CN114729026B - 用于稳定免疫突触的嵌合抗原受体(car)t细胞 - Google Patents
用于稳定免疫突触的嵌合抗原受体(car)t细胞 Download PDFInfo
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Abstract
本发明涉及将参与免疫突触稳定的CD99区域用作嵌合抗原受体的骨架(backbone)的新型嵌合抗原受体以及包含其的免疫细胞及其用途。与具有现有骨架的CAR‑T细胞相比,基于CD99的CAR‑T细胞与肿瘤细胞形成更稳定的免疫突触,并表现出改善的肿瘤治疗效果,因此可用于免疫细胞治疗。
Description
技术领域
本发明涉及一种新型嵌合抗原受体、包含其的免疫细胞及其用途,所述新型嵌合抗原受体将参与免疫突触稳定的CD99区域用作嵌合抗原受体的骨架(backbone)。
背景技术
利用免疫细胞的抗癌治疗法的开发一直以T细胞为中心发展,随着可以对肿瘤抗原特异性T细胞进行体外培养和增殖,抗癌T细胞治疗法已获得可见的成果(Gattinoni L等人,Nat Rev Immunol.2006;6(5):383-93)。然而,由于患者体内存在的肿瘤抗原特异性T细胞的数量非常少,因此缺点在于,通过在体外增殖这些T细胞来确保足够的T细胞需要1个月以上的长时间。
因此,基于治疗用抗体领域积累的重组抗体制备技术,开发了一种在短时间内获得大量肿瘤特异性T细胞的技术,通过将连接识别在癌细胞表面表达的肿瘤抗原的重组抗体与诱导T细胞活化的信号转导结构域的嵌合抗原受体(chimeric antigen receptor,CAR)基因导入T细胞,这些T细胞被命名为CAR-T细胞(Kershaw MH等人,Nat RevImmunol.2005;5(12):928-40;Restifo NP等人,Nat Rev Immunol.2012;12(4):269-81)。
CAR-T细胞治疗剂因其显著效果而备受关注,尤其在以血液肿瘤为对象的临床试验中。也就是说,利用识别B淋巴细胞类血液肿瘤抗原CD19的抗体的CAR-T细胞治疗显示出惊人的治疗效果,在以所有现有治疗均无反应的急性淋巴细胞白血病患者为对象的早期临床试验中,90%的患者(30名中的27名)在1个月内达到完全缓解,6个月整体存活率达到78%(Maude SL等人,N Engl J Med.2014;371(16):1507-17.)。基于这些结果,2017年年底,两种CD19 CAR-T细胞治疗剂在美国食品药品监督管理局(FDA)批准下成功商业化。
据报告,目前CAR-T细胞治疗的成功案例仅限于CD19阳性急性白血病,而实体瘤的治疗效率较低。认为部分原因在于,实体瘤更牢固地构建了具有免疫抑制力的肿瘤微环境(Springuel L等人,BioDrugs.2019;33(5):515-37)。作为一例,众所周知,就CD19阳性血液肿瘤而言,与肿瘤细胞主要在血液中增殖的白血病相比,形成实体瘤的淋巴瘤的CAR-T细胞治疗效率更低(Sadelain M等人,Nature.2017;545(7655):423-31)。因此,迫切需要进一步提高CAR-T细胞的功能(Mardiana S等人,Sci Transl Med.2019;11(495))。
CAR蛋白被设计成识别癌抗原的抗体的可变区(variable region)(单链可变片段(single chain variable fragment;scFv))通过骨架(backbone)与胞内信号转导结构域(intracellular signaling domain)相连接的形态(Dotti G等人,Immunol Rev.2014;257(1):107-26)。胞内信号转导结构域主要基于作为T细胞受体(T cell receptor)的信号转导亚基(subunit)的CD3截塔(ζ)链的胞内信号转导结构域(第一代CAR),向其中添加用于促进T细胞的生长和分化的共刺激分子(co-stimulatory molecule)的胞内信号转导结构域形态进化。
迄今为止,致力于通过CAR蛋白修饰(modification)来提高CAR-T细胞的功能,其大部分是以替换或添加共刺激分子的信号转导结构域的形式进行。例如,目前市售的两种CAR-T细胞治疗剂分别使用CD28和4-1BB共刺激分子的胞内信号转导结构域(第二代CAR),此后正在尝试同时包含CD28和4-1BB胞内信号转导结构域的CAR(第三代CAR)等(van derStegen SJ等人,Nat Rev Drug Discov.2015;14(7):499-509)。然而,相对而言,包含跨膜结构域(transmembrane domain)的骨架(backbone)到目前为止仅用于连接scFv和胞内信号转导结构域的物理功能,而很少有关于对该区域赋予功能的CAR设计的报告。
在本发明中,确认到被称为CD99的膜蛋白通过免疫突触稳定新机制来提高T细胞功能,并确认可通过将CD99的部分区域用作CAR蛋白的骨架(backbone)来提高CAR-T细胞的功能,从而开发了利用其的新型CAR-T细胞治疗法。
背景部分所描述的上述信息仅用于增进对本发明背景的理解,因此,可能不包括构成本发明所属领域的普通技术人员已知的现有技术的信息。
发明内容
本发明的目的在于,提供一种嵌合抗原受体及包含其的免疫细胞,其通过使形成于免疫细胞与靶细胞之间的接触区域的免疫突触稳定来示出改善的肿瘤治疗效果。
本发明的另一目的在于,提供编码上述嵌合抗原受体的核酸、包含上述核酸的表达载体及包含上述表达载体的病毒。
本发明另一目的在于,提供包含上述免疫细胞的癌治疗用组合物、利用上述免疫细胞的癌治疗方法、用于治疗癌症的上述免疫细胞的用途及用于制备癌治疗用药剂的上述免疫细胞的使用。
为了实现上述目的,本发明提供一种包含CD99蛋白衍生的跨膜结构域的嵌合抗原受体。
本发明还提供编码上述嵌合抗原受体的核酸、包含上述核酸的表达载体、包含上述表达载体的病毒及表达上述嵌合抗原受体的免疫细胞。
本发明还提供包含上述免疫细胞的癌治疗用组合物、利用上述免疫细胞的癌症治疗方法、用于治疗癌症的上述免疫细胞的用途及用于制备癌治疗用药剂的上述免疫细胞的使用。
附图说明
图1为嵌合抗原受体(chimeric antigen receptor,CAR)的示意图。
图2示出T细胞受体(TCR)刺激引起的CD99缺陷T细胞的活化障碍现象,其为示出TCR刺激引起的从正常小鼠(WT)和CD99敲除(knockout)小鼠(CD99KO)淋巴结中分离并羧基荧光素二醋酸盐琥珀酰亚胺酯(CFSE)标记的CD8 T细胞的分裂能力和细胞因子(cytokine)分泌能力分析结果的图。图2的A部分为示出TCR刺激后第二天和第三天通过细胞分裂的CFSE稀释率流式细胞分析(左侧),以及总T细胞中以CFSE稀释倍数测量的每个分裂数的细胞群比例(%)(右侧)的图表。图2的B部分为TCR刺激后随时间的IL-2或IFN-γ产生CD8T细胞比例分析结果图表。在t检验(t-test)分析中,*p<0.05,**p<0.01,***p<0.001。
图3为示出CD99缺陷T细胞的免疫突触障碍的图。
图3的A部分为比较抗原呈递细胞与WT细胞或CD99-KO T细胞形成免疫突触形成,其示出共培养使用抗-TCRβ和LFA-1抗体染色的T细胞与抗原呈递细胞,经30分钟后共聚焦显微镜图像(左侧),以及在图像上TCRβ和LFA-1的细胞之间接触近端(proximal)区域和远端(distal)区域的荧光强度值的比例(右侧)的图,图3的B部分为形成免疫突触时F-肌动蛋白(F-actin)的共聚焦显微镜分析结果,其示出共培养T细胞与抗原呈递细胞,经30分钟后通过鬼笔环肽(Phalloidin)染色的F-肌动蛋白的显微镜图像(左侧)以及在一个视野内显示密集F-肌动蛋白的细胞的比例(5个视野内的综合测量)(右侧)的图。图3的C部分至G部分为示出形成免疫突触时F-肌动蛋白动态重排分析(在包被抗-CD3抗体的载玻片上表达Life-Act荧光蛋白的活化的WT或CD99-KO T细胞的实时共聚焦显微镜分析)结果的图,图3的C部分示出胞内F-肌动蛋白的分布和细胞形状随时间的变化,图3的D部分示出初始细胞扩增所需的时间,图3的E部分示出细胞的横截面积随时间的变化,图3的F部分和图3的G部分示出板状伪足(lamellipodia)厚度测量和距肌动蛋白微簇(actin microcluster)的细胞中心的距离的检测示例(图3的F部分),以及测量结果值的定量分析(图3的G部分)。在t检验分析中,*p<0.05,**p<0.01,***p<0.001。
