CN113913385A - 一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞及其用途 - Google Patents
一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞及其用途 Download PDFInfo
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Abstract
一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞及其用途,该抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞用于治疗恶性肿瘤的药物,是通过阻断蛋白与嵌合抗原受体共表达于免疫细胞;其中,阻断蛋白的核酸序列如SEQ ID NO:3,蛋白序列如SEQ ID NO:4;阻断蛋白与嵌合抗原受体共表达的核酸序列如SEQ ID NO:5,蛋白序列如SEQ ID NO:6。本发明从阻断免疫细胞负调控信号的转导角度出发,使CAR‑T细胞表达阻断蛋白,减弱/阻止负调控信号传递,增强CAR‑T细胞抗肿瘤活性;无需与免疫检查点抗体药联合使用就能增强抗肿瘤免疫反应,降低用药成本,且给药量可以精准确定,疗效确切显著。
Description
技术领域
本发明涉及生物医药领域,尤其涉及一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞及其用途。
背景技术
目前,CAR-T免疫疗法在肿瘤治疗领域取得了令人瞩目的临床进展,同时免疫检查点阻断剂如PD1/PD-L1抗体药也在肿瘤治疗中取得了喜人的疗效。CAR-T免疫疗法是提取免疫细胞,通过体外的培养进行扩增,再利用基因工程技术给免疫细胞镶嵌上能识别癌细胞的基因片段,再将该免疫细胞回输到病人的体内;PD-1抗体药本身是不会杀灭癌细胞的,它是通过解除对免疫细胞的抑制,重新激活免疫细胞;二者的抗肿瘤机理不同,为进一步提高疗效,临床已有研究进行CAR-T和PD1抗体药联用,以解除CAR-T的免疫抑制。然而,两种抗体药价格均较昂贵,且二者联合用药,其给药量很难精准确定,疗效存在不确切性,因此两种疗法联用无论从治疗费用还是临床给药都带来更大的压力。
PD1抗体药的机制是以竞争PD-L1的方式阻断免疫细胞的负调控信号,解除免疫细胞的抑制,增强抗肿瘤活性。事实上,阻断PD1胞内的信号转导,即使PD1与PD-L1相互作用,也会解除免疫细胞的免疫抑制。阻断蛋白Blocker是SHP2蛋白酪氨酸磷酸酶的N端截短蛋白。SHP2在PD1的下游,通过使TCR受体去磷酸化(如CD3zeta的ITAM)来帮助PD1抑制T细胞的活性。
阻断蛋白Blocker可以结合PD1的胞内区但不具备去磷酸化功能,因此过表达的Blocker可以竞争结合PD1胞内结构域,阻断正常SHP2的抑制功能。因此联合CAR共表达阻断蛋白Blocker,可以起到甚至优于PD1抗体联用的效果,增强抗肿瘤功能。
但是,目前还没有文献公开阻断蛋白(Blocker)来增强CAR-T细胞抗肿瘤活性的内容。
发明内容
本发明为解决上述技术问题,提供一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞及其用途。
为了能够达到上述所述目的,本发明采用以下技术方案:
一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞,其特殊之处在于:抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞通过阻断蛋白与嵌合抗原受体共表达于免疫细胞,所述阻断蛋白阻隔免疫细胞负调控信号的转导,增强免疫细胞激活信号;所述阻断蛋白的核酸序列如SEQ ID NO:3、蛋白序列如SEQ ID NO:4。
作为进一步的优选,所述阻断蛋白与嵌合抗原受体共表达的核酸序列如SEQ IDNO:5、蛋白序列如SEQ ID NO:6。
作为进一步的优选,所述免疫细胞为T细胞或NK细胞。
一种如上述的抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞在制备治疗恶性肿瘤的药物的用途。
作为进一步的优选,所述药物用于血液恶性肿瘤。
作为进一步的优选,所述药物用于靶向CD19的血液恶性肿瘤。
表1
由于本发明采用了以上技术方案,具有以下有益效果:
(1)本发明从阻断免疫细胞负调控信号的转导(包括且不限PD1)角度出发,使CAR-T细胞表达阻断蛋白(Blocker),减弱或阻止负调控信号传递,增强CAR-T细胞抗肿瘤活性。
(2)本发明获得的抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞在增强肿瘤免疫细胞抗肿瘤功能的应用,包括且不仅限于在T细胞、NK细胞中的应用。
(3)本发明衍生的产品不需与PD1/PD-L1等免疫检查点抗体药联合使用就可以增强抗肿瘤免疫反应,降低用药成本,且给药量可以精准确定,疗效确切显著。
附图说明
为了更清楚地说明本发明实例或现有技术中的技术方案,下面将对实施实例或现有技术描述中所需要的附图做简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实例,对于本领域普通技术人员来说,在不付出创造性的前提下,还可以根据这些附图获得其他的附图:
图1为本发明CAR-T组和CAR-Blocker-T组转染效率检测结果图;
图2为本发明表达阻断蛋白的CAR-Blocker-T细胞在杀伤肿瘤的增殖活性图;
图3为本发明CAR+:肿瘤细胞=1:5的表达阻断蛋白的CAR-Blocker-T细胞在杀伤肿瘤细胞的活性图;
图4为本发明CAR+:肿瘤细胞=1:1的表达阻断蛋白的CAR-Blocker-T细胞在杀伤肿瘤细胞的活性图;
图5为本发明CAR+:肿瘤细胞=5:1的表达阻断蛋白的CAR-Blocker-T细胞在杀伤肿瘤细胞的活性图;
图6为本发明表达阻断蛋白的CAR-Blocker-NK细胞在杀伤肿瘤细胞的活性图。
具体实施方式
下面对本发明的具体实施方式作进一步详细的说明,但本发明并不局限于这些实施方式,任何在本实施例基本精神上的改进或代替,仍属于本发明权利要求所要求保护的范围。
