CN109748975B - 一种双特异性嵌合抗原受体及其应用 - Google Patents
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Abstract
一种双特异性嵌合抗原受体及其应用，该双特异性嵌合抗原受体由CD8α，人源化抗Trop2和抗PD‑L1单链抗体，跨膜区CD8TM，以及胞内区CD28，CD137，和CD3ζ串联构成。本发明提供的嵌合抗原受体CD8α‑Trop2/PD‑L1 scFv‑CD8TM‑CD28‑CD137‑CD3ζ采用了逆转录病毒技术，可体外感染人T淋巴细胞，所获得的CAR‑T细胞可以通过CAR的单链抗体部分特异性的识别同时表达Trop2和PD‑L1抗原的肿瘤细胞，同时激活CAR‑T细胞，使其释放多种细胞因子，实现对肿瘤细胞的特异性杀伤作用。
Description
技术领域
本发明属于细胞免疫技术，具体涉及一种Trop2/PD-L1双特异性嵌合抗原受体及其应用。
背景技术
嵌合抗原受体T细胞免疫治疗（Chimeric Antigen Receptor T-cellImmunotherapy, CAR-T）用于肿瘤免疫细胞治疗己经取得很大的进展，特别是在血液系统肿瘤治疗方面取得了令人振奋的疗效。CAR-T细胞是将抗体的高亲和性和T淋巴细胞的杀伤作用相结合，通过构建特异性嵌合抗原受体载体，经基因修饰使T细胞表达这种嵌合抗原受体，即可特异性识别靶抗原从而杀伤肿瘤细胞。CAR的结构包括能够识别肿瘤抗原的单链抗体序列（scFv）和胞内免疫受体酪氨酸活化基序（ITMA，通常为CD3ζ）以及共刺激分子信号（CM，通常为CD28、CD134、CD137等），这样制备的CAR-T细胞一方面可以通过scFv靶向肿瘤细胞，另一方面通过胞内分子激活T细胞对肿瘤细胞的杀伤力。T细胞作为肿瘤免疫细胞治疗的效应细胞，主要原因有T细胞反应具有特异性，分泌各种细胞因子，杀伤肿瘤细胞；CAR-T细胞在体内可增殖，一旦被活化可进行1000倍的克隆扩增；CAR-T细胞可到达抗原所在位点并清除癌灶；CAR-T细胞反应具有记忆性，可较长时间维持治疗效果等。目前临床上采用的CAR-T细胞为各种T细胞的混合细胞群，包括CD4+，CD8+，记忆T细胞，效应T细胞等，不同的T细胞亚群可能在T细胞过继治疗过程中起着协同作用。
虽然CD19-CAR-T细胞治疗急性白血病已取得重大突破，但对实体瘤的治疗仍存在很多问题，从而导致疗效不佳。CAR-T嵌合的理想目标抗原是仅在肿瘤细胞高表达，而在正常组织中不表达。CAR-T细胞利用靶向抗原的单链抗体分子能特异性识别肿瘤细胞，进而通过免疫共刺激信号分子刺激，特异性地杀伤肿瘤细胞，并避免杀伤正常组织，减少毒副作用。一个单链抗体的CAR-T细胞仍然存在on-target/off tumor toxicity的风险，双特异性单链抗体则可大大降低这种风险。另外，抗原特异性T细胞在患者体内会受到负性调节因子的调控，使其抗肿瘤效应丧失或被削弱。经研究发现，体内的这种免疫抑制性环境主要来自肿瘤微环境，大量免疫抑制性分子和细胞可部分或完全抑制肿瘤特异性T细胞的增殖活化，发挥抗肿瘤效应，进而使抗原特异性T细胞回输治疗的效果被显著削弱，如目前研究较多的是程序性死亡受体-1（programmed death-1，PD-1）及其配体PD-L1（programmed deathligand 1，PD-L1）。
PD-1为负性协同刺激分子受体，其胞浆区含有一个免疫受体酪氨酸抑制基序（ITIM）和一个免疫受体酪氨酸转换基序（ITSM）。PD-1主要在活化的T、B和NK细胞上诱导表达。PD-1有PD-L1和PD-L2两个配体，PD-L1广泛表达于多种类型肿瘤细胞上，而PD-L2仅表达于活化的巨噬细胞、树突状细胞、骨髓来源的基质细胞和个别肿瘤细胞株。研究表明，PD-1随T细胞活化程度而逐渐上调，PD-1和PD-L1相互结合后引发抑制信号的产生，在肿瘤微环境中发挥着关键作用，不但能阻断T细胞活化第一、二信号，阻止效应性T细胞活化增殖，发挥抗肿瘤效应，而且还能辅助调节性T细胞（regμLatory cell, Treg）发挥抑制性功能，甚至诱导辅助性T细胞（T helper cells，Th）向Treg转化。PD-1/PD-L1在多种实体瘤中广泛存在，可能是CAR-T技术在实体瘤中效果不佳的主要原因之一。PD-1/PD-L1单克隆抗体在治疗实体瘤的临床试验中已经取得非常显著的疗效。有报道称，PD-L1在胃癌组织及胃癌转移淋巴组织中显著高表达，并与患者的生存预后相关。
人滋养层细胞表面抗原2（human trophoblast cell surface antigen 2，TACSTD2/Trop2/M1S1/GA733-1) 是一个膜表面抗原，位于染色体1q32。Trop2最早发现在人滋养层细胞表面，分子量约为36 kDa，是单跨膜蛋白，分为膜外区、跨膜区、膜内区和一个磷酸化的胞质尾。Trop2被TNF-α转化酶裂解为胞外域和胞内域，胞内域离开跨膜区后可以进入胞浆或者核内发挥作用。Trop2常过表达于不同的上皮组织肿瘤，特别是胃腺癌细胞膜表面，对肿瘤的恶性生物学行为有促进作用。可以作为许多恶性肿瘤靶向治疗的靶点。
发明内容
解决的技术问题：基于背景技术存在的技术问题，本发明的目的在于提供一种双特异性嵌合抗原受体及其应用。
技术方案：一种双特异性嵌合抗原受体，该双特异性嵌合抗原受体由CD8α，人源化抗Trop2和抗PD-L1单链抗体，跨膜区CD8TM，以及胞内区CD28，CD137，和CD3ζ串联构成。
编码上述双特异性嵌合抗原受体的氨基酸序列如SEQ ID NO.1所示。
含有编码双特异性嵌合抗原受体的核酸序列如SEQ ID NO.2所示。
编码上述人抗Trop2单链抗体的重链氨基酸序列如SEQ ID NO.3所示，轻链氨基酸序列如SEQ ID NO.4所示。
编码上述人抗Trop2单链抗体的重链核酸序列如SEQ ID NO.5所示，轻链核酸序列如SEQ ID NO.6所示。
编码上述人抗PD-L1单链抗体的重链氨基酸序列如SEQ ID NO.7所示，轻链氨基酸序列如SEQ ID NO.8所示。
编码上述人抗PD-L1单链抗体的重链核酸序列如SEQ ID NO.9所示，轻链核酸序列如SEQ ID NO.10所示。