图4为示出CD99缺陷T细胞免疫突触中的肌动蛋白(actin)和微管网络(microtubule network)形成障碍的图。
图4的A部分至D部分为示出正常T细胞及CD99缺陷T细胞的免疫突触形成时F-肌动蛋白和微管(microtubule)的重排分析(在WT T细胞及CD99-KO细胞中表达Life-Act荧光蛋白,并使用SIR微管蛋白(SiR-tubulin)试剂进行染色后,在包被抗-CD3抗体的载玻片上活化的T细胞的实时共聚焦显微镜分析)结果的图,图4的A部分为肌动蛋白(红色)和微管(青蓝色)随时间的变化。图4的B部分为在突触形成早期(5分钟)和晚期(20分钟)存在于一个胞内部的垂直型(轨迹(trajectory))微管的数量(左侧)和长度(右侧)的定量分析结果,图4的C部分为胞内F-肌动蛋白和微管排列的比较,沿细胞的横截面分布的肌动蛋白和微管的的相对定量比较分析(强度(Intensity):任意荧光强度),黄色区域表示板状伪足区域。图4的D部分为放大板状伪足区域的图像,示出板状伪足内微管(cyan blue)及肌动蛋白(红色)分布图像(左侧)和在图像上两个荧光的共定位(co-localization)系数(皮尔逊系数(Pearsons’coefficient))的定量分析(右侧)。图4的E部分为微管蛋白(Tubulin)和肌动蛋白的共免疫沉淀结果,抗-CD3抗体刺激后在WT和CD99-KO T细胞中利用抗-微管蛋白抗体免疫沉淀物的抗-微管蛋白抗体及抗-肌动蛋白抗体的免疫印迹(左侧),同种(Isotype)对照组IgG免疫沉淀物的免疫印迹(中央)和实施免疫沉淀前细胞提取液的免疫印迹(右侧)。在t检验分析中,*p<0.05,****p<0.0001。
图5为示出在正常细胞中CD99在免疫突触细胞膜中的位置与细胞质中肌动蛋白和微管分布的相关性分析结果的图。
图5的A部分为确认CD99在免疫突触细胞膜中位置的结果,示出将使用抗-TCR抗体和抗-CD99(上图)或者使用抗-LAF-1抗体和抗-CD99抗体(下图)染色的T细胞与抗原呈递细胞进行共培养,经1小时后的共聚焦显微镜图像(左侧),以及CD99和TCRβ或CD99和LFA-1的共定位常数分析(右侧)。图5的B部分为确认在形成有免疫突触的细胞中CD99与F-肌动蛋白及微管蛋白的分布的结果,示出在包被抗-CD3抗体的载玻片上将表达WT-CD99-GFP的T细胞活化15分钟后,使用鬼笔环肽(上图)或抗-微管蛋白抗体(下图)染色的共聚焦显微镜图像(左侧)和在图像中选定的位置(虚线方块)中WT CD99-GFP蛋白与F-肌动蛋白或微管蛋白的共定位系数定量分析(右侧)结果。图5的C部分为CD99与肌动蛋白和微管蛋白的共免疫沉淀分析结果,其是在WT T细胞中利用抗-CD99抗体免疫沉淀物的抗-肌动蛋白和抗-微管蛋白抗体的免疫印迹(右侧泳道(lane))、对照组IgG抗体免疫沉淀物的免疫印迹(中央泳道)以及实施免疫沉淀前细胞提取液(左侧泳道)的免疫印迹结果。在t检验分析中,***p<0.001。
图6为确认CD99蛋白与肌动蛋白和微管的相互作用区域的结果的图。
图6的A部分为各个CD99突变蛋白的结构设计示意图,即胞质域突变体(Cytoplamsic domain mutant,Cyt)、跨膜域突变体(Transmembrane domain mut ant,TM)、跨膜部分置换突变体(Transmembrane partial replacement mutants,TMrst-S,TMrst -L)及仅存在于胞质区(Cytoplasmic region)中近膜区(juxtamemb rane region)的突变体(mutant)(CytJuxt)的示意图。图6的B部分为表达CD99突变蛋白-GFP的T细胞的免疫突触形成时F-肌动蛋白和微管的分布,是使用SIR微管蛋白试剂对表达Life-Act荧光蛋白和各个突变蛋白-GFP的T细胞进行染色后,在包被抗-CD3抗体的载玻片上活化,经15分钟后的共聚焦显微镜分析结果,是单荧光和双荧光(CD99/微管蛋白;微管蛋白/F-肌动蛋白)和细胞形状(DIC)图像。
图7为示出基于CD99骨架(backbone)的CAR-T细胞设计和试管内活性验证结果的图。
图7的A部分为各个CAR蛋白的结构设计示意图,即hCD8 L:人CD8α前导(human CD8αleader)、αCD19 scFv:抗CD19抗体(anti-CD19 antibody)(克隆FMC63)单链可变片段(single chain variable fragment)、EC:胞外区(extracellular region)、EC58:胞外58个氨基酸区(extracellular 58amino aci d region)、EC45:胞外45个氨基酸区(extracellular 45amino acid region)、EC35:胞外35个氨基酸区(extracellular35amino acid region)、TM:跨膜区(membrane region)、jTM:近膜区(juxtamembraneregion)、cyt:胞质区(cytoplasmic region)。图7的B部分为示出CAR-T细胞表面的CAR蛋白的表达程度(曲线图上方数字:CAR阳性细胞的比例(%),曲线图下方数字(平均荧光强度(mean fluorescence intensity,MFI);CAR阳性细胞的平均荧光强度)的图,图7的C部分为各个CAR-T细胞对Raji-Luc淋巴瘤细胞的杀伤力(相对光单位(Relative light unit):CAR-T细胞与过夜培养后存活的Raji-Luc细胞中的荧光素酶(luciferase)活性值;E:T比(Effector:Target ratio):共培养的CAR-T细胞(Effector)与Raji-Luc细胞(Target)的细胞数比例)的曲线图,图7的D部分为示出将CAR-T细胞和Raji细胞共培养后分泌到上清液中的IFN-γ的量的图表。
图8为示出基于CD99骨架(backbone)的CAR-T细胞的体内肿瘤去除增强效果的图。
图8的A、B部分为示出将Raji-Luc细胞静脉注射到NSG小鼠之后(第0天),当在第7天静脉注射CAR-T细胞时,CAR-T细胞注入前(第6天)和注入后(第14天至第98天)肿瘤细胞的体内增殖程度利用生物发光成像(biolum inescence imaging)测量的每个时间点的代表性图像(图8的A部分)和示出定量测量值(图8的B部分)的图,图8的C部分为示出接种上述Raji-Luc细胞和CAR-T细胞的小鼠的存活率随时间变化的曲线图。
图9为示出基于CD99骨架(backbone)的CAR-T细胞的免疫突触形成增强效果的图。
图9的A、B部分为示出共培养CAR-T细胞和Raji细胞时形成免疫突触的细胞的共聚焦显微镜图像(经1小时后)(图9的A部分)和随时间的定量趋势(每个视野中存在的Raji细胞中与T细胞结合的Raji细胞比例,3-5个视野的综合测量值)(图9的B部分)的图。图9的C部分示出Raji细胞与CAR-T细胞结合体的代表性图像(经1小时后),图9的D部分示出与Raji细胞结合的CAR-T细胞的平均数量(经1小时后)。
具体实施方式
除非另有定义,本说明书中使用的所有技术及科学术语与本发明所属领域的普通技术人员通常理解的含义相同。一般而言,本说明书中使用的命名法是本领域公知和常用的。
