CN103145849B - 嵌合抗原受体及其用途 - Google Patents
嵌合抗原受体及其用途 Download PDFInfo
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- CN103145849B CN103145849B CN201310053109.7A CN201310053109A CN103145849B CN 103145849 B CN103145849 B CN 103145849B CN 201310053109 A CN201310053109 A CN 201310053109A CN 103145849 B CN103145849 B CN 103145849B
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Abstract
本发明属于肿瘤生物技术领域，公开了一种嵌合抗原受体的制备及其应用。该嵌合抗原受体由人抗EB病毒潜伏膜蛋白1的单链抗体、人抗体IgG1的CH2CH3及免疫共刺激信号分子CD28、CD134及CD3ζ的胞内信号结构串联构成。该嵌合抗原受体用于修饰T淋巴细胞，修饰后的淋巴细胞可用于EB病毒相关的肿瘤的治疗，以及制备抗EB病毒相关肿瘤的药物。
Description
技术领域
本发明属于肿瘤生物制药领域，具体涉及一种嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ的制备及其用途。
背景技术
嵌合抗原受体（chimeric antigen receptor，CAR）是由抗原特异性的受体（如单链抗体scFv），间隔序列（spacer），跨膜序列（TM Domain）和胞内共刺激信号分子组成。间隔序列可以是hIgG1、hIgG4、hIgD、CD7或CD8等，跨膜序列可以是CD3ζ、CD4、CD7、CD8、FcεRIγ、H2-Kb等。胞内共刺激信号分子可以是CD28、CD134、CD137、CD244、FcεRIγ、CD3ζ等。根据胞内共刺激信号分子的组成的差异，CAR被分为三代。第一代CAR仅含有一个胞内的信号分子（FcεRIγ或CD3ζ）。通过对CAR分子胞内区的信号分子的改变，显著提高了CAR修饰的的T淋巴细胞在体内对肿瘤细胞的杀伤力及在增强了在体内抗原刺激下的增殖能力及延长了存活周期。根据共刺激信号分子的数量将CAR又分为第二代（含有两个共刺激信号分子）和第三代（含有三个共刺激信号分子）。CAR修饰的T淋巴细胞在体内能够通过其单链抗体特异的识别相关肿瘤表面抗原，然后通过胞内共刺激信号分子将识别的信号传递到细胞内，激活T淋巴细胞的杀伤性，杀伤肿瘤细胞。
CAR修饰的T细胞（CART）用于治疗相关肿瘤，通过对患者的T淋巴细胞的改造，使T淋巴细胞能够通过其表达的CAR分子识别肿瘤相关抗原，从而激活，释放各种细胞因子，杀伤肿瘤细胞。因此这种改造的T淋巴细胞具有很好的靶向性，对肿瘤抗原的识别不受主要组织相容性复合体（MHC）的限制。另外在治疗过程中是对患者自身的T细胞进行改造，并且改造的T细胞表达的scFv也是人的，所以避免患者自身对CART细胞的排斥，保证CART细胞回输到患者体内后的活性。
目前的过继细胞免疫治疗主要有CIK细胞，DC-CIK细胞等，但是CIK细胞由于没有特异性的肿瘤杀伤作用，故在临床上的疗效有限，而DC-CIK虽然对肿瘤有特异性杀伤，但是DC细胞的制备成本较高，并且从外周血能够分离的DC细胞的数量也有限，并且用于刺激DC细胞的特异抗原制备较困难，而目前使用较多的是肿瘤细胞的裂解物，大大降低了DC-CIK细胞的特异性，故在临床上DC-CIK的疗效不显著。
LMP1是EB病毒表达潜在膜蛋白，是EB病毒表达的唯一确定具有转化能力的蛋白，可使大鼠成纤维细胞发生转化，使其能够不依赖于生长。本实验通过LMP1胞外区制备的抗原筛选天然人Fab噬菌体库，获得的抗LMP1的Fab与鼻咽癌细胞表面的LMP1有很好的亲和力，并且在0.5μM浓度时对肿瘤细胞的生长抑制大于率50%。本发明以该Fab序列设计合成的抗LMP1的scFv。
发明内容
本发明的目的是为解决目前T细胞治疗过程中，抗原呈递细胞制备困难，且成本较高，制备周期较长，重复性差等问题。
为了解决上述问题，本发明提供一种嵌合抗原受体，该嵌合抗原受体由人抗EB病毒潜伏膜蛋白1（LMP1）的单链抗体（scFv），人IgG1分子Fc区的CH2CH3及T细胞共刺激信号分子CD28、CD134（OX40）及CD3ζ的胞内信号结构串联构成；其氨基酸序列如序列表SEQ ID NO.1 所示；其编码的基因序列如序列表中的SEQ ID NO.3所示。
