CN107034196A - 表达重组Tα1的过继免疫细胞及其制备方法和用途 - Google Patents
表达重组Tα1的过继免疫细胞及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种表达重组胸腺肽α1的过继免疫细胞及其制备方法和用途，过继免疫细胞为人源免疫细胞，过继免疫细胞表达的重组胸腺肽α1包括信号肽和胸腺肽α1。重组胸腺肽α1的氨基末端连接上人源分泌信号肽，将其编码基因利用基因工程技术转染过继免疫细胞，回输使用者体内后，可持续稳定表达重组胸腺肽α1，发挥“微型细胞药厂”的作用。如此，通过过继免疫细胞作为载体细胞，可在体内长期稳定表达重组胸腺肽α1，有效解决胸腺肽α1半衰期短、对制备纯度要求较高、经常注射给患者带来不便等弊端。
Description
技术领域
本发明涉及生物治疗与生物医药领域，特别涉及一种表达重组Tα1的过继免疫治疗细胞及其制备方法和用途。
背景技术
胸腺肽是一类胸腺上皮细胞产生的对淋巴细胞的分化、成熟和免疫活性具有重要作用的多肽激素的总称，又称胸腺激素或胸腺素。胸腺肽α1(Tα1)为胸腺肽α家族中的一员。近年来由于其具有较高的生物学活性和稳定性等而受到极大关注。Tα1由28个氨基酸组成，是一种针对T细胞的免疫增强剂。Tα1分子中不含半胱氨酸，因此无二硫键。Tα1无糖基化，唯一的修饰是N-端的乙酰化，但乙酰基的存在与否对Tα1生物活性并无显著影响。体外生物活性测定表明，Tα1的活性为TF5(胸腺五肽)的10～1000倍，且更耐酸、耐碱、耐热。
由于Tα1在组织中含量极少，要获得足够的天然的Tα1必须依赖于大量小牛胸腺和丙酮，而且在生产过程中还可能会带入多种变应原，这些因素限制了组织分离的Tα1在临床和科研中的应用。目前在中国市场上取得Tα1批准文号的产品有美国赛生公司的日达仙、海南双城的基泰、海南中和的和日和成都地奥的迈普欣。这些企业均通过化学合成方法生产。化学合成Tα1由于产率较低，致使其成本较高，而且作为进口药品，日达仙一直享受单独定价的权利，价格大约是国内仿制药的五倍，相应增加了患者的费用，使其临床应用受到了限制。
人工合成的Tα1具有效率高、无内毒素和的污染等特点，但其成本高，产量低，仍然做使其无法满足临床上的需求。随着基因工程技术的发展，出现了用真核或原核表达体系生产具有生物活性的Tα1的新途径。大肠杆菌是最常用的表达外源性蛋白的微生物，具有生长快，易培养和产量高的特点。由于Tα1分子量小，转录产物不需要剪切修饰，适合用大肠杆菌表达，国内外研究人员已经建立了相应的表达体，利用大肠杆菌可以对Tα1进行大规模生产。大肠杆菌毕竟是原核生物，其表达的Tα1在功能上是否会有所影响尚不清楚，于是很多研究人员开始着手于用真核表达体系表达Tα1。酵母菌是一种真核细胞微生物，广泛应用于工业生产过程。虽然通过基因工程技术能够利用原核和真核细胞大量表达Tα1，但分离和纯化它们有一定的难度，特别是纯化至临床应用水平，难度极大。所以至今为止，通过基因工程技术生产的还没能够应用于临床治疗当中。
此外，Tα1分子量小，体内半衰期短，临床应用需要反复静脉给药，给使用者带来不便，依从度差。因此，开发出新形式的Tα1给药方式，以求降低成本和方便临床应用，对于满足临床的需求显得十分重要和迫切。本发明因此而来。
发明内容
本发明的目的是提供一种表达重组Tα1的过继免疫细胞及其制备方法和用途，至少能够解决上述问题之一。
为实现上述目的，根据本发明的一个方面，提供了一种表达重组Tα1的过继免疫细胞，所述过继免疫细胞为人源免疫细胞，所述过继免疫细胞表达的重组Tα1包括人源分泌表达信号肽和人源Tα1。
进一步的，重组Tα1为人源GM-CSFR信号肽和人源Tα1的融合序列GS-Tα1，其氨基酸序列为：SEQ ID NO.1，基因序列为：SEQ ID NO.2；
或者，所述重组Tα1为人源酰胺化酶(PAM)信号肽和人源Tα1的融合序列PS-Tα1，其氨基酸序列为：SEQ ID NO.3，基因序列为：SEQ ID NO.4。
或者，所述重组Tα1为带有信号肽的人血白蛋白(HSA)和人源Tα1的融合序列HSA-Tα1，其氨基酸序列为：SEQ ID NO.5，基因序列为：SEQ ID NO.6。
进一步的，过继免疫细胞为αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种，所述过继免疫细胞为天然或人工培养的免疫细胞。
进一步的，过继免疫细胞的膜表面表达有靶标分子，靶标分子通过跨膜序列定位在细胞膜表面。
进一步的，靶标分子为CD19的全长或其截短片段，或CD20的全长或其截短片段。
进一步的，重组Tα1组成性表达或通过偶联诱导表达系统进行诱导表达。
进一步的，表达重组Tα1的过继免疫细胞还表达自杀基因/前药系统。