CD99是一种包括T细胞在内的各种细胞群中表达的膜蛋白,已知参与细胞粘着(cell adhesion)、细胞的迁移(cell migration)、蛋白质胞内迁移(proteintrafficking)等(Pasello M等人,J Cell Commun Signal.2018;12(1):55-68))。据报告,T细胞作为共刺激分子(co-stimulatory molecule)在促进T细胞活化方面具有作用(Oh KI等人,Exp Mol Med.2007;39(2):176-84),并报告,其可促进细胞膜蛋白如MHC I、TCR的细胞表面表达(Sohn HW等人,J Immunol.2001;166(2):787-94)。作为这种T细胞活化过程的机制,虽然已提出CD99迁移到脂筏(lipid raft)并调节T细胞内部的肌动蛋白细胞骨架重排(actin cytoskeleton rearrangement)的可能性,但尚未研究具体的分子机制(Yoon SS等人,FEBS Lett.2003;540(1-3):217-22)。
当T细胞与如树突状细胞的抗原呈递细胞接触时,通过T细胞受体(T cellreceptor,TCR)识别抗原呈递细胞呈递的肽抗原,并将TCR信号转导至内部而被活化。此时,T细胞的细胞膜区域与抗原呈递细胞的细胞膜区域在很长时间内保持着强烈的接触,将此接触区域统称为免疫突触(immune synapse)(Grakoui A等人,Science.1999;285(5425):221-7)。众所周知,免疫突触的形成在T细胞活化信号转导中起着重要作用,而T细胞内部的肌动蛋白细胞骨架重排(cytoskeletal rearrangement)对于免疫突触的形成是必须的(Dustin ML,Cooper JA,Nat Immunol.2000;1(1):23-9)。并且,最近,已知微管细胞骨架也与肌动蛋白一起参与免疫突触,但尚未明确研究其相互关系。(Martin-Cofreces NB,Sanchez-Madrid F,Front Immunol.2018;9:1174;Dogterom M,Koenderink GH,Nat RevMol Cell Biol.2019;20(1):38-54)。
在本发明中,证明了CD99在免疫突触的形成中起重要作用,这是因为CD99介导细胞内部的细胞骨架重排。并且,作为具体机制,阐明了CD99作为连接肌动蛋白细胞骨架与以往尚未得到很好的研究的微管细胞骨架的骨桥(bridge)分子。
并且,阐明了CD99分子的跨膜结构域和胞内近膜结构域(intracellularjuxtamembrane domain)分别在与微管和肌动蛋白的结合中起独立作用。
就CAR-T细胞而言,当使用CAR蛋白的抗体区域来接触肿瘤细胞表面的抗原时,已知形成类似于正常T细胞与抗原呈递细胞接触时的免疫突触,据报告,免疫突触的形成与CAR-T细胞的活性相关(Davenport AJ等人,Proc Natl Acad Sci U S A.2018;115(9):E2068-E76)。因此,促进免疫突触形成的CAR蛋白设计可以大大增加CAR-T细胞的活性。
基于CD99在细胞骨架重排和免疫突触形成中起重要作用的实验结果,测试了使用包含CD99的跨膜结构域的结构取代现有CAR蛋白的结构中包含跨膜结构域的CAR骨架(backbone)时,CAR-T细胞的功能是否有所提高。其结果,确认了与使用现有CD8蛋白区域的CAR-T细胞相比,表达包含CD99的部分胞外域、跨膜结构域、胞内近膜结构域的CAR蛋白的CAR-T细胞具有更优越的肿瘤治疗效率。并且,确认了与现有CD8骨架(backbone)CAR-T细胞相比,包含CD99衍生的骨架(backbone)的CAR-T细胞具有更优越的免疫突触形成能力。
最终目的在于,通过本发明导入引入有CD99区域的CAR蛋白,借助增强免疫突触形成来提出功能得以改善的CAR-T细胞的新概念。
因此,本发明的一方面涉及一种嵌合抗原受体(chimeric antigen receptor;CAR),包含:(a)抗原结合结构域(antigen binding domain),(b)骨架(backbone),包含胞外连接部和跨膜结构域(transmembrane domain),以及(c)胞内信号转导结构域(intracellular signaling domain);上述嵌合抗原受体(chimeric antigen receptor;CAR)的特征在于,上述跨膜结构域包含CD99衍生的跨膜结构域。
在本发明中,“骨架(backbone)”是指包含胞外连接部(extracellular spacerdomain)和跨膜结构域(transmembrane domain)的区域。
在本发明中,“胞外连接部(extracellular spacer domain)”是指连接抗原结合结构域与跨膜结构域的区域。
在本发明中,上述跨膜结构域(transmembrane domain,TM)可以包括全部或部分CD99衍生的跨膜结构域,优选的,上述CD99为具有SEQ ID NO.1的序列的人CD99,但不限于此。
具有上述SEQ ID NO.1的序列人CD9可由9SEQ ID NO.2的核苷酸序列或其简并(degenerative)序列编码,但不限于此。
表1人CD99的氨基酸序列及编码其的核苷酸序列
在具有上述SEQ ID NO.1的氨基酸序列的人CD99中,D23至D122的氨基酸序列为CD99的胞外域(extracellular domain),A123至A147的氨基酸序列为CD99的跨膜结构域,Y148至N158的氨基酸序列对应于CD99的近膜结构域(juxtamembrane domain)。
如上述“D23”,由氨基酸的单字母密码(one-letter code)和数字组合而成的表述是指上述数字的位置的氨基酸残基。也就是说,D23是指第23个氨基酸为天冬氨酸(Aspartic acid,D)。
优选地,上述CD99衍生的跨膜结构域可包含由SEQ ID NO.3表示的氨基酸序列,但不限于此。具有上述SEQ ID NO.3的序列的人CD99衍生的跨膜结构域可由SEQ ID NO.4的核苷酸序列或其简并序列编码,但不限于此。
在本发明中,上述胞外连接部可包含CD99衍生的和/或CD8衍生的胞外域(extracellular domain),优选地,可包含人CD99衍生的胞外域(extracellular domain)。
上述CD99衍生的胞外域可包含全部或一部分由SEQ ID NO.5表示的氨基酸序列,但不限于此。具有上述SEQ ID NO.5的序列的人CD99衍生的胞外域可由SEQ ID NO.6的核苷酸序列或其简并序列编码,但不限于此。
在本发明中,上述CD99衍生的胞外域可由SEQ ID NO.5表示,或由SEQ ID NO.5中的包含连续的20个至70个,优选地包含30个至60个氨基酸残基的氨基酸序列表示。
更优选地,上述CD99衍生的胞外域可包含由SEQ ID NO.5、SEQ ID NO.7、SEQ IDNO.9或SEQ ID NO.11表示的氨基酸序列,但不限于此。
并且,在本发明中,上述嵌合抗原受体还可包含CD99衍生的胞内近膜结构域(intracellular juxtamembrane domain)。
在本发明中,上述“胞内近膜结构域”可位于嵌合抗原受体的跨膜结构域与胞内信号转导结构域之间。在本发明的一实施例中,已确认上述CD99衍生的胞内近膜结构域通过介导肌动蛋白与肌动蛋白的相互作用来助于稳定免疫突触的形成。
上述CD99衍生的胞内近膜结构域可包含全部或一部分CD99衍生的胞内近膜结构域,优选地,可包含由SEQ ID NO.13表示的氨基酸序列。
表2人CD99衍生的跨膜结构及胞外域的序列
在本发明中,上述胞外连接部还可包含铰链(hinge)结构域。
上述铰链结构域由任意寡肽或多肽组成,可包含1个至100个氨基酸残基,优选地,可包含10个至70个氨基酸残基。优选地,其可以包含全部或一部分由SEQ ID NO.15表示的氨基酸序列的CD8衍生铰链结构域,但不限于此。