上述CD8α，跨膜区CD8TM，以及胞内区CD28，CD137，和CD3ζ的胞内区串联构成的结果为信号转导结构域，其中氨基酸序列分别如SEQ ID NO.11、SEQ ID NO.13、SEQ IDNO.15、SEQ ID NO.17、SEQ ID NO.19所示。
编码上述信号转导结构域的核酸序列分别如SEQ ID NO.12、SEQ ID NO.14、SEQID NO.16、SEQ ID NO.18、SEQ ID NO.20所示。
上述双特异性嵌合抗原受体修饰的T淋巴细胞。
上述双特异性嵌合抗原受体修饰的T淋巴细胞在制备抗肿瘤药物中的应用。
一种抗胃癌药物，有效成分为上述双特异性嵌合抗原受体修饰的T淋巴细胞。
有益效果：本发明根据本实验室从全人源抗体库筛选出的抗Trop2抗体Fab和抗PD-L1抗体的Fab，经过密码子优化，在5’段加上信号肽，全基因合成嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28-CD137-CD3ζ，并将该合成的序列克隆到逆转录病毒载体中，构建出抗人Trop2/PD-L1 CAR表达质粒，即获得本发明的嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28-CD137-CD3ζ。
利用该嵌合抗原受体与逆转录病毒的包装质粒RD114env在293T细胞中对病毒进行包装，利用此逆转录病毒感染T淋巴细胞，使T细胞表达该嵌合抗原受体。将获得的CAR-T细胞在体外与肿瘤细胞共培养，通过流式细胞术检测CAR-T细胞表面抗原表达情况，CCK-8法检测该CAR-T细胞对Trop2/PD-L1不同表达水平的胃癌细胞的特异性杀伤作用，以证实该双特异性嵌合抗原受体修饰的T淋巴细胞对胃癌细胞的特异性杀伤作用，且效应细胞（E）和靶细胞（T）在20:1时，双特异性Trop2/PD-L1 CAR-T细胞杀伤能力(88.12%±6.08)高于单特异性CAR-T细胞(Trop2 CAR-T(67.07%±6.05)和PD-L1 CAR-T(51.03%±2.99))和独立对照组(CD19-CAR-T(36.97%± 4.07) 和CIK(33.12%±3.15))。因此本发明所述的嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28- CD137- CD3ζ可以在相关肿瘤治疗中得到应用。
本发明提供的嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28- CD137-CD3ζ采用了逆转录病毒技术，体外感染人T淋巴细胞，ELISA实验检测该双特异性Trop2/PD-L1CAR-T细胞在杀伤表达的Trop2和PD-L1的胃癌细胞时，释放出IFN-γ和IL- 2，且相比于单特异性CAR-T细胞组和独立对照组，双特异性的CAR-T细胞在杀伤过程中，能释放出最多的细胞因子（IFN-γ和IL- 2）。
本发明提供的嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28- CD137-CD3ζ采用了逆转录病毒技术，可体外感染人T淋巴细胞，所获得的CAR-T细胞可以通过CAR的单链抗体部分特异性的识别表达同时Trop2和PD-L1的肿瘤细胞，同时激活CAR-T细胞，使其释放多种细胞因子，实现对肿瘤细胞的特异性杀伤作用。
附图说明
图1是本发明所述的合成Trop2，PD-L1 scFv及跨膜区和胞内区序列条带的电泳图，A图泳道1为10000bp核酸分子量标准，泳道2为Trop2 scFv，泳道3为跨膜区和胞内信号区；B图泳道1为PD-L1 scFv，泳道2为2000bp核酸分子量标准。
图2是本发明所述的Trop2/PD-L1 CAR克隆到逆转录病毒载体中，用BamH I和Xho I双酶切鉴定，释放片段为CD8α-Trop2/PD-L1 scFv-CD8TM-CD28-CD137-CD3ζ，大小约为1.8kb，泳道1为2000bp的核酸分子量标准，泳道2为未酶切的CAR质粒，泳道3为经BamH I和Xho I双酶切的质粒。
图3是western blot检测本发明构建的CD8α-Trop2/PD-L1 scFv- CD8TM- CD28-CD137-CD3ζ转染293T细胞后的表达图，用抗人CD3ζ单克隆抗体检测。泳道1为转染了Trop2/PD-L1-CAR载体的293T细胞；泳道2为转染了CD19-CAR载体的293T细胞；泳道3为未转染CAR载体的293T细胞。
图4是流式检测本发明构建的Trop2/PD-L1-CAR修饰的T细胞中CAR分子的表达图。
图5是western blot检测胃癌细胞株BGC823上Trop2和PD-L1的表达图，正常胃上皮细胞株GES-1为对照细胞株。
图6是本发明Trop2/PD-L1-CAR双特异性嵌合抗原受体修饰T细胞对Trop2和PD-L1不同表达水平的胃癌细胞的杀伤作用检测图。将转染后的细胞转入无IL-12培养基中24h，分别与表达Trop2+和PD-L1+的BGC823、BGC823 shRNA-Trop2和shRNA-PD-L1、BGC823-shRNA-Trop2、BGC823-shRNA-PD-L1细胞单独孵育4h。均值±标准差由三个独立的实验计算。(A)以表达Trop2和PD-L1细胞的BGC823细胞作为CCK-8检测的靶细胞（T）。按x轴上指示的比例添加效应器细胞(E)。在各E：T比值上，不同组间的差异均有统计学意义(P<0.0 5)。(2)以Trop2+/PD-L1-BGC823细胞作为CCK-8检测的靶细胞。按x轴上指示的比例添加效应器细胞。(C)以Trop2-/PD-L1+BGC823细胞作为CCK-8检测的靶细胞。按x轴上指示的比例添加效应器细胞。(D)以Trop2-/PD-L1-BGC823细胞作为CCK-8检测的靶细胞。按x轴上指示的比例添加效应器细胞。**与单特异性CAR-T组比较，##与双特异性CAR-T组比较，P<0.001。
