CN112759652A - 一种嵌合抗原受体及其应用 - Google Patents
一种嵌合抗原受体及其应用 Download PDFInfo
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- CN112759652A CN112759652A CN201911061313.7A CN201911061313A CN112759652A CN 112759652 A CN112759652 A CN 112759652A CN 201911061313 A CN201911061313 A CN 201911061313A CN 112759652 A CN112759652 A CN 112759652A
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Abstract
本发明提供了一种以PGT135的人单链抗体为胞外抗原结合结构域的嵌合抗原受体、表达所述嵌合抗原受体的T细胞,以及其在制备药物中的用途,所述的药物可以特异性的清除HIV感染病人体内的细胞储存库、实现对HIV潜伏细胞特异性的MHC非依赖性的识别杀伤,甚至所述的药物根除AIDS。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种嵌合抗原受体、表达嵌合抗原受体的T细胞以及其在制备治疗HIV感染或AIDS中的应用。
背景技术
人类免疫缺陷病毒(Human immunodeficiency virus,HIV),即获得性免疫缺陷综合征(艾滋病,AIDS)病毒,是一种感染人类免疫系统细胞的慢病毒(Lentivirus),是诱发人类产生获得性免疫缺陷综合症(AIDS)的罪魁祸首。
由于HIV直接侵犯人体的免疫系统,破坏人体的细胞免疫和体液免疫,HIV感染患者常常伴随着各种并发症,如脑膜炎、肺结核、癌症、肝炎等。根据联合国AIDS规划署(UNAIDS)统计显示,自艾滋病毒蔓延以来,全球已有约7610万(6520万-8800万)人感染该病毒。2016年,全球共有约3670万(3080万-4290万)名艾滋病毒感染者,其中1950万人获得抗逆转录病毒治疗。
目前,针对HIV感染者的治疗方法主要是抗病毒药物的联合使用(combinationanti-retroviral therapy,cART)组成的高效抗逆转录病毒疗法(highly active anti-retroviral therapy,HAART),抗病毒药物包括HIV复制抑制剂或者HIV的抗体,例如:专利CN103429595A公开了2,3,4-取代的5,6,7,8-四氢[1]苯并噻吩并[2,3-b]吡啶化合物及其药物可接受的盐,并且涉及包含这类化合物的组合物以及这类化合物作为HIV复制抑制剂的用途。专利CN103797029A公开了针对人类免疫缺陷病毒或HIV的表位的广谱中和抗体序列。专利CN106459186A公开了针对HIV-1V1V2ENV区域的广谱中和性单克隆抗体序列。专利CN107022027A、CN107033241A公开了HIV-1广谱中和抗体序列,所述抗体特异性结合HIV-lgp120。
经过长期的实践检验,该疗法能够抑制AIDS患者体内病毒复制,从而大大减缓AIDS疾病进程。然而,该疗法存在如下明显的缺陷:
(1)该疗法成本很高,且造成了更大量HIV携带者的存在,且完全依赖抗逆转录病毒药物且不得不承受其带来的严重负作用和经济负担;
(2)该疗法针对部分患者无效,部分患者体内HIV仍然得不到抑制反而大量扩增;
(3)该疗法不能靶向或清除患者体内静息CD4+中心记忆T细胞中存在的潜伏HIV病毒,这些潜伏感染的细胞是非常稳定的,在体内持续增加,将导致停药之后病毒立即反弹。
由此可见,治愈AIDS病人的关键问题是如何彻底清除病人体内的HIV病毒。研究表明,CD4+中心记忆T细胞(central memory T cell,Tcm)占所有HIV细胞储存库总数的95%。找到明确的HIV细胞储存库的生物标志物(biomarker),即可实现精确定位并最终清除HIV细胞储存库细胞。
嵌合抗原受体(chimeric antigen receptor,CAR)修饰的T细胞免疫疗法是当前过继性细胞治疗技术中最新技术之一。嵌合抗原受体(CAR)赋予T细胞HLA非依赖的方式识别肿瘤抗原的能力,这使得经过CAR改造的T细胞相对于天然T细胞表面受体TCR能够识别更广泛的目标。近年来,CAR-T技术在急性白血病和非霍奇金淋巴瘤的治疗上有着显著的疗效,被认为是最有前景的肿瘤治疗方式之一。因此,基因修饰的T细胞有可能成为清除HIV细胞储存库的重要途径。并且,对于清除HIV-1感染细胞也有一定的进展,例如:文献:HIV-1广谱中和抗体PGT135的结构和识别的抗原表位研究,中国医学科学院北京协和医学院博士研究生学位论文,公开了PGT135晶体结构以及其所识别的抗原表位研究,可以将PGT135抗体所识别的表位用于设计HIV-1疫苗的免疫原,也可以将PGT135用于被动免疫中疫苗的设计。同时指出PGT135抗体比VRC01类抗体的重链有较长的互补决定区,对于抗体识别隐蔽的糖基化位点有一定的帮助。但是现有技术均尚未公开以PGT135的人单链抗体(scFv)作为CAR分子的胞外抗原结合结构域,并将其应用于清除HIV细胞储存库,甚至是根除AIDS。因此,研究以PGT135的人单链抗体(scFv)作为CAR分子的胞外抗原结合结构域的CAR-T细胞在清除HIV细胞储存库中的作用和阐明相关机制,具有重要的基础研究意义和临床应用价值。
发明内容
本发明人经过一系列创造性的研究,制备获得了以PGT135的人单链抗体(single-chain antibody fragment,scFv)为胞外抗原结合结构域的嵌合抗原受体(CAR),该CAR可有效实现激活T细胞信号使其具有杀伤靶细胞功能,其中,PGT135在多种人来源的HIV抗体中具有较强的和HIV囊膜蛋白特异性结合的特征,将正常PGT135抗体制备成的具备VL-VH顺序的多种scFv形式的PGT135具有较强的和HIV囊膜蛋白特异性结合的特征,制备出的以PGT135的scFv为胞外抗原结合结构域的CAR可特异性识别HIV囊膜蛋白或HIV潜伏细胞。优选的,所述的以PGT135的scFv为胞外抗原结合结构域的CAR为PGT135-CD28-41BB-CD3ζ-CAR。进一步的,本发明制备出的PGT135-CD28-41BB-CD3ζ-CART细胞可有效的被HIV潜伏细胞特异性识别激活并具有杀伤能力,降低HIV病毒数量。更进一步的,本发明制备了包含PGT135-CD28-41BB-CD3ζ-CART的药物组合物用于清除人类免疫缺陷病毒(HIV)在HIV感染病人体内的细胞储存库,甚至达到了治疗AIDS的目的。
具体地,本发明的第一方面,提供了一种嵌合抗原受体(CAR),所述的嵌合抗原受体包括胞外抗原结合结构域,所述的胞外抗原结合结构域为PGT135的人单链抗体。
优选的,所述的人单链抗体包括重链可变区、接头和轻链可变区。
更优选的,所述的重链可变区是与SEQ ID NO:3的氨基酸序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的氨基酸序列。
在本发明的一个具体实施方式中,所述重链可变区的氨基酸序列如SEQ ID NO:3所示。
更优选的,所述的轻链可变区是与SEQ ID NO:2的氨基酸序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的氨基酸序列。
在本发明的一个具体实施方式中,所述轻链可变区的氨基酸序列如SEQ ID NO:2所示。
更优选的,所述的接头为包含甘氨酸(Gly)和/或丝氨酸(Ser)的氨基酸序列,进一步优选的,所述接头的序列如SEQ ID NO:4-9任一项所示。
在本发明的一个具体实施方式中,所述接头的氨基酸序列如SEQ ID NO:4所示。
在本发明的另一个具体实施方式中,所述的人单链抗体的氨基酸序列如SEQ IDNO:1或SEQ ID NO:10所示。
优选的,所述的嵌合抗原受体还包括跨膜区,所述的跨膜区选自CD3ζ多肽、CD4多肽、CD8多肽、CD28多肽、CD28-41BB多肽、OX40多肽、ICOS多肽、CTLA-4多肽、PD-1多肽、LAG-3多肽、2B4多肽或BTLA多肽中的一种或两种以上的组合。
更优选的,所述的跨膜区选自如下组合中的任一组:
(1)CD8多肽、CD28多肽和CD3ζ多肽;
(2)CD4多肽、CD8多肽、CD28、4-1BB多肽和CD3ζ多肽;
(3)CD4多肽、CD8多肽、CD28、4-1BB多肽和CD3ζ多肽。
在本发明的一个具体实施方式中,所述的跨膜区为CD28多肽。
在本发明的一个具体实施方式中,所述的跨膜区的氨基酸序列如SEQ ID NO:14所示。
优选的,所述的嵌合抗原受体还包括胞外铰链区,所述的胞外铰链区选自CD8或IgG的胞外铰链区。
在本发明的一个具体实施方式中,所述的胞外铰链区的氨基酸序列如SEQ ID NO:15所示。
优选的,所述的嵌合抗原受体还包括胞浆区,所述的胞浆区选自CD28-4-1BB-CD3ζ或4-1BB-CD3ζ或CD28-CD3ζ。
在本发明的一个具体实施方式中,所述的胞浆区的氨基酸序列如SEQ ID NO:16所示。
优选的,所述的嵌合抗原受体还包括控制细胞存活或者死亡的基因。更优选的,所述的控制细胞存活或者死亡的基因选自IL12或TK基因。当在外部加药的情况下,可以控制细胞的死亡。
在本发明的一个具体实施方式中,所述的嵌合抗原受体包括胞外抗原结合结构域、跨膜区、胞外铰链区和胞浆区。
在本发明的一个具体实施方式中,所述的嵌合抗原受体的氨基酸序列是与SEQ IDNO:11所示序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的氨基酸序列。
在本发明的另一个具体实施方式中,所述的嵌合抗原受体的氨基酸序列如SEQ IDNO:11所示。
本发明的第二方面,提供了一种分离的免疫应答细胞,所述的免疫应答细胞包含上述第一方面所述的嵌合抗原受体。
优选的,所述的免疫应答细胞表达控制细胞存活或者死亡的基因。更优选的,所述的控制细胞存活或者死亡的基因选自IL12或TK基因。当在外部加药的情况下,可以控制细胞的死亡。
优选的,将所述的免疫应答细胞与其他细胞混合控制该免疫应答细胞的存活或者死亡。所述的其他细胞选自表达IL12或TK基因的细胞。更优选的,所述的其他细胞为表达IL12或TK基因CAR-T细胞。
优选的,所述的免疫应答细胞选自T细胞、NK细胞、CTL、人胚胎干细胞、淋巴祖细胞和/或T细胞前体细胞。
在本发明的一个具体实施方式中,所述的免疫应答细胞为T细胞,即CAR-T细胞。
其中,所述的免疫应答细胞有效的被HIV潜伏细胞特异性识别、激活、有效降低HIV病毒以及治疗AIDS。
优选的,所述的免疫应答细胞为PGT135-CD28-41BB-CD3ζ-CART。
本发明的第三方面,提供了一种核酸分子,所述的核酸分子编码上述第一方面所述嵌合抗原受体。优选的,所述的核酸分子包括TK或IL12基因片段,所述的TK或IL12基因片段可以控制细胞的存活或者死亡,例如可以通过外部加药让细胞死亡。
优选的,所述的核酸分子是与SEQ ID NO:12所示序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的核苷酸序列。
在本发明的一个具体实施方式中,所述的核酸分子的核苷酸序列如SEQ ID NO:12所示。
本发明的第四方面,提供了一种载体,所述的载体包含上述第三方面所述的核酸分子。