在本发明中,上述胞内信号转导结构域(intracellular signaling domain)位于免疫细胞的细胞膜内侧,即位于细胞质的部分,是指当包含在胞外域的抗原结合结构域与靶抗原结合时,将信号传转导给细胞中来活化免疫细胞的免疫反应的区域。
在本发明中,优选地,上述胞内信号转导结构域为选自由CD3截塔(ζ)、CD3伽马(γ)、CD3德尔塔(δ)、CD3伊普西龙(ε)、FcR伽马、FcR贝塔、CD5、CD22、CD79a、CD79b及CD66d组成的组中的一种以上的胞内信号转导结构域,但不限于此。更优选地,其可以是CD3截塔(ζ)。根据本发明的CD3截塔(ζ)的胞内信号转导结构域可具有如下所述的氨基酸序列:上述氨基酸序列包含SEQ ID NO.17或SEQ ID NO.17的序列中作为第14个氨基酸残基的谷氨酰胺(Q)被赖氨酸(K)取代的SEQ ID NO.19的氨基酸序列,但不限于此。
并且,根据本发明的上述胞内信号转导结构域还可包含共刺激(co-stimulatory)结构域,但不限于此。优选地,根据本发明的共刺激(co-stimulatory)结构域为选自由与CD2、CD7、CD27、CD28、CD30、CD40、4-1BB(CD137)、OX40(CD134)、ICOS、LFA-1、GITR、MyD88、DAP1、PD-1、LIGHT、NKG2C、B7-H3及CD83特异性结合的配体组成的组中的一种以上的共刺激结构域,但不限于此。
优选地,根据本发明的胞内信号转导结构域可包含胞内信号转导结构域和4-1BB的共刺激结构域,上述胞内信号转导结构域包含SEQ ID NO.17或SEQ ID NO.19的氨基酸序列的CD3截塔(ζ),上述4-1BB的共刺激结构域包含由SEQ ID NO.21表示的氨基酸序列,但不限于此。
表3CD3截塔(ζ)的胞内信号转导结构域及4-1BB共刺激结构域的序列
尤其,根据本发明的嵌合抗原受体可包含一个以上的胞内信号转导结构域和一个以上的共刺激结构域。
在根据本发明的嵌合抗原受体包含一个以上的胞内信号转导结构域和一个以上的共刺激结构域的情况下,一个以上的共刺激结构域和一个以上的胞内信号转导结构域可以彼此串联连接。在此情况下,每个结构域可以直接连接,或者选择性地通过由2个至10个氨基酸残基组成的寡肽连接体或多肽连接体连接,优选地,作为这些连接体序列,可举出甘氨酸-丝氨酸序列。
在本发明中,上述嵌合抗原受体还可包含T细胞的免疫功能促进因子,作为上述T细胞的免疫功能促进因子,可列举白细胞介素-7(interleukin 7,IL-7)、IL-12、IL-15、IL-18、IL-21或CCL19,但不限于此。关于T细胞的免疫功能促进因子可参照WO2016/056228A。
在本发明中,上述嵌合抗原受体还可包含白细胞介素受体链(interleukinreceptor chain),上述白细胞介素受体链包含JAK结合基序和STAT3/5缔合基序,可列举IL-2Rβ,但不限于此。与此相关地,可参照WO2016/127257A。
第一代CAR包含胞外域、跨膜结构域及胞内信号转导结构域,上述胞外域包含癌细胞中特异性表达的抗原识别位点,仅使用CD3ζ作为信号转导结构域,但对癌症的治疗效果微乎其微,并且存在持续时间短的问题。这些第一代CAR在美国授权专利第6319494号中有具体描述,通过引用将其并入本文。
为了提高对免疫细胞的反应性,制备了结合共刺激结构域(CD28或CD137/4-1BB)与CD3ζ的第二代CAR,与第一代CAR相比,体内残留的包含CAR的免疫细胞数量显著增加。第二代CAR使用一种共刺激结构域,而第三代CAR用两种以上的共刺激结构域。为了实现体内包含CAR的免疫细胞的扩增和持续性,可结合共刺激结构域与4-1BB、CD28或OX40等。第二代CAR在美国授权专利第7741465号、第7446190号或第9212229号中具体描述,第三代CAR在美国授权专利第8822647号中具体描述,通过引用将其并入本文。
在第四代CAR中,包含用于编码IL-12或IL-15等细胞因子的额外基因,使其还可表达基于细胞因子的CAR的免疫蛋白,而第五代CAR还包含用于增强免疫细胞的白细胞介素受体链,例如,IL-2Rβ。第四代CAR在美国授权专利第10316102号中具体描述,第五代CAR在美国授权专利第10336810中具体描述,通过引用将其并入本文。
在本发明中,上述抗原结合结构域可包含但不限于与选自下组的抗原特异性结合的抗体或其抗原结合片段(antigen binding fragment):4-1BB、B细胞成熟抗原(B cellmaturation antigen,BCMA)、B细胞活化因子(B-cell activating factor,BAFF)、B7-H3、B7-H6、碳酸酐酶9(carbonic anhydrase 9,CA9;或也称为CAIX或G250)、癌症/睾丸抗原1B(cancer/testis antigen 1B,CTAG1B;或也称为NY-ESO-1或LAGE2B)、癌胚抗原(carcinoembryonic antigen,CEA),细胞周期蛋白(cyclin)、细胞周期蛋白A2、细胞周期蛋白B1、CC基序趋化因子配体1(C-C Motif Chemokine Ligand 1,CCL-l)、CCR4、CD3、CD4、CD19、CD20、CD22、CD23、CD24、CD30、CD33、CD38、CD40、CD44、CD44v6、CD44v7/8、CD52、CD58、CD62、CD79A、CD79B、CD80、CD123、CD133、CD138、CD171、硫酸软骨素蛋白聚糖4(chondroitinsulfate proteoglycan 4,CSPG4)、密封蛋白-18(claudin-18,CLDN18)、CLDN6、细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4,CTLA-4)、酪氨酸蛋白激酶Met(tyrosine-protein kinase Met,c-Met)、DLL3、表皮生长因子受体(epidermal growth factor receptor,EGFR)、截短型表皮生长因子受体(truncatedepidermal growth factor receptor,tEGFR)、III型表皮生长因子受体突变体(type IIIepidermal growth factor receptor mutation,EGFRvIII)、上皮糖蛋白2(epithelialglycoprotein 2,EPG-2)、上皮糖蛋白40(epithelial glycoprotein 40,EPG-40)、ephrinB2、ephrin受体A2(EPHA2)、雌激素受体(estrogen receptor)、Fc受体(Fc receptor)、Fc受体样5(Fc receptor like 5,FCRL5;或也称为Fe受体同源物5(Fe receptor homolog5)或FCRH5)、成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)、叶酸结合蛋白(folate binding protein,FBP)、叶酸受体α(folate receptor alpha,FOLR1)、叶酸受体β(folate receptor beta,FOLR2)、GD2(神经节苷脂(ganglioside)GD2和O-乙酰化GD2(O-acetylated GD2,OGD2))、神经节苷脂(ganglioside)GD3、糖蛋白100(glycoprotein 100,gp100)、磷脂酰肌醇聚糖-3(glypican-3,GPC3)、G蛋白偶联受体5D(G Protein CoupledReceptor 5D,GPCR5D)、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophagecolony-stimulating factor,GM-CSF)、Her2/neu(受体酪氨酸激酶erb-B2(receptortyrosine kinase erb-B2))、Her3(erb-B3)、Her4(erb-B4)、erbB二聚体(erbB