图7是本发明Trop2/PD-L1-CAR双特异性嵌合抗原受体修饰T细胞在对Trop2和PD-L1不同表达水平的胃癌细胞杀伤过程中细胞因子释放的检测图。(A) ELISA检测Trop2/PD-L1双特异性CAR-T细胞与Trop2+/PD-L1+BGC823细胞以10：1的比例孵育24h后产生的干扰素-γ，并与其他类型的CAR-T细胞进行比较。(B)用ELISA法检测Trop2/PD-L1 CAR-T细胞与Trop2+/PD-L1-BGC823细胞按E:T=10:1的比例培养24h后产生的IFN-γ，并与其他类型的CAR-T细胞进行比较。(C)用ELISA法检测双特异性Trop2/PD-L1 CAR-T细胞与Trop2-/PD-L1+BGC823细胞在E:T=10:1的条件下培养24h后产生的IFN-γ，并与其它类型的CAR-T细胞进行比较。(D)用ELISA法检测Trop2/PD-L1-CAR-T细胞与Trop2-/PD-L1-BGC823细胞按E:T=10:1的比例培养24h后产生的IFN-γ，并与其他类型的CAR-T细胞进行比较。(5)双特异性Trop2/PD-L1 CAR-T细胞与Trop2+/PD-L1+BGC823细胞按E:T=10:1的比例培养24h后，用ELISA法检测其释放的IF-2，并与其它类型的CAR-T细胞进行比较。(F)双特异性Trop2/PD-L1 CAR-T细胞与Trop2+/PD-L1-BGC823细胞按E:T=10:1的比例孵育24h后，用ELISA法检测IF-2的释放，并与其它类型的CAR-T细胞进行比较。(G)双特异性Trop2/PD-L1 CAR-T细胞与Trop2-/PD-L1+BGC823细胞按E:T=10:1的比例孵育24h后，用ELISA法检测IF-2的释放，并与其它类型的CAR-T细胞进行比较。(H)双特异性Trop2/PD-L1 CAR-T细胞与Trop2-/PD-L1-BGC823细胞按E:T=10:1的比例孵育24h后，用ELISA法检测IF-2的释放，并与其它类型的CAR-T细胞进行比较。**与单特异性CAR-T组比较，##与双特异性CAR-T组比较，P<0.001。
具体实施方式
下面通过具体实施例对本发明的技术方案进行详细说明。
实施例1
Trop2/PD-L1双特异性嵌合抗原受体逆转录病毒质粒的构建：
1. 根据本实验室噬菌体展示技术筛选到的抗Trop2及抗PD-L1胞外区的人Fab序列的VH和VL的氨基酸序列，Trop2 ：VH（SEQ ID NO.3）、VL（SEQ ID NO.4）；PD-L1：VH（SEQ IDNO.7）、VL（SEQ ID NO.8），利用Optimum Gene TM基因设计软件优化密码子序列，在不改变氨基酸序列的情况下使其更适合人的表达系统。在VH和VL之间加入连接肽(G4S)3，前面加上信号肽CD8α，构建获得的双特异性嵌合抗原受体的scFv部分结构为CD8α-Trop2 VH-(G4S)3-Trop2VL-(G4S)3-PD-L1 VH-(G4S)3- Trop2VL，连接处引入BamH I和Xho I酶切位点。同样的方法酶切Psfg- CD8TM- CD28-CD137-CD3ζ载体，用琼脂糖凝胶电泳，回收目的条带，结果如图1所示。
2. 回收的片段与酶切后的载体通过In-Fusion PCR（Takara公司）进行连接，连接体系如下，目的基因酶切产物 100ng、载体酶切产物 300ng、In-Fusion 1μL，加水补足至20μL体系，37℃ 15min，50℃ 15min，连接产物转化，取10μL产物加入DH5α感受态细胞中，37℃培养过夜，挑取单个菌落，扩大培养，用质粒提取试剂盒（Axygene公司）提取阳性克隆质粒，经酶切和测序检测，将正确的载体命名为CD8α-Trop2/PD-L1 scFv-CD8TM-CD28-CD137-CD3ζ。核酸序列如SEQ ID NO.2所示。
双特异性嵌合抗原受体逆转录病毒质粒用限制性内切酶BamH I和Xho I进行双酶切，酶切体系如下，BamH I 2μL、Xho I 2μL、10×K buffer 5μL、BSA 5μL、CAR质粒 5μg，加水补足到20μL，37℃水浴过夜，酶切产物用1%琼脂糖凝胶电泳，在紫外下切取目的条带，采用DNA凝胶回收试剂盒（Axygene公司）回收目的片段，其结果如图2所示。
实施例2
双特异性嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28- CD137- CD3ζ表达鉴定：
参照无内毒素质粒大提试剂盒内（天根生物）的操作说明书提取该双特异性嵌合抗原受体逆转录病毒质粒，用PI转染试剂转染到人胚肾细胞293T细胞中，48h后，用PBS洗一遍，用细胞蛋白提取试剂RIPA裂解细胞，提取转染后的293T细胞的蛋白经10%的SDS-PAGE进行凝胶电泳，转膜，用鼠抗人CD3ζ抗体孵育4℃过夜，再用辣根过氧酶标记的抗小鼠的二抗孵育1h，ECL显色。结果如图3所示，抗人CD3ζ抗体能检测到CAR分子表达，蛋白分子大小与理论相符，为75kDa（如图3）。
实施例3
双特异性嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28- CD137- CD3ζ 修饰的T淋巴细胞的制备：
1. 表达CAR分子的逆转录病毒的包装制备
质粒提取试剂盒提取逆转录病毒的包装质粒pRD114和Peg-pam3质粒，与CD8α-Trop2/PD-L1 scFv-CD8TM- CD28-CD137-CD3ζ逆转录病毒质粒共转染293T细胞，孵育48h后收集细胞上清，4000rpm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30mL健康志愿者的新鲜的抗凝血，用淋巴细胞分离液（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的孔板刺激48h，用T淋巴细胞培养基GT-T551（Takara公司）加3%自身血浆进行诱导培养，得到T淋巴细胞。
3. CAR-T细胞的制备
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CD8α-Trop2/PD-L1 scFv-CD8TM- CD28- CD137- CD3ζ T 细胞即CAR-T 细胞。