实施例1
(1)构建CAR-Blocker的表达质粒
CAR是靶向CD19的CAR分子,序列是表1中的SEQIDNO:1~2,阻断蛋白Blocker的序列是SEQIDNO:3~4,CAR和阻断蛋白Blocker由自切割多肽连接序列2A连接,使得CAR和Blocker可以共同表达,获得抑制蛋白阻断型嵌合抗原受体CAR-Blocker,CAR-Blocker的序列是SEQIDNO:5~6。所用病毒表达质粒(AddgeneID:#12257)用BamHI/NdeI酶切作为骨架,合成CAR-Blocker连入载体。
(2)慢病毒的制备
采用三质粒包装方法,三质粒包括表达质粒、包装辅助质粒psPAX2(AddgeneID:#12260)和pMD2.G(AddgeneID:#12259)。制备流程如下:将冻存HEK293T细胞(购自中科院上海细胞研究所)复苏,用DMEM培养基(+10%FBS+1%P/S)(Cellgro10-013-CMR)置于10cm培养皿培养,复苏传代,采用PEI作为转染试剂,PEI:CAR-Blocker的表达质粒(质量比)=2:1的条件转染。将CAR-Blocker的表达质粒与PEI的混合物加入到Opti-MEM培养基(Gibco,cat#31985-070)中,再将此混合溶液加入到HEK293T细胞中。转染6小时后用2%FBS的新鲜培养基换液,72小时后,收集上清,超离的方式(80000g,4℃离心3小时)进行浓缩,浓缩好的病毒用0.22μm滤膜过滤除菌后重悬,待用。
(3)原代T细胞激活
原代T细胞来源于健康人志愿者的外周血(PBMC)。激活培养基采用ImmunoCultTM-XF T Cell Expansion Medium(Stem Cell Technology,cat#10981)+200IU/mL IL2(cat#78036)。ImmunoCultHumanCD3/CD28TCellActivator试剂盒(cat#10971)进行激活。T细胞被激活后形态上明显聚团、变大。
(4)慢病毒基因转导
T细胞激活后24h,取5×105个细胞于24孔培养板,加入步骤(2)制备的慢病毒,以MOI=10(Multiplicity of Infection,感染复数,病毒量与细胞数的比值),补充激活培养基至1mL(培养基与前述原代T细胞激活所用培养基一致)。
(5)CAR-Blocker-T转染效率检测
CAR-Blocker-T细胞培养至12天,早期增殖慢,9~12天快速增殖。取出少量细胞,加入1mLPBS(Gibco,cat#C10010500BT)清洗细胞1遍,用100μLPBS重悬,加入3μL生物素偶联的CD19蛋白(Cat.No.CD9-H8259,10μg/mL)检测CAR,4℃孵育30min后,加入1mLPBS混匀,350g离心3min收集细胞去上清,加入0.5μLFITC标记的链霉亲和素(FITC-SA,Biolegend,Cat.No.405201)4℃孵育30min,加入1mLPBS混匀,350g离心3min收集细胞去上清,加入200μLPBS重悬细胞,流式细胞仪上机检测。检测结果如图1所示,CAR-Blocker-T组为44.6%。
一、CAR-T转染效率检测比对试验
(1)构建CAR的表达质粒
CAR是靶向CD19的CAR分子,序列是表1中的SEQIDNO:1~2。
(2)慢病毒的制备
采用三质粒包装方法,三质粒包括表达质粒、包装辅助质粒psPAX2(AddgeneID:#12260)和pMD2.G(AddgeneID:#12259)。制备流程如下:将冻存HEK293T细胞(购自中科院上海细胞研究所)复苏,用DMEM培养基(+10%FBS+1%P/S)(Cellgro10-013-CMR)置于10cm培养皿培养,复苏传代,采用PEI作为转染试剂,PEI:CAR的表达质粒(质量比)=2:1的条件转染。将CAR的表达质粒与PEI的混合物加入到Opti-MEM培养基(Gibco,cat#31985-070)中,再将此混合溶液加入到HEK293T细胞中。转染6小时后用2%FBS的新鲜培养基换液,72小时后,收集上清,超离的方式(80000g,4℃离心3小时)进行浓缩,浓缩好的病毒用0.22μm滤膜过滤除菌后重悬,待用。
(3)原代T细胞激活同实施例1步骤(3)。
(4)慢病毒基因转导
T细胞激活后24h,取5×105个细胞于24孔培养板,加入步骤(2)制备的慢病毒,以MOI=10(Multiplicity of Infection,感染复数,病毒量与细胞数的比值),补充激活培养基至1mL(培养基与前述原代T细胞激活所用培养基一致)。
(5)CAR-T转染效率检测
CAR-T细胞培养至12天,早期增殖慢,9~12天快速增殖。取出少量细胞,加入1mLPBS(Gibco,cat#C10010500BT)清洗细胞1遍,用100μLPBS重悬,加入3μL生物素偶联的CD19蛋白(Cat.No.CD9-H8259,10μg/mL)检测CAR,4℃孵育30min后,加入1mLPBS混匀,350g离心3min收集细胞去上清,加入0.5μLFITC标记的链霉亲和素(FITC-SA,Biolegend,Cat.No.405201)4℃孵育30min,加入1mLPBS混匀,350g离心3min收集细胞去上清,加入200μLPBS重悬细胞,流式细胞仪上机检测。检测结果如图1所示,CAR-T组的转染效率约52.1%。
由实施例1和对比例1可以看出CAR-T组的转染效率与CAR-Blocker-T组的转染效率相当。
二、CAR-T和CAR-Blocker-T细胞增殖活性比较
将CAR-T(或CAR-Blocker-T)细胞与靶细胞Raji肿瘤细胞(或K562肿瘤细胞)以1:3的比例体外共培养,其中,Raji是CD19阳性细胞,可以激发CAR-T细胞增殖;K562细胞是CD19阴性细胞;K562作为阴性对照组。CAR阳性细胞数为1×105/ml,Raji细胞数是3×105/ml共培养于24孔培养板,37℃培养,培养基同实施例1。在不同时间点记录不同组别CAR阳性细胞的数目。CAR阳性细胞的染色方法参照实施例1。实验结果如图2所示。