dimers)、人高分子量黑色素瘤相关抗原(Human high molecular weight melanoma-associatedantigen,HMW-MAA)、乙型肝炎表面抗原(hepatitis B surface antigen,HBsAg)、人白细胞抗原A1(Human leukocyte antigen A1,HLA-A1)、人白细胞抗原A2(Human leukocyteantigen A2,HLA-A2)、IL-22受体α(IL-22 receptor alpha,IL-22Ra)、IL-13受体α2(IL-13receptor alpha 2,IL-13Ra2)、诱导T细胞共刺激物(inducible T-cell costimulator,ICOS)、胰岛素样生长因子1受体(insulin-like growth factor1receptor,IGF-1受体(receptor))、整合素(integrin)αvβ6、干扰素受体(interferon receptor)、IFNγ、白细胞介素2受体(interleukin-2receptor,IL-2R)、白细胞介素4受体(interleukin-4receptor,IL-4R)、白细胞介素5受体(interleukin-5receptor,IL-5R)、白细胞介素6受体(interleukin-6receptor,IL-6R)、白细胞介素17受体A(interleukin-17receptor A,IL-17RA)、白细胞介素31受体(interleukin-31receptor,IL-31R)、白细胞介素36受体(interleukin-36receptor,IL-36R)、激酶插入域受体(kinase insert domain receptor,kdr)、L1细胞粘附分子(L1 cell adhesion molecule,L1-CAM)、L1-CAM的CE7表位(CE7epitope of L1-CAM)、富含亮氨酸重复序列的蛋白家族成员8A(Leucine Rich RepeatContaining 8Family Member A,LRRC8A)、Lewis Y、淋巴细胞激活基因3(lymphocyte-activation gene 3,LAG3)、黑色素瘤相关抗原(Melanoma-associated antigen,MAGE)Al、MAGEA3、MAGEA6、MAGEAl0、间皮素(mesothelin,MSLN)、鼠巨细胞病毒(murinecytomegalovirus,CMV)、粘蛋白1(mucin 1,MUC1)、自然杀伤组2成员D(natural killergroup 2member D,NKG2D)配体(ligands)、黑色素A(melan A,MART-l)、神经生长因子(nerve growth factor,NGF)、神经细胞粘附分子(neural cell adhesion molecule,NCAM)、neuropilin-1(NRP-1)、neuropilin-2(NRP-2)、癌胚抗原(oncofetal antigen)、PD-L1、黑色素瘤优先表达抗原(Preferentially expressed antigen of melanoma,PRAME)、黄体酮受体(progesterone receptor)、前列腺特异性抗原(prostate specificantigen)、前列腺干细胞抗原(prostate stem cell antigen,PSCA)、前列腺特异性膜抗原(prostate specific membrane antigen,PSMA)、核因子κ-B配体受体激活剂(receptoractivator of nuclear factor kappa-B ligand,RANKL)、酪氨酸激酶样孤儿素受体1(receptor tyrosine kinase like orphan receptor 1,ROR1)、SLAM家族成员7(SLAMfamily member 7,SLAMF7)、存活素(survivin)、滋养层糖蛋白(trophoblastglycoprotein,TPBG;或也称为5T4)、肿瘤相关糖蛋白72(tumor-associated glycoprotein72,TAG72)、酪氨酸相关蛋白1(tyrosine related protein 1,TRP1;或或也称为TYRP1或gp75)、酪氨酸相关蛋白2(tyrosine related protein 2,TRP2;或也称为多巴色素互变异构酶(dopachrome tautomerase)、多巴色素δ-异构酶(dopachrome delta-isomerase)或DCT)及威尔姆氏肿瘤(Wilms Tumor 1;WT1)。
在本发明中,抗体的“片段”是指具有抗原结合功能的片段,旨包含scFv、Fab、F(ab’)2、F及纳米抗体(nanobody)片段等。
“单链Fv”或“scFv”抗体片段包含抗体的重链可变(VH)结构域及轻链可变(VL)结构域,这些结构域存在于单个多肽链中。Fv多肽还可包含位于VH结构域和VL结构域之间的多肽连接体,使得scFv能够形成用于抗原结合的所需结构。
“Fv”片段是包含完整抗体识别和结合位点的抗体片段。该区域由一个重链可变结构域和一个轻链可变结构域通过如scFv紧密且基本上共价结合的二聚体组成。
“Fab”片段包含轻链的可变域和恒定结构域以及重链的可变域和第一恒定结构域(CH1)。“F(ab’)2”抗体片段通常包含一对Fab片段,它们在其羧基末端附近通过它们之间的铰链半胱氨酸共价连接。
“纳米抗体(nanobody)”是包含单体可变抗体结构域(monomeric variableantibody domain)的片段。主要由来自如骆驼等的抗体结构域的低分子量的片段组成,其仅通过单体重链显示靶特异性。
在本发明中,上述抗原结合片段可以为抗体的单链可变片段(single chainvariable fragment,scFv)或纳米抗体(nanobody)。
在本发明中,优选地,上述抗原结合结构域包含抗-CD19抗体或其scFv。上述抗-CD19抗体的scFv可包含由SEQ ID NO.23表示的氨基酸序列,但不限于此。
表4抗-CD19抗体的scFv序列
在本发明中,上述抗原结合结构域的N-末端部还可包含信号肽(signal peptide,SP)。在本发明中,上述信号肽可衍生自选自由CD8α、GM-CSF受体α、Ig-κ及IgG1重链组成的组中的分子,但不限于此。优选地,其可以为CD8α信号肽,上述CD8α信号肽包含由SEQ IDNO.25表示的氨基酸序列。
表5CD8α信号肽的序列
作为优选的例子,根据本发明的嵌合抗原受体,包含:由SEQ ID NO.5、SEQ IDNO.7、SEQ ID NO.9或SEQ ID NO.11表示的CD99衍生的胞外域;由SEQ ID NO.3表示的CD99衍生的跨膜结构域;以及由SEQ ID NO.13表示的CD99衍生的胞内近膜结构域。
并且,还可包含:由SEQ ID NO.21表示的4-1BB共刺激结构域;由SEQ ID NO.17或SEQ ID NO.19表示的CD3截塔(ζ)的胞内信号转导结构域;和/或由SEQ ID NO.25表示的CD8信号肽,但不限于此。
在本发明中,示例性地,包含针对CD19的抗原结合位点的嵌合抗原受体,可包含由SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31或SEQ ID NO.33表示的氨基酸序列或与上述氨基酸序列具有80%以上,优选地具有90%以上,更优选地,具有95%,最优选地,具有99%以上的序列同源性的突变体。
表6本发明的嵌合抗原受体蛋白的序列
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本发明的另一方面涉及一种编码上述嵌合抗原受体的核酸。