4. 流式检测CAR-T细胞中CAR分子的表达
将表达CD8α-Trop2/PD-L1 scFv-CD8TM- CD28-CD137-CD3ζ T 细胞即CAR-T 细胞用PE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，结果表明本方法制备的CAR-T细胞效率大于90%。
实施例4
嵌合抗原受体CD8α-Trop2/PD-L1 scFv-CD8TM- CD28-CD137-CD3ζ 修饰的T淋巴细胞对表达Trop2和PD-L1的胃癌细胞的杀伤作用：
1. Western blot检测胃癌细胞中Trop2和PD-L1的表达
BGC823为胃癌细胞，人胃粘膜上皮细胞GES-1（凯基公司），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30 min后，提取细胞蛋白，进行western blot 检测，检测结果如图5。
3. CAR-T细胞对胃癌细胞杀伤力检测
将肿瘤细胞用培养基调整到4×106/mL，冰上放置30min，用PBS洗涤三遍后，用1640培养基重悬细胞，计数。分别调整胃癌细胞（Trop2+/PD-L1+、Trop2+/PD-L1-、Trop2-/PD-L1+、Trop2-/PD-L1-）至4×106/mL，取250μL 加入到24孔板内，按E:T为20:1；10:1；5:1；2:1分别加入CAR-T细胞5×105；2×105；1×105；5×104，共培养4h，每孔设置3个复孔，细胞混匀后，置于96孔板内放入37℃，5%CO2的培养箱中孵育24小时。吸去细胞上清，使用PBS溶液清洗3遍，清洗掉孔中未贴壁的细胞，每孔加入10μL CCK-8溶液+90μL RPMI 1640培养基的混合液，37℃，5%CO2的培养箱中孵育4小时。CCK-8检测结果（如图6）表明CAR-T细胞对Trop2/PD-L1表达较高的BGC823细胞有较好的杀伤力，且杀伤能力高于单特异性CAR-T细胞(Trop2CAR-T和PD-L1 CAR-T)和独立对照组(CD19-CAR-T和CIK)。
4. ELISA检测CAR-T胞在杀伤过程中细胞因子IFN-γ和IL-2的释放情况。
用无菌包被液来稀释 IFN-γ抗体（1:250稀释）和IL-2（1:250稀释）, 在ELISA板上加入每孔100μL，放在4℃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200μL含ELISA Dliuent，在37℃放置1小时。吸去上清，用PBS再洗3次。
按E:T=10:1，将效应细胞（E）和靶细胞（T）加入24孔板中，置于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抗体和IL-2抗体，每孔加100μL，室温孵育1小时。洗掉抗体，再用PBS洗4 次。准备Avidin-HRP，加100μL 进每孔。室温放置1小时。洗掉Avidin-HRP，用PBS-tween20 洗3次，然后用PBS洗3次。准备TMB溶液，加入100μL 每孔，室温15分钟，加入50μL 1M H3PO4溶液终止反应。酶标仪测定各孔于450nm 处吸光度值(结果如图7)，结果表明双特异性Trop2/PD-L1 CAR-T细胞在杀伤表达的Trop2和PD-L1的胃癌细胞株BGC823时，释放出IFN-γ和IL- 2，且相比于单特异性CAR-T细胞组和独立对照组，双特异性的CAR-T细胞在杀伤过程中，能释放出最多的细胞因子（IFN-γ和IL- 2）。
序列表
<110> 南京市第一医院
<120> 一种双特异性嵌合抗原受体及其应用
<160> 20
<170> SIPOSequenceListing 1.0
<210> 1
<211> 826
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
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 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Asp Pro Gly Trp Gly Phe Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu
145 150 155 160
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
165 170 175
Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
195 200 205
Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
210 215 220
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
225 230 235 240
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe Thr Phe
245 250 255
Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly
260 265 270
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala
275 280 285
Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr
290 295 300
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val
305 310 315 320
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr
325 330 335
Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser
340 345 350
Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu
355 360 365
Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Arg
370 375 380
Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gly Gly Gly Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
405 410 415
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
420 425 430
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ile
435 440 445
Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
450 455 460
Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Ser Val Lys
465 470 475 480
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
485 490 495
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
500 505 510
Lys Asp Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln Gly
515 520 525
Thr Leu Val Thr Val Ser Ser Phe Trp Val Leu Val Val Val Gly Gly
530 535 540
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
545 550 555 560
Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn
565 570 575
Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr
580 585 590
Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Thr Thr Pro Ala
595 600 605
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
610 615 620
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
625 630 635 640
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
645 650 655
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
660 665 670
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
675 680 685
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
690 695 700
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
705 710 715 720
Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn
725 730 735
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
740 745 750
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
755 760 765
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
770 775 780
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
785 790 795 800
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
805 810 815
Ala Leu His Met Gln Ala Leu Pro Pro Arg
820 825
<210> 2
<211> 4177
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
ttgtctgctg cagcatcgtt ctgtgttgtc tctgtctgac tgtgtttctg tatttgtctg 60
aaaatatggg cccgggctag cctgttacca ctcccttaag tttgacctta ggtcactgga 120
aagatgtcga gcggatcgct cacaaccagt cggtagatgt caagaagaga cgttgggtta 180
ccttctgctc tgcagaatgg ccaaccttta acgtcggatg gccgcgagac ggcaccttta 240
accgagacct catcacccag gttaagatca aggtcttttc acctggcccg catggacacc 300
cagaccaggt cccctacatc gtgacctggg aagccttggc ttttgacccc cctccctggg 360
tcaagccctt tgtacaccct aagcctccgc ctcctcttcc tccatccgcc ccgtctctcc 420
cccttgaacc tcctcgttcg accccgcctc gatcctccct ttatccagcc ctcactcctt 480
