CN109825528A - A kind of CAR-NK cell preparation method for Huppert's disease - Google Patents
A kind of CAR-NK cell preparation method for Huppert's disease Download PDFInfo
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- CN109825528A CN109825528A CN201910128781.5A CN201910128781A CN109825528A CN 109825528 A CN109825528 A CN 109825528A CN 201910128781 A CN201910128781 A CN 201910128781A CN 109825528 A CN109825528 A CN 109825528A
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Abstract
The invention discloses a kind of CAR-NK cell preparation methods for Huppert's disease.This method comprises the following steps: making NK cell expressed fusion protein, obtains the CAR-NK cell for Huppert's disease；The fusion protein is that the IgG spline structure domain of NK cell surface activation receptor CD244 is changed to the recombinant protein obtained after the specific antibody for Huppert's disease marker BCMA.The amino acid sequence of the fusion protein is shown in SEQ ID No.1.Technical solution of the present invention has good effect, the treatment of the tumour that can be used for having Huppert's disease marker BCMA (such as Huppert's disease) for the treatment of the tumour with Huppert's disease marker BCMA.The present invention has great application value.
Description
Technical field
The invention belongs to field of biotechnology, and in particular to a kind of CAR-NK cell preparation side for Huppert's disease
Method.
Background technique
In recent years, the T cell (CAR-T) of Chimeric antigen receptor (chimeric antigen receptor, CAR) modification
Important breakthrough is achieved in leukaemia research, brings new hope for patients with hematological tumor.But along with swollen to blood
While tumor significant curative effect, there is also some problems, such as undershooting-effect, cytokine storm, insertion mutation for CAR-T treatment
Deng, and significant curative effect is not yet obtained to solid tumor.The new effector cell with powerful antitumor action of research and development has important
Theory significance and clinical value.
Mechanism, of short duration physiological period, extensive tumor-killing ability etc. of the NK cell because of its special identification target cell
Advantage is considered as the same potential effector cell that its anti-tumor capacity of enhancing is modified by CAR.NK cell is one kind to tumour
Cell has strength lethal effect and the non-dependent lymphocyte of MHC, depends on its surface to the identification of tumour cell
The regulation that intersects of Activating receptor and Inhibitory receptor.After tumor cell, NK cell is situated between by release killing
The cell that matter perforin and granzyme make target cell apoptosis, express film TNF family molecule inducing target cell apoptosis and antibody-dependant
The number of ways killing tumor cell such as toxic action.But due to the decline and tumour of NK cell quantity, quality in tumor patient body
The presence of escape mechanism, anti-tumor function in vivo fail to be not fully exerted.NK cell is modified by CAR to be expected to enhance
The ability of its target killing tumor cell simultaneously develops the effector cell with powerful antitumor action.
Huppert's disease (MM) is a kind of the malignant plasma cell dyscrasia, and tumour cell originates from the thick liquid cell in marrow, and
Thick liquid cell is cell of the bone-marrow-derived lymphocyte development to final function phases.Therefore Huppert's disease can be grouped into bone-marrow-derived lymphocyte leaching
The range of bar tumor.WHO is classified as one kind of B lymphocytic lymphoma at present, referred to as plasma cell myeloma/plasmacytoma,
Feature is that bone marrow plasma cells paraplasm is excessively generated with monoclonal immunoglobulin or light chain (M albumen), only a few patient
It can be the non-secreting type MM for not generating M albumen.Huppert's disease is often accompanied by multiple osteolytic damage, hypercalcinemia, poor
Blood, kidney damage.Since the generation of normal immunoglobulin is suppressed, it is easy to appear various bacterial infections.Currently without
For the CAR-NK cellular immunotherapy technology of Huppert's disease.
Summary of the invention
The object of the present invention is to provide a kind of methods for preparing the CAR-NK cell for Huppert's disease.
In a first aspect, a kind of claimed method for preparing the CAR-NK cell for Huppert's disease.
Method of the preparation provided by the present invention for the CAR-NK cell of Huppert's disease, it may include following steps:
Make NK cell expressed fusion protein, obtains the CAR-NK cell for Huppert's disease.The fusion protein can be that NK is thin
The IgG spline structure domain of cellular surface activated receptor CD244 (2B4) is changed to the specificity for Huppert's disease marker BCMA
The recombinant protein obtained after antibody.