优选的,所述的载体是与SEQ ID NO:13所示序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的核苷酸序列。
在本发明的一个具体实施方式中,所述载体的核苷酸序列如SEQ ID NO:13所示。
本发明的第五方面,提供了一种宿主细胞,所述的宿主细胞包含上述第三方面所述的核酸分子或上述第四方面所述的载体。
优选的,所述的宿主细胞为T细胞。
本发明的第六方面,提供了一种细胞群,所述的细胞群包含至少1个上述第五方面所述的宿主细胞。
本发明的第七方面,提供了特异性结合上述第一方面所述的嵌合抗原受体的抗体或其抗原结合部分。
本发明的第八方面,提供了一种药物组合物,所述的药物组合物包含有效量的上述第一方面所述的嵌合抗原受体、第二方面所述的免疫应答细胞、第三方面所述的核酸分子、第四方面所述的载体、第五方面所述的宿主细胞、第六方面所述的细胞群和/或第七方面所述的抗体或其抗原结合部分,以及药用载体。
优选的,所述的药物组合物用于治疗HIV感染或AIDS。
本发明的第九方面,提供了上述第一方面所述的嵌合抗原受体、第二方面所述的免疫应答细胞、第三方面所述的核酸分子、第四方面所述的载体、第五方面所述的宿主细胞、第六方面所述的细胞群、第七方面所述的抗体或其抗原结合部分和/或第八方面所述的药物组合物在制备用于治疗和/或诊断HIV感染或AIDS的药物中的用途。
本发明的第十方面,提供了一种用于治疗和/或诊断HIV感染或AIDS的试剂盒,所述的试剂盒包含上述第一方面所述的嵌合抗原受体、第二方面所述的免疫应答细胞、第三方面所述的核酸分子、第四方面所述的载体、第五方面所述的宿主细胞、第六方面所述的细胞群、第七方面所述的抗体或其抗原结合部分和/或第八方面所述的药物组合物。
本发明的第十一方面,提供了一种清除HIV感染细胞或治疗AIDS的方法,所述的方法包括将有效量的上述第一方面所述的嵌合抗原受体、第二方面所述的免疫应答细胞、第三方面所述的核酸分子、第四方面所述的载体、第五方面所述的宿主细胞、第七方面所述的抗体或其抗原结合部分、第六方面所述的细胞群和/或第八方面所述的药物组合物给予受试者。
优选的,所述的方法可以为治疗目的,也可以为非治疗目的。其中,所述的治疗目的包括但不限于清除HIV细胞储存库或杀伤HIV潜伏细胞、增加或延长HIV感染者或AIDS患者生存期。所述的非治疗目的包括但不限于特异性识别HIV囊膜蛋白、免疫应答细胞被HIV潜伏细胞特异性识别激活。
本发明的第十二方面,提供了一种检测方法,所述的方法包括使包含来自所述宿主的一个或多个细胞的样品与上述第一方面所述的嵌合抗原受体、第二方面所述的免疫应答细胞、第三方面所述的核酸分子、第四方面所述的载体、第五方面所述的宿主细胞、第七方面所述的抗体或其抗原结合部分、第六方面所述的细胞群和/或第十方面所述的试剂盒相接触,形成复合物,并且,检测所述的复合物,其中检测到所述复合物指示HIV病毒在所述宿主中的存在。
本发明所述的检测方法可以为治疗目的,也可以为非治疗目的。其中,所述的治疗目的包括但不限于诊断AIDS。所述的非治疗目的包括但不限于检测HIV病毒的存在,或者用于分离HIV病毒。
本发明的第十三方面,提供了一种增加或延长HIV感染或AIDS患者生存期的方法,所述的方法包括将有效量上述第二方面所述的免疫应答细胞给予受试者,从而增加或延长所述受试者的生存期。
本发明的第十四方面,提供了一种清除HIV细胞储存库的方法,所述的方法包括将有效量的上述第二方面所述的免疫应答细胞给予HIV感染或AIDS的受试者,从而清除HIV细胞储存库。
本发明的第十五方面,提供了一种特异性识别HIV囊膜蛋白的方法,所述的方法包括将有效量的上述第二方面所述的免疫应答细胞给予受试者。
本发明的第十六方面,提供了一种免疫应答细胞被HIV潜伏细胞特异性识别激活的方法,所述的方法包括将有效量的上述第二方面所述的免疫应答细胞给予受试者。
本发明的第十七方面,涉及一种杀伤HIV潜伏细胞的方法,所述的方法包括将有效量的上述第二方面所述的免疫应答细胞给予受试者,从而增加或延长所述受试者的生存期。
本发明所述的方法为HIV CART的细胞免疫疗法。
本发明所述的“药用载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质。
本发明所述的“同源性”是指在使用蛋白序列或核苷酸序列的方面,本领域技术人员可以根据实际工作需要对序列进行调整,使使用序列与现有技术获得的序列相比,具有(包括但不限于)1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,70%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,99.1%,99.2%,99.3%,99.4%,99.5%,99.6%,99.7%,99.8%,99.9%的同源性。
本发明所述的“和/或”是指包括择一列出的项目以及任何数量的项目组合。
本发明所述的“包括”是指开放式的描述,含有所描述的指定成分或步骤,以及不会实质上影响的其他指定成分或步骤。
本发明所述的“治疗”是指在疾病已开始发展后减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性,但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。
本发明所述的“诊断”是指以查明患者过去、诊断时或将来是否患有疾病或病症,或者是查明疾病的进展或将来可能的进展,或者是评估患者对治疗的反应。
本发明所述的“有效量”是指在以单个或多个剂量给予至患者或器官之后提供所希望的治疗或预防的本发明的CAR、CAR-T、核酸分子、载体、宿主细胞、免疫应答细胞、抗体或其抗原结合部分、细胞群、药物组合物的量或剂量。本发明所述的“预防”是指通过施用本发明所述的CAR、CAR-T、核酸分子、载体、宿主细胞、免疫应答细胞、抗体或其抗原结合部分、细胞群、药物组合物来抑制症状或者延缓特定症状紧张的所有行为。
本发明所述的“受试者”是指哺乳动物或人,优选为灵长类动物。
附图说明
以下,结合附图来详细说明本发明的实施例,其中:
图1:显示了实施例1构建的PGT135 scFv结合HIV潜伏细胞的结果图;流式分析结果显示,较对照组Mers(图A)抗体,PGT135 scFv(图B)可特异性识别ACH2,虽然这种识别能力较PGT135抗体(图C)略弱。
图2:显示了实施例1制备PGT135 scFv-CAR的流程,其中,所述的PGT135 scFv-CAR具体为PGT135 scFv-CD8-CD8-CD28-CD3ζ-CAR,更具体的,由CD8胞外铰链区、CD28跨膜区、CD28-41BB胞浆区和CD3ξ胞浆区以及PGT135 scFv组成了CAR。
图3A:显示了PGT135-CD28-41BB-CD3ζ-CART(试验组)细胞可有效的被HIV潜伏细胞特异性识别激活,并产生IL2细胞因子,其中,对照组为CD19scFv-CD28-41BB-CD3ζ-CART。
图3B:显示了PGT135-CD28-41BB-CD3ζ-CART(试验组)细胞可有效的被HIV潜伏细胞特异性识别激活,并产生TNFα细胞因子,其中,对照组为CD19scFv-CD28-41BB-CD3ζ-CART。
图3C:显示了PGT135-CD28-41BB-CD3ζ-CART(试验组)细胞可有效的被HIV潜伏细胞特异性识别激活,并产生INFγ细胞因子,其中,对照组为CD19scFv-CD28-41BB-CD3ζ-CART。
图4:显示了PGT135-CD28-41BB-CD3ζ-CART(实验组)与对照组细胞对P24浓度的影响,表明PGT135-CD28-41BB-CD3ζ-CART细胞可有效的降低HIV病毒,其中,对照组为CD19scFv-CD28-41BB-CD3ζ-CART。
图5:显示了在不同效靶比情况下,来自3BNC117、N6和PGT135多种中和抗体的scFv做成的CART(实验组)与对照组细胞对P24浓度的影响,表明PGT135-CD28-41BB-CD3ζ-CART细胞可相对最有效的降低HIV病毒,其中,对照组为CD19scFv-CD28-41BB-CD3ζ-CART。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
除非另有说明,本发明的实施采用分子生物学、微生物学、细胞生物学、生物化学和免疫学的常规技术,其均在本领域技术人员知晓的范围内。
实施例1 PGT135-CD28-41BB-CD3ξ-CAR的构建
制备多种PGT135 scFv,并产生基于这些scFv的CAR,具体过程如下:
(一)制备多种PGT135 scFv
1、基于PGT135的核苷酸序列(SEQ ID NO:17),进行抗体重链(VH)及轻链(VL)序列合成,基于其序列设计Overlap PCR引物。
2、利用DNA聚合酶进行PCR扩增,扩增PGT135的VL片段(其核苷酸序列为SEQ IDNO:19,氨基酸序列为SEQ ID NO:2)及VH片段(其核苷酸序列为SEQ ID NO:18,其氨基酸序列为SEQ ID NO:3),完成后进行PCR产物回收及DNA琼脂糖凝胶电泳验证PCR条带大小是否正确。其中扩增VH片段所用引物为,引物PGT135-VH-F序列:acattccgctagcCAGCTGCAGATGCAGGAATCTGGCCCTGGC(SEQ ID NO:20);引物op-PGT135-VH-VL-R序列:CCGCCTCCACCAGATCCTCCACCTCCGCTAGACACTGTGACCTGCACGCCAGGTCCC(SEQ ID NO:21);扩增VL片段所用引物为,引物op-PGT135-VH-VL-F序列:GATCTGGTGGAGGCGGAAGTGGCGGAGGGGGATCTGAGATTGTGATGACCCAGAGCCCC(SEQ ID NO:22);引物PGT135-VL-R序列:cgtggtcatatgCTTGATGTCCACCTTGGTGCCCTGGC(SEQ ID NO:23)。
3、利用鉴定正确的PGT135 VL及VH片段作为模板,采用Overlap PCR引物进行overlap PCR扩增,完成后进行DNA琼脂糖凝胶电泳验证,验证正确的条带进行切胶回收得到PGT135 scFv。其中扩增所用引物PGT135-VH-F序列:acattccgctagcCAGCTGCAGATGCAGGAATCTGGCCCTGGC(SEQ ID NO:24);引物PGT135-VL-R序列:cgtggtcatatgCTTGATGTCCACCTTGGTGCCCTGGC(SEQ ID NO:25)。
4、胶回收的PGT135 scFv以及带有Fc片段的载体(实验室保存)同时进行双酶切,酶切后进行DNA琼脂糖凝胶电泳验证,验证正确的条带进行切胶回收。
5、将得到的酶切后PGT135 scFv目的片段及载体利用T4连接酶连接,转化至DH5α菌株在氨苄平板上涂板。
6、挑选平板上长出的3个单菌落送至公司利用CMV-F进行测序,测序正确的片段即为PGT135 scFv(其氨基酸序列为SEQ ID NO:1或SEQ ID NO:10)克隆;
7、验证制备的PGT135 scFv结合HIV潜伏细胞的特异性和亲和力;
8.表达纯化带有his标签的PGT135 scFv、PGT135抗体及Mers抗体,并将其分别与激活的HIV潜伏细胞ACH2孵育,再通过anti-his PE抗体检测其是否与HIV潜伏细胞ACH2特异结合。实验结果显示(见图1),较对照Mers抗体,PGT135 scFv可特异性识别ACH2,虽然这种识别能力较PGT135抗体略弱。
其中,连接VH片段及VL片段的linker如下:
Linker序列-1(SEQ ID NO:4):GGGGSGGGGSGGGGS
Linker序列-2(SEQ ID NO:5):GGGGSGGGGS
Linker序列-3(SEQ ID NO:6):GGGGSGGGGSGGGGSGGGGS
Linker序列-4(SEQ ID NO:7):GGGGSGGGGSHMESKYGPPCPPCP
Linker序列-5(SEQ ID NO:8):GGGGSGGGGSGGGGSHMESKYGPPCPPCP
Linker序列-6(SEQ ID NO:9):GGGGSGGGGSGGGGSGGGGSHMESKYGPPCPPCP
经过实验验证,上述SEQ ID NO:4-9的Linker序列均为有效的,但是本实验所用linker为SEQ ID NO:4。
(二)制备PGT135 scFv-CAR(使用编码SEQ ID NO:1的PGT135 scFv的核苷酸序列SEQ ID NO:17)
其制备过程及质粒结构图如图2所示。
1、基于CD8 IgG区、CD28跨膜区(TM)、CD28-41BB胞浆区和CD3ξ胞浆区的核苷酸序列设计Overlap PCR引物。
2、利用DNA聚合酶进行PCR扩增,分别扩增CD8 IgG区、CD28跨膜区、CD28-41BB胞浆区和CD3ξ胞浆区片段,完成后进行PCR产物回收及DNA琼脂糖凝胶电泳验证PCR条带大小是否正确。
3、利用鉴定正确的CD8 IgG区、CD28跨膜区、CD28-41BB胞浆区和CD3ξ胞浆区片段作为模板,采用Overlap PCR引物进行overlap PCR扩增,完成后进行DNA琼脂糖凝胶电泳验证,验证正确的条带进行切胶回收得到CD8-CD8TM-CD28-41BB-CD3ξ片段;
4、胶回收的CD8-CD8TM-CD28-41BB-CD3ξ片段以及慢病毒载体phage-IRES-RFP(本实施例使用)或phage-IRES-GFP(实验室保存)同时进行双酶切,酶切后进行DNA琼脂糖凝胶电泳验证,验证正确的条带进行切胶回收;
5、将得到的酶切CD8-CD8TM-CD28-41BB-CD3ξ片段及载体利用T4连接酶连接,转化至stable 3菌株在氨苄平板上涂板;
6、挑选平板上长出的3个单菌落送至公司进行测序,测序正确的片段即为PGT135-CAR,其表达质粒命名为phage-PGT135 scFv-CAR;
其中,
(1)CD8-CD28TM-CD28-41BB-CD3ξ序列如下所示(SEQ ID NO:26):
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(2)CD8LS-PGT135 scFv-CD28-41BB-CD3ξCAR的氨基酸序列如SEQ ID NO:11所示;
(3)CD8LS-PGT135 scFv-CD28-41BB-CD3ξCAR的核苷酸序列如SEQ ID NO:12所示;
(4)phage-PGT135 scFv-CAR的核苷酸序列如SEQ ID NO:13所示。
实施例2、CAR-T细胞的制备(示例性采用如SEQ ID NO:13所述的phage-PGT135scFv-CAR)
(一)慢病毒包装、浓缩及滴度检测
1.1复苏调整293T细胞状态,转染前24小时左右重新铺板,以包装转染时细胞融合度达7成以上为宜;
1.2转染病毒包装体系所需要的质粒psPAX2、pMD2.G和表达CAR的慢病毒质粒phage-PGT135 scFv-CAR,转染前将培养基换成无血清培养基,对于15cm细胞培养皿按以下体系进行操作:
1mL DMEM中滴加混入60μL PEI,静置5分钟,
另取一tube管加入
phage-PGT135 scFv-CAR 15μg
psPAX2 10μg
pMD2.G 5μg
加DMEM至1mL,
将PEI混合液滴加混入包装质粒混合液,静置20分钟;
1.3将上述混合液均匀滴入细胞培养基使其覆于细胞表面,放入培养箱;
1.4 10小时后在病毒操作台中弃去培养基,添加约20mL新鲜培养基;
1.5 2天后收取上层培养基,另再补加20mL新鲜培养基;另1-2天后再次收取上层培养基,合并两次收取的培养基上清;
1.6离心培养基上清,3000rpm 10分钟;用0.45μm滤膜过滤,取过滤后的培养基36mL置于超速离心管中,19500rpm 2小时;
1.7小心取出离心管,将上清在病毒操作台中弃除,倒扣在喷过酒精的纸上;加入360μL1640培养基,至少吹打底块含病毒结块10次;按一定体积分装病毒置于-80℃冰箱快速冷冻保存;
(二)人原代T细胞分离、激活及感染
2.1新鲜或冻存的人血液经Ficoll液分离得到人PBMC,用正常1640培养基培养1天;
2.2第2天将上述培养液中悬浮细胞按Stem cell的EasySepTM Human T CellIsolation Kit(Catalog#17951)说明进行阴筛得到人原代T细胞;
2.3用正常1640培养基培养上述分离得到的人原代T细胞,并按说明加入Stemcell的ImmunoCultTM Human CD3/CD28/CD2 T Cell Activator(货号#10970)及IL2(PeproTech货号96-200-02-50),持续激活2天;
2.4以MOI小于20的慢病毒量感染一定数目上述激活的人原代T细胞,并加入8μg/mL polybrene(Sigma货号H9268)混匀;室温1000-1500rpm离心1-2小时;放于培养箱培养10小时后离心换液;
2.5扩增细胞,3-4天后检测感染效率,将PGT135-scFv CAR构建入phage-IRES-RFP载体中,并将其包装成病毒按实验操作步骤感染人原代T细胞,通过载体自带的RFP标签衡量感染效率,筛选富集CAR阳性的T细胞用于后续实验。
实施例3、HIV潜伏细胞与PGT135-CD28-41BB-CD3ζ-CAR特异性识别激活验证实验
研究PGT135-CD28-41BB-CD3ζ-CART细胞是否可有效的被HIV潜伏细胞特异性识别激活,首先从人PBMC中将T细胞分离出来,激活培养后将对照组CD19scFv-CD28-41BB-CD3ζ-CAR-RFP及实验组PGT135-CD28-41BB-CD3ζ-CAR-RFP转化到T细胞中,分选获得纯化的对照组CD19scFv-CD28-41BB-CD3ζ-CART细胞及实验组PGT135-CD28-41BB-CD3ζ-CART细胞;将上述CART细胞与HIV阴性细胞A3.01或HIV阳性细胞ACH2分别共培养,24小时后,检测INFγ、TNFα阳性CART细胞的比率及分泌到培养基中的INFγ、TNFα和IL2的水平。
1、细胞及试剂
(1)实验用细胞:A3.01和ACH2细胞,购买于NIH AIDS试剂平台,并培养于清华大学细胞实验平台;PBMC来自合作医院。
(2)实验用试剂:人原代T细胞分离试剂盒(货号#17951)、激活试剂盒(货号#10970)均购买于Stem cell公司,细胞因子IL2(货号96-200-02-50)购买于Pepro Tech公司;流式抗体TNFα(货号17-7349)、INFγ(货号48-7319)及ELISA试剂盒TNFα(货号88-7346-88)、INFγ(货号88-7316-88)和IL2(货号88-7025-88)均购买于eBioscience公司。
2、实验方法
将人PBMC细胞铺到10cm培养皿中,第2天将上述培养液中悬浮细胞按Stem cell的T细胞分离试剂盒说明进行阴筛得到人原代T细胞,并按说明加入T细胞激活剂及IL2;用一定量包装好的慢病毒感染上述激活的人原代T细胞,并经流式分选获得CART细胞;将上述CART细胞与HIV阴性细胞A3.01或HIV阳性细胞ACH2按1:2、1:5比例分别共培养,24小时后,检测INFγ、TNFα阳性CART细胞的比率及分泌到培养基中的INFγ、TNFα和IL2的水平。
3、实验结果
PGT135-CD28-41BB-CD3ζ-CART细胞可有效的被HIV潜伏细胞特异性识别激活如图3A、3B、3C所示,对照组CD19scFv-CD28-41BB-CD3ζ-CART既不能被HIV阴性细胞A3.01也不能被HIV阳性细胞ACH2激活而产生INFγ、TNFα等细胞因子;而实验组PGT135-CD28-41BB-CD3ζ-CART只能被HIV阳性细胞ACH2而不能被HIV阴性细胞A3.01激活而产生INFγ、TNFα等细胞因子。
实施例4、PGT135-CD28-41BB-CD3ζ-CART细胞有效降低HIV病毒验证实验
研究PGT135-CD28-41BBζ-CART细胞是否可有效降低HIV病毒,首先从人PBMC中将T细胞分离出来,激活培养后将CD19scFv-CD28-41BB-CD3ζ-CAR-RFP及PGT135-CD28-41BB-CD3ζ-CAR-RFP转化到T细胞中,分选获得纯化的对照组CD19scFv-CD28-41BB-CD3ζ-CART细胞及实验组PGT135-CD28-41BB-CD3ζ-CART细胞;将上述CART细胞与HIV阴性细胞A3.01或HIV阳性细胞ACH2(A3.01是CD4阳性,而ACH2是CD4阴性)分别共培养,24小时后,检测培养基上清中HIV病毒量(以p24为指标)的变化。
1、细胞及试剂
(1)实验用细胞:A3.01和ACH2细胞,购买于NIH AIDS试剂平台,并培养于清华大学细胞实验平台;PBMC来自合作医院。
(2)实验用试剂:人原代T细胞分离试剂盒(货号#17951)、激活试剂盒(货号#10970)均购买于Stem cell公司,细胞因子IL2(货号96-200-02-50)购买于Pepro Tech公司;流式抗体CD4购买于eBioscience公司。
2、实验方法
将人PBMC细胞铺到10cm培养皿中,第2天将上述培养液中悬浮细胞按Stem cell的T细胞分离试剂盒说明进行阴筛得到人原代T细胞,并按说明加入T细胞激活剂及IL2;用一定量包装好的慢病毒感染上述激活的人原代T细胞,并经流式分选获得CART细胞;将上述CART细胞与HIV阴性细胞A3.01或HIV阳性细胞ACH2按2:1比例分别共培养,24小时后,检测培养基上清中HIV病毒量(以p24为指标)的变化。
3、实验结果
PGT135-CD28-41BB-CD3ζ-CART细胞可有效的降低HIV病毒如图4所示,存在HIV阳性细胞ACH2的情况下,相较对照组,实验组PGT135-CD28-41BB-CD3ζ-CART共培养能显著下调上清中的p24水平。
实施例5、PGT135-CD28-4-1BB-CD3ζ-CART细胞相对最有效降低HIV病毒对比实验
研究多种中和抗体来源的scFv做成的HIV CAR-T细胞是否可有效降低HIV病毒,首先从人PBMC中将T细胞分离出来,激活培养后将CD19scFv-CD28-4-1BB-CD3ζ-CAR-RFP及各种HIV-CD28-4-1BB-CD3ζ-CAR-RFP转化到T细胞中,分选获得纯化的对照组CD19scFv-CD28-4-1BB-CD3ζ-CART细胞及试验组HIV-CD28-4-1BB-CD3ζ-CART细胞;将上述CART细胞与HIV阴性细胞A3.01或HIV阳性细胞ACH2(A3.01是CD4阳性,而ACH2是CD4阴性)以不同效靶比分别共培养,24小时后,检测培养基上清中HIV病毒量(以p24为指标)的变化。
1、细胞及试剂
(1)实验用细胞:A3.01和ACH2细胞,购买于NIH AIDS试剂平台,并培养于清华大学细胞实验平台;PBMC来自合作医院。
(2)实验用试剂:人原代T细胞分离试剂盒(货号#17951)、激活试剂盒(货号#10970)均购买于Stem cell公司,细胞因子IL2(货号96-200-02-50)购买于Pepro Tech公司;流式抗体CD4购买于eBioscience公司。