该嵌合抗原受体针对的人抗EB病毒潜伏膜蛋白1(LMP1)的单链抗体，其氨基酸序列如序列表中的SEQ ID NO.4 所示。其编码的基因序列如序列表中的SEQ ID NO.5所示。
该嵌合抗原受体的氨基末端含有一个信号肽，其氨基酸序列如序列表中的SEQ ID NO.6 所示。
该嵌合抗原受体的单链抗体的重链和轻链分子之间有个(gly4ser)3连接肽，(gly4ser)3连接肽即Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
Ser。
该嵌合抗原受体以IgG1分子的CH2CH3及CD28、CD134、CD3ζ的胞内信号结构域串联而成的结构域为T细胞共刺激信号传导结构，其氨基酸序列如序列表中的SEQ ID NO.9所示。
该嵌合抗原受体中的T细胞共刺激信号分子除了是CD28-CD134-CD3ζ还可以是CD28-CD3ζ，CD28-CD137(4-1BB)-CD3ζ。
所述的嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ在制备EB病毒相关肿瘤药物中的应用。
所述的嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ用于EB病毒相关的肿瘤治疗。该嵌合抗原受体采用逆转录病毒或慢病毒感染T细胞，制备嵌合抗原受体T细胞（CART），用于EB病毒相关的肿瘤治疗。
EB病毒相关的肿瘤包括鼻咽癌、淋巴瘤、神经母细胞瘤、胃癌。
本发明根据本实验室噬菌体展示技术筛选到的人抗LMP1的Fab序列（专利申请号：201110364065），经密码子优化，在5’加上信号肽，全基因合成抗LMP1的scFv序列，并将合成的scFV序列克隆到pSFG-CH2CH3-CD28
-CD3ζ载体中，即构建成LMP1- scFv-CH2CH3-CD28-CD3ζ嵌合抗原受体，然后通过Gateway重组克隆技术将合成的CD134片段克隆到LMP1-scFv-CH2CH3-CD28-CD3ζ中，即获得本发明的嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ。
利用该嵌合抗原受体与逆转录病毒的包装质粒PeqPam3及RD114
env在293T细胞中包装成逆转录病毒。利用该逆转录病毒感染T淋巴细胞，使淋巴细胞表达该抗原受体。通过ELISPLOT检测该嵌合抗原受体T（CART）细胞在LMP1抗原刺激下IFN-γ的分泌及通过流式检测该CART细胞对LMP1阳性的鼻咽癌细胞的杀伤作用。因此本发明所述的嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ可以在EB病毒相关的肿瘤的T细胞治疗中应用，可以用于制备抗EB病毒相关肿瘤的药物。
有益效果：本发明提供的嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ是通过逆转录病毒技术制备的逆转录病毒，可以在体外感染患者的自身T淋巴细胞，修饰的T淋巴细胞即为LMP1特异的CART细胞。该CART细胞能够依赖LMP1特异的scFv序列特异识别EB病毒相关的表达LMP1的肿瘤的细胞，从而激活CART细胞，释放IFN-γ等杀伤肿瘤细胞。释放的IFN-γ除了自身能对肿瘤细胞有杀伤作用力，还能增强CART细胞进入肿瘤的内部，增强细胞治疗的效果。采用CAR技术制备的CART细胞制备的周期短，重复性较好。可以在EB病毒相关的肿瘤的T细胞治疗中应用，制备与EB病毒相关肿瘤的抗肿瘤药物。
附图说明
图1是本发明所述的合成LMP1 scFv序列在pUC57载体上用NcoI和BamHI酶切后释放的LMP1 scFv序列部分。泳道1为pUC57-LMP1-scFv用NcoI和BamHI双酶切；泳道2为15kb核酸分子量标准。
图2 是本发明所述的LMP1 scFv克隆到逆转录病毒pSFG-CH2CH3-CD28-CD134-CD3ζ中，用NcoI和SphI酶切鉴定，释放片段为LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ，大小为2.2kb，泳道1为CAR载体经NcoI和SphI酶切；泳道2为未酶切的CAR载体；泳道3为15kb的核酸分子量标准。
图3 是Western Blotting本发明构建的LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ转染293T细胞后的表达，分别用了抗人Fc的抗体和抗人CD3ζ检测。泳道1为293T对照；泳道2为转染的CAR载体的293T细胞。