The amino acid sequence in the IgG spline structure domain of the NK cell surface activation receptor CD244 (2B4) specifically can be such as sequence
In table shown in sequence 3.
The amino acid sequence of the specific antibody for Huppert's disease marker BCMA concretely SEQ ID
Shown in 22-260 of No.1.
Further, the method may include following steps: the recombination of the encoding gene containing the fusion protein is carried
Body imports NK cell, obtains the NK cell for expressing the fusion protein, and the as CAR-NK for Huppert's disease is thin
Born of the same parents.
Wherein, the fusion protein from N-terminal to C-terminal successively by the upper film signaling zone of CD244 (2B4), single-chain antibody area and
" transmembrane structure of CD244 (2B4) and the structural area intracellular of CD244 (2B4) " composition.
The amino acid sequence of the upper film signaling zone of the CD244 (2B4) can be for shown in 1-21 of SEQ ID No.1.
The amino acid sequence in the single-chain antibody area can be for shown in 22-260 of SEQ ID No.1.
The amino acid sequence of " transmembrane structure of CD244 (2B4) and the structural area intracellular of CD244 (2B4) " can be SEQ
Shown in 261-415 of ID No.1.
Further, the amino acid sequence of the fusion protein can be for shown in SEQ ID No.1.
Corresponding to gene level, the upper film signaling zone of the CD244 (2B4) is encoded in the encoding gene of the fusion protein
Nucleotide sequence can be for shown in 1-63 of SEQ ID No.2.The list is encoded in the encoding gene of the fusion protein
The nucleotide sequence in chain antibody area can be for shown in 64-780 of SEQ ID No.2.In the encoding gene of the fusion protein
The nucleotide sequence of " transmembrane structure of CD244 (2B4) and the structural area intracellular of CD244 (2B4) " can be SEQ ID described in coding
Shown in 781-1248 of No.2.
Further, the nucleotide sequence of the encoding gene of the fusion protein can be for shown in SEQ ID No.2.
In the method, the recombinant vector can be recombined lentivirus vector.
Correspondingly, the method may include following steps:
(a) slow virus incasing cells is transfected using the recombined lentivirus vector and slow virus packaging plasmid, is cultivated,
Obtain recombinant slow virus；
(b) recombinant slow virus is infected into NK cell, so that it is thin to obtain the CAR-NK for Huppert's disease
Born of the same parents.
In a specific embodiment of the invention, the recombined lentivirus vector specially will be shown in SEQ ID No.2
The encoding gene of the fusion protein obtains after being inserted between the multiple cloning sites (BamHI and XbaI) of plenti slow virus carrier
The recombinant plasmid arrived.The slow virus packaging plasmid is specially PspaX2 plasmid and PMD2.0G plasmid.The slow virus packaging is thin
Born of the same parents are specially 293T cell.In transfection, the recombined lentivirus vector, the PspaX2 plasmid and the PMD2.0G plasmid
Consumption proportion can be 5:3.2:1.8 (mass ratio).More specifically, such as the recombined lentivirus vector, the PspaX2 matter
Grain and the PMD2.0G plasmid are respectively 5 μ g, 3.2 μ g, 1.8 μ g, transfection 3 × 106A 293T cell.
The plenti slow virus carrier, the PspaX2 plasmid and the PMD2.0G plasmid can be addgene company
Product, catalog number is respectively #17481, #12260 and #12259.
Second aspect, claimed following any shown biomaterial:
(a1) using method described above be prepared described in be directed to Huppert's disease CAR-NK cell.
(a2) fusion protein described previously.
(a3) encoding gene of fusion protein described previously.
(a4) contain recombinant vector, expression cassette, recombinant bacterium or the recombinant cell of the encoding gene；Here recombinant vector
It can be any recombinant vector above (can be recombined lentivirus vector be also to recombinate non-slow virus carrier).
The third aspect, claimed following any shown application:
(A1) the previously described CAR-NK cell for Huppert's disease has multiple bone for treating in preparation
Application in the product of the tumour of myeloma marker BCMA；
(A2) the previously described CAR-NK cell for Huppert's disease has multiple bone for killing in preparation
Application in the product of the tumour cell of myeloma marker BCMA；
(A3) previously described encoding gene, recombinant vector or expression cassette are described for Huppert's disease in preparation
Application in CAR-NK cell.
Further, the tumour with Huppert's disease marker BCMA can be Huppert's disease.The tool
The tumour cell for having Huppert's disease marker BCMA can be multiple myeloma cells.