2、实验方法
将人PBMC细胞铺到10cm培养皿中,第2天将上述培养液中悬浮细胞按Stem cell的T细胞分离试剂盒说明进行阴筛得到人原代T细胞,并按说明加入T细胞激活剂及IL2;用一定量包装好的慢病毒感染上述激活的人原代T细胞,并经流式分选获得CART细胞;将上述CART细胞与HIV阴性细胞A3.01或HIV阳性细胞ACH2按不同比例分别共培养,24小时后,检测培养基上清中HIV病毒量(以p24为指标)的变化。
3、实验结果
如图5所示,在不同效靶比情况下,来自3BNC117、N6和PGT135多种中和抗体的scFv做成的HIV CAR-T细胞较对照组,均可有效地下调p24水平,并且这一下调趋随着效靶比的增加而增加。其中,在所有效靶比条件下,PGT135-CD28-4-1BB-CD3ζ-CART细胞显现出比其它中和抗体的scFv做成的HIV CAR-T细胞更强的下调p24水平的能力。
综上所述,PGT135-CD28-41BB-CD3ζ-CART细胞可有效的被HIV潜伏细胞特异性识别激活并有效降低病毒水平。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
序列表
<110> 清华大学
北京华夏清医治疗科技有限公司
<120> 一种嵌合抗原受体及其应用
<130> 1
<160> 26
<170> PatentIn version 3.5
<210> 1
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Glu Ile Val Met Thr Gln Ser Pro Asp Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Thr Val Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Asn Lys Asn
20 25 30
Leu Ala Trp Tyr Gln Tyr Lys Pro Gly Gln Ser Pro Arg Leu Val Ile
35 40 45
Phe Glu Thr Tyr Ser Lys Ile Ala Ala Phe Pro Ala Arg Phe Val Ala
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Asn Met Gln Ser
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Glu Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Leu Gln Met Gln Glu
115 120 125
Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Ser Cys
130 135 140
Thr Val Ser Gly Asp Ser Ile Arg Gly Gly Glu Trp Gly Asp Lys Asp
145 150 155 160
Tyr His Trp Gly Trp Val Arg His Ser Ala Gly Lys Gly Leu Glu Trp
165 170 175
Ile Gly Ser Ile His Trp Arg Gly Thr Thr His Tyr Lys Glu Ser Leu
180 185 190
Arg Arg Arg Val Ser Met Ser Ile Asp Thr Ser Arg Asn Trp Phe Ser
195 200 205
Leu Arg Leu Ala Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys
210 215 220
Ala Arg His Arg His His Asp Val Phe Met Leu Val Pro Ile Ala Gly
225 230 235 240
Trp Phe Asp Val Trp Gly Pro Gly Val Gln Val Thr Val Ser Ser
245 250 255
<210> 2
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Glu Ile Val Met Thr Gln Ser Pro Asp Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Thr Val Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Asn Lys Asn
20 25 30
Leu Ala Trp Tyr Gln Tyr Lys Pro Gly Gln Ser Pro Arg Leu Val Ile
35 40 45
Phe Glu Thr Tyr Ser Lys Ile Ala Ala Phe Pro Ala Arg Phe Val Ala
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Asn Met Gln Ser
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Glu Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys
100 105
<210> 3
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Gln Leu Gln Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Ser Cys Thr Val Ser Gly Asp Ser Ile Arg Gly Gly
20 25 30
Glu Trp Gly Asp Lys Asp Tyr His Trp Gly Trp Val Arg His Ser Ala
35 40 45
Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile His Trp Arg Gly Thr Thr
50 55 60
His Tyr Lys Glu Ser Leu Arg Arg Arg Val Ser Met Ser Ile Asp Thr
65 70 75 80
Ser Arg Asn Trp Phe Ser Leu Arg Leu Ala Ser Val Thr Ala Ala Asp
85 90 95
Thr Ala Val Tyr Phe Cys Ala Arg His Arg His His Asp Val Phe Met
100 105 110
Leu Val Pro Ile Ala Gly Trp Phe Asp Val Trp Gly Pro Gly Val Gln
115 120 125
Val Thr Val Ser Ser
130
<210> 4
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 5
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 6
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 7
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His Met Glu Ser Lys Tyr
1 5 10 15
Gly Pro Pro Cys Pro Pro Cys Pro
20
<210> 8
<211> 29
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His
1 5 10 15
Met Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
20 25
<210> 9
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser His Met Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
20 25 30
Cys Pro
<210> 10
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gln Leu Gln Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Ser Cys Thr Val Ser Gly Asp Ser Ile Arg Gly Gly
20 25 30
Glu Trp Gly Asp Lys Asp Tyr His Trp Gly Trp Val Arg His Ser Ala
35 40 45
Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile His Trp Arg Gly Thr Thr
50 55 60
His Tyr Lys Glu Ser Leu Arg Arg Arg Val Ser Met Ser Ile Asp Thr
65 70 75 80
Ser Arg Asn Trp Phe Ser Leu Arg Leu Ala Ser Val Thr Ala Ala Asp
85 90 95
Thr Ala Val Tyr Phe Cys Ala Arg His Arg His His Asp Val Phe Met
100 105 110
Leu Val Pro Ile Ala Gly Trp Phe Asp Val Trp Gly Pro Gly Val Gln
115 120 125
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Asp Thr Leu Ser
145 150 155 160
Val Ser Pro Gly Glu Thr Val Thr Leu Ser Cys Arg Ala Ser Gln Asn
165 170 175
Ile Asn Lys Asn Leu Ala Trp Tyr Gln Tyr Lys Pro Gly Gln Ser Pro
180 185 190
Arg Leu Val Ile Phe Glu Thr Tyr Ser Lys Ile Ala Ala Phe Pro Ala
195 200 205
Arg Phe Val Ala Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn
210 215 220
Asn Met Gln Ser Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Glu
225 230 235 240
Glu Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys
245 250 255
<210> 11
<211> 545
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Ala Ser Gln Leu Gln Met Gln Glu Ser Gly Pro Gly Leu
20 25 30