图2显示在不同的时间点CAR-T和CAR-Blocker-T在被Raji细胞刺激下均表现出扩增能力,而CAR-Blocker-T的扩增活性更强。K562共培养组,二者均未增殖。结果发现,表达阻断蛋白的CAR-Blocker-T比常规CAR-T细胞具备更强的增殖活性。
三、CAR-T和CAR-Blocker-T肿瘤杀伤活性比较
将CAR-T(或CAR-Blocker-T)细胞与靶细胞Raji-GFP肿瘤细胞(或K562-GFP肿瘤细胞)进行体外共培养,分别以1:5、1:1、5:1的比例进行试验。Raji肿瘤细胞数目定为5×105/ml,CAR-T细胞按比例添加,24孔培养板,37℃培养,培养基同实施例1。不同时间点比较Raji-GFP肿瘤细胞的残余数目。实验结果如图3、图4、图5所示。
K562作为阴性对照(1:1)不会被杀伤。K562细胞随时间数目增加,Raji细胞在不同组别均被杀伤,CAR-Blocker-T体现出更强的杀伤活性。图3、图4、图5显示三组比例下,肿瘤杀伤活性CAR-Blocker-T均较CAR-T有一定的优势,且CAR比例越低的组别,优势更明显。这暗示在较低的计量下CAR-Blocker-T可能具备更强的优势。可见,表达阻断蛋白的CAR-Blocker-T细胞体现出更强的肿瘤细胞杀伤活性。
四、阻断蛋白在NK细胞中的功能评估
NK细胞属固有免疫淋巴细胞,不需要激活即可以杀伤肿瘤细胞,本实施例探究阻断蛋白自身是否可以提高NK细胞的杀伤活性。PBMC来源健康人供者的外周血,NK细胞扩增试剂盒采用Corning NK Expansion kit(康宁,88-57-kit)。细胞培养至第5d时,开始进入快速扩增状态,进行病毒转染(GFP-Blocker共表达),转染方法同实施例1。细胞扩增至第12d,进行体外杀伤试验,NK(或Blocker-NK)分别与Raji细胞和K562细胞以1:1的比例共培养,96孔培养板,37℃培养,培养基同实施例1。培养6h后进行CD107a表达检测,采用试剂盒BDFastImmuneTMCD107a(H4A3)(BD,cat#641561)。实验结果如图6所示。
从图6可以看出,K562是对NK杀伤敏感的细胞,原代NK细胞对K562具备较强的杀伤,Blocker-NK的杀伤更强,而对Raji杀伤较弱;Raji是NK杀伤不敏感的细胞,NK仅仅具备微弱的杀伤活性,而Blocker-NK可以显著增强杀伤活性。实验结果可知,表达阻断蛋白的CAR-Blocker-NK细胞对K562和Raji细胞均具备更强的杀伤活性。
以上仅为本发明的具体实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
SEQUENCE LISTING
<110> 苏州璞惠卓越生物科技有限公司
<120> 一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞及其用途
<130> 2021
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 1458
<212> DNA
<213> 人工序列
<223> CAR19核酸序列
<400> 1
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140
agcgcagacg cccccgcgta caagcagggc cagaaccagc tctataacga gctcaatcta 1200
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1260
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1440
caggccctgc cccctcgc 1458
<210> 2
<211> 486
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<213> 人工序列
<223> CAR19蛋白序列
<400> 2
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His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
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Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
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Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
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Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
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Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
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Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
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Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
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Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
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Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