ctctaggcgc ccccatatgg ccatatgaga tcttatatgg ggcacccccg ccccttgtaa 540
acttccctga ccctgacatg acaagagtta ctaacagccc ctctctccaa gctcacttac 600
aggctctcta cttagtccag cacgaagtct ggagacctct ggcggcagcc taccaagaac 660
aactggaccg accggtggta cctcaccctt accgagtcgg cgacacagtg tgggtccgcc 720
gacaccagac taagaaccta gaacctcgct ggaaaggacc ttacacagtc ctgctgacca 780
cccccaccgc cctcaaagta gacggcatcg cagcttggat acacgccgcc cacgtgaagg 840
ctgccgaccc cgggggtgga ccatcctcta gggatccatg gccttaccag tgaccgcctt 900
gctcctgccg ctggccttgc tgctccacgc cgccaggccg caggtgcagc tggtggagtc 960
tgggggaggc gtggtccagc ctgggaggtc cctgagactc tcctgtgcag cgtctggatt 1020
caccttcagt agctatggca tgcactgggt ccgccaggct ccaggcaagg ggctggagtg 1080
ggtggcagtt atatggtatg atggaagtaa taaatactat gcagactccg tgaagggccg 1140
attcaccatc tccagagaca attccaagaa cacgctgtat ctgcaaatga acagcctgag 1200
agccgaggac acggctgtgt attactgtgc gagagatccg ggctggggat ttgactactg 1260
gggccaggga accctggtca ccgtctcctc aggtggtggt ggttctggtg gtggtggttc 1320
tggcggcggc ggctccggtg gtggtggttc ggagctccag atgacccagt ctccatcctc 1380
cctgtctgca tctgtaggag acagagtcac catcacttgc cgggcaagtc agagcattag 1440
cagctattta aattggtatc agcagaaacc agggaaagcc cctaagctcc tgatctatgc 1500
tgcatccagt ttgcaaagtg gggtcccatc aaggttcagt ggcagtggat ctgggacaga 1560
tttcactctc accatcagca gtctgcaacc tgaagatttt gcaacttact actgtcaaca 1620
gagttacagt accccattca ctttcggccc tgggaccaaa gtggatatca aaggtggtgg 1680
tggttctggt ggtggtggtt ctggcggcgg cggctccggt ggtggtggtt cgcagtctgc 1740
cctgactcag cctgcctccg tgtctgggtc tcctggacag tcgatcacca tcagctgcac 1800
tggcacctcc agtgacgttg gcggctataa ctacgtctcc tggtaccaac agcacccagg 1860
caaggccccc aaactcatga tctacgaggt gtccaaccgg ccctcagggg tttctaacag 1920
attctctggc tccaagtccg gcaacacggc ctccctgacc atcagcggac tgcaggctga 1980
ggacgaggct gattattact gctcctcata tacctcctcc agcactagag tgttcggcac 2040
cggcacaaaa gtgaccgtgc tgggtggtgg tggttctggt ggtggtggtt ctggcggcgg 2100
cggctccggt ggtggtggtt cggaggtgca gctgttggag tctgggggag gactggtaca 2160
gcctgggggg tccctgagac tctcctgtgc agcctccgga ttcacctttt ccagctacat 2220
catgatgtgg gtccgccagg ctccagggaa gggcctggaa tgggtgtcat ccatttaccc 2280
ctccggcggc atcaccttct acgccgactc cgtgaagggc cggttcacca tctcccggga 2340
caattccaag aacacgctgt acctgcaaat gaactccctg cgggccgagg acacggccgt 2400
atattactgc gcgaaagaca agctgggcac cgtgaccacc gtggactact ggggccaggg 2460
caccctggtg acagtgtcct ccttttgggt gctggtggtg gttggtggag tcctggcttg 2520
ctatagcttg ctagtaacag tggcctttat tattttctgg gtgaggagta agaggagcag 2580
gctcctgcac agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca 2640
ttaccagccc tatgccccac cacgcgactt cgcagcctat cgctccacca cgacgccagc 2700
gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag cccctgtccc tgcgcccaga 2760
ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg gggctggact tcgcctgtga 2820
tatctacatc tgggcgccct tggccgggac ttgtggggtc cttctcctgt cactggttat 2880
caccctttac tgcaaacggg gcagaaagaa actcctgtat atattcaaac aaccatttat 2940
gagaccagta caaactactc aagaggaaga tggctgtagc tgccgatttc cagaagaaga 3000
agaaggagga tgtgaactga gagtgaagtt cagcaggagc gcagacgccc ccgcgtacaa 3060
gcagggccag aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt 3120
tttggacaag agacgtggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc 3180
tcaggaaggc ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat 3240
tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggtctcag 3300
tacagccacc aaggacacct acgacgccct tcacatgcag gccctgcccc ctcgctaaac 3360
gcgttagcat gcacctcgag atcgatccgg attagtccaa tttgttaaag acaggatatc 3420
agtggtccag gctctagttt tgactcaaca atatcaccag ctgaagccta tagagtacga 3480
gccatagata aaataaaaga ttttatttag tctccagaaa aaggggggaa tgaaagaccc 3540
cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat ggaaaaatac 3600
ataactgaga atagagaagt tcagatcaag gtcaggaaca gatggaacag ctgaatatgg 3660
gccaaacagg atatctgtgg taagcagttc ctgccccggc tcagggccaa gaacagatgg 3720
aacagctgaa tatgggccaa acaggatatc tgtggtaagc agttcctgcc ccggctcagg 3780
gccaagaaca gatggtcccc agatgcggtc cagccctcag cagtttctag agaaccatca 3840
gatgtttcca gggtgcccca aggacctgaa atgaccctgt gccttatttg aactaaccaa 3900
tcagttcgct tctcgcttct gttcgcgcgc ttctgctccc cgagctcaat aaaagagccc 3960
acaacccctc actcggggcg ccagtcctcc gattgactga gtcgcccggg tacccgtgta 4020
tccaataaac cctcttgcag ttgcatccga cttgtggtct cgctgttcct tgggagggtc 4080
tcctctgagt gattgactac ccgtcagcgg gggtctttca catgcagcat gtatcaaaat 4140
taatttggtt ttttttctta agtatttaca ttaaatg 4177
<210> 3
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Gly Trp Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 4
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Glu Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 5
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatccg 300
ggctggggat ttgactactg gggccaggga accctggtca ccgtctcctc a 351
<210> 6
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
gagctccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta ccccattcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 7
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 8
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 9
<211> 330
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
agctgcactg gcacctccag tgacgttggc ggctataact acgtctcctg gtaccaacag 120
cacccaggca aggcccccaa actcatgatc tacgaggtgt ccaaccggcc ctcaggggtt 180