It is demonstrated experimentally that CAR-NK cell is to tumour cell (such as multiple bone with Huppert's disease marker BCMA
Myeloma cells) there is fragmentation effect, and the usage amount of CAR-NK cell is higher, fragmentation effect is better.It can be seen that skill of the present invention
Art scheme has good effect for the treatment of the tumour (such as Huppert's disease) with Huppert's disease marker BCMA,
The treatment for the tumour (such as Huppert's disease) that can be used for that there is Huppert's disease marker BCMA.Due to that can be made with allosome
With patient will being made to get timely medical treatment.The present invention has great application value.
Specific embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Plenti slow virus carrier, PspaX2 plasmid and PMD2.0G plasmid are the product of addgene company, product mesh
Record number is respectively #17481, #12260 and #12259.
Embodiment 1, for Huppert's disease CAR-NK cell preparation and identification
For the CAR-NK cellular immunotherapy method of Huppert's disease, cardinal principle is to NK (natural killer cells)
Cell carries out special gene modification, enhances the tumour that its specific killing has the function of Huppert's disease marker BCMA.
The IgG spline structure domain of NK cell surface activation receptor CD244 (2B4) is mainly changed to by CAR-NK modifier
For the specific antibody of Huppert's disease marker BCMA, the CAR-NK cell specificity by gene modification is enable to know
Other Huppert's disease marker BCMA, and then to tumour (such as multiple marrow with Huppert's disease marker BCMA
Tumor) cell killed.The amino acid sequence in the IgG spline structure domain of NK cell surface activation receptor CD244 (2B4) specifically can be such as
In sequence table shown in sequence 3.
One, for the preparation of the CAR-NK cell of Huppert's disease
1, recombined lentivirus vector plenti-CD244-antiBCMA is constructed
By DNA fragmentation shown in SEQ ID No.2 insertion plenti slow virus carrier restriction enzyme BamHI and
Between XbaI, recombined lentivirus vector plenti-CD244-antiBCMA is obtained.In SEQ ID No.2,1-63 are upper film
The encoding gene of signaling zone, the 64-780 encoding genes for single-chain antibody area, 781-1248 are transmembrane structure and born of the same parents
The encoding gene of interior structural area.
DNA fragmentation shown in SEQ ID No.2 encodes protein shown in SEQ ID No.1.In SEQ ID No.1, the
1-21 are upper film signaling zone, and 22-260 are single-chain antibody area, and 261-415 are transmembrane structure and structural area intracellular.
2, CD244-antiBCMA recombinant slow virus is packed
Recombined lentivirus vector plenti-CD244-antiBCMA, PspaX2 plasmid and PMD2.0G prepared by step 1
Plasmid (PspaX2 plasmid and PMD2.0G plasmid be slow virus packaging plasmid) takes 5 μ g, 3.2 μ g and 1.8 μ g respectively, turns after mixing
Contaminate 293T cell (about 3 × 106A cell, 10cm plate, 10mL contain the DMEM culture medium of 10% (v/v) FBS), it is received every for 24 hours
Take a slow virus supernatant, 0.45 μm of membrane filtration, 72h collect after 3 total 30mL using 4 DEG C of ultracentrifuge, 50000g from
Heart 2h, carefully siphons away supernatant, precipitates slow virus with 100 μ L DPBS and is resuspended, obtains Car-NK slow virus concentrate.
3, CD244-antiBCMA recombinant slow virus infects NK cell
(1) 5 × 10 are taken5Source of people NK cell (peripheral blood is separately cultured acquisition) cultivating system of a cell concentration volume, 300g
It is centrifuged 10min (raising speed: 150s, reduction of speed: 150s), collects precipitating.
(2) precipitating for taking step (1) to obtain is added 1mL NK cell culture medium and is resuspended, obtains re-suspension liquid.
(3) 12 orifice plates are taken, be added into the 1st hole the re-suspension liquid, 100 μ L Car-NK slow virus concentrates,
Polybrene, PHA, IL2 and IL12 mix, obtain cultivating system.In the cultivating system, the concentration of polybrene is 5 μ g/
The concentration that the concentration of mL, PHA are 1 μ g/mL, IL2 is 500U/mL, and the concentration of IL12 is 20U/mL.