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Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
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Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
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Gln Ala Leu Pro Pro Arg
485
<210> 3
<211> 657
<212> DNA
<213> 人工序列
<223> 阻断蛋白Blocker核酸序列
<400> 3
atgacatcgc ggagatggtt tcaccccaac atcactggtg tggaggcaga gaatctcctg 60
ctgaccagag gagtcgatgg cagtttttta gcaaggccca gtaagagtaa ccctggagac 120
ttcactctgt ctgttagaag aaatggagct gttacccaca tcaagattca gaacactggg 180
gactactatg acctctatgg tggggagaag tttgccactt tggctgaact ggttcagtat 240
tacatggaac accatgggca gctgaaagag aagaatggag atgttatcga gctcaagtac 300
ccgctgaact gtgcagaccc tacctctgaa aggtggttcc atggtcactt gtctggaaaa 360
gaagcagaga agctgctgac ggagaagggc aagcatggca gcttcctcgt tcgagagagc 420
cagagccacc ccggagactt cgttctctcc gtgcgcactg gtgacgacaa aggggagagc 480
aacgacggca agtccaaagt gacccacgtc atgatccgct gtcaggagct gaaatacgac 540
gttggtgggg gagagcgctt tgactctctg acagacctgg tggagcatta caagaagaac 600
cccatggtgg agacgctggg cacagtcctg cagctcaagc agcccctcaa cacaact 657
<210> 4
<211> 219
<212> PRT
<213> 人工序列
<223> 阻断蛋白Blocker蛋白序列
<400> 4
Met Thr Ser Arg Arg Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala
1 5 10 15
Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg
20 25 30
Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn
35 40 45
Gly Ala Val Thr His Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp
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Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr
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Tyr Met Glu His His Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile
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Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu
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Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro
130 135 140
Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser
145 150 155 160
Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln Glu
165 170 175
Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp
180 185 190
Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr
195 200 205
Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Thr
210 215
<210> 5
<211> 2172
<212> DNA
<213> 人工序列
<223> CAR-Blocker的核酸序列
<400> 5
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140
agcgcagacg cccccgcgta caagcagggc cagaaccagc tctataacga gctcaatcta 1200
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1260
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1440
caggccctgc cccctcgcgc cacgaacttc tctctgttaa agcaagcagg agacgtggaa 1500
gaaaaccccg gtcctatgac atcgcggaga tggtttcacc ccaacatcac tggtgtggag 1560