图4 是流式检测本发明构建的LMP1-CAR修饰的T细胞中CAR分子的表达。
图5 是Western Blotting检测鼻咽癌SUNE1-LMP1-TOFA及SUNE1-LMP1-TONA细胞中，加强力霉素（DOX）前后的LMP1的表达，泳道1为SUNE1-LMP1-TOFA细胞蛋白，泳道2为SUNE1-LMP1-TOFA经DOX诱导的细胞蛋白，泳道3为SUNE1-LMP1-TONA细胞蛋白，泳道4为SUNE1-LMP1-TONA经DOX诱导的细胞蛋白。
图6 是Western Blotting检测淋巴瘤细胞U937，Raji，RPMI6666细胞中LMP1的表达，泳道1为U937细胞蛋白，泳道2为Raji细胞蛋白，泳道3为RPMI6666细胞蛋白。
图7 是本发明中LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ修饰的T细胞对鼻咽癌SUNE1-LMP1-TOFA及SUNE1-LMP1-TONA细胞在用DOX诱导前后的杀伤作用。
图8 是本发明中LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ修饰的T细胞对淋巴瘤细胞U937，Raji，RPMI6666的杀伤检测。
图9 是本发明中LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ修饰的T细胞在收到LMP1抗原刺激后IFN-γ的表达。
具体实施方式
实施例1：嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ逆转录病毒载体构建。
1.
根据本实验室噬菌体展示技术筛选到的抗LMP1胞外区的人Fab序列的VH链和VL链的氨基酸序列（序列参考专利“一种人源抗鼻咽癌LMP1胞外区抗体及其应用”，该专利申请号为201110364065），在OptimumGeneTM 基因设计软件内输入VH和VL的氨基酸序列，密码子偏爱性参数选择人，软件计算出优化VH（SEQ ID NO 2）和VL（SEQ ID NO 10）的核酸序列。参照Dutour,
A., V. Marin, et al. (2012). "In Vitro and In Vivo Antitumor Effect of
Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33 Acute Myeloid
Leukemia." Adv Hematol 2012 在构建嵌合抗原受体的时在单链抗体抗体（scFv）的5’端加上信号肽序列（SEQ ID NO 6 ），在VH和VL之间加入连接序列(gly4ser)3，故设计构建到嵌合抗原受体的scFv部分的结构为：信号肽-VH-(gly4ser)3-VL，对应的核酸序列（SEQ
ID NO 5）由南京金斯瑞生物技术有限公司进行合成，该公司将该片段合成后克隆在pUC57载体中，命名为pUC57-LMP1-scFv。
2.
提取pUC57-LMP1-scFv质粒用限制性内切酶NcoI和BamHI（Takara公司）进行酶切，酶切体系如下：pUC57-LMP1-scFv
2μg，NcoI和BamHI各1μl，10×酶切缓冲液2μl，用水补到20μl，37℃水浴过夜，酶切后的产物经琼脂糖凝胶电泳分离后，用琼脂糖凝胶DNA片段回收试剂盒（购自Axygene公司）进行DNA片段回收（结果见图1，从电泳图上可以看出pUC57-LMP1-scFv载体经NcoI和BamHI酶切后释放出LMP1-scFv的条带）；用同样的方法NcoI和BamH酶切pSFG-CH2CH3-CD28-CD3ζ载体(由Xiaotong Song博士赠送)，用琼脂糖凝胶电泳分离并回收酶切后的载体片段。将回收后的LMP1-scFv片段与酶切后的载体通过T4连接酶（购自Takara公司）进行连接，反应体系及条件如下：经NcoI和BamHI酶切的LMP1-scFv和pSFG-CH2CH3-CD28-CD3ζ载体各2μl，10×连接缓冲液1μl，连接酶1μl，用水补到10μl，16℃连接过夜。连接产物转化入E.coli DH5α感受态细菌中，37℃过夜培养后，挑取单个菌落，扩大培养后，用质粒提取试剂盒（购自Axygene公司）按照试剂盒操作说明提取阳性克隆的质粒，经酶切和测序检测，将正确的载体命名为LMP1-scFv--CH2CH3-CD28-CD3ζ。
3.