(4) cultivating system for taking step (3) to obtain is placed in 37 DEG C, 5%CO2 incubator culture, obtains and is directed to multiple bone
The CAR-NK cell of myeloma, abbreviation CAR-NK cell.
Two, the identification of CAR-NK cell
1, extract CAR-NK cell genomic DNA and using it as template, using primers F: 5 '-
The primer pair of ATGCTGGGGCAAGTGGTCAC-3 ' and primer R:5 '-TCAGGAATAAACATCAAAGT-3 ' composition carries out PCR
Amplification, obtains pcr amplification product.
Pcr amplification product is connected with carrier T, is then sequenced.
Sequencing result shows in pcr amplification product containing DNA molecular shown in SEQ ID No.2.As it can be seen that step 1 system
Protein shown in standby CAR-NK cell expression SEQ ID No.1.
CAR-NK cell prepared by embodiment 2, embodiment 1 detects the fragmentation effect of people's multiple myeloma cells U266
Cell to be measured is CAR-NK cell or source of people NK cell prepared by embodiment 1 (peripheral blood is separately cultured acquisition).
People's multiple myeloma cells U266 is the product of ATCC company.People's multiple myeloma cells U266 has multiple
Property marrow tumor markers BCMA.
1, people's multiple myeloma cells U266 (about 10 is taken4It is a), cell to be measured is added, obtains incubation system.It is incubated for body
In system, the number of cell to be measured is 1.25 × 103It is a, 2.5 × 103It is a, 5 × 103It is a, 1 × 104It is a, 2 × 104It is a or 4 × 104
It is a.
2, after completing step 1, take the incubation system, 37 DEG C, 5%CO2 culture for 24 hours.
3, the system for taking into step 2, using ToxGreen detection method, (specific steps refer to CellToxTMGreen
Cytotoxicity Assay technical manual) detection cell to be measured (kills the killing-efficiency of people's multiple myeloma cells U266
Hurt living cells quantity/10 efficiency=incubation descendant's multiple myeloma cells U2664A × 100%)；Then with cell to be measured
Number and people's multiple myeloma cells U266 ratio be abscissa, killing-efficiency is ordinate, draw killing curve.
The result shows that CAR-NK cell prepared by embodiment 1 is to people's multiple myeloma cells compared with source of people NK cell
U266 has better fragmentation effect, and the usage amount of the CAR-NK cell of the preparation of embodiment 1 is higher, and fragmentation effect is better.
<110>Beijing is in promise medical science and technology Co., Ltd
<120>a kind of CAR-NK cell preparation method for Huppert's disease
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 415
<212> PRT
<213> Artificial sequence
<400> 1
Met Leu Gly Gln Val Val Thr Leu Ile Leu Leu Leu Leu Leu Lys Val
1 5 10 15
Tyr Gln Gly Lys Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe
35 40 45
Ala Leu Ser Asn His Gly Met Ser Trp Val Arg Arg Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ser Gly Ile Val Tyr Ser Gly Ser Thr Tyr Tyr
65 70 75 80
Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala
100 105 110
Ile Tyr Tyr Cys Ser Ala His Gly Gly Glu Ser Asp Val Trp Gly Gln
115 120 125
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Arg Ala Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
145 150 155 160
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
165 170 175
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
180 185 190
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln
195 200 205
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
210 215 220
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
225 230 235 240
Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys
245 250 255
Val Glu Ile Lys Gln Asp Cys Gln Asn Ala His Gln Glu Phe Arg Phe