gcagagaatc tcctgctgac cagaggagtc gatggcagtt ttttagcaag gcccagtaag 1620
agtaaccctg gagacttcac tctgtctgtt agaagaaatg gagctgttac ccacatcaag 1680
attcagaaca ctggggacta ctatgacctc tatggtgggg agaagtttgc cactttggct 1740
gaactggttc agtattacat ggaacaccat gggcagctga aagagaagaa tggagatgtt 1800
atcgagctca agtacccgct gaactgtgca gaccctacct ctgaaaggtg gttccatggt 1860
cacttgtctg gaaaagaagc agagaagctg ctgacggaga agggcaagca tggcagcttc 1920
ctcgttcgag agagccagag ccaccccgga gacttcgttc tctccgtgcg cactggtgac 1980
gacaaagggg agagcaacga cggcaagtcc aaagtgaccc acgtcatgat ccgctgtcag 2040
gagctgaaat acgacgttgg tgggggagag cgctttgact ctctgacaga cctggtggag 2100
cattacaaga agaaccccat ggtggagacg ctgggcacag tcctgcagct caagcagccc 2160
ctcaacacaa ct 2172
<210> 6
<211> 724
<212> PRT
<213> 人工序列
<223> CAR-Blocker的蛋白序列
<400> 6
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
340 345 350
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
355 360 365
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
485 490 495
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Thr Ser Arg Arg Trp Phe
500 505 510
His Pro Asn Ile Thr Gly Val Glu Ala Glu Asn Leu Leu Leu Thr Arg
515 520 525
Gly Val Asp Gly Ser Phe Leu Ala Arg Pro Ser Lys Ser Asn Pro Gly
530 535 540
Asp Phe Thr Leu Ser Val Arg Arg Asn Gly Ala Val Thr His Ile Lys
545 550 555 560
Ile Gln Asn Thr Gly Asp Tyr Tyr Asp Leu Tyr Gly Gly Glu Lys Phe
565 570 575
Ala Thr Leu Ala Glu Leu Val Gln Tyr Tyr Met Glu His His Gly Gln
580 585 590
Leu Lys Glu Lys Asn Gly Asp Val Ile Glu Leu Lys Tyr Pro Leu Asn
595 600 605
Cys Ala Asp Pro Thr Ser Glu Arg Trp Phe His Gly His Leu Ser Gly
610 615 620
Lys Glu Ala Glu Lys Leu Leu Thr Glu Lys Gly Lys His Gly Ser Phe
625 630 635 640
Leu Val Arg Glu Ser Gln Ser His Pro Gly Asp Phe Val Leu Ser Val
645 650 655
Arg Thr Gly Asp Asp Lys Gly Glu Ser Asn Asp Gly Lys Ser Lys Val
660 665 670
Thr His Val Met Ile Arg Cys Gln Glu Leu Lys Tyr Asp Val Gly Gly
675 680 685
Gly Glu Arg Phe Asp Ser Leu Thr Asp Leu Val Glu His Tyr Lys Lys
690 695 700
Asn Pro Met Val Glu Thr Leu Gly Thr Val Leu Gln Leu Lys Gln Pro
705 710 715 720
Leu Asn Thr Thr
Claims (6)
1.一种抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞,其特征在于:阻断蛋白与嵌合抗原受体共表达于免疫细胞,阻断蛋白阻隔免疫细胞负调控信号的转导,增强免疫细胞激活信号;所述阻断蛋白的核酸序列如SEQ ID NO:3、蛋白序列如SEQ ID NO:4。
2.根据权利要求1所述的抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞,其特征在于:所述阻断蛋白与嵌合抗原受体共表达的核酸序列如SEQ ID NO:5、蛋白序列如SEQ ID NO:6。
3.根据权利要求1所述的抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞,其特征在于:所述免疫细胞为T细胞或NK细胞。
4.如权利要求1-3任意一项所述的抑制蛋白阻断型嵌合抗原受体修饰的免疫细胞在制备治疗恶性肿瘤的药物的用途。
5.根据权要求4所述的用途,其特征在于:所述药物用于血液恶性肿瘤。
6.根据权要求4所述的用途,其特征在于:所述药物用于靶向CD19的血液恶性肿瘤。
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