Val Lys Pro Ser Glu Thr Leu Ser Leu Ser Cys Thr Val Ser Gly Asp
35 40 45
Ser Ile Arg Gly Gly Glu Trp Gly Asp Lys Asp Tyr His Trp Gly Trp
50 55 60
Val Arg His Ser Ala Gly Lys Gly Leu Glu Trp Ile Gly Ser Ile His
65 70 75 80
Trp Arg Gly Thr Thr His Tyr Lys Glu Ser Leu Arg Arg Arg Val Ser
85 90 95
Met Ser Ile Asp Thr Ser Arg Asn Trp Phe Ser Leu Arg Leu Ala Ser
100 105 110
Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala Arg His Arg His
115 120 125
His Asp Val Phe Met Leu Val Pro Ile Ala Gly Trp Phe Asp Val Trp
130 135 140
Gly Pro Gly Val Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
145 150 155 160
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser
165 170 175
Pro Asp Thr Leu Ser Val Ser Pro Gly Glu Thr Val Thr Leu Ser Cys
180 185 190
Arg Ala Ser Gln Asn Ile Asn Lys Asn Leu Ala Trp Tyr Gln Tyr Lys
195 200 205
Pro Gly Gln Ser Pro Arg Leu Val Ile Phe Glu Thr Tyr Ser Lys Ile
210 215 220
Ala Ala Phe Pro Ala Arg Phe Val Ala Ser Gly Ser Gly Thr Glu Phe
225 230 235 240
Thr Leu Thr Ile Asn Asn Met Gln Ser Glu Asp Val Ala Val Tyr Tyr
245 250 255
Cys Gln Gln Tyr Glu Glu Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys
260 265 270
Val Asp Ile Lys His Met Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
275 280 285
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
290 295 300
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
305 310 315 320
Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys
325 330 335
Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser
340 345 350
Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg
355 360 365
Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg
370 375 380
Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr
385 390 395 400
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
405 410 415
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
420 425 430
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
435 440 445
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
450 455 460
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
465 470 475 480
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
485 490 495
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
500 505 510
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
515 520 525
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
530 535 540
Arg
545
<210> 12
<211> 1638
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgct 60
agccagctgc agatgcagga atctggccct ggcctggtca agcccagcga gacactgagc 120
ctgagctgta ccgtgtccgg cgactctatc agaggcggcg agtggggcga caaggactat 180
cactggggat gggtccgaca cagcgccggc aaaggcctgg aatggatcgg ctctatccac 240
tggcggggca ccacccacta caaagagtcc ctgcggcgga gagtgtccat gagcatcgac 300
accagccgga actggttcag cctgagactg gcctctgtga cagccgccga taccgccgtg 360
tacttctgcg ccagacaccg gcaccacgac gtgttcatgc tggtgcctat cgccggatgg 420
ttcgacgtgt ggggacctgg cgtgcaggtc acagtgtcta gcggaggtgg aggatctggt 480
ggaggcggaa gtggcggagg gggatctgag attgtgatga cccagagccc cgacaccctg 540
agcgtgtccc caggcgaaac agtgaccctg agctgcagag ccagccagaa catcaacaag 600
aacctggcct ggtatcagta caagcccggc cagagcccca gactggtcat cttcgagaca 660
tacagcaaga tcgccgcctt ccccgccaga tttgtggcct ctggcagcgg caccgagttc 720
accctgacca tcaacaacat gcagagcgag gacgtggccg tgtactactg ccagcagtac 780
gaggaatggc cccggacctt tggccagggc accaaggtgg acatcaagca tatgaccacg 840
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 900
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 960
gcctgtgatt tttgggtgct ggtggtggtt ggtggagtcc tggcttgcta tagcttgcta 1020
gtaacagtgg cctttattat tttctgggtg aggagtaaga ggagcagggg cgggcacagt 1080
gactacatga acatgactcc ccgccgcccc gggcccaccc gcaagcatta ccagccctat 1140
gccccaccac gcgacttcgc agcctatcgc tccaaacggg gcagaaagaa actcctgtat 1200
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1260
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1320
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1380
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1440
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1500
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1560
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1620
gccctgcccc ctcgctaa 1638
<210> 13
<211> 8682
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 13
tggaagggct aattcactcc caaagaagac aagatatcct tgatctgtgg atctaccaca 60
cacaaggcta cttccctgat tagcagaact acacaccagg gccaggggtc agatatccac 120
tgacctttgg atggtgctac aagctagtac cagttgagcc agataaggta gaagaggcca 180
ataaaggaga gaacaccagc ttgttacacc ctgtgagcct gcatgggatg gatgacccgg 240
agagagaagt gttagagtgg aggtttgaca gccgcctagc atttcatcac gtggcccgag 300
agctgcatcc ggagtacttc aagaactgct gatatcgagc ttgctacaag ggactttccg 360
ctggggactt tccagggagg cgtggcctgg gcgggactgg ggagtggcga gccctcagat 420
cctgcatata agcagctgct ttttgcctgt actgggtctc tctggttaga ccagatctga 480
gcctgggagc tctctggcta actagggaac ccactgctta agcctcaata aagcttgcct 540
tgagtgcttc aagtagtgtg tgcccgtctg ttgtgtgact ctggtaacta gagatccctc 600
agaccctttt agtcagtgtg gaaaatctct agcagtggcg cccgaacagg gacttgaaag 660