260 265 270
Trp Pro Phe Leu Val Ile Ile Val Ile Leu Ser Ala Leu Phe Leu Gly
275 280 285
Thr Leu Ala Cys Phe Cys Val Trp Arg Arg Lys Arg Lys Glu Lys Gln
290 295 300
Ser Glu Thr Ser Pro Lys Glu Phe Leu Thr Ile Tyr Glu Asp Val Lys
305 310 315 320
Asp Leu Lys Thr Arg Arg Asn His Glu Gln Glu Gln Thr Phe Pro Gly
325 330 335
Gly Gly Ser Thr Ile Tyr Ser Met Ile Gln Ser Gln Ser Ser Ala Pro
340 345 350
Thr Ser Gln Glu Pro Ala Tyr Thr Leu Tyr Ser Leu Ile Gln Pro Ser
355 360 365
Arg Lys Ser Gly Ser Arg Lys Arg Asn His Ser Pro Ser Phe Asn Ser
370 375 380
Thr Ile Tyr Glu Val Ile Gly Lys Ser Gln Pro Lys Ala Gln Asn Pro
385 390 395 400
Ala Arg Leu Ser Arg Lys Glu Leu Glu Asn Phe Asp Val Tyr Ser
405 410 415
<210> 2
<211> 1248
<212> DNA
<213> Artificial sequence
<400> 2
atgctggggc aagtggtcac cctcatactc ctcctgctcc tcaaggtgta tcagggcaaa 60
ggagaagtgc aattggtgga atcaggggga ggacttgtgc agcctggagg atcgctgaga 120
ctgtcatgtg ccgtgtccgg ctttgccctg tccaaccacg ggatgtcctg ggtccgccgc 180
gcgcctggaa agggcctcga atgggtgtcg ggtattgtgt acagcggtag cacctactat 240
gccgcatccg tgaaggggag attcaccatc agccgggaca actccaggaa cactctgtac 300
ctccaaatga attcgctgag gccagaggac actgccatct actactgctc cgcgcatggc 360
ggagagtccg acgtctgggg acaggggacc accgtgaccg tgtctagcgc gtccggcgga 420
ggcggcagcg ggggtcgggc atcagggggc ggcggatcgg acatccagct cacccagtcc 480
ccgagctcgc tgtccgcctc cgtgggagat cgggtcacca tcacgtgccg cgccagccag 540
tcgatttcct cctacctgaa ctggtaccaa cagaagcccg gaaaagcccc gaagcttctc 600
atctacgccg cctcgagcct gcagtcagga gtgccctcac ggttctccgg ctccggttcc 660
ggtactgatt tcaccctgac catttcctcc ctgcaaccgg aggacttcgc tacttactac 720
tgccagcagt cgtactccac cccctacact ttcggacaag gcaccaaggt cgaaatcaag 780
caggactgtc agaatgccca tcaggaattc agattttggc cgtttttggt gatcatcgtg 840
attctaagcg cactgttcct tggcaccctt gcctgcttct gtgtgtggag gagaaagagg 900
aaggagaagc agtcagagac cagtcccaag gaatttttga caatttacga agatgtcaag 960
gatctgaaaa ccaggagaaa tcacgagcag gagcagactt ttcctggagg ggggagcacc 1020
atctactcta tgatccagtc ccagtcttct gctcccacgt cacaagaacc agcatataca 1080
ttatattcat taattcagcc ttccaggaag tctggttcca ggaagaggaa ccacagccct 1140
tccttcaata gcactatcta tgaagtgatt ggaaagagtc aacctaaagc ccagaaccct 1200
gctcgattga gccgcaaaga gctggagaac tttgatgttt attcctga 1248
<210> 3
<211> 194
<212> PRT
<213> Artificial sequence
<400> 3
Cys Gln Gly Ser Ala Asp His Val Val Ser Ile Ser Gly Val Pro Leu
1 5 10 15
Gln Leu Gln Pro Asn Ser Ile Gln Thr Lys Val Asp Ser Ile Ala Trp
20 25 30
Lys Lys Leu Leu Pro Ser Gln Asn Gly Phe His His Ile Leu Lys Trp
35 40 45
Glu Asn Gly Ser Leu Pro Ser Asn Thr Ser Asn Asp Arg Phe Ser Phe
50 55 60
Ile Val Lys Asn Leu Ser Leu Leu Ile Lys Ala Ala Gln Gln Gln Asp
65 70 75 80
Ser Gly Leu Tyr Cys Leu Glu Val Thr Ser Ile Ser Gly Lys Val Gln
85 90 95
Thr Ala Thr Phe Gln Val Phe Val Phe Glu Ser Leu Leu Pro Asp Lys
100 105 110
Val Glu Lys Pro Arg Leu Gln Gly Gln Gly Lys Ile Leu Asp Arg Gly
115 120 125
Arg Cys Gln Val Ala Leu Ser Cys Leu Val Ser Arg Asp Gly Asn Val
130 135 140
Ser Tyr Ala Trp Tyr Arg Gly Ser Lys Leu Ile Gln Thr Ala Gly Asn
145 150 155 160
Leu Thr Tyr Leu Asp Glu Glu Val Asp Ile Asn Gly Thr His Thr Tyr
165 170 175
Thr Cys Asn Val Ser Asn Pro Val Ser Trp Glu Ser His Thr Leu Asn
180 185 190
Leu Thr
Claims (10)
1. a kind of method for preparing the CAR-NK cell for Huppert's disease includes the following steps: to melt the expression of NK cell
Hop protein obtains the CAR-NK cell for Huppert's disease；
The fusion protein is that the IgG spline structure domain of NK cell surface activation receptor CD244 is changed to for multiple marrow
The recombinant protein obtained after the specific antibody of tumor markers BCMA.