相应地，本发明还提供了上述表达重组Tα1的过继免疫细胞的方法，包括以下步骤：体外培养人源免疫细胞，制备编码重组Tα1和膜型分子靶标的基因载体，基因载体由信号肽序列-Tα1序列和信号肽序列-靶标分子序列-Linker-跨膜序列组合而成；将上述基因载体通过基因工程技术转染免疫细胞。
相应地，本发明还提供了上述表达重组Tα1的过继免疫细胞的应用，表达重组Tα1的过继免疫细胞用于肝病、肿瘤、严重感染的辅助治疗和保健、抗衰老应用。
本发明的有益效果为：
1、以过继免疫细胞为载体，在体内持续表达重组Tα1或HSA-Tα1融合蛋白，可解决Tα1半衰期短的弊端，无需短时间内反复给药，更加适合需要长期使用Tα1的患者或保健人群。
2、以过继免疫细胞为载体，在体内持续表达重组Tα1，可避免反复给药引起过敏或诱导抗体产生。
3、表达重组Tα1的过继免疫细胞同时膜表达靶标分子，可作为靶标检测外源基因转染效率、分离纯化重组免疫细胞、体内监测过继免疫细胞的增殖情况和在必要时靶向灭活过继免疫细胞，使本技术临床使用更加安全可控。
4、表达重组Tα1的过继免疫细胞可靶向免疫组织，在免疫组织局部分泌表达Tα1，提高机体免疫力，可用于肝病、肿瘤、严重感染的辅助治疗和保健、抗衰老应用。
具体实施方式
下面对本发明作进一步详细的说明。
本发明公开了一种表达重组Tα1的过继免疫细胞，所述过继免疫细胞为人源免疫细胞，所述过继免疫细胞表达的重组Tα1包括人源分泌表达信号肽和人源Tα1。过继免疫细胞为αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种，所述过继免疫细胞为天然或人工培养的免疫细胞。过继免疫细胞的膜表面表达有靶标分子，靶标分子通过跨膜序列定位在细胞膜表面。重组Tα1组成性表达或通过偶联诱导表达系统进行诱导表达。过继免疫细胞表达自杀基因/前药系统。
重组Tα1可以组成性表达，也可以偶联诱导表达系统进行诱导表达。诱导表达系统为四环素诱导表达系统、蜕皮激素(ecdysone)诱导表达系统、他克莫司(tacrolimus，FK506)/雷帕霉素(rapamycin)诱导系统或RU486诱导系统中的一种。
自杀基因/前药系统为单纯疱疹病毒1型胸腺嘧啶激酶/戊环鸟苷(HSV-tk/GCV)系统、带状疱疹病毒胸腺嘧啶激酶/阿糖甲氧基嘌呤(VZV-tk/Ara-M)系统、胞嘧啶脱氨酶/5氟胞嘧啶(CD/5FC)系统、细胞色素P450微粒体酶CYP2B1/环磷酰胺(CYP2B1/CPA)系统；细胞色素P450CYP4B1/氨基蒽(CYP4B1/2AA)系统、脱氧胞苷激酶/阿糖胞苷(dCK/Ara-C)系统、乌苷-黄嘌呤磷酸核糖基转移酶/6-硫黄嘌呤(gpt/6TX)系统、硝基还原酶/CB1954(NTR/CB1954)系统、嘌呤核苷磷酸化酶/6-甲基嘌呤脱氧核苷(PNP/6-MeP-dR)系统、胸腺嘧啶磷酸化酶/5’-脱氧-5-氟尿嘧啶(TP/5’-DFUR)系统、羧基肽酶G2/CMDA系统(CPG2/CMDA)、羧酸酯酶/CPT-11(CE/CPT-11)系统中的一种。
本发明还提供了上述的表达重组Tα1的过继免疫细胞的制备方法，包括以下步骤：体外培养人源免疫细胞，制备编码重组水蛭素和膜型分子靶标的基因载体，基因载体由信号肽序列-Tα1序列和信号肽序列-靶标分子序列-Linker-跨膜序列组合而成；将上述编码重组胸腺肽α1和靶标分子的基因载体通过基因工程技术转染免疫细胞。
基因工程技术为公知技术，所用基因转染系统包括慢病毒转染系统、逆转录病毒转染系统、腺病毒转染系统、腺相关病毒转染系统、睡美人转座子转染系统、质粒电转染系统。优选的，采用睡美人转座子转染系统或电转染系统。以瞬时表达载体，将重组胸腺肽α1基因导入过继免疫细胞，可使其外源基因表达量可控，避免过量表达的风险。
编码重组Tα1和膜型分子靶标的基因载体的结构为：信号肽-Tα1-IRES-信号肽-靶标分子-Linker-跨膜段，或者，信号肽-靶标分子-Linker-跨膜段-P2A-信号肽-Tα1。
上述的表达重组Tα1的过继免疫细胞用于肝病、肿瘤、严重感染的辅助治疗和保健、抗衰老应用，提高机体免疫力。
下面结合具体实施例对本发明作进一步详细的说明。
实施例1
表达重组Tα1的过继免疫细胞，过继免疫细胞为人源免疫细胞，过继免疫细胞表达的重组Tα1包括人源分泌表达信号肽和人源Tα1。过继免疫细胞为αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种，过继免疫细胞为天然或人工培养的免疫细胞。优选的过继免疫载体细胞为CIK、NK或γδT细胞，可同时发挥抗衰、保健、抗感染、抗肿瘤的细胞免疫治疗作用。
