is thin
Born of the same parents treat the cellular immunotherapy best as current targeting highest, curative effect, and after being developed by four generation techniques, CAR-T is
It is more long through becoming sensitiveer, immune continuation, there is special effect to neoplastic hematologic disorders such as lymthomas.But due to the target spot lacked
Prevent the solid tumor patients such as osteosarcoma from benefiting from it.The present embodiment passes through substantial amounts of experimental data, screens a kind of special
Property identification osteosarcoma antigen MAGEA, there is no the problem of target spot so as to solve original CAR-T treatment osteosarcoma.And should
Antigen is built on CAR-T expression vector, obtains specific recognition MAGEA CAR-T lymphocyte cells.
It is the wherein specific implementation of the present invention above, its description is more specific and detailed, but can not therefore manage
Solve as the limitation to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, do not departing from
On the premise of present inventive concept, various modifications and improvements can be made, these obvious alternative forms belong to this hair
Bright protection domain.
Claims (5)
- A kind of 1. selectively targeted receptor protein MAGEA and its CAR-T carriers construction method, it is characterised in that the structure Method includes, and first extracts the RNA of the monoclonal hybridoma of anti-osteosarcoma, is then entered with the specific primer of monoclonal antibody Row RT-PCR, the variable region DNA fragmentation of heavy chain of antibody and light chain is cloned into carrier T, be sequenced, obtained specific recognition and swell The receptor protein MAGEA of oncocyte, and its expressed sequence is cloned on CAR-T carriers, obtain selectively targeted MAGEA's Novel C AR-T carriers.
- 2. a kind of selectively targeted receptor protein MAGEA according to claim 1 and its CAR-T carriers construction method, Characterized in that, the receptor protein MAGEA of the specific recognition tumour cell, its nucleotide sequence NCBI code are NM_ 005362.3。
- 3. a kind of selectively targeted receptor protein MAGEA according to claim 1 and its CAR-T carriers construction method, Characterized in that, the amino acid sequence NCBI codes of the receptor protein MAGEA are NP_005353.1.
- 4. a kind of selectively targeted receptor protein MAGEA according to claim 1 and its CAR-T carriers construction method, Characterized in that, the preparation method of the monoclonal hybridoma comprises the following steps：Using MAGEA albumen as immunogene Mouse is immunized, the mouse spleen after immune processing is then taken, obtains bone-marrow-derived lymphocyte, then chooses myeloma cell, B leaching Bar cell is realized with myeloma cell by chaotropic agent merge, is passed through HAT culture mediums and is carried out the heteronuclear that preliminary screening is completed to merge Body hybridoma, and screened by ELISA antibody analysis and obtain monoclonal hybridoma.
- 5. a kind of selectively targeted receptor protein MAGEA according to claim 1 and its CAR-T carriers construction method, Characterized in that, receptor protein monoclonal antibody gene structure is packed on CAR-T expression vector by slow virus System, pseudovirion is prepared, a kind of T lymphocytes of specially recognizing tumor cells can be obtained by carrying out transfection.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112034188A (en) * | 2020-09-03 | 2020-12-04 | 山西农业大学 | Method for detecting whether bovine CART active peptide is combined with bovine follicular particle cell membrane receptor |
-
2016
- 2016-05-31 CN CN201610371950.4A patent/CN107446938A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112034188A (en) * | 2020-09-03 | 2020-12-04 | 山西农业大学 | Method for detecting whether bovine CART active peptide is combined with bovine follicular particle cell membrane receptor |
| CN112034188B (en) * | 2020-09-03 | 2023-10-20 | 山西农业大学 | Method for detecting whether bovine CART active peptide is combined with bovine follicular granule cell membrane receptor |
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