从CD134的3’端选择从214-255位的氨基酸（SEQ ID NO 7 ）作为CAR分子的共刺激信号分子与CD28及CD3ζ串联表达，由南京金斯瑞生物科技有限公司合成对应的核苷酸序列（SEQ
ID NO 8），然后通过gateway重组克隆技术（南京金斯瑞公司的CloneEZ®重组克隆试剂盒）将CD134的序列克隆到LMP1-scFv--CH2CH3-CD28-CD3ζ的CD28和CD3ζ之间，构建成功的质粒用NcoI和SphI进行酶切鉴定（如图2酶切结果表明阳性克隆能释放出目的条带）及测序鉴定正确。
实施例2：
嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ表达鉴定
采用大提试剂盒（天根生物）提取LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ逆转录病毒载体，并将质粒用PI转染试剂转染到人胚肾细胞293T中，24h后，用PBS洗涤一遍，加入RIPA细胞裂解液（已加Roche的蛋白酶抑制剂Cocktail Tablets），提取转染后293T细胞的蛋白，进行SDS-PAGE凝胶电泳，半干转膜，用鼠抗人CD3ζ抗体及兔抗人Fc抗体4℃过夜孵育，然后用辣根过氧酶标记的抗小鼠及抗兔的二抗37℃孵育1h，最后在膜上加上ECL显色液进行显色。结果用抗人CD3ζ抗体及兔抗人Fc抗体均能购检测到CAR分子的表达，蛋白大小与理论的CAR蛋白一致，均为80kD（如图3）。
实施例3：
嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ修饰的T淋巴细胞的制备
1、 表达CAR分子逆转录病毒的包装制备
用天根质粒大提试剂盒提取逆转录病毒的包装载体pRD114和Peq-pam3质粒(由Xiaotong Song博士赠送)与LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ逆转录病毒载体共转染到293T细胞中，转染后48h收集细胞上清，用4000prm离心10min，然后用0.45μm的滤膜过滤，-80℃分装冻存。
2、 T淋巴细胞的制备
采取20ml健康志愿者的新鲜抗凝血，用淋巴分离液（购自GE公司）分离外周血单核细胞（PBMC）。分离的细胞用包被过CD3和CD28的平板刺激48h，用T淋巴细胞培养基GT-T551（购自TAKARA公司）加3%自身血浆进行诱导培养，得到T淋巴细胞。
3、 CART细胞制备
用50μg/ml的RetroNectin（购自TAKARA公司）包被非组织培养24孔板，每孔500μl，4℃过夜，然后每孔加入1.5ml逆转录病毒，32℃放置1h，弃上清，再次加入1.5ml的逆转录病毒，32℃放置1h，弃去上清后再孔内加入T淋巴细胞及逆转录病毒，从而获得表达LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ T细胞即CART细胞。
4、 流式检测CART细胞中CAR分子的表达
将表达LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ T细胞即CART细胞用FITC标记的抗人Fc抗体（购自Jackson公司）37℃孵育1h后，进行流式检测，检测结果如图4，白色的峰表示作为对照的T淋巴细胞，黑色的峰表示感染嵌合抗原受体的逆转录病的T淋巴细胞，结果表明本方法制备的CART细胞效率大于90%。
实施例4：
嵌合抗原受体LMP1-scFv-CH2CH3-CD28-CD134-CD3ζ修饰的T淋巴细胞对EB相关肿瘤细胞的杀伤作用
1、 Western Blotting检测鼻咽癌细胞中LMP1的表达
SUNE1-LMP1-TOFA和SUNE1-LMP1-TONA细胞均为鼻咽癌细胞（诺华公司赠送），前者采用Tet-off表达系统转入LMP1基因，该细胞在没有DOX刺激时能够表达LMP1蛋白，在加入DOX刺激后LMP1表达被抑制，而后采用Tet-on表达系统转入LMP1基因，该细胞在没有DOX刺激时不能够诱导表达LMP1，在DOX刺激后能够诱导细胞表达LMP1。培养SUNE1-LMP1-TOFA和SUNE1-LMP1-TONA分别用DOX刺激和未刺激，细胞用RIPA细胞裂解液（已加Roche的蛋白酶抑制剂Cocktail Tablets）冰上裂解30min后，提取细胞蛋白，进行Western Blotting检测，检测结果如图5，SUNE1-LMP1-TOFA和用DOX诱导的SUNE1-LMP1-TONA的细胞能够检测到LMP1的高表达，而SUNE1-LMP1-TONA和经DOX诱导的SUNE1-LMP1-TOFA细胞LMP1的表达明显下降。
2、 Western Blotting检测淋巴瘤细胞中LMP1的表达
选取对数生长期的不同的淋巴瘤细胞（U937，Raji，RPMI6666），提取细胞蛋白（方法同上），进行Western Blotting检测，检测结果如图6，Raji和RPMI6666细胞能够检测到LMP1的表达，而U937细胞不能检测到LMP1的表达。
3、 CART细胞对肿瘤细胞杀伤力检测
将肿瘤细胞用培养基调整到4×106/ml，加入终浓度为0.5μM calcein violet进行标记，冰上放置30min，用PBS洗涤三遍后，用1640培养基重悬细胞，计数。调整肿瘤细胞至4×106/ml，取250μl加入到24孔板内，按E:T为20:1；10:1；5:1； 1:1分别加入T细胞2×107；1×107；5×106； 1×106，共培养4h，每孔加入50μg PI，转到流式管中进行FACS检测。肿瘤细胞有鼻咽癌细胞SUNE1-LMP1-TOFA，SUNE1-LMP1-TOFA加DOX诱导，SUNE1-LMP1-TONA，SUNE1-LMP1-TONA加DOX诱导，检测结果（如图7）表明CART细胞对LMP1表达较高的SUNE1-LMP1-TOFA和DOX诱导的SUNE1-LMP1-TONA细胞杀伤力高于SUNE1-LMP1-TONA和DOX诱导的SUNE1-LMP1-TOFA细胞；淋巴瘤细胞U937，Raji，RPMI6666，检测结果（如图8）CART细胞对LMP1表达较高的Raji和RPMI6666的杀伤力高于未能检测到LMP1表达U937细胞。
4、 ELISPOT 检测CART细胞在受到LMP1抗原刺激后IFN-γ表达
用无菌ELISPOT包被液来稀释 IFN-γ抗体（1:250稀释），在 ELISPOT 板(Millipore, Cat. No. MAIPS4510) 上加入每孔 100μl， 放在4°C冰箱过夜，进行包被。第二天从板上吸掉包被液。用PBS 洗板两次， 200 μl/孔。每孔加入200 μl 含血清的细胞培养液RPMI-1640， 在37℃放置1小时。洗去含血清的细胞培养液RPMI-1640， 用PBS再洗三次。准备LMP1胞外区多肽， 稀释在含血清的细胞培养液RPMI-1640， 调至终浓度为1μg/ml。每孔加100ul。
准备CART细胞，调至1×106/ml，每孔加100ul，终浓度为1×105/孔。37℃, 5% CO2
培养24 小时。24小时后， 洗掉细胞， 用PBS洗板三次。稀释生物素标记的抗IFN-γ抗体（1:250稀释）， 每孔加100μl。培养2小时。洗掉抗体， 再用PBS洗4次。准备Avidin-HRP， 加100ul进每孔。室温放置45分钟。洗掉Avidin-HRP， 用PBS-tween20洗3次，然后用PBS洗3次。准备AEC溶液，加入100ul每孔，室温10-60分钟，观察斑点形成用流水洗孔， 中止反应。等板干，计数(结果如图9)，结果表明CART细胞在特异的LMP1抗原刺激下能够分泌IFN-γ。