cgaaagggaa accagaggag ctctctcgac gcaggactcg gcttgctgaa gcgcgcacgg 720
caagaggcga ggggcggcga ctggtgagta cgccaaaaat tttgactagc ggaggctaga 780
aggagagaga tgggtgcgag agcgtcagta ttaagcgggg gagaattaga tcgcgatggg 840
aaaaaattcg gttaaggcca gggggaaaga aaaaatataa attaaaacat atagtatggg 900
caagcaggga gctagaacga ttcgcagtta atcctggcct gttagaaaca tcagaaggct 960
gtagacaaat actgggacag ctacaaccat cccttcagac aggatcagaa gaacttagat 1020
cattatataa tacagtagca accctctatt gtgtgcatca aaggatagag ataaaagaca 1080
ccaaggaagc tttagacaag atagaggaag agcaaaacaa aagtaagacc accgcacagc 1140
aagcggccgg ccgctgatct tcagacctgg aggaggagat atgagggaca attggagaag 1200
tgaattatat aaatataaag tagtaaaaat tgaaccatta ggagtagcac ccaccaaggc 1260
aaagagaaga gtggtgcaga gagaaaaaag agcagtggga ataggagctt tgttccttgg 1320
gttcttggga gcagcaggaa gcactatggg cgcagcgtca atgacgctga cggtacaggc 1380
cagacaatta ttgtctggta tagtgcagca gcagaacaat ttgctgaggg ctattgaggc 1440
gcaacagcat ctgttgcaac tcacagtctg gggcatcaag cagctccagg caagaatcct 1500
ggctgtggaa agatacctaa aggatcaaca gctcctgggg atttggggtt gctctggaaa 1560
actcatttgc accactgctg tgccttggaa tgctagttgg agtaataaat ctctggaaca 1620
gatttggaat cacacgacct ggatggagtg ggacagagaa attaacaatt acacaagctt 1680
aatacactcc ttaattgaag aatcgcaaaa ccagcaagaa aagaatgaac aagaattatt 1740
ggaattagat aaatgggcaa gtttgtggaa ttggtttaac ataacaaatt ggctgtggta 1800
tataaaatta ttcataatga tagtaggagg cttggtaggt ttaagaatag tttttgctgt 1860
actttctata gtgaatagag ttaggcaggg atattcacca ttatcgtttc agacccacct 1920
cccaaccccg aggggacccg acaggcccga aggaatagaa gaagaaggtg gagagagaga 1980
cagagacaga tccattcgat tagtgaacgg atctcgacgg tatcgccgaa ttcacaaatg 2040
gcagtattca tccacaattt taaaagaaaa ggggggattg gggggtacag tgcaggggaa 2100
agaatagtag acataatagc aacagacata caaactaaag aattacaaaa acaaattaca 2160
aaaattcaaa attttcgggt ttattacagg gacagcagag atccagtttg gactagtcgt 2220
gaggctccgg tgcccgtcag tgggcagagc gcacatcgcc cacagtcccc gagaagttgg 2280
ggggaggggt cggcaattga accggtgcct agagaaggtg gcgcggggta aactgggaaa 2340
gtgatgtcgt gtactggctc cgcctttttc ccgagggtgg gggagaaccg tatataagtg 2400
cagtagtcgc cgtgaacgtt ctttttcgca acgggtttgc cgccagaaca caggtaagtg 2460
ccgtgtgtgg ttcccgcggg cctggcctct ttacgggtta tggcccttgc gtgccttgaa 2520
ttacttccac gcccctggct gcagtacgtg attcttgatc ccgagcttcg ggttggaagt 2580
gggtgggaga gttcgaggcc ttgcgcttaa ggagcccctt cgcctcgtgc ttgagttgag 2640
gcctggcctg ggcgctgggg ccgccgcgtg cgaatctggt ggcaccttcg cgcctgtctc 2700
gctgctttcg ataagtctct agccatttaa aatttttgat gacctgctgc gacgcttttt 2760
ttctggcaag atagtcttgt aaatgcgggc caagatctgc acactggtat ttcggttttt 2820
ggggccgcgg gcggcgacgg ggcccgtgcg tcccagcgca catgttcggc gaggcggggc 2880
ctgcgagcgc ggccaccgag aatcggacgg gggtagtctc aagctggccg gcctgctctg 2940
gtgcctggcc tcgcgccgcc gtgtatcgcc ccgccctggg cggcaaggct ggcccggtcg 3000
gcaccagttg cgtgagcgga aagatggccg cttcccggcc ctgctgcagg gagctcaaaa 3060
tggaggacgc ggcgctcggg agagcgggcg ggtgagtcac ccacacaaag gaaaagggcc 3120
tttccgtcct cagccgtcgc ttcatgtgac tccacggagt accgggcgcc gtccaggcac 3180
ctcgattagt tctcgagctt ttggagtacg tcgtctttag gttgggggga ggggttttat 3240
gcgatggagt ttccccacac tgagtgggtg gagactgaag ttaggccagc ttggcacttg 3300
atgtaattct ccttggaatt tgcccttttt gagtttggat cttggttcat tctcaagcct 3360
cagacagtgg ttcaaagttt ttttcttcca tttcaggtgt cgtgaagcgg ccgcgccacc 3420
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgct 3480
agccagctgc agatgcagga atctggccct ggcctggtca agcccagcga gacactgagc 3540
ctgagctgta ccgtgtccgg cgactctatc agaggcggcg agtggggcga caaggactat 3600
cactggggat gggtccgaca cagcgccggc aaaggcctgg aatggatcgg ctctatccac 3660
tggcggggca ccacccacta caaagagtcc ctgcggcgga gagtgtccat gagcatcgac 3720
accagccgga actggttcag cctgagactg gcctctgtga cagccgccga taccgccgtg 3780
tacttctgcg ccagacaccg gcaccacgac gtgttcatgc tggtgcctat cgccggatgg 3840
ttcgacgtgt ggggacctgg cgtgcaggtc acagtgtcta gcggaggtgg aggatctggt 3900
ggaggcggaa gtggcggagg gggatctgag attgtgatga cccagagccc cgacaccctg 3960
agcgtgtccc caggcgaaac agtgaccctg agctgcagag ccagccagaa catcaacaag 4020
aacctggcct ggtatcagta caagcccggc cagagcccca gactggtcat cttcgagaca 4080
tacagcaaga tcgccgcctt ccccgccaga tttgtggcct ctggcagcgg caccgagttc 4140
accctgacca tcaacaacat gcagagcgag gacgtggccg tgtactactg ccagcagtac 4200
gaggaatggc cccggacctt tggccagggc accaaggtgg acatcaagca tatgaccacg 4260
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 4320
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 4380
gcctgtgatt tttgggtgct ggtggtggtt ggtggagtcc tggcttgcta tagcttgcta 4440
gtaacagtgg cctttattat tttctgggtg aggagtaaga ggagcagggg cgggcacagt 4500
gactacatga acatgactcc ccgccgcccc gggcccaccc gcaagcatta ccagccctat 4560
gccccaccac gcgacttcgc agcctatcgc tccaaacggg gcagaaagaa actcctgtat 4620
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 4680
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 4740
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 4800
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 4860
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 4920
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 4980