过继免疫细胞的膜表面表达有靶标分子，靶标分子通过跨膜序列定位在细胞膜表面。靶标分子为CD19的全长或其截短片段，或CD20的全长或其截短片段。
重组Tα1组成性表达或通过偶联诱导表达系统进行诱导表达。
表达重组Tα1的过继免疫细胞还可以表达自杀基因/前药系统。
本实施例的过继免疫细胞表达的重组Tα1人源GM-CSFR信号肽和人源Tα1的融合序列GS-Tα1，其氨基酸序列为：SEQ ID NO.1，基因序列为：SEQ ID NO.2。
表达重组Tα1的过继免疫细胞用于肝病、肿瘤、严重感染的辅助治疗和保健、抗衰老应用。
实施例2
本实施例的表达重组Tα1的过继免疫细胞与实施例1基本相同，不同之处在于，过继免疫细胞表达的重组Tα1为人源酰胺化酶信号肽和人源Tα1的融合序列PS-Tα1，其氨基酸序列为：SEQ ID NO.3，基因序列为：SEQ ID NO.4。
实施例3
本实施例的表达重组Tα1的过继免疫细胞与实施例1基本相同，不同之处在于，过继免疫细胞表达的重组Tα1为带有信号肽的人血白蛋白和人源Tα1的融合序列HSA-Tα1，其氨基酸序列为：SEQ ID NO.5，基因序列为：SEQ ID NO.6。
实施例4
本实施例提供了制备表达重组Tα1的免疫细胞的方法。包括步骤S-1～S4，具体如下。
S1、体外培养人源CIK细胞，包括步骤A的外周血单个核细胞(PBMC)采集和步骤B的CIK细胞培养。
A、PBMC的采集具有以下步骤：
A1、自患者体内抽取外周血50-100ml；
A2、淋巴细胞分离液密度梯度离心法进一步纯化PBMC；
A3、无血清培养液洗涤2次，获得纯度在90％以上的PBMC。
B、CIK细胞的培养：
B1、将PBMC按1～2×106/ml的浓度悬浮于无血清培养液中，加入1,000U/ml的重组人IFN-γ，37℃，5％CO2培养箱中培养；
B2、24h后加入50ng/ml的CD3单克隆抗体和300U/ml的重组人IL-2，刺激CIK细胞的生长和增殖；
注：此时也可同时加入100U/ml的重组人IL-1α。
B3、每3天半量换液或扩瓶一次，并补加重组人IL-2 300U/ml；
B4、在培养的第14d，收获CIK细胞。
其中，细胞培养基中还可添加5％～20％的自体血清。
在其他实施方式中，免疫细胞还可采用人源的αβT、γδT、NKT、NK、DC、CAR-T、CAR-NK、TCR-T等免疫细胞，也可以采用人源间充质干细胞(MSC)、人脐带血干细胞。
S2、制备重组基因载体。
C、依照Tα1的基因序列，在其N末端添加人源信号肽序列，化学合成基因片段，将其连接成编码基因。本实施列采用GS-Tα1，GS-Tα1的氨基酸序列为：SEQ ID NO.1，基因序列为：SEQ ID NO.2。化学合成基因片段，N端添加NheⅠ限制性酶切位点，C端添加EcoRⅠ限制性酶切位点。
D、本实施列采用靶标分子结构为：GM-CSFR信号肽-ΔCD20-Linker2-CD28跨膜段，其氨基酸序列为：SEQ ID NO.7，基因序列为SEQ ID NO.8。化学合成基因片段，N端添加BamHⅠ限制性酶切位点，C端添加NotⅠ限制性酶切位点。
E、应用基因工程技术制备编码重组水蛭素和膜型分子靶标的基因载体，将信号肽序列-重组水蛭素序列和信号肽序列-靶标分子序列-Linker序列-跨膜段序列两段基因分别克隆入pIRES质粒的两个克隆位点。所用基因工程技术为公知技术，简述如下：
按照已有的方法建立标准的限制性内切酶消化体系，然后利用NheⅠ和EcoRⅠ处理pIRES质粒，回收大片段；利用相同的限制性内切酶NheⅠ和EcoRⅠ处理并回收GS-Tα1基因片段，然后与上述酶切好的载体pIRES大片段相连，构建出重组水蛭素表达质粒pIRES-GS-Tα1；转化大肠杆菌DH5α后，筛选出阳性克隆并扩增。
纯化pIRES-GS-Tα1质粒，然后利用BamHⅠ和NotⅠ处理pIRES-GS-Tα1质粒，回收大片段；利用相同的限制性内切酶BamHⅠ和NotⅠ处理并回收重组GM-CSFR信号肽-ΔCD20-Linker2-CD28跨膜段基因片段，然后与上述酶切好的pIRES-GS-Tα1载体大片段相连，构建出同时表达重组水蛭素和膜型分子靶标CD20的双表达质粒pIRES-GS-Tα1/CD20。转化大肠杆菌DH5α后，筛选出阳性克隆并扩增，纯化pIRES-GS-Tα1/CD20质粒。
S3、纯化经步骤S2得到的pIRES-GS-Tα1/CD20重组质粒，用该重组载体以质粒电转染方法转染步骤S1得到的CIK细胞，之后进行细胞培养36h以上，得到表达重组水蛭素的CIK细胞。
在其他实施方式中，重组载体通过基因转染免疫细胞的基因转染系统还可采用慢病毒转染系统、逆转录病毒转染系统、腺病毒转染系统、腺相关病毒转染系统或睡美人转座子转染系统。
S4、采用流式细胞仪检测靶标分子CD20的表达率，计算表达GS-Tα1的CIK的阳性转染率，按需要回输患者。