SEQUENCE LISTING
<110> 冯, 振卿
<120> 嵌合抗原受体及其用途
<130>
<160> 10
<170> PatentIn version 3.3
<210> 1
<211> 718
<212> PRT
<213> 人工序列
<400> 1
Met Asp Trp
Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro
20 25 30
Gly Arg Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
35 40 45
Ser Tyr Gly
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
50 55 60
Trp Val Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
65 70 75 80
Ser Val Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
85 90 95
Leu Tyr Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala
Ser Arg Tyr Cys Ser Ser Thr Ser Cys Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly
Gly Ser Gly Gly Gly Gly Ser Glu Leu Gln Met Thr Gln
145 150 155 160
Ser Pro Ser
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
165 170 175
Cys Arg Ala
Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
195 200 205
Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
225 230 235 240
Tyr Cys Gln
Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr
245 250 255
Lys Leu Glu
Ile Lys Leu Glu Asp Pro Ala Glu Pro Lys Ser Pro Asp
260 265 270
Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
275 280 285
Pro Ser Val
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
290 295 300
Ser Arg Thr
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
305 310 315 320
Asp Pro Glu
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
325 330 335
Asn Ala Lys
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
340 345 350
Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
355 360 365
Glu Tyr Lys
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
370 375 380
Lys Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
385 390 395 400
Thr Leu Pro
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
405 410 415
Thr Cys Leu
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
420 425 430
Glu Ser Asn
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
435 440 445
Leu Asp Ser
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
450 455 460
Lys Ser Arg
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
465 470 475 480
Glu Ala Leu
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
485 490 495
Gly Lys Lys
Asp Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val
500 505 510
Leu Ala Cys
Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
515 520 525
Val Arg Ser
Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
530 535 540
Thr Pro Arg
Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
545 550 555 560
Pro Pro Arg
Asp Phe Ala Ala Tyr Arg Ser Arg Asp Gln Arg Leu Pro
565 570 575
Pro Asp Ala
His Lys Pro Pro Gly Gly Gly Ser Phe Arg Thr Pro Ile
580 585 590
Gln Glu Glu
Gln Ala Asp Ala His Ser Thr Leu Ala Lys Ile Arg Val
595 600 605
Lys Phe Ser
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
610 615 620
Gln Leu Tyr
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
625 630 635 640
Leu Asp Lys
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
645 650 655
Arg Lys Asn
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
660 665 670
Met Ala Glu
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
675 680 685