2. according to the method described in claim 1, it is characterized by: described method includes following steps: the fusion will be contained
The recombinant vector of the encoding gene of albumen imports NK cell, obtains the NK cell for expressing the fusion protein, as described to be directed to
The CAR-NK cell of Huppert's disease.
3. method according to claim 1 or 2, it is characterised in that: the fusion protein is from N-terminal to C-terminal successively by CD244
The upper film signaling zone of (2B4), single-chain antibody area and " transmembrane structure of CD244 (2B4) and the structural area intracellular of CD244 (2B4) "
Composition.
4. according to the method described in claim 3, it is characterized by: the amino acid sequence of the upper film signaling zone of the CD244 (2B4)
Shown in 1-21 for being classified as SEQ ID No.1；The amino acid sequence in the single-chain antibody area is the 22- of SEQ ID No.1
Shown in 260；The amino acid sequence of " transmembrane structure of CD244 (2B4) and the structural area intracellular of CD244 (2B4) " is SEQ
Shown in 261-415 of ID No.1；
Further, the amino acid sequence of the fusion protein is shown in SEQ ID No.1.
5. according to the method any in claim 2 to 4, it is characterised in that: compiled in the encoding gene of the fusion protein
The nucleotides sequence of the upper film signaling zone of the code CD244 (2B4) is classified as shown in 1-63 of SEQ ID No.2；The fusion
The nucleotides sequence that the single-chain antibody area is encoded in the encoding gene of albumen is classified as shown in 64-780 of SEQ ID No.2；
" transmembrane structure of CD244 (2B4) and the structure intracellular of CD244 (2B4) described in coding in the encoding gene of the fusion protein
The nucleotides sequence in area " is classified as shown in 781-1248 of SEQ ID No.2；
Further, the nucleotides sequence of the encoding gene of the fusion protein is classified as shown in SEQ ID No.2.
6. according to the method any in claim 2 to 5, it is characterised in that: the recombinant vector is recombinant slow virus load
Body.
7. according to the method described in claim 6, it is characterized by: described method includes following steps:
(a) slow virus incasing cells is transfected using the recombined lentivirus vector and slow virus packaging plasmid, is cultivated, obtained
Recombinant slow virus；
(b) recombinant slow virus is infected into NK cell, to obtain the CAR-NK cell for being directed to Huppert's disease.
8. method according to claim 6 or 7, it is characterised in that: the recombined lentivirus vector is by SEQ ID No.2
Shown in the fusion protein encoding gene be inserted between the multiple cloning sites of plenti slow virus carrier after obtained weight
Group plasmid；And/or the slow virus packaging plasmid is PspaX2 plasmid and PMD2.0G plasmid；And/or the slow virus packaging is carefully
Born of the same parents are 293T cell.
9. following any shown biomaterial:
(a1) the CAR-NK cell for Huppert's disease being prepared using any the method for claim 1 to 8；
(a2) any fusion protein in claim 1 to 8；
(a3) in claim 1 to 8 any fusion protein encoding gene；
(a4) recombinant vector, expression cassette, the recombinant bacterium of the encoding gene containing the fusion protein any in claim 1 to 8
Or recombinant cell；
Further, the recombinant vector is any recombinant vector in claim 2 to 8.
10. following any shown application:
(A1) it is used to treat with multiple in preparation for the CAR-NK cell of Huppert's disease described in claim 9
Application in the product of the tumour of marrow tumor markers BCMA；
(A2) it is used to kill with multiple in preparation for the CAR-NK cell of Huppert's disease described in claim 9
Application in the product of the tumour cell of marrow tumor markers BCMA；
(A3) encoding gene described in claim 9, recombinant vector or expression cassette are described for Huppert's disease in preparation
CAR-NK cell in application.
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| CN120904358A (en) * | 2025-10-10 | 2025-11-07 | 赛德特生物制药有限公司 | Novel IL-15 fusion protein and application thereof |
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