以上所述的仅是本发明的一些实施方式。对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
序 列 表
<110>何向锋
<120>表达重组Tα1 的过继免疫细胞及其制备方法和用途
<160>8
<210>1
<211>50
<212>PRT
<213>人工序列
<400>1
Met Val Leu Ala Gln Gly Leu Leu Ser Met Ala Leu Leu Ala Leu
5 10 15
Cys Trp Glu Arg Ser Leu Ala Ser Asp Ala Ala Val Asp Thr Ser
20 25 30
Ser Glu Ile Thr Thr Lys Asp Leu Lys Glu Lys Lys Glu Val Val
35 40 45
Glu Glu Ala Glu Asn
50
<210>2
<211>153
<212> DNA
<213>人工序列
<400>2
atggtgctgg cccaggggct gctctccatg gccctgctgg ccctgtgctg ggagcgcagc 60
ctggcatcag acgcagccgt agacaccagc tccgaaatca ccaccaagga cttaaaggag 120
aagaaggaag ttgtggaaga ggcagaaaat tag 153
<210>3
<211>48
<212>PRT
<213>人工序列
<400>3
Met Ala Gly Arg Val Pro Ser Leu Leu Val Leu Leu Val Phe Pro
5 10 15
Ser Ser Cys Leu Ala Ser Asp Ala Ala Val Asp Thr Ser Ser Glu
20 25 30
Ile Thr Thr Lys Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu
35 40 45
Ala Glu Asn
<210>4
<211>147
<212> DNA
<213>人工序列
<400>4
atggctggcc gcgtccctag cctgctagtt ctccttgttt ttccaagcag ctgtttggct 60
tcagacgcag ccgtagacac cagctccgaa atcaccacca aggacttaaa ggagaagaag 120
gaagttgtgg aagaggcaga aaattag 147
<210>5
<211>637
<212>PRT
<213>人工序列
<400>5
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser
5 10 15
Ala Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu
20 25 30
Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala
35 40 45
Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
50 55 60
Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys
65 70 75
Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu
80 85 90
His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg
95 100 105
Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
110 115 120
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn
125 130 135
Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala
140 145 150
Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu
155 160 175
Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
180 185 190
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala
195 200 205
Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg
210 215 220
Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala
225 230 235
Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
240 245 250
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val
255 260 265
Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys
270 275 280
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala
285 290 295
Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
300 305 310
Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala
315 320 325
Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala
330 335 340
Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu
345 350 355
Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
360 365 370
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys
375 380 385
Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro
390 395 400
His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val
405 410 415
Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Lys
420 425 430
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr
435 440 445
Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val
450 455 450
Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro
455 460 465
Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp
485 490 495
Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro
500 505 510
Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu
515 520 525
Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
530 535 540
Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu
545 550 555
Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala
560 565 570
Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala
575 580 585
Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
590 595 600
Ala Ala Ser Gln Ala Ala Leu Gly Leu Ser Asp Ala Ala Val Asp
605 610 615
Thr Ser Ser Glu Ile Thr Thr Lys Asp Leu Lys Glu Lys Lys Glu
620 625 630
Val Val Glu Glu Ala Glu Asn
635
<210>6
<211>1914
<212> DNA
<213>人工序列
<400>6
atgaagtggg taacctttat ttcccttctt tttctcttta gctcggctta ttccaggggt 60
gtgtttcgtc gagatgcaca caagagtgag gttgctcatc ggtttaaaga tttgggagaa 120
gaaaatttca aagccttggt gttgattgcc tttgctcagt atcttcagca gtgtccattt 180
gaagatcatg taaaattagt gaatgaagta actgaatttg caaaaacatg tgtagctgat 240
gagtcagctg aaaattgtga caaatcactt catacccttt ttggagacaa attatgcaca 300
gttgcaactc ttcgtgaaac ctatggtgaa atggctgact gctgtgcaaa acaagaacct 360
gagagaaatg aatgcttctt gcaacacaaa gatgacaacc caaacctccc ccgattggtg 420
agaccagagg ttgatgtgat gtgcactgct tttcatgaca atgaagagac atttttgaaa 480
aaatacttat atgaaattgc cagaagacat ccttactttt atgccccgga actccttttc 540
tttgctaaaa ggtataaagc tgcttttaca gaatgttgcc aagctgctga taaagctgcc 600
tgcctgttgc caaagctcga tgaacttcgg gatgaaggga aggcttcgtc tgccaaacag 660
agactcaaat gtgccagtct ccaaaaattt ggagaaagag ctttcaaagc atgggcagtg 720
gctcgcctga gccagagatt tcccaaagct gagtttgcag aagtttccaa gttagtgaca 780
gatcttacca aagtccacac ggaatgctgc catggagatc tgcttgaatg tgctgatgac 840
agggcggacc ttgccaagta tatctgtgaa aatcaggatt cgatctccag taaactgaag 900
gaatgctgtg aaaaacctct gttggaaaaa tcccactgca ttgccgaagt ggaaaatgat 960
gagatgcctg ctgacttgcc ttcattagct gctgattttg ttgaaagtaa ggatgtttgc 1020
aaaaactatg ctgaggcaaa ggatgtcttc ctgggcatgt ttttgtatga atatgcaaga 1080
aggcatcctg attactctgt cgtgctgctg ctgagacttg ccaagacata tgaaaccact 1140
ctagagaagt gctgtgccgc tgcagatcct catgaatgct atgccaaagt gttcgatgaa 1200
tttaaacctc ttgtggaaga gcctcagaat ttaatcaaac aaaactgtga gctttttaag 1260
cagcttggag agtacaaatt ccagaatgcg ctattagttc gttacaccaa gaaagtaccc 1320
caagtgtcaa ctccaactct tgtagaggtc tcaagaaacc taggaaaagt gggcagcaaa 1380
tgttgtaaac atcctgaagc aaaaagaatg ccctgtgcag aagactatcta tccgtggtc 1440
ctgaaccagt tatgtgtgtt gcatgagaaa acgccagtaa gtgacagagtc acaaaatgc 1500
tgcacagagt ccttggtgaa caggcgacca tgcttttcag ctctggaagtc gatgaaaca 1560
tacgttccca aagagtttaa tgctgaaaca ttcaccttcc atgcagatat atgcacactt 1620
tctgagaagg agagacaaat caagaaacaa actgcacttg ttgagcttgt gaaacacaag 1680
cccaaggcaa caaaagagca actgaaagct gttatggatg atttcgcagc ttttgtagag 1740
aagtgctgca aggctgacga taaggagacc tgctttgccg aggagggtaa aaaacttgtt 1800