Gly Lys Gly
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
690 695 700
Asp Thr Tyr
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
705 710 715
<210> 2
<211> 330
<212> DNA
<213> 人工序列
<400> 2
gctgcagatg
acacagagcc cctcctctct gtcagcaagc gtgggcgatc gagtcaccat 60
cacatgccgg
gcctcccagt ctattagttc atacctgaac tggtatcagc agaagcccgg 120
caaagcccct
aagctgctga tctacgcagc cagctccctg cagtccggag tgccatctcg 180
attcagtggg
tcaggaagcg gcacagactt tactctgacc atttctagtc tgcagcccga 240
agatttcgct
acttactatt gtcagcagag ctacagcaca ccatacacct ttgggcaggg 300
aactaaactg
gaaatcaagc tcgaggatcc 330
<210> 3
<211> 2157
<212> DNA
<213> 人工序列
<400> 3
atggattgga
tttggaggat tctgtttctg gtgggggctg ctactggggc tcacgaagtg 60
cagctgctgg
agtcaggggg cggggtggtc cagcctggcc ggtccctgag actgtcttgt 120
gccgctagtg
ggttcacctt tagctcctac ggaatgcact gggtgcgcca ggcaccaggc 180
aaaggactgg
agtgggtggc tgtcatctgg tatgacggca gcaacaaata ctatgctgat 240
agcgtcaagg
ggaggttcac catttcacgc gacaacagca agaatacact gtacctgcag 300
atgaatagcc
tgagagctga agatactgca gtgtactatt gcgcatccag gtattgttct 360
agtacctctt
gctactttga ctattgggga cagggcacac tggtgactgt ctcaagcgga 420
ggaggaggca
gtggaggagg agggtccgga ggcgggggat ctgagctgca gatgacacag 480
agcccctcct
ctctgtcagc aagcgtgggc gatcgagtca ccatcacatg ccgggcctcc 540
cagtctatta
gttcatacct gaactggtat cagcagaagc ccggcaaagc ccctaagctg 600
ctgatctacg
cagccagctc cctgcagtcc ggagtgccat ctcgattcag tgggtcagga 660
agcggcacag
actttactct gaccatttct agtctgcagc ccgaagattt cgctacttac 720
tattgtcagc
agagctacag cacaccatac acctttgggc agggaactaa actggaaatc 780
aagctcgagg
atcccgccga gcccaaatct cctgacaaaa ctcacacatg cccaccgtgc 840
ccagcacctg
aactcctggg gggaccgtca gtcttcctct tccccccaaa acccaaggac 900
accctcatga
tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 960
gaccctgagg
tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1020
aagccgcggg
aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1080
caccaggact
ggctgaatgg caaggagtac aagtgcaagg tctccaacaa agccctccca 1140
gcccccatcg
agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1200
accctgcccc
catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc 1260
aaaggcttct
atcccagcga catcgccgtg gagtgggaga gcaatgggca accggagaac 1320
aactacaaga
ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1380
ctcaccgtgg
acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1440
gaggctctgc acaaccacta
cacgcagaag agcctctccc tgtctccggg taaaaaagat
1500
cccaaatttt
gggtgctggt ggtggttggt ggagtcctgg cttgctatag cttgctagta 1560
acagtggcct
ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 1620
tacatgaaca
tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1680
ccaccacgcg
acttcgcagc ctatcgctcc agggaccaga ggctgccccc cgatgcccac 1740
aagccccctg
ggggaggcag tttccggacc cccatccaag aggagcaggc cgacgcccac 1800
tccaccctgg
ccaagatcag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1860
cagggccaga
accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1920
ttggacaaga
gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1980
caggaaggcc
tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 2040
gggatgaaag
gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 2100
acagccacca
aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 2157
<210> 4
<211> 264
<212> PRT
<213> 人工序列