编码根据本发明的嵌合抗原受体的核酸(多核苷酸)可以通过密码子优化进行修饰,这是缘于密码子简并性(degeneracy),本领域技术人员将充分理解,存在许多编码多肽或其突变体片段的核苷酸序列。这些多核苷酸(核酸)中的一些与任何天然存在基因的核苷酸序列具有最小的同源性。
尤其,由于密码子利用法的差异,优选为可变多核苷酸(核酸),例如,对灵长类和/或哺乳动物的密码子选择优化的多核苷酸(核酸)。
在本发明中,编码上述嵌合抗原受体的核酸,包含:编码由SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10或SEQ ID NO.12表示的CD99衍生的胞外域的核苷酸序列;编码由SEQID NO.4表示的CD99衍生的跨膜结构域的核苷酸序列;以及编码由SEQ ID NO.14表示的CD99衍生的胞内近膜结构域的核苷酸序列,还可包含:编码由SEQ ID NO.22表示的4-1BB共刺激结构域的核苷酸序列;编码由SEQ ID NO.18或SEQ ID NO.20表示的CD3截塔(ζ)的胞内信号转导结构域的核苷酸序列;和/或编码由SEQ ID NO.26表示的CD8信号肽的核苷酸序列,但不限于此。
优选地,还可包含编码由SEQ ID NO.24表示的抗-CD19抗体的单链可变片段(scFv)的核苷酸序列。
作为优选例,编码根据本发明的嵌合抗原受体的核酸序列可包含由SEQ IDNO.28、SEQ ID NO.30、SEQ ID NO.32或SEQ ID NO.34表示的核苷酸序列或与上述核苷酸序列具有80%以上,优选地,具有90%以上,更优选地,具有95%以上,最优选地,具有99%以上的序列同源性的突变体。
本发明的另一方面涉及包含上述核酸的表达载体及包含上述表达载体的病毒。
本发明的术语“载体”是指能够转移或转运另一种核酸分子的核酸分子。转移的核酸通常与载体核酸分子连接,例如,插入到载体核酸分子中。载体可包含指导在细胞中自主复制的序列,或者可包含足以允许整合到宿主细胞DNA中的序列。上述载体可选自DNA、RNA、质粒、慢病毒载体、腺病毒载体及逆转录病毒载体,但不限于此。
在本发明中,将上述核酸或上述载体转染(transfection)到病毒产生细胞(packaging cell line)。为了“转染”,可以使用通常用于将外源性核酸(DNA或RNA)引入原核或真核宿主细胞内的各种技术,例如,电泳、磷酸钙沉淀、DEAE-右旋糖转染或脂质体转染(lipofection)等。
在本发明中,由病毒产生细胞产生的病毒被转导(transduction)到免疫细胞。“转导”到细胞中的病毒的核酸以插入或未插入细胞基因组的状态下用于产生嵌合抗原受体蛋白。
本发明的另一方面涉及在表面表达上述嵌合抗原受体的免疫细胞。
在本发明中,上述免疫细胞可以为T细胞、NK细胞、NKT细胞或巨噬细胞,但不限于此,优选地可以为T细胞。
表达本发明的嵌合抗原受体的免疫细胞可以为CAR-T细胞(嵌合抗原受体T细胞)、CAR-NK细胞(嵌合抗原受体自然杀伤细胞(Chimeric Antigen Receptor T Cell))、CAR-NKT细胞(嵌合抗原受体自然杀伤T细胞(Chimeric Antigen Receptor Natural killer TCell))或CAR-巨噬细胞(嵌合抗原受体巨噬细胞(Chimeric Antigen ReceptorMacrophage))。
在本发明中,上述T细胞可选自由CD4阳性T细胞、CD8阳性细胞毒性T淋巴细胞(Cytotoxic T lymphocyte,CTL)、γ-δ-T细胞、肿瘤浸润淋巴细胞(Tumor infiltratinglymphocyte,TIL)及外周血单核细胞(Peripheral blood mononuclear cell,PBMC)中分离的T细胞组成的组中。
本发明的另一方面涉及包含用于表达上述嵌合抗原受体的免疫细胞(例如,T细胞)的癌治疗用组合物。
在本发明中,“癌症”和“肿瘤”含义相同,是指哺乳动物中典型的不受调节的细胞生长/增殖为特征的生理状况。
可以使用本发明的CAR治疗的癌症不仅包括血管生成肿瘤,还包括未生成血管或目前为止实质上未生成血管的肿瘤。上述癌症可包括非实体瘤(例如,血液肿瘤,如白血病和淋巴瘤),或者可包括实体瘤。作为可以使用本发明的CAR治疗的癌症类型可列举癌、母细胞瘤、肉瘤、特定白血病或淋巴恶性肿瘤、良性和恶性肿瘤如肉瘤、癌和黑色素瘤,但不限于此。还包括成人肿瘤/癌症和儿童肿瘤/癌症。
血癌是血液或骨髓的癌症。作为血液(或造血性)癌症的例子,可列举包括急性白血病(例如,急性淋巴细胞白血病、急性髓性白血病、成髓细胞性白血病、幼淋巴细胞性白血病、髓单核细胞性白血病、单核细胞性白血病及红白血病)、慢性白血病(例如,慢性淋巴细胞(粒细胞)白血病、慢性髓性白血病及慢性淋巴细胞性白血病)、真性红细胞增多症、淋巴瘤、霍奇金病、非霍奇金淋巴瘤(延迟型和高分期)、多发性骨髓瘤、沃尔丹斯特伦巨球蛋白血症(Waldenstrom'smacroglobulinemia)、重链病、骨髓增生异常综合征、毛细胞白血病及骨髓增生异常症的白血病。
实体瘤是通常不包含皮囊或液体区域的异常组织块。实体瘤可以是良性或恶性。不同类型的实体瘤以形成它们(例如,肉瘤、癌及淋巴瘤)的细胞类型命名。作为肉瘤及癌等实体瘤的例子,可列举纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤及其他肉瘤、滑膜瘤(synovioma)、间皮瘤(mesothelioma)、尤文(Ewing)瘤、平滑肌肉瘤、横纹肌肉瘤、直肠癌、淋巴恶性肿瘤、大肠癌、胃癌、胰腺癌、乳腺癌、肺癌、卵巢癌、前列腺癌、咽喉癌、肝细胞癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、甲状腺髓样癌、甲状腺乳头状癌、嗜铬细胞瘤、皮脂腺癌、乳头状癌、乳头状腺癌、髓样癌、支气管癌、肾细胞癌、肝肿瘤、胆管癌、绒毛膜癌、维尔姆斯瘤(Wilms'tumor)、宫颈癌、睾丸肿瘤、精原细胞瘤(seminoma)、膀胱癌、黑色素瘤及CNS肿瘤(例如,神经胶质瘤(例如,脑干神经胶质瘤和混合神经胶质瘤)、胶质母细胞瘤(也称为多形性胶质母细胞瘤)、星形细胞瘤、CNS淋巴瘤、胚组织瘤、髓母细胞瘤、神经鞘瘤颅咽管瘤(Schwannoma craniopharyogioma)、室管膜瘤(ependymoma)、松果体瘤(pinealoma)、血管母细胞瘤、听神经瘤(acoustic neuroma)、少突胶质细胞瘤(oligodendroglioma)、脑膜瘤、神经母细胞瘤、视网膜母细胞瘤及脑转移瘤。
本发明的治疗用组合物为预防或治疗用组合物,本发明的术语“预防”是指通过施用本发明的组合物来抑制或延缓癌症进行的任何行为,“治疗”是指抑制癌症的发展、减轻或消除症状。
包含表达本发明的嵌合抗原受体的免疫细胞的药学组合物还可包含药学上可接收的赋形剂。作为这种赋形剂的例子,可包括:表面活性剂,优选为聚山梨醇酯类的非离子表面活性剂;缓冲液,如中性缓冲盐水和人盐缓冲盐水;糖或糖醇,如葡萄糖、甘露糖、蔗糖或右旋糖、甘露醇;如甘氨酸和组氨酸的氨基酸、蛋白质或多肽;抗氧化剂;螯合剂,如EDTA或谷胱甘肽;渗透剂;辅助剂;以及保存剂,但不限于此。
可以使用本领域已知的方法对本发明的组合物进行剂型化,以在对人以外的哺乳动物进行给药后,快速、持续或延迟释放活性成分。剂型可以是粉末、颗粒、片剂、乳剂、糖浆、气雾剂、软质或硬质明胶胶囊、灭菌注射溶液、灭菌粉末形式。
本发明的另一方面涉及一种癌症治疗方法,包括向受试者给药表达上述嵌合抗原受体的免疫细胞的步骤。
本发明还涉及一种用于治疗癌症的上述免疫细胞的用途。
本发明还涉及一种在制备癌治疗用药剂中的上述免疫细胞的使用。
上述受试者可以是具有肿瘤的哺乳类,具体地,可以是人类,但不限于此。