gctgcaagtc aagctgcctt aggcttatca gacgcagccg tagacaccag ctccgaaatc 1860
accaccaagg acttaaagga gaagaaggaa gttgtggaag aggcagaaaa ttag 1914
<210>7
<211>83
<212> PRT
<213>人工序列
<400>7
Met Val Leu Ala Gln Gly Leu Leu Ser Met Ala Leu Leu Ala Leu
5 10 15
Cys Trp Glu Arg Ser Leu Ala Asn Ile Tyr Asn Cys Glu ProAla
20 25 30
Asn Pro Ser Glu Lys Asn Ser Pro Ser Thr Gln Tyr Cys Tyr Ser
35 40 45
Ile Gln Ser Gly Gly Ser Gly Gly Pro Phe Trp Val Leu Val Val
50 55 60
Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala
65 70 75
Phe Ile Ile Phe Trp Val Arg Ser
80
<210>8
<211>252
<212> DNA
<213>人工序列
<400>8
atggtgctgg cccaggggct gctctccatg gccctgctgg ccctgtgctg ggagcgcagc 60
ctggcaaaca tatacaactg tgaaccagct aatccctctg agaaaaactc cccatctacc 120
caatactgtt acagcataca atctggcgga agcggaggcc ccttttgggt gctggtggtg 180
gttggtggag tcctggcttg ctatagcttg ctagtaacag tggcctttat tattttctgg 240
gtgaggagtt aa 252
Claims (9)
1.表达重组Tα1的过继免疫细胞，其特征在于，所述过继免疫细胞为人源免疫细胞，所述过继免疫细胞表达的重组Tα1包括人源分泌表达信号肽和人源胸腺肽α1。
2.根据权利要求1所述的表达重组Tα1的过继免疫细胞，其特征在于，所述重组Tα1为人源GM-CSFR信号肽和人源胸腺肽α1的融合序列GS-Tα1，其氨基酸序列为：SEQ ID NO.1，基因序列为：SEQ ID NO.2；
或者，所述重组Tα1为人源酰胺化酶信号肽和人源胸腺肽α1的融合序列PS-Tα1，其氨基酸序列为：SEQ ID NO.3，基因序列为：SEQ ID NO.4。
或者，所述重组Tα1为带有信号肽的人血白蛋白和人源胸腺肽α1的融合序列HSA-Tα1，其氨基酸序列为：SEQ ID NO.5，基因序列为：SEQ ID NO.6。
3.根据权利要求1所述的表达重组Tα1的过继免疫细胞，其特征在于，所述过继免疫细胞为αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种，所述过继免疫细胞为天然或人工培养的免疫细胞。
4.根据权利要求1所述的表达重组Tα1的过继免疫细胞，其特征在于，所述过继免疫细胞的膜表面表达有靶标分子，靶标分子通过跨膜序列定位在细胞膜表面。
5.根据权利要求4所述的表达重组Tα1的过继免疫细胞，其特征在于，所述靶标分子为CD19的全长或其截短片段，或CD20的全长或其截短片段。
6.根据权利要求1所述的表达重组Tα1的过继免疫细胞，其特征在于，所述重组Tα1组成性表达或通过偶联诱导表达系统进行诱导表达。
7.根据权利要求1所述的表达重组Tα1的过继免疫细胞，其特征在于，所述过继免疫细胞表达自杀基因/前药系统。
8.制备权利要求4所述的表达重组Tα1的过继免疫细胞的方法，其特征在于，包括以下步骤：体外培养人源免疫细胞；分别合成编码重组Tα1和膜型分子靶标的基因片段，并在重组编码基因的两端添加限制性酶切位点；将重组Tα1和膜型分子靶标的编码基因插入载体中制备成重组基因载体，基因载体含有信号肽序列-Tα1序列和信号肽序列-靶标分子序列-Linker-跨膜序列两段重组外源基因；将上述基因载体通过基因工程技术转染过继免疫细胞，获得表达重组Tα1和膜型分子靶标的过继免疫细胞。
9.权利要求1～7任一项所述表达重组Tα1的过继免疫细胞的应用，其特征在于，所述表达重组Tα1的过继免疫细胞用于肝病、肿瘤、严重感染的辅助治疗和保健、抗衰老应用。
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