<400> 4
Met Asp Trp
Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro
20 25 30
Gly Arg Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
35 40 45
Ser Tyr Gly
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
50 55 60
Trp Val Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
65 70 75 80
Ser Val Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
85 90 95
Leu Tyr Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala
Ser Arg Tyr Cys Ser Ser Thr Ser Cys Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly
Gly Ser Gly Gly Gly Gly Ser Glu Leu Gln Met Thr Gln
145 150 155 160
Ser Pro Ser
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
165 170 175
Cys Arg Ala
Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
195 200 205
Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
210 215 220
Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
225 230 235 240
Tyr Cys Gln
Gln Ser Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr
245 250 255
Lys Leu Glu
Ile Lys Leu Glu Asp
260
<210> 5
<211> 794
<212> DNA
<213> 人工序列
<400> 5
atggattgga
tttggaggat tctgtttctg gtgggggctg ctactggggc tcacgaagtg 60
cagctgctgg
agtcaggggg cggggtggtc cagcctggcc ggtccctgag actgtcttgt 120
gccgctagtg
ggttcacctt tagctcctac ggaatgcact gggtgcgcca ggcaccaggc 180
aaaggactgg
agtgggtggc tgtcatctgg tatgacggca gcaacaaata ctatgctgat 240
agcgtcaagg
ggaggttcac catttcacgc gacaacagca agaatacact gtacctgcag 300
atgaatagcc
tgagagctga agatactgca gtgtactatt gcgcatccag gtattgttct 360
agtacctctt
gctactttga ctattgggga cagggcacac tggtgactgt ctcaagcgga 420
ggaggaggca
gtggaggagg agggtccgga ggcgggggat ctgagctgca gatgacacag 480
agcccctcct
ctctgtcagc aagcgtgggc gatcgagtca ccatcacatg ccgggcctcc 540
cagtctatta gttcatacct
gaactggtat cagcagaagc ccggcaaagc ccctaagctg
600
ctgatctacg
cagccagctc cctgcagtcc ggagtgccat ctcgattcag tgggtcagga 660
agcggcacag
actttactct gaccatttct agtctgcagc ccgaagattt cgctacttac 720
tattgtcagc
agagctacag cacaccatac acctttgggc agggaactaa actggaaatc 780
aagctcgagg
atcc
794
<210> 6
<211> 18
<212> PRT
<213> 人工序列
<400> 6
Met Asp Trp
Ile Trp Arg Ile Leu Phe Leu Val Gly Ala Ala Thr Gly
1 5 10 15
Ala His
<210> 7
<211> 36
<212> PRT
<213> 人工序列
<400> 7
Arg Asp Gln
Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly Gly
1 5 10 15
Ser Phe Arg
Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser Thr
20 25 30
Leu Ala Lys
Ile
35
<210> 8
<211> 108
<212> DNA
<213> 人工序列
<400> 8
agggaccaga
ggctgccccc cgatgcccac aagccccctg ggggaggcag tttccggacc 60
cccatccaag
aggagcaggc cgacgcccac tccaccctgg ccaagatc 108
<210> 9
<211> 454
<212> PRT
<213> 人工序列
<400> 9
Pro Ala Glu
Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10 15
Pro Ala Pro
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
20 25 30
Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
35 40 45
Val Val Val
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
50 55 60
Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
65 70 75 80
Glu Gln Tyr
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
85 90 95
His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
100 105 110
Lys Ala Leu
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
115 120 125
Gln Pro Arg
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
130 135 140
Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
145 150 155 160
Pro Ser Asp
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
165 170 175
Asn Tyr Lys
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
180 185 190
Leu Tyr Ser
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
195 200 205
Val Phe Ser
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
210 215 220
Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys Lys Asp Pro Lys Phe Trp
225 230 235 240
Val Leu Val
Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
245 250 255
Thr Val Ala
Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu
260 265 270
Leu His Ser
Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
275 280 285
Arg Lys His
Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
290 295 300
Arg Ser Arg
Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly
305 310 315 320
Gly Gly Ser
Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His
325 330 335
Ser Thr Leu
Ala Lys Ile Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
340 345 350
Pro Ala Tyr
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
355 360 365
Gly Arg Arg
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
370 375 380
Pro Glu Met
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
385 390 395 400
Tyr Asn Glu
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
405 410 415
Gly Met Lys
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
420 425 430
Gln Gly Leu
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
435 440 445
Gln Ala Leu
Pro Pro Arg
450
<210> 10
<211> 360
<212> DNA
<213> 人工序列
<400> 10
gaagtgcagc
tgctggagtc agggggcggg gtggtccagc ctggccggtc cctgagactg 60
tcttgtgccg
ctagtgggtt cacctttagc tcctacggaa tgcactgggt gcgccaggca 120
ccaggcaaag
gactggagtg ggtggctgtc atctggtatg acggcagcaa caaatactat 180
gctgatagcg
tcaaggggag gttcaccatt tcacgcgaca acagcaagaa tacactgtac 240
ctgcagatga
atagcctgag agctgaagat actgcagtgt actattgcgc atccaggtat 300
tgttctagta
cctcttgcta ctttgactat tggggacagg gcacactggt gactgtctca 360
Claims (5)
1.一种嵌合抗原受体，其特征在于：该嵌合抗原受体由人抗EB病毒潜伏膜蛋白1的单链抗体scFv，人IgG1分子Fc区的CH2CH3及T细胞共刺激信号分子CD28、CD134及CD3ζ的胞内信号结构串联构成；该嵌合抗原受体针对的人抗EB病毒潜伏膜蛋白1的单链抗体，其氨基酸序列如序列表中的SEQ ID NO.4 所示；该嵌合抗原受体的氨基末端含有一个信号肽，其氨基酸序列如序列表中的SEQ ID NO.6 所示；该嵌合抗原受体的单链抗体的重链和轻链分子之间有个Gly Gly Gly Gly Ser Gly Gly Gly Gly
Ser Gly Gly Gly Gly Ser连接肽。
2.如权利要求1中所述的嵌合抗原受体，其特征在于：该嵌合抗原受体的氨基酸序列如序列表SEQ ID NO.1 所示。
3.如权利要求1中所述的嵌合抗原受体，其特征在于：该嵌合抗原受体的核酸序列如序列表SEQ ID NO.3 所示。
4.如权利要求1中所述的嵌合抗原受体，其特征在于：该嵌合抗原受体以IgG1分子的CH2CH3及CD28、CD134、CD3ζ的胞内信号结构域串联而成的结构域为T细胞共刺激信号传导结构，其氨基酸序列如序列表中的SEQ ID NO.9所示。
5.如权利要求1中所述的嵌合抗原受体在制备抗EB病毒相关肿瘤药物中的应用。
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| WO2014039961A1 (en) | 2012-09-07 | 2014-03-13 | University Of Miami | Fusion proteins for promoting an immune response, nucleic acids encoding same, and methods of making and use thereof |
| GB201317929D0 (en) * | 2013-10-10 | 2013-11-27 | Ucl Business Plc | Chimeric antigen receptor |
| CN104561069A (zh) * | 2013-10-23 | 2015-04-29 | 深圳先进技术研究院 | 含重组嵌合抗原受体基因表达盒的微环dna重组母质粒、含该表达盒的微环dna及应用 |
| US10640569B2 (en) | 2013-12-19 | 2020-05-05 | Novartis Ag | Human mesothelin chimeric antigen receptors and uses thereof |
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