表达本发明的嵌合抗原受体的免疫细胞或包含其的组合物可通过口服给药、注射(infusion)、静脉内给药(intravenous injection)、肌肉内给药(intramuscularinjection)、皮下给药(subcutaneous injection)、腹腔内给药(intraperitonealinjection)、直肠内给药(Intrarectal administration)、局部给药(topicaladministration)、鼻腔内给药(intranasal injection)等方式进行给药,但不限于此。
活性成分的给药量可根据给药途径、患者的年龄、性别、体重及严重程度等各种因素来适当选择,根据本发明的治疗用组合物可以与具有预防、改善或治疗癌症症状效果的公知化合物联合给药。
以下,通过实施例进一步详细说明本发明。这些实施例仅用于说明本发明,对于本领域普通技术人员显而易见的是,本发明的范围不应被解释为受这些实施例的限制。
实施例1:CD99衍生的跨膜蛋白的功能鉴定研究
实施例1-1:小鼠及细胞株
CD99-敲除(knockout)小鼠(B6.Cd99Gt(pU-21T)44Imeg)购自熊本(Kumamoto)大学的资源开发与分析研究所(Institute of Resource Development and Analysis),且H60同类系小鼠(H60 congenic mice,(B6.CH60))由美国杰克逊实验室(Jackson laboratory)的德里·鲁本尼安博士(Dr.Derry Roopenian)提供。免疫缺陷NSG小鼠购自杰克逊实验室。Raji淋巴瘤细胞购自ATCC。
实施例1-2:WT、CD99-KO小鼠CD8 T细胞系(T cell line)的确立
向CD99正常(WT)B6小鼠和CD99缺陷(CD99-KO)B6小鼠分别以2×107cells/300μl腹腔注射从B6.CH60小鼠中分离的脾细胞后,在第30天从每只小鼠中取出的脾细胞(2.5×106cells/ml)和辐照(2000rad)过的B6.CH60脾细胞(3.5×106cells/ml)并在人IL-2(50U/ml,西格玛奥德里奇(Sigma-Aldrich))的存在下共培养,以增殖WT和CD99-KO H60特异性CD8 T细胞。以一周为周期,将这些T细胞与辐照过的B6.CH60脾细胞在人IL-2(50U/ml)的存在下共培养以诱导再活化,从而确立H60特异性正常CD8 T细胞系和CD99缺陷CD8 T细胞系。
实施例1-3:用于表达小鼠CD99正常蛋白和突变蛋白的逆转录病毒载体(retrovirus vector)的制备
通过聚合酶链式反应(PCR)制备编码(coding)小鼠CD99正常蛋白(WT)和跨膜结构域(TM)、胞内信号转导结构域(Cyt)突变蛋白的cDNA,并将其克隆到(cloning)pcDNA3-YFP质粒(plasmid)(Addgene#13033)的EcoRI限制酶位点。使用HindIII/XbaI限制酶从该质粒切割提取CD99-YFP DNA部分,使用XhoI限制酶切割MSCV Puro质粒(Addgene#68469)后,分别使用克莱诺(klenow)酶处理并通过平末端克隆(blunt-end cloning)制备了pMSCV-CD99-YFP、pMSCV-CD99TM-YFP、pMSCV-CD99Cyto-YFP载体。每个CD99蛋白质的氨基酸序列如下述表7所示。
表7Myc-tag标记的小鼠CD99 WT蛋白质和突变蛋白的序列
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实施例1-4:用于CD99表达的逆转录病毒(retrovirus)的生成及小鼠T细胞中的转导(transduction)
使用聚乙烯亚胺(polyethylenimine)(Polysciences公司)将各WT或突变CD99-YFP表达用逆转录病毒质粒(retroviral plasmid)转染(transfection)到作为逆转录病毒包装细胞系(retroviral packaging cell line)的铂-E(Platinum-E)细胞(细胞生物实验室(Cell Biolabs))后,收获并过滤含有分泌24-48小时的逆转录病毒的培养上清液(0.45μm过滤器)。在聚凝胺(polybrene)(4μg/ml,圣克鲁斯(Santa Cruz))存在下,将该培养上清液加入活化的CD99-KO CD8 T细胞系以转导逆转录病毒。接着,对这些细胞处理嘌呤霉素(puromycin)(1mg/ml,佐治亚理化工(Georgiachem))以仅筛选转导的细胞。然后,使用流式细胞仪(FACS-Aria II,BD生物科学(BD Biosciences))分离表达YFP融合蛋白(fusionprotein)的细胞以确立每个T细胞系,通过周期性的活化维持细胞株。
实施例1-5:确认T细胞分裂和细胞因子产生能力
从正常小鼠和CD99缺陷小鼠的淋巴结中获得的细胞使用CFSE(5μM,e生物科学(eBioscience))标记后,加入到包被抗-CD3抗体(145-2C11,1μg/ml,BD Pharmigen公司)的96孔板(well plate)(5×105细胞/孔),并与抗-CD28抗体(37.51,0.5μg/ml,BD Pharmigen公司)一起培养以活化T细胞。活化24小时、48小时、72小时后收获细胞,并使用抗-CD8抗体(53-6.7,eBioscien ce)对细胞表面进行染色后,采用流式细胞术(flow cytometry)(FACS-LSRII,BD Biosciences)测量染色到CD8 T细胞的CFSE被稀释的程度,从而确认细胞分裂。
为了确认T细胞的细胞因子产生能力,以活化后的每个时间段,对收获前使用布雷菲德菌素A(brefeldin A)(3μg/ml,eBioscience)处理4小时的细胞进行收获,并使用多聚甲醛(paraformaldehyde)(4%,CellNest)在室温固定20分钟。接着,通过加入含有Triton-×100(0.5%,Amresco)和牛血清蛋白(BSA)(0.1%,Bovoge)的磷酸缓冲盐溶液(PBS)以进行透化(permeabilize)后,利用抗-CD8抗体、抗-IL-2抗体(JES6-5H4,eBioscience)、抗-IFN-γ抗体(XMG1.2,eBioscience)进行染色来采用流式细胞术测量被染色的细胞的百分比和平均荧光强度。
实施例1-6:用于确认免疫突触形成的T细胞共聚焦显微镜分析
为了观察T细胞与抗原呈递细胞之间的免疫突触形成,使用CMTMR(10μM,Invitrogen)或抗ICAM-1抗体(YN1/1.7.4,eBioscience)对表达H60抗原的DC2.4细胞系进行染色,并使用抗-TCRβ抗体(H57-597,eBioscience)、抗-LFA-1抗体(2D7,BD Pharmigen)对通过与B6.CH60脾细胞混合培养活化第4天的WT或CD99-KO CD8 T细胞系进行了染色。然后,将两个细胞组分别以1×105cells/200μl进行混合,并在包被聚-L-赖氨酸(poly-L-lysine)的载玻片(covers lip)上共培养30分钟或1小时。然后使用温PBS洗涤,添加4%的多聚甲醛(paraformaldehyde)在室温固定(fix)20分钟后,将载玻片转移到载玻片上,进行封片(mounting)。将对F-肌动蛋白进行成像(imaging)时,固定后使用含Tri ton-×100(0.25%)的PBS渗透(permeabilize)10分钟。然后,在室温使用Phal loidin-Alexa Fluor647(英杰(Invitrogen))染色30分钟并使用PBS洗涤后,转移到载玻片进行封片。
为了对T细胞的免疫突触横截面进行成像,分离活化7天的T细胞,并在包被抗-CD3抗体(10μg/ml)的载玻片上(1×105cells/200μl)培养15分钟后,固定并透化(permeabilzation)。然后,使用Phalloidin-Alexa Fluor 647和抗-α-微管蛋白抗体(DM1A,密理博(Millipore))对F-肌动蛋白和微管网络进行染色并观察。