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 5040
gccctgcccc ctcgctaaat cgatagatcc taatcaacct ctggattaca aaatttgtga 5100
aagattgact ggtattctta actatgttgc tccttttacg ctatgtggat acgctgcttt 5160
aatgcctttg tatcatgcta ttgcttcccg tatggctttc attttctcct ccttgtataa 5220
atcctggttg ctgtctcttt atgaggagtt gtggcccgtt gtcaggcaac gtggcgtggt 5280
gtgcactgtg tttgctgacg caacccccac tggttggggc attgccacca cctgtcagct 5340
cctttccggg actttcgctt tccccctccc tattgccacg gcggaactca tcgccgcctg 5400
ccttgcccgc tgctggacag gggctcggct gttgggcact gacaattccg tggtgttgtc 5460
ggggaaatca tcgtcctttc cttggctgct cgcctgtgtt gccacctgga ttctgcgcgg 5520
gacgtccttc tgctacgtcc cttcggccct caatccagcg gaccttcctt cccgcggcct 5580
gctgccggct ctgcggcctc ttccgcgtct tcgccttcgc cctcagacga gtcggatctc 5640
cctttgggcc gcctccccgc ctgagatcct ttaagaccaa tgacttacaa ggcagctgta 5700
gatcttagcc actttttaaa agaaaagggg ggactggaag ggctaattca ctcccaacga 5760
agacaagatc tgctttttgc ttgtactggg tctctctggt tagaccagat ctgagcctgg 5820
gagctctctg gctaactagg gaacccactg cttaagcctc aataaagctt gccttgagtg 5880
cttcaagtag tgtgtgcccg tctgttgtgt gactctggta actagagatc cctcagaccc 5940
ttttagtcag tgtggaaaat ctctagcagt agtagttcat gtcatcttat tattcagtat 6000
ttataacttg caaagaaatg aatatcagag agtgagaggc ccgggttaat taaggaaagg 6060
gctagatcat tcttgaagac gaaagggcct cgtgatacgc ctatttttat aggttaatgt 6120
catgataata atggtttctt agacgtcagg tggcactttt cggggaaatg tgcgcggaac 6180
ccctatttgt ttatttttct aaatacattc aaatatgtat ccgctcatga gacaataacc 6240
ctgataaatg cttcaataat attgaaaaag gaagagtatg agtattcaac atttccgtgt 6300
cgcccttatt cccttttttg cggcattttg ccttcctgtt tttgctcacc cagaaacgct 6360
ggtgaaagta aaagatgctg aagatcagtt gggtgcacga gtgggttaca tcgaactgga 6420
tctcaacagc ggtaagatcc ttgagagttt tcgccccgaa gaacgttttc caatgatgag 6480
cacttttaaa gttctgctat gtggcgcggt attatcccgt gttgacgccg ggcaagagca 6540
actcggtcgc cgcatacact attctcagaa tgacttggtt gagtactcac cagtcacaga 6600
aaagcatctt acggatggca tgacagtaag agaattatgc agtgctgcca taaccatgag 6660
tgataacact gcggccaact tacttctgac aacgatcgga ggaccgaagg agctaaccgc 6720
ttttttgcac aacatggggg atcatgtaac tcgccttgat cgttgggaac cggagctgaa 6780
tgaagccata ccaaacgacg agcgtgacac cacgatgcct gtagcaatgg caacaacgtt 6840
gcgcaaacta ttaactggcg aactacttac tctagcttcc cggcaacaat taatagactg 6900
gatggaggcg gataaagttg caggaccact tctgcgctcg gcccttccgg ctggctggtt 6960
tattgctgat aaatctggag ccggtgagcg tgggtctcgc ggtatcattg cagcactggg 7020
gccagatggt aagccctccc gtatcgtagt tatctacacg acggggagtc aggcaactat 7080
ggatgaacga aatagacaga tcgctgagat aggtgcctca ctgattaagc attggtaact 7140
gtcagaccaa gtttactcat atatacttta gattgattta aaacttcatt tttaatttaa 7200
aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt aacgtgagtt 7260
ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt gagatccttt 7320
ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag cggtggtttg 7380
tttgccggat caagagctac caactctttt tccgaaggta actggcttca gcagagcgca 7440
gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca agaactctgt 7500
agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg ccagtggcga 7560
taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg cgcagcggtc 7620
gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct acaccgaact 7680
gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga gaaaggcgga 7740
caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc ttccaggggg 7800
aaacgcctgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg agcgtcgatt 7860
tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg cggccttttt 7920
acggttcctg gccttttgct ggccttttgc tcacatgttc tttcctgcgt tatcccctga 7980
ttctgtggat aaccgtatta ccgcctttga gtgagctgat accgctcgcc gcagccgaac 8040
gaccgagcgc agcgagtcag tgagcgagga agcggaagag cgcccaatac gcaaaccgcc 8100
tctccccgcg cgttggccga ttcattaatg cagcaagctc atggctgact aatttttttt 8160
atttatgcag aggccgaggc cgcctcggcc tctgagctat tccagaagta gtgaggaggc 8220
ttttttggag gcctaggctt ttgcaaaaag ctccccgtgg cacgacaggt ttcccgactg 8280
gaaagcgggc agtgagcgca acgcaattaa tgtgagttag ctcactcatt aggcacccca 8340
ggctttacac tttatgcttc cggctcgtat gttgtgtgga attgtgagcg gataacaatt 8400
tcacacagga aacagctatg acatgattac gaatttcaca aataaagcat ttttttcact 8460
gcattctagt tgtggtttgt ccaaactcat caatgtatct tatcatgtct ggatcaactg 8520
gataactcaa gctaaccaaa atcatcccaa acttcccacc ccatacccta ttaccactgc 8580
caattacctg tggtttcatt tactctaaac ctgtgattcc tctgaattat tttcatttta 8640
aagaaattgt atttgttaaa tatgtactac aaacttagta gt 8682
<210> 14
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
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
20 25
<210> 15
<211> 45
<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
35 40 45
<210> 16
<211> 195
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu
35 40 45
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
50 55 60
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
65 70 75 80
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
85 90 95
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
100 105 110
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
115 120 125
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
130 135 140
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
145 150 155 160
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
165 170 175
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
180 185 190
Pro Pro Arg
195
<210> 17
<211> 765
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 17
cagctgcaga tgcaggaatc tggccctggc ctggtcaagc ccagcgagac actgagcctg 60
agctgtaccg tgtccggcga ctctatcaga ggcggcgagt ggggcgacaa ggactatcac 120
tggggatggg tccgacacag cgccggcaaa ggcctggaat ggatcggctc tatccactgg 180
cggggcacca cccactacaa agagtccctg cggcggagag tgtccatgag catcgacacc 240
agccggaact ggttcagcct gagactggcc tctgtgacag ccgccgatac cgccgtgtac 300
ttctgcgcca gacaccggca ccacgacgtg ttcatgctgg tgcctatcgc cggatggttc 360
gacgtgtggg gacctggcgt gcaggtcaca gtgtctagcg gaggtggagg atctggtgga 420
ggcggaagtg gcggaggggg atctgagatt gtgatgaccc agagccccga caccctgagc 480
gtgtccccag gcgaaacagt gaccctgagc tgcagagcca gccagaacat caacaagaac 540
ctggcctggt atcagtacaa gcccggccag agccccagac tggtcatctt cgagacatac 600
agcaagatcg ccgccttccc cgccagattt gtggcctctg gcagcggcac cgagttcacc 660
ctgaccatca acaacatgca gagcgaggac gtggccgtgt actactgcca gcagtacgag 720
gaatggcccc ggacctttgg ccagggcacc aaggtggaca tcaag 765
<210> 18
<211> 399
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 18
cagctgcaga tgcaggaatc tggccctggc ctggtcaagc ccagcgagac actgagcctg 60
agctgtaccg tgtccggcga ctctatcaga ggcggcgagt ggggcgacaa ggactatcac 120
tggggatggg tccgacacag cgccggcaaa ggcctggaat ggatcggctc tatccactgg 180
cggggcacca cccactacaa agagtccctg cggcggagag tgtccatgag catcgacacc 240
agccggaact ggttcagcct gagactggcc tctgtgacag ccgccgatac cgccgtgtac 300
ttctgcgcca gacaccggca ccacgacgtg ttcatgctgg tgcctatcgc cggatggttc 360
gacgtgtggg gacctggcgt gcaggtcaca gtgtctagc 399
<210> 19
<211> 321
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 19
gagattgtga tgacccagag ccccgacacc ctgagcgtgt ccccaggcga aacagtgacc 60
ctgagctgca gagccagcca gaacatcaac aagaacctgg cctggtatca gtacaagccc 120
ggccagagcc ccagactggt catcttcgag acatacagca agatcgccgc cttccccgcc 180
agatttgtgg cctctggcag cggcaccgag ttcaccctga ccatcaacaa catgcagagc 240
gaggacgtgg ccgtgtacta ctgccagcag tacgaggaat ggccccggac ctttggccag 300
ggcaccaagg tggacatcaa g 321
<210> 20
<211> 43
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 20
acattccgct agccagctgc agatgcagga atctggccct ggc 43
<210> 21
<211> 57
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 21
ccgcctccac cagatcctcc acctccgcta gacactgtga cctgcacgcc aggtccc 57
<210> 22
<211> 59
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 22
gatctggtgg aggcggaagt ggcggagggg gatctgagat tgtgatgacc cagagcccc 59
<210> 23
<211> 38
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 23
cgtggtcata tgcttgatgt ccaccttggt gccctggc 38
<210> 24
<211> 43
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 24
acattccgct agccagctgc agatgcagga atctggccct ggc 43
<210> 25
<211> 38
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 25
cgtggtcata tgcttgatgt ccaccttggt gccctggc 38
<210> 26
<211> 267
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
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 Phe Trp Val
35 40 45
Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr
50 55 60
Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly
65 70 75 80
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
85 90 95
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
100 105 110
Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
115 120 125
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
130 135 140
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
145 150 155 160
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
165 170 175
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
180 185 190
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
195 200 205
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
210 215 220
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
225 230 235 240
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
245 250 255
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
260 265
Claims (10)
1.一种嵌合抗原受体,其特征在于,所述的嵌合抗原受体包括胞外抗原结合结构域,所述的胞外抗原结合结构域为PGT135的人单链抗体。
2.根据权利要求1所述的嵌合抗原受体,其特征在于,所述的人单链抗体包括重链可变区、接头和轻链可变区;
优选的,所述的重链可变区是与SEQ ID NO:3的氨基酸序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的氨基酸序列;
优选的,所述的轻链可变区是与SEQ ID NO:2的氨基酸序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的氨基酸序列;
优选的,所述的接头为包含甘氨酸和/或丝氨酸的氨基酸序列,更优选的,所述接头的序列如SEQ ID NO:4-9任一项所示。
3.根据权利要求2所述的嵌合抗原受体,其特征在于,所述的人单链抗体的氨基酸序列如SEQ ID NO:1或SEQ ID NO:10所示。
4.根据权利要求1-3任一所述的嵌合抗原受体,其特征在于,所述的嵌合抗原受体的氨基酸序列是与SEQ ID NO:11所示序列具有至少为80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%同源性的氨基酸序列。
5.一种分离的免疫应答细胞,其特征在于,所述的免疫应答细胞包含权利要求1-4任一所述的嵌合抗原受体。
6.一种核酸分子,其特征在于,所述的核酸分子编码权利要求1-4任一所述嵌合抗原受体。
7.一种载体,其特征在于,所述的载体包含权利要求6所述的核酸分子。
8.一种宿主细胞,其特征在于,所述的宿主细胞包含权利要求6所述的核酸分子或权利要求7所述的载体。
9.一种细胞群,其特征在于,所述的细胞群包含至少1个权利要求8所述的宿主细胞。
10.特异性结合如权利要求1-4任一所述的嵌合抗原受体的抗体或其抗原结合部分。
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