tctaacagat tctctggctc caagtccggc aacacggcct ccctgaccat cagcggactg 240
caggctgagg acgaggctga ttattactgc tcctcatata cctcctccag cactagagtg 300
ttcggcaccg gcacaaaagt gaccgtgctg 330
<210> 10
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
gaggtgcagc tgttggagtc tgggggagga ctggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctccggatt caccttttcc agctacatca tgatgtgggt ccgccaggct 120
ccagggaagg gcctggaatg ggtgtcatcc atttacccct ccggcggcat caccttctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca attccaagaa cacgctgtac 240
ctgcaaatga actccctgcg ggccgaggac acggccgtat attactgcgc gaaagacaag 300
ctgggcaccg tgaccaccgt ggactactgg ggccagggca ccctggtgac agtgtcctcc 360
<210> 11
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
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
20
<210> 12
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 13
<211> 68
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
20 25 30
Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly
35 40 45
Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala
50 55 60
Ala Tyr Arg Ser
65
<210> 14
<211> 204
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
ttttgggtgc tggtggtggt tggtggagtc ctggcttgct atagcttgct agtaacagtg 60
gcctttatta ttttctgggt gaggagtaag aggagcaggc tcctgcacag tgactacatg 120
aacatgactc cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca 180
cgcgacttcg cagcctatcg ctcc 204
<210> 15
<211> 69
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
35 40 45
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
50 55 60
Ile Thr Leu Tyr Cys
65
<210> 16
<211> 207
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgatatcta catctgggcg cccttggccg ggacttgtgg ggtccttctc 180
ctgtcactgg ttatcaccct ttactgc 207
<210> 17
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 18
<211> 126
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 19
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 20
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
tacgacgccc ttcacatgca ggccctgccc cctcgc 336
Claims (4)
1.双特异性嵌合抗原受体，其特征在于该双特异性嵌合抗原受体由CD8α，人源化抗Trop2和抗PD-L1单链抗体，跨膜区CD8TM，以及胞内区CD28，CD137，和CD3ζ串联构成，所述双特异性嵌合抗原受体的氨基酸序列如SEQ ID NO.1所示。
2.编码权利要求1所述双特异性嵌合抗原受体的核酸，其特征在于序列如SEQ ID NO.2所示。
3.根据权利要求1所述双特异性嵌合抗原受体，其特征在于所述人抗Trop2单链抗体的重链氨基酸序列如SEQ ID NO.3所示，轻链氨基酸序列如SEQ ID NO.4所示；所述人抗PD-L1单链抗体的重链氨基酸序列如SEQ ID NO.8所示，轻链氨基酸序列如SEQ ID NO.7所示；。
4.编码权利要求3所述双特异性嵌合抗原受体的核酸，其特征在于编码所述人抗Trop2单链抗体的重链核酸序列如SEQ ID NO.5所示，轻链核酸序列如SEQ ID NO.6所示；编码所述人抗PD-L1单链抗体的重链核酸序列如SEQ ID NO.10所示，轻链核酸序列如SEQ ID NO.9所示。
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| CN112080527A (zh) * | 2020-09-16 | 2020-12-15 | 南京市第一医院 | 重组表达载体、耗竭减少的嵌合抗原受体t细胞及其应用 |
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