为了实时成像F-肌动蛋白和微管重排(rearrangement),利用电穿孔(electroporation,Amaxa)将LifeAct-mCherry载体转染到WT或CD99-KO T细胞系,并且,为了测量微管蛋白动力学,使用SIR微管蛋白试剂盒(SiR-tubulin Kit)(Cytoskeleton)将微管蛋白染色探针(probe)渗入细胞后,在包被抗-CD3抗体(10μg/ml)的载玻片上培养,同时每隔20秒用共聚焦显微镜实时捕获T细胞生产免疫突触时的F-肌动蛋白和微管的重排。所有显微镜拍摄利用了FluoView1000或FluoView3000共聚焦显微镜(奥林巴斯(Olympus)),图像分析使用了FluoView软件(Olympus)、cellSens软件(software)(Olympus)或Image J(NIH)。
实施例1-7:免疫沉淀(immunoprecipitation)和免疫印迹(immunoblotting)
使用Ficoll-Paque(GE healthcare)从活化4天的CD99正常或缺陷T细胞系仅收获存活的CTL,在37℃使用抗-CD3抗体(10μg/ml)培养15分钟,从而诱导活化。然后,使用冷PBS洗涤并停止刺激,收获细胞,使用含NP-40(1%,Biosesang)的提取缓冲液(lysis buffer)在4℃裂解细胞20分钟后,将100μg的细胞提取液(cell lysate)与蛋白G-琼脂糖珠(protein G-sepharose bead)(35μl,BioVision)混合并在4℃温度进行了1小时的预洗涤(preclearing)。接着,在4℃使用抗α-微管蛋白抗体、小鼠IgG同种型(mouse IgG isotype)抗体或抗-CD99抗体(EJ2)、大鼠IgG同种型(rat IgG isotype)抗体进行处理后,使用蛋白G-琼脂糖珠(protein G-sepharose bead)进行了免疫沉淀。将免疫沉淀物进行SDS-PAGE并转移(transfer)到PVDF膜(membrane)后,使用抗-β-肌动蛋白(4C2,Sigma-Aldrich)、抗-α-微管蛋白、抗-CD99抗体及抗-小鼠IgG-HRP抗体进行染色,使用West-Femto试剂(ThermoFisher)发光。LAS-4000mini(GE Healthcare)检测相应蛋白质的条带(band)。
实施例1-8:CAR表达用逆转录病毒载体(retroviral vector)的制备
CD19靶点CD8骨架CAR(h19BBz)ORF cDNA通过根据以往公开的序列(美国专利2013/0287748A)委托DNA合成来制备(Integrated DNA Technologies)。从NCBI数据库的人CD99 ORF序列(NM_002414.4)中提取CD99胞外域、跨膜结构域及近膜结构域的序列,与抗CD19 scFv(克隆FMC63)和人4-1BB胞内信号转导结构域、人CD3ζ链胞内信号转导结构域,通过DNA合成(Integrated DNA Technologies)和PCR连接来制备了CD19靶点CD99骨架CARORF cDNA(F58BBz、F45BBz、F35BBz、F35BBz-1)。将CD19 scFv及人CD8胞外域通过PCR与人CD99跨膜结构域及近膜结构域、人4-1BB胞内信号转导结构域、人CD3ζ链胞内信号转导结构域连接,从而制备了F8TJBBz。在去除MSCV Hu受体逆转录病毒质粒(MSCV Hu Acceptorretroviral plasmid)(Addgene#64269)的插入片段(insert)后,将各CAR ORF cDNA克隆(cloning)到HindIII/SalI限制酶位点来构建了各CAR表达用逆转录病毒载体。
根据本实施例的CAR制备中使用的结构域的序列信息如上述表2至表5中所示,各CAR蛋白的氨基酸序列及核酸序列如表6及表8所示。
表8嵌合抗原受体蛋白的氨基酸序列及核酸序列
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实施例1-9:CAR表达用逆转录病毒的生产
使用Lipofectamin 3000(Invitrogen)将每个逆转录病毒质粒转染到PhoenixECO细胞系(ATCC)后,将含有分泌24-48小时的亲嗜性逆转录病毒(ecotropic retrovirus)的培养上清液添加到PG13逆转录病毒包装细胞系(PG13 retroviral packaging cellline)(ATCC)中并进行旋转感染(spin infection)(2500rpm,90分钟)。将通过如上所述的方法制备的PG13逆转录病毒生产细胞株的培养上清液收获并过滤(0.45μm过滤器),去除细胞残留颗粒,并使用离心过滤装置(centrifugal filtration device,Millipore Amicon100KD cut-off)浓缩4次后,被用作CAR-T细胞构建用逆转录病毒浓缩液。
实施例1-10:CAR-T细胞的制备
将通过正常人的白细胞成分采血(leukapheresis)获得的白细胞与抗-CD28抗体(CD28.2,2μg/ml,BD Biosciences)一起添加到包被抗-CD3抗体(OKT3,10μg/ml,BioXcell)的24孔板后,培养48小时来活化T细胞。将活化的T细胞洗涤2次后,用于逆转录病毒转导(transduction)。在4℃温度条件下将纤维连接蛋白(Retronectin)(20μg/ml,TaKaRa)过夜包被后,向洗过的24孔板中加入2%BSA-DPBS,并在37℃条件下封闭(blocking)30分钟,进行洗涤后,添加1ml的逆转录病毒浓缩液,在2000×g、32℃条件下离心2小时,以将逆转录病毒粘附于孔(well)的底面。去除病毒(Virus)浓缩液并洗涤孔后,将1ml的活化的T细胞(1×106cells/ml)加入孔中并离心10分钟(1000×g,32℃),以将细胞粘附于逆转录病毒。接着,在人IL-2(300IU/ml,Proleukin,诺华(Novartis))存在下,培养48小时。像这样,将逆转录病毒转导的T细胞洗涤2次后,加入含人IL-2(200IU/ml)的新鲜的培养液来增殖3-6天,以用作CAR-T细胞。针对于细胞表面的CAR蛋白的表达,将逆转录病毒转导后增殖3天的CAR-T细胞用CD19-Ck蛋白(CD19胞外区与人免疫球蛋白κ链恒定区(Ck)的融合蛋白)和标记有APC的抗-Ck抗体(anti-Ck-APC,BioLegend)进行染色后,通过流式细胞术(FACS-Calibur,BDBiosciences)来测量。
实施例1-11:表达荧光素酶的Raji细胞(Raji-Luc)的制备
为了在细胞中人工表达荧光素酶,构建了能够同时表达荧光素酶和绿色荧光蛋白(GFP)的慢病毒载体(lentiviral vector)。在EF1α启动子(EF1αpromoter)下具有多酶切割位点(multi-cloning site)的同时,在人巨细胞病毒启动子(CMV promoter)下,通过向克隆有GFP的双顺反子慢病毒载体(biscistronic lentiviral vector)(pLECE3)(Lee SH,etal.,PLoS One.2020;15(1):e0223814)的多酶切割位点克隆从pGL3类质粒(pGL3-basicplasmid)(Promega)切割并提取的萤火虫萤光素酶ORF cDNA(firefly luciferase ORFcDNA)来构建了pLECE3-Luc载体。使用Lipofectamin 2000试剂将pLECE3-luc质粒与3种慢病毒包装质粒(lentiviral packaging plasmid)(pMDLg/pRRE,pRSVrev,pMD.G)一起转染到慢病毒包装细胞系(lentivirus packaging cell line)(293FT细胞,Invitrogen),24-48小时后,收获含有分泌的慢病毒的培养上清液并使用离心过滤装置浓缩10倍。将慢病毒浓缩液添加到Raji细胞,并在聚