CN111944054B - 抗bcma的car及其表达载体和应用 - Google Patents
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Abstract
本发明属于基因工程技术领域，具体涉及一种抗BCMA抗原的CAR及其表达载体、CAR细胞及应用。所述CAR包含可识别BCMA抗原的抗原识别区、铰链区，跨膜区和胞内信号域；所述识别BCMA抗原的抗原识别区为抗BCMA单链抗体，其重链氨基酸序列如SEQ ID NO:1‑5任一所示，轻链氨基酸序列如SEQ ID NO:6‑10任一所示。所述CAR可稳定表达于病人来源的T淋巴细胞，并且具有更好的清除肿瘤细胞的能力，可以用于制备治疗恶性血液病的药物中针对恶性血液病的过继细胞治疗；所述抗BCMA抗原的CAR细胞不仅可以有效的清除表达BCMA抗原的肿瘤靶细胞，而对阴性抗原也就是不表达BCMA的肿瘤细胞没有毒性作用，因此安全性很高。
Description
技术领域
本发明属于基因工程技术领域，具体涉及一种抗BCMA抗原的CAR及其表达载体、CAR细胞及应用。
背景技术
BCMA全称为tumor necrosis factor receptor superfamily member 17，又称为B-cell maturation antigen(BCMA)或CD269或TNFRSF13A，主要表达于成熟B淋巴细胞和浆细胞表面，在MM组织和细胞中高表达，是治疗恶性血液病多的合适的靶点，而发性骨髓瘤(MM)属于恶性血液病中的一种。
多发性骨髓瘤又称multiple myeloma，简写为MM，具有高度异质性和耐药性MM复发概率高，目前不能治愈，已有的药物远不能解决MM患者的生存危机。而靶向CD19的CAR-T治疗在血液系统肿瘤中起到了较传统药物更优的疗效，利用CAR-T疗法治疗MM可能是一种可行并且有效的治疗方式。
虽然靶向CD19的嵌合抗原受体T细胞治疗在血液系统肿瘤治疗中取得了优异的成绩，但由于不同疾病所表达表面分子不同，MM细胞并不表达CD19，加之针对不同抗原不同抗体所激活的信号强度不同，因而筛选出针对MM的CAR组合仍然是CAR-T疗法治疗MM的关键点和难点。
单链抗体作为CAR中重要的组成部分，其选择对CAR-T疗效起到至关重要的作用，传统的鼠源抗体，因为鼠抗的异质性会引起人抗鼠抗体反应(Human anti-mouse antibodyreaction，HAMA)，导致CAR-T在循环系统中被很快清除，失去疗效。因此，治疗用鼠源单抗需要进行人源化修饰以提高抗体的人源化程度、减弱HAMA。但是抗体的改造通常会导致抗体失去原有抗原结合活性，因此需要对抗体进行改造，而后通过大量抗原抗体结合特异性、亲和力检测，从而筛选得到具有活性的抗体序列。目前以BCMA为靶标的靶向药物的临床试验，功效均很有限并且仍有安全性问题的发生。
因此，采用适用于CAR-T治疗的单链抗体(ScFv)以及筛选适合改造的人源化ScFv的CAR对于解决利用靶向BCMA的CAR-T治疗包括MM在内的恶性血液肿瘤是很有必要的。
发明内容
有鉴于此，本发明的目的之一在于提供一种抗BCMA抗原的CAR。所述抗BCMA抗原的CAR可以起到稳定表达于病人或健康供者来源的T淋巴细胞，并且具有更好的清除肿瘤细胞的能力，用于针对恶性血液病的过继细胞治疗。
为实现上述目的，本发明采用以下方案：
所述CAR包含可识别BCMA抗原的抗原识别区、铰链区，跨膜区和胞内信号域；所述识别BCMA抗原的抗原识别区为抗BCMA单链抗体，其重链的氨基酸序列如SEQ ID NO:1，轻链氨基酸序列如SEQ ID NO:6；或重链氨基酸序列如SEQ ID NO:2，轻链氨基酸序列如SEQ IDNO:7所示；或重链氨基酸序列如SEQ ID NO:3，轻链氨基酸序列如SEQ ID NO:8；或重链氨基酸序列如SEQ ID NO:4，轻链氨基酸序列如SEQ ID NO:9；或重链氨基酸序列如SEQ ID NO:5，轻链氨基酸序列如SEQ ID NO:10所示。
在有些实施例中ScFv的连接方式为VH-Linker-VL，在有些实施例中ScFv的连接方式也可以是VL-Linker-VH；Linker的序列可以是：GGGGSGGGGSGGGGS也可以是(GGGGS)n其中n＝1-6，还可以是GSTSGSGKPGSGEGSTKG。
进一步，所述CAR还包含前导肽序列，所述前导肽序列来源于CD8前导肽序列。
进一步，所述的CAR，其特征在于，所述抗BCMA单链抗体如SEQ ID NO11或SEQ IDNO:12或SEQ ID NO:13或SEQ ID NO:14或SEQ ID NO:15所示。
进一步，所述识别BCMA抗原的单链抗体的核苷酸序列如SEQ ID NO:20或SEQ IDNO:21或SEQ ID NO:22或SEQ ID NO:23或SEQ ID NO:24所示。
优选的，所述识别BCMA抗原的抗原识别区核苷酸序列如SEQ ID NO:21或SEQ IDNO:22或SEQ ID NO:23或SEQ ID NO:24所示
进一步，所述铰链区来源于CD8或IgG4或CD7。
进一步，所述铰链区的氨基酸序列如SEQ ID NO:16或SEQ ID NO:17或SEQ ID NO:18或SEQ ID NO:19所示。
进一步，所述铰链区的核苷酸序列如SEQ ID NO:25或26所示。
进一步，所述跨膜区来源于CD8分子或CD28分子跨膜区；所述包内信号来源于CD28或CD137包内信号区和CD3胞内序列。
进一步，所述胞内信号域的核苷酸序列如SEQ ID NO:27/28所示。
进一步，所述CAR的核苷酸序列如SEQ ID NO:29/30/31/32/33/34/35/36所示。
本发明的目的之二在于提供一种表达载体，具体为包含所述CAR的表达载体。所述包含所述CAR的表达载体进行T细胞转导时，CAR阳性表达率高，在病人细胞培养过程中很稳定，并且不会随着时间的推移会导致阳性率下降。
为实现上述目的，本发明采用以下方案：
所述载体选自慢病毒表达载体、逆转录病毒表达载体、腺病毒表达载体、腺相关病毒表达载体、DNA载体，RNA载体或质粒。
进一步，所述载体为慢病毒载体，所述慢病毒载体含有RRE元件和oPRE元件。
进一步，所述载体包含pUCOri序列、卡纳霉素或者氨苄青霉素抗性基因序列、SV40Ori序列、顺式元件、真核转录的启动子和CAR编码基因。
具体的，所述的载体，包含用于质粒复制的原核复制子pUCOri序列；用于目的菌株大量扩增的卡纳霉素或者氨苄青霉素抗性基因序列；用于增强真核细胞内的复制病毒复制子SV40Ori序列；用于慢病毒包装的慢病毒包装顺式元件；用于嵌合抗原受体基因的真核转录的启动子；以及用于组成集靶点识别、信号传递、信号启动于一体的CAR编码基因。
某些实施例中，所述载体包含CAR基因的表达载体启动子采用重复的5个HRE调控元件与弱启动的CMV mini Promoter联用构成5HRE-CMVmini启动子。
在某些实施方案中，载体包含左(5')逆转录病毒LTR、Psi(Ψ)包装信号、中心多嘌呤段/DNA瓣(cPPT/FLAP)、逆转录病毒导出元件、可操作地连接到编码本文所涵盖的CAR的多核苷酸的启动子和右(3')逆转录病毒LTR。
在某些实施方案中，CAR载体包含乙型肝炎病毒转录后调节元件(HPRE)或土拔鼠转录后调节元件(WPRE)；5'LTR的启动子经异源启动子置换，所述异源启动子是巨细胞病毒(CMV)启动子、劳斯肉瘤病毒(Rous Sarcoma Virus，RSV)启动子或猿猴病毒40(SV40)启动子。
本发明的目的之三在于提供一种CAR细胞，具体为包含所述表达载体的CAR细胞。肿瘤细胞表面的BCMA与所述的嵌合抗原受体的抗原识别区结合时，通过铰链区和跨膜区将信号传递至胞内，胞内信号域将信号转化为活化信号，激活效应细胞，效应细胞增殖、产生细胞因子从而杀伤肿瘤细胞。
为实现上述目的，本发明采用以下方案：
所述细胞选自干细胞、T细胞、NK细胞、单核细胞或巨噬细胞。
优选的，所述细胞为T细胞。
某些实施例中，所述细胞可以是γδT细胞、CD4阳性T细胞、CD8阳性T细胞，或者CD4阳性T细胞和CD8阳性T细胞以特定的比例混合的细胞；在某些实施例中，包含编码CAR基因的病毒转导NK细胞、单核细胞或巨噬细胞。
优选为慢病毒载体感染的T细胞。
本发明的目的之六在于提供一种所述CAR、所述表达载体和所述的CAR细胞的一种应用。
为实现上述目的，本发明采用以下方案：
所述应用具体为在制备治疗恶性血液病药物中的应用。
进一步，所述恶性血液病包括多发性骨髓瘤、急性粒细胞白血病、急性淋巴细胞白血病、B细胞淋巴瘤以及B细胞慢性淋巴细胞增殖性疾病。
进一步，所述恶性血液病的肿瘤细胞能够表达BCMA。
进一步，所述CAR细胞与活性剂联合使用，所述活性剂为免疫检查点抑制剂和/或多肽和/融合蛋白和/或抗体药物和/或激酶抑制剂。
具体的，这些活性剂可以是免疫检查点抑制剂，如PD1/PDL1、TIM3、CTLA4、LAG3以及TGFRβ抑制剂等；在其他实施方案中，这些活性剂可以是多肽或融合蛋白，如PD-1-CD137-CD3分子形成的融合蛋白；在其他实施方案中，这些活性剂可以是抗体药物，如单抗药物、双特异性抗体药物等；在其他实施方案中，这些活性剂可以是激酶抑制剂，如酪氨酸激酶抑制剂达沙替尼。具体的，所述药物的使用途径包括：口服、静脉注射、腹膜输注、皮下注射以及肿瘤或器官局部给药。
本发明的有益效果在于：
1)本发明提供的所述抗BCMA抗原的CAR可稳定表达于病人来源的T淋巴细胞，并且具有更好的清除肿瘤细胞的能力，可以用于制备治疗恶性血液病的药物中针对恶性血液病的过继细胞治疗。
2)本发明提供的所述抗BCMA抗原的CAR细胞不仅可以有效的清除表达BCMA抗原的肿瘤靶细胞，而对阴性抗原(不表达BCMA)的肿瘤细胞没有毒性作用，因此安全性很高；
3)本发明提供的所述抗BCMA抗原的CAR-T细胞因使用了人源化程度高的抗BCMA的抗体，因此具有降低CAR的免疫原性，，并且增强CAR-T在体内的持续和安全性。
附图说明
图1为不同的CAR示意图。
图2为多发性骨髓瘤细胞H929和阴性K562细胞BCMA表达检测。
图3为不同来源的肿瘤细胞BCMA表达检测。
图4为不同CAR的CAR-T细胞对BCMA阳性靶细胞的杀伤结果。
图5为不同CARCAR-T细胞对多种不表达BCMA的阴性杀伤作用。
图6为不同CARCAR-T细胞杀伤阳性靶细胞后细胞因子分泌。
图7为不同CARCAR-T细胞动物体内疗效。
图8为不同CARCAR-T细胞在低剂量时的体内疗效。
图9为不同CARCAR-T细胞受可溶性BCMA的影响情况。
具体实施方式
以下将参照附图，对本发明的优选实施例进行详细描述。优选实施例中未注明具体条件的实验方法，通常按照常规条件，例如分子克隆实验指南(第三版，J.萨姆布鲁克等著)中所述的条件，或按照制造厂商所建议的条件。所举实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
实施例1表达靶向人BCMA抗原的嵌合抗原受体的慢病毒制备
(1)制备靶向人BCMA抗原的嵌合抗原受体
合成含抗人BCMA抗原的单链抗体ScFv，hFc铰链区、跨膜区和胞内信号段的嵌合抗原受体序列。其结构如图1所示。其中抗人BCMA抗原的人源化单链抗体核苷酸序列如SEQ IDNO:20或SEQ ID NO:21或SEQ ID NO:22或SEQ ID NO:23或SEQ ID NO:24所示；铰链区的核苷酸序列是编码氨基酸SEQ ID NO:16或SEQ ID NO:17或SEQ ID NO:18或SEQ ID NO:19的DNA序列；跨膜区来源于CD8或CD28序列；胞内信号段来源于CD28或CD137及CD3序列。
(2)构建表达嵌合抗原受体的慢病毒载体
根据装载ScFv和跨膜结构以及胞内信号的不同，将嵌合抗原受体表达载体分别命名为BCMA016、BCMA017、BCMA018、BCMA019、BCMA028、BCMA029、BCMA038以及BCMA040。其核苷酸序列为SEQ ID NO:29或SEQ ID NO:30或SEQ ID NO:31或SEQ ID NO:32或SEQ ID NO:33或SEQ ID NO:34或SEQ ID NO:35或SEQ ID NO:36，并设计鼠源对照BCMA021。酶切反应按说明书进行。酶切产物分离后回收，然后将目的片段和载体片段通过T4连接酶(购自Promega公司)进行连接，获得表达嵌合抗原受体的慢病毒载体，质粒抽提试剂盒(Invitrogen公司)抽提质粒，具体方法见说明书。
(3)病毒制备
采用磷酸钙法对上述含有CAR基因的载体进行慢病毒的包装，分别收集培养48h、72h包装细胞上清利用PEG6000、NaCl进行病毒纯化。纯化后的病毒用培养基重悬，1.5mL EP管分装，-80℃保存备用。
(4)慢病毒滴度测定
病毒感染工程细胞细胞，感染72h后利用流式细胞技术测定病毒滴度，CAR抗原识别区的ScFv序列的轻链可被Protein-L识别，因此利用Protein-L可检测CAR阳性率，以CAR阳性率表示病毒感染293T细胞的能力，根据病毒感染293T细胞的能力计算病毒滴度，结果用TU/mL表示。滴度如下表所示，不同结构CAR均具有较好的病毒滴度。
| 病毒 | 滴度 | 病毒 | 滴度 |
| BCMA016 | 4.12E+08 | BCMA028 | 3.46E+08 |
| BCMA017 | 1.20E+08 | BCMA029 | 1.36E+08 |
| BCMA018 | 1.14E+08 | BCMA038 | 2.30E+08 |
| BCMA019 | 1.10E+08 | BCMA040 | 1.27E+08 |
| BCMA021 | 9.80E+07 |
实施例2BCMA抗原的嵌合抗原受体修饰T细胞的制备
(1)慢病毒感染T细胞
1)人外周血单核细胞的分离
利用梯度离心法进行淋巴细胞分离；离心后，取第二层白色淋巴细胞层，生理盐水洗涤，加入含有10％FBS的RPMI 1640完全培养基培养，得人外周血单核细胞。
2)慢病毒载体感染T淋巴细胞
获得PBMC细胞经抗CD3、CD28单克隆抗体活化后进行慢病毒感染；感染后继续培养10天左右进行CAR-T细胞体内体外生物学特性验证。获得的嵌合抗原受体T细胞，以对应慢病毒载体命名。
3)靶向人BCMA抗原的嵌合抗原受体(CAR)表达检测
在培养过程中对培养至第6天和9天的已感染病毒的T细胞进行CAR阳性率检测。检测方法为流式检测，抗体为：Protein-L-PE，Protein-L可识别抗体轻链，CAR抗原识别区的ScFv序列的轻链可被Protein-L识别，因此利用Protein-L可检测CAR阳性率。结果如下表所示不同病毒感染T细胞后CAR阳性率，不同结构的CAR均可以表达在细胞表面。
| 病毒 | CAR+ | 病毒 | CAR+ |
| BCMA016 | 84.4％ | BCMA016 | 53.52％ |
| BCMA016 | 64.7％ | BCMA016 | 26.00％ |
| BCMA016 | 80.5％ | BCMA016 | 6.40％ |
| BCMA016 | 39.00％ | BCMA016 | 4.20％ |
| BCMA016 | 40.2％ |
实施例3、表达靶向BCMA的嵌合抗原受体的T淋巴细胞抗肿瘤效果验证
以稳定表达萤火虫荧光素酶的BCMA阳性H929细胞(简称为H929-luc)、阴性细胞K562-Luc以及利用K562体外构建的BCMA高表达细胞K562-BCMA-Luc作为靶细胞，靶细胞BCMA表达检测如图2和图3所示，分别利用流式细胞术和RT方法检测H929为BCMA高表达阳性细胞，K562为BCMA阴性细胞。
由于CAR过多，因此有效性验证分为3组进行；采用实施例2的方法分别利用3批次白膜制备CAR-T细胞，制备CAR-T细胞。白膜为健康供者外周血单核细胞来源，第一批次CAR-T细胞按照16:1/8:1/4:1/2:1效靶比铺效应细胞，第二和第三批次CAR-T细胞均采用8:1/4:1/2:1效靶比铺效应细胞。使用
Luciferase Assay System(Promega Cat.#E2520)试剂盒提供的标准方法检测杀伤效果，杀伤率用下列公式计算：
杀伤结果如图4所示，由于不同供者细胞感染CAR阳性率有所差别，因此A、B和C这3批次最高杀伤率有所差异，但是并不影响不同CAR-T细胞杀伤趋势，在每批次杀伤组组内对比杀伤效果，结果表明所有构建的CAR-T均可以发挥体外的杀伤功能，其中BCMA016、BCMA017、BCMA018、BCMA019、BCMA028和BCMA029、具有更好的体外杀伤效果。
实施例4靶向BCMA的嵌合抗原受体T细胞特异性验证
BCMA阴性细胞选择：A549、PLC、Lovo、Hela和K562。效靶比8:1共培养6小时，观察与Control T相比CAR-T细胞对阴性细胞的杀伤能力，验证发明人所筛选的CAR-T细胞是否存在对BCMA阴性细胞脱靶杀伤。效应细胞为实施例3的第二和第三批次CAR-T细胞，结果如图5所示，其中A的阴性细胞选用A549、PLC、LOVO和K562细胞，其中B的阴性细胞选择A549、Hela和K562细胞，人源化ScFv来源的CAR-T细胞对阴性细胞均具有较好的特异性。
实施例5嵌合抗原受体T细胞经靶抗原刺激后细胞因子分泌能力检测
实施例2进行体外有效性杀伤的CAR-T细胞与靶细胞效靶比8:1共培养6小时后收集其上清，利用ELISA(酶联免疫)方法检测IFN-γ和IL-2的分泌情况。IFN-γ检测采用BDIFN-γ试剂盒检测，货号555142，实验步骤依据产品说明书进行。
结果如图6所示，其中A和B所有构建的CAR-T细胞杀伤阳性靶细胞后均可以分泌IFN-γ，证明所有构建的人源化CAR-T均可以识别靶细胞表面的BCMA并被其激活，其中BCMA019、BCMA021、BCMA016、BCMA029、BCMA038以及BCMA040均具有高的因子分泌能力。
实施例6表达靶向BCMA嵌合抗原受体T淋巴细胞在动物模型中的抗肿瘤效果验证
建立人BCMA阳性肿瘤细胞系的小鼠移植瘤模型用于验证表达靶向CD19的嵌合抗原受体的T淋巴细胞在动物模型中的抗肿瘤效果。
体内验证使用小鼠为NOD.Cg-PrkdcscidII2rgtm1Sug/JicCrl，简称NOG小鼠，为国际上CAR-T体内相关成瘤实验最常见品系。体内验证使用的成瘤靶细胞为K562-BCMA细胞。小鼠成瘤后，分别尾静脉注射CAR-T细胞，未感染病毒的PBMC细胞。注射CAR T细胞后每隔7天通过PerkinElmer公司的IVS活体成像系统拍照成像，显示肿瘤生长情况，荧光值越小存活小鼠越多治疗效果越好。期间每天观察小鼠存活情况并记录。结果如图7和图8所示：我们构建的BCMA016、BCMA017、BCMA018、BCMA019以及BCMA028均具有由于Control T的体内疗效，其中BCMA018、BCMA019、BCMA017以及BCMA028具有好的体内疗效。
实施例7可溶性BCMA对CAR-T有效性影响
在多发性骨髓瘤患者血液中具有高浓度的可溶性BCMA(sBCMA)，需要验证是否sBCMA的存在会影响CAR-T的有效性。
利用K562体外构建的BCMA高表达细胞K562-BCMA-Luc作为靶细胞，采用实施例5的方法制备CAR-T细胞，分为加入sBCMA组和未加sBCMA组两组，杀伤效靶比16:1，使用
Luciferase Assay System(Promega Cat.#E2520)试剂盒提供的标准方法检测杀伤效果，杀伤率用下列公式计算：
杀伤结果如图9所示，结果表明BCMA017、BCMA018、BCMA019和BCMA028体外活性均不受高浓度sBCMA的影响。
综上，我们筛选的包含氨基酸序列为SEQ ID NO:12或核酸序列为SEQ ID NO:21；氨基酸序列为SEQ ID NO:11或核酸序列为SEQ ID NO:20；氨基酸序列为SEQ ID NO:13或核酸序列为SEQ ID NO:22；氨基酸序列为SEQ ID NO:14或核酸序列为SEQ ID NO:23的CAR及其构建的CAR-T细胞发挥正常发挥功能。
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。
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<110> 重庆精准生物技术有限公司
<120> 抗BCMA的CAR及其表达载体和应用
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Tyr Ser Ile Asn Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Lys Trp
165 170 175
Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp
180 185 190
Phe Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala
195 200 205
Tyr Leu Gln Ile Ser Ser Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe
210 215 220
Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Ser Val Thr Val Ser Ser
245
<210> 16
<211> 47
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 16
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 17
<211> 36
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 17
Ala Pro Pro Arg Ala Ser Ala Leu Pro Ala Pro Pro Thr Gly Ser Ala
1 5 10 15
Leu Pro Asp Pro Gln Thr Ala Ser Ala Leu Pro Asp Pro Pro Ala Ala
20 25 30
Ser Ala Leu Pro
35
<210> 18
<211> 45
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 18
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Arg Pro Ala Ala
20 25 30
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Asp
35 40 45
<210> 19
<211> 229
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 19
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 20
<211> 738
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 20
gatatcgtgc tgacacagag ccctgcctcc ctggccgtga gcctgggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc gtgatcggcg cccacctgat ccactggtac 120
cagcagaagc ctggccagcc ccctaagctg ctgatctatc tggcctctaa cctggagacc 180
ggagtgcctg cacggttctc cggctctggc agcggcacag actttaccct gacaatcgat 240
ccagtggagg ccgaggacgt gggcgtgtac tattgcctgc agtccaggat cttcccccgc 300
acctttggcg gcggcacaaa gctggagatc aagggatcca cctctggaag cggcaagcca 360
ggatctggag agggaagcac aaagggacag gtgcagctgg tgcagagcgg accagaggtg 420
aagaagccag gagcctccgt gaaggtgtct tgtaaggcca gcggctacac cttcacagat 480
tattccatca actgggtgag gcaggcacca ggacagggac tggagtggat gggctggatc 540
aataccgaga cacgcgagcc cgcctacgcc tatgattttc ggggcagatt cgtgttttcc 600
ctggacacct ccgtgtctac agcctacctg cagatcagct ccctgaaggc cgaggacacc 660
gccgtgtact attgtgccct ggattactcc tatgccatgg actattgggg ccagggcacc 720
tctgtgacag tgtctagc 738
<210> 21
<211> 738
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 21
gacatcgtgc tgacacagag ccctgcctcc ctggccgtga gcccaggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc gtgatcggcg cccacctgat ccactggtac 120
cagcagaagc caggacagcc acctaagctg ctgatctatc tggcctctaa cctggagacc 180
ggagtgccag cacggttctc cggctctggc agcggcacag actttaccct gacaatcaat 240
cccgtggagg ccgaggatgt gggcgtgtac tattgcctgc agtccaggat cttccctcgc 300
acctttggcg gcggcacaaa gctggagatc aagggatcca cctctggaag cggcaagcca 360
ggatctggag agggaagcac aaagggacag gtgcagctgg tgcagagcgg agcagaggtg 420
aagaagccag gagcctccgt gaaggtgtct tgtaaggcca gcggctacac cttcacagac 480
tattccatca actgggtgag gcaggcacca ggacagggac tggagtggat gggctggatc 540
aataccgaga cacgcgagcc tgcctacgcc tatgactttc ggggcagatt cgtgttttcc 600
ctggatacct ccgtgtctac agcctacctg cagatcagct ccctgaaggc cgaggatacc 660
gccgtgtact attgtgccct ggactactcc tatgccatgg attattgggg ccagggcacc 720
tctgtgacag tgtctagc 738
<210> 22
<211> 738
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 22
gatatcgtgc tgacacagag ccctgcctcc ctggccgtga gcccaggaca gagggcaacc 60
atcacatgca gggcctccga gtctgtgagc gtgatcggcg cccacctgat ccactggtac 120
cagcagaagc caggacagcc acctaagctg ctgatctatc tggcctctaa cctggagacc 180
ggagtgccag cacggttctc cggctctggc agcggcacag actttaccct gacaatcgat 240
cccgtggagg aggaggacgt gggcgtgtac tattgcctgc agtcccggat cttccctaga 300
acctttggcg gcggcacaaa gctggagatc aagggatcca cctctggaag cggcaagcca 360
ggatctggag agggaagcac aaagggacag gtgcagctgg tgcagagcgg agcagaggtg 420
aagaagccag gagcctccgt gaaggtgtct tgtaaggcca gcggctacac cttcacagac 480
tattccatca actgggtgcg gagagcacca ggcaagggcc tgaagtggat gggatggatc 540
aataccgaga caagagagcc tgcctacgcc tatgacttcc ggggccgctt cgccttttcc 600
ctggagacct ccgcctctac agcctacctg cagatcagct ccctgaaggc cgaggacacc 660
gccgtgtact attgtgccct ggattactcc tatgccatgg actattgggg ccagggcacc 720
tctgtgacag tgtctagc 738
<210> 23
<211> 738
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 23
gacatcgtgc tgacccagag cccagccaca ctgagcctgt ccctgggaga gagggccaca 60
ctgtcctgca gagcctctga gagcgtgtcc gtgatcggcg cccacctgat ccactggtac 120
cagcagaagc caggacagcc acctaggctg ctgatctatc tggcctctaa cctggagacc 180
ggcgtgccta gcagattctc tggcagcggc tccggcacag actttaccct gacaatctct 240
ccactggagc ccgaggattt cgccgtgtac tattgcctgc agagcaggat cttcccacgc 300
acctttggcg gcggcacaaa gctggagatc aagggatcta ccagcggatc cggcaagcct 360
ggatccggag agggctctac aaagggacag gtgcagctgg tgcagtccgg acctgagctg 420
aagaagccag gcagctccgt gaaggtgagc tgtaaggcct ccggctacac cttcacagac 480
tatagcatca actgggtgag gcaggcacct ggacagggac tggagtggat gggctggatc 540
aataccgaga cacgcgagcc agcctacgcc tatgactttc ggggcagagt gaccatgaca 600
agggatacct ctatcagcac agcctacatg gagctgtcta gcctgcgctc cgaggatacc 660
gccgtgtact attgtgccct ggactactct tatgccatgg attattgggg ccagggcacc 720
ctggtgacag tgtcctct 738
<210> 24
<211> 738
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 24
gatatcgtgc tgacccagag cccagcctcc ctggccgtgt ccctgggcaa gagggccaca 60
atctcttgcc gcgcctccga gtctgtgagc gtgatcggcg cccacctgat ccactggtac 120
cagcagaagc ctggccagcc ccctaagctg ctgatctatc tggccagcaa cctggagacc 180
ggagtgccag cacggttctc cggctctggc agcggcacag actttaccct gacaatcgat 240
cccgtggagg aggaggacgt gggcgtgtac tattgcctgc agtcccggat cttccctaga 300
acctttggcg gcggcacaaa gctggagatc aagggatcca cctctggaag cggcaagcca 360
ggatctggag agggaagcac aaagggacag gtgcagctgg tgcagtctgg agcagaggtg 420
aagaagccag gagagtccgt gaaggtgtct tgtaaggcca gcggctacac cttcacagat 480
tattccatca actgggtgcg gagagcacca ggcaagggcc tgaagtggat gggatggatc 540
aataccgaga caagagagcc tgcctacgcc tatgatttca ggggccgctt cgtgtttagc 600
ctggacacct ccgcctctac agcctacctg cagatcagct ccctgaagta cgaggacacc 660
gccacatatt tttgtgccct ggattacagc tatgccatgg actattgggg ccagggcacc 720
tccgtgacag tgtctagc 738
<210> 25
<211> 135
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 25
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 26
<211> 108
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 26
gcaccacctc gggccagcgc cctgcctgca ccacccaccg gctccgccct gccagaccct 60
cagacagcat ctgccctgcc agatcctcca gcagcaagcg ccctgccc 108
<210> 27
<211> 537
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 27
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 120
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 180
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtacaag 240
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 300
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 360
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 420
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 480
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 537
<210> 28
<211> 462
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 28
aggagcaagc ggagcagagg cggccacagc gactacatga acatgacccc ccggaggcct 60
ggccccaccc ggaagcacta ccagccctac gcccctccca gggacttcgc cgcctaccgg 120
agccgggtga agttcagccg gagcgccgac gcccctgcct accagcaggg ccagagccag 180
ctgtacaacg agctgaacct gggccggagg gaggagtacg acgtgctgga caagcggaga 240
ggccgggacc ctgagatggg cggcaagccc cggagaaaga accctcagga gggcctgtat 300
aacgaactgc agaaagacaa gatggccgag gcctacagcg agatcggcat gaagggcgag 360
cggcggaggg gcaagggcca cgacggcctg taccagggcc tgagcaccgc caccaaggat 420
acctacgacg ccctgcacat gcaggccctg ccccctcgct aa 462
<210> 29
<211> 1497
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 29
gctagcatgg ccctgccagt gaccgccctg ctgctgcccc tggccctgct gctgcacgca 60
gcaaggcctg acatcgtgct gacacagagc cctgcctccc tggccgtgag cccaggacag 120
cgggccacca tcacatgcag agcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc aggacagcca cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgccagc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcaatc ccgtggaggc cgaggatgtg ggcgtgtact attgcctgca gtccaggatc 360
ttccctcgca cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
gcagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagact attccatcaa ctgggtgagg caggcaccag gacagggact ggagtggatg 600
ggctggatca ataccgagac acgcgagcct gcctacgcct atgactttcg gggcagattc 660
gtgttttccc tggatacctc cgtgtctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggataccg ccgtgtacta ttgtgccctg gactactcct atgccatgga ttattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgaga ccacgacgcc agcgccgcga 840
ccaccaacac cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc 900
cggccagcgg cggggggcgc agtgcacacg agggggctgg acttcgcctg tgatgaattc 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1080
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1140
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtacaag 1200
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1260
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1320
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1380
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1440
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1497
<210> 30
<211> 1497
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 30
gctagcatgg cactgcctgt gaccgccctg ctgctgccac tggccctgct gctgcacgca 60
gcaaggccag atatcgtgct gacacagagc cctgcctccc tggccgtgag cctgggacag 120
cgggccacca tcacatgcag agcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc tggccagccc cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgcctgc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcgatc cagtggaggc cgaggacgtg ggcgtgtact attgcctgca gtccaggatc 360
ttcccccgca cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
ccagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagatt attccatcaa ctgggtgagg caggcaccag gacagggact ggagtggatg 600
ggctggatca ataccgagac acgcgagccc gcctacgcct atgattttcg gggcagattc 660
gtgttttccc tggacacctc cgtgtctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggacaccg ccgtgtacta ttgtgccctg gattactcct atgccatgga ctattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgaga ccacgacgcc agcgccgcga 840
ccaccaacac cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc 900
cggccagcgg cggggggcgc agtgcacacg agggggctgg acttcgcctg tgatgaattc 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1080
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1140
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtacaag 1200
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1260
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1320
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1380
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1440
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1497
<210> 31
<211> 1497
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 31
gctagcatgg ccctgccagt gaccgccctg ctgctgcccc tggccctgct gctgcacgca 60
gcacggcctg atatcgtgct gacacagagc cctgcctccc tggccgtgag cccaggacag 120
agggcaacca tcacatgcag ggcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc aggacagcca cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgccagc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcgatc ccgtggagga ggaggacgtg ggcgtgtact attgcctgca gtcccggatc 360
ttccctagaa cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
gcagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagact attccatcaa ctgggtgcgg agagcaccag gcaagggcct gaagtggatg 600
ggatggatca ataccgagac aagagagcct gcctacgcct atgacttccg gggccgcttc 660
gccttttccc tggagacctc cgcctctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggacaccg ccgtgtacta ttgtgccctg gattactcct atgccatgga ctattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgaga ccacgacgcc agcgccgcga 840
ccaccaacac cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc 900
cggccagcgg cggggggcgc agtgcacacg agggggctgg acttcgcctg tgatgaattc 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1080
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1140
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtacaag 1200
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1260
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1320
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1380
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1440
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1497
<210> 32
<211> 1497
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 32
gctagcatgg cactgccagt gaccgccctg ctgctgcctc tggccctgct gctgcacgca 60
gcaaggccag acatcgtgct gacccagagc ccagccacac tgagcctgtc cctgggagag 120
agggccacac tgtcctgcag agcctctgag agcgtgtccg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc aggacagcca cctaggctgc tgatctatct ggcctctaac 240
ctggagaccg gcgtgcctag cagattctct ggcagcggct ccggcacaga ctttaccctg 300
acaatctctc cactggagcc cgaggatttc gccgtgtact attgcctgca gagcaggatc 360
ttcccacgca cctttggcgg cggcacaaag ctggagatca agggatctac cagcggatcc 420
ggcaagcctg gatccggaga gggctctaca aagggacagg tgcagctggt gcagtccgga 480
cctgagctga agaagccagg cagctccgtg aaggtgagct gtaaggcctc cggctacacc 540
ttcacagact atagcatcaa ctgggtgagg caggcacctg gacagggact ggagtggatg 600
ggctggatca ataccgagac acgcgagcca gcctacgcct atgactttcg gggcagagtg 660
accatgacaa gggatacctc tatcagcaca gcctacatgg agctgtctag cctgcgctcc 720
gaggataccg ccgtgtacta ttgtgccctg gactactctt atgccatgga ttattggggc 780
cagggcaccc tggtgacagt gtcctctctc gagctcgaga ccacgacgcc agcgccgcga 840
ccaccaacac cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc 900
cggccagcgg cggggggcgc agtgcacacg agggggctgg acttcgcctg tgatgaattc 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1080
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1140
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtacaag 1200
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1260
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1320
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1380
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1440
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1497
<210> 33
<211> 1491
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 33
gctagcatgg cactgcctgt gaccgccctg ctgctgccac tggccctgct gctgcacgca 60
gcaaggccag atatcgtgct gacacagagc cctgcctccc tggccgtgag cctgggacag 120
cgggccacca tcacatgcag agcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc tggccagccc cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgcctgc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcgatc cagtggaggc cgaggacgtg ggcgtgtact attgcctgca gtccaggatc 360
ttcccccgca cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
ccagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagatt attccatcaa ctgggtgagg caggcaccag gacagggact ggagtggatg 600
ggctggatca ataccgagac acgcgagccc gcctacgcct atgattttcg gggcagattc 660
gtgttttccc tggacacctc cgtgtctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggacaccg ccgtgtacta ttgtgccctg gattactcct atgccatgga ctattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgaga ccacgacgcc agcgccgcga 840
ccaccaacac cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgcgg 900
ccagcggcgg ggggcgcagt gcacacgagg gggctggact tcgccgatga attcatctac 960
atctgggcgc ccttggccgg gacttgtggg gtccttctcc tgtcactggt tatcaccctt 1020
tactgcaaac ggggcagaaa gaaactcctg tatatattca aacaaccatt tatgagacca 1080
gtacaaacta ctcaagagga agatggctgt agctgccgat ttccagaaga agaagaagga 1140
ggatgtgaac tgagagtgaa gttcagcagg agcgcagacg cccccgcgta caagcagggc 1200
cagaaccagc tctataacga gctcaatcta ggacgaagag aggagtacga tgttttggac 1260
aagagacgtg gccgggaccc tgagatgggg ggaaagccga gaaggaagaa ccctcaggaa 1320
ggcctgtaca atgaactgca gaaagataag atggcggagg cctacagtga gattgggatg 1380
aaaggcgagc gccggagggg caaggggcac gatggccttt accagggtct cagtacagcc 1440
accaaggaca cctacgacgc ccttcacatg caggccctgc cccctcgcta a 1491
<210> 34
<211> 1491
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 34
gctagcatgg ccctgccagt gaccgccctg ctgctgcccc tggccctgct gctgcacgca 60
gcacggcctg atatcgtgct gacacagagc cctgcctccc tggccgtgag cccaggacag 120
agggcaacca tcacatgcag ggcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc aggacagcca cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgccagc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcgatc ccgtggagga ggaggacgtg ggcgtgtact attgcctgca gtcccggatc 360
ttccctagaa cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
gcagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagact attccatcaa ctgggtgcgg agagcaccag gcaagggcct gaagtggatg 600
ggatggatca ataccgagac aagagagcct gcctacgcct atgacttccg gggccgcttc 660
gccttttccc tggagacctc cgcctctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggacaccg ccgtgtacta ttgtgccctg gattactcct atgccatgga ctattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgaga ccacgacgcc agcgccgcga 840
ccaccaacac cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgcgg 900
ccagcggcgg ggggcgcagt gcacacgagg gggctggact tcgccgatga attcatctac 960
atctgggcgc ccttggccgg gacttgtggg gtccttctcc tgtcactggt tatcaccctt 1020
tactgcaaac ggggcagaaa gaaactcctg tatatattca aacaaccatt tatgagacca 1080
gtacaaacta ctcaagagga agatggctgt agctgccgat ttccagaaga agaagaagga 1140
ggatgtgaac tgagagtgaa gttcagcagg agcgcagacg cccccgcgta caagcagggc 1200
cagaaccagc tctataacga gctcaatcta ggacgaagag aggagtacga tgttttggac 1260
aagagacgtg gccgggaccc tgagatgggg ggaaagccga gaaggaagaa ccctcaggaa 1320
ggcctgtaca atgaactgca gaaagataag atggcggagg cctacagtga gattgggatg 1380
aaaggcgagc gccggagggg caaggggcac gatggccttt accagggtct cagtacagcc 1440
accaaggaca cctacgacgc ccttcacatg caggccctgc cccctcgcta a 1491
<210> 35
<211> 1470
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 35
gctagcatgg ccctgccagt gaccgccctg ctgctgcccc tggccctgct gctgcacgca 60
gcaaggcctg acatcgtgct gacacagagc cctgcctccc tggccgtgag cccaggacag 120
cgggccacca tcacatgcag agcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc aggacagcca cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgccagc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcaatc ccgtggaggc cgaggatgtg ggcgtgtact attgcctgca gtccaggatc 360
ttccctcgca cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
gcagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagact attccatcaa ctgggtgagg caggcaccag gacagggact ggagtggatg 600
ggctggatca ataccgagac acgcgagcct gcctacgcct atgactttcg gggcagattc 660
gtgttttccc tggatacctc cgtgtctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggataccg ccgtgtacta ttgtgccctg gactactcct atgccatgga ttattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgagg caccacctcg ggccagcgcc 840
ctgcctgcac cacccaccgg ctccgccctg ccagaccctc agacagcatc tgccctgcca 900
gatcctccag cagcaagcgc cctgcccgaa ttcatctaca tctgggcgcc cttggccggg 960
acttgtgggg tccttctcct gtcactggtt atcacccttt actgcaaacg gggcagaaag 1020
aaactcctgt atatattcaa acaaccattt atgagaccag tacaaactac tcaagaggaa 1080
gatggctgta gctgccgatt tccagaagaa gaagaaggag gatgtgaact gagagtgaag 1140
ttcagcagga gcgcagacgc ccccgcgtac aagcagggcc agaaccagct ctataacgag 1200
ctcaatctag gacgaagaga ggagtacgat gttttggaca agagacgtgg ccgggaccct 1260
gagatggggg gaaagccgag aaggaagaac cctcaggaag gcctgtacaa tgaactgcag 1320
aaagataaga tggcggaggc ctacagtgag attgggatga aaggcgagcg ccggaggggc 1380
aaggggcacg atggccttta ccagggtctc agtacagcca ccaaggacac ctacgacgcc 1440
cttcacatgc aggccctgcc ccctcgctaa 1470
<210> 36
<211> 1470
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 36
gctagcatgg ccctgccagt gaccgccctg ctgctgcccc tggccctgct gctgcacgca 60
gcacggcctg atatcgtgct gacacagagc cctgcctccc tggccgtgag cccaggacag 120
agggcaacca tcacatgcag ggcctccgag tctgtgagcg tgatcggcgc ccacctgatc 180
cactggtacc agcagaagcc aggacagcca cctaagctgc tgatctatct ggcctctaac 240
ctggagaccg gagtgccagc acggttctcc ggctctggca gcggcacaga ctttaccctg 300
acaatcgatc ccgtggagga ggaggacgtg ggcgtgtact attgcctgca gtcccggatc 360
ttccctagaa cctttggcgg cggcacaaag ctggagatca agggatccac ctctggaagc 420
ggcaagccag gatctggaga gggaagcaca aagggacagg tgcagctggt gcagagcgga 480
gcagaggtga agaagccagg agcctccgtg aaggtgtctt gtaaggccag cggctacacc 540
ttcacagact attccatcaa ctgggtgcgg agagcaccag gcaagggcct gaagtggatg 600
ggatggatca ataccgagac aagagagcct gcctacgcct atgacttccg gggccgcttc 660
gccttttccc tggagacctc cgcctctaca gcctacctgc agatcagctc cctgaaggcc 720
gaggacaccg ccgtgtacta ttgtgccctg gattactcct atgccatgga ctattggggc 780
cagggcacct ctgtgacagt gtctagcctc gagctcgagg caccacctcg ggccagcgcc 840
ctgcctgcac cacccaccgg ctccgccctg ccagaccctc agacagcatc tgccctgcca 900
gatcctccag cagcaagcgc cctgcccgaa ttcatctaca tctgggcgcc cttggccggg 960
acttgtgggg tccttctcct gtcactggtt atcacccttt actgcaaacg gggcagaaag 1020
aaactcctgt atatattcaa acaaccattt atgagaccag tacaaactac tcaagaggaa 1080
gatggctgta gctgccgatt tccagaagaa gaagaaggag gatgtgaact gagagtgaag 1140
ttcagcagga gcgcagacgc ccccgcgtac aagcagggcc agaaccagct ctataacgag 1200
ctcaatctag gacgaagaga ggagtacgat gttttggaca agagacgtgg ccgggaccct 1260
gagatggggg gaaagccgag aaggaagaac cctcaggaag gcctgtacaa tgaactgcag 1320
aaagataaga tggcggaggc ctacagtgag attgggatga aaggcgagcg ccggaggggc 1380
aaggggcacg atggccttta ccagggtctc agtacagcca ccaaggacac ctacgacgcc 1440
cttcacatgc aggccctgcc ccctcgctaa 1470
Claims (21)
1.一种抗BCMA抗原的CAR在制备治疗表达BCMA的恶性血液病药物中的应用，其特征在于，所述CAR包含可识别BCMA抗原的抗原识别区、铰链区，跨膜区和胞内信号域；所述识别BCMA抗原的抗原识别区为抗BCMA单链抗体，其重链氨基酸序列如SEQ ID NO:4，轻链氨基酸序列如SEQ ID NO:9所示。
2.根据权利要求1所述的应用，其特征在于，还包含前导肽，所述前导肽序列来源于CD8的前导肽序列。
3.根据权利要求1所述的应用，其特征在于，所述抗BCMA单链抗体如SEQ ID NO:14所示。
4.根据权利要求1所述的应用，其特征在于，所述抗原识别区的核苷酸序列如SEQ IDNO:23所示。
5.根据权利要求1所述的应用，其特征在于，所述铰链区来源于CD8或IgG4或CD7。
6.根据权利要求5所述的应用，其特征在于，所述铰链区的氨基酸序列如SEQ ID NO:16或SEQ ID NO:17或SEQ ID NO:18或SEQ ID NO:19所示。
7.根据权利要求6所述的应用，其特征在于，所述铰链区的核苷酸序列如SEQ ID NO:25或26所示。
8.根据权利要求1所述的应用，其特征在于，所述跨膜区来源于CD8或CD28。
9.根据权利要求1所述的应用，其特征在于，所述胞内信号域来源于CD28和/或CD137和CD3或单独的CD3。
10.根据权利要求9所述的应用，其特征在于，所述胞内信号域的核苷酸序列如SEQ IDNO:27-28所示。
11.根据权利要求1所述的应用，其特征在于，所述CAR的核苷酸序列如SEQ ID NO:32所示。
12.根据权利要求1所述的应用，其特征在于，所述恶性血液病包括多发性骨髓瘤、急性粒细胞白血病、急性淋巴细胞白血病、B细胞淋巴瘤以及B细胞慢性淋巴细胞增殖性疾病。
13.包含CAR的表达载体，其特征在于，所述CAR包含可识别BCMA抗原的抗原识别区、铰链区，跨膜区和胞内信号域；所述识别BCMA抗原的抗原识别区为抗BCMA单链抗体，其重链氨基酸序列如SEQ ID NO:4，轻链氨基酸序列如SEQ ID NO:9所示；所述载体选自慢病毒表达载体、逆转录病毒表达载体、腺相关病毒表达载体、RNA载体。
14.根据权利要求13所述的表达载体，其特征在于，所述载体为慢病毒载体，所述慢病毒载体含有RRE元件和oPRE元件。
15.根据权利要求13所述的表达载体，其特征在于，所述载体包含pUCOri序列、卡纳霉素或者氨苄青霉素抗性基因序列、SV40Ori序列、顺式元件、真核转录的启动子和CAR编码基因。
16.包含权利要求13-15任一项所述表达载体的CAR细胞。
17.根据权利要求16所述的CAR细胞，其特征在于，所述细胞为T细胞。
18.权利要求13所述的表达载体和/或权利要求16所述的CAR细胞在制备治疗恶性血液病药物中的应用。
19.根据权利要求18所述的应用，其特征在于，所述恶性血液病包括多发性骨髓瘤、急性粒细胞白血病、急性淋巴细胞白血病、B细胞淋巴瘤以及B细胞慢性淋巴细胞增殖性疾病。
20.根据权利要求18所述的应用，其特征在于，所述恶性血液病的肿瘤细胞能够表达BCMA。
21.根据权利要求18所述的应用，其特征在于，所述CAR细胞与活性剂联合使用，所述活性剂为免疫检查点抑制剂和/或多肽和/或抗体-药物缀合物和/或激酶抑制剂。
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| CN114149505B (zh) * | 2021-01-12 | 2022-11-04 | 北京门罗生物科技有限公司 | 治疗b细胞相关疾病的免疫细胞、制备方法及其应用 |
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| EP4331678A1 (en) * | 2021-04-27 | 2024-03-06 | Oricell Therapeutics Co., Ltd. | Bcma-targeting chimeric antigen receptor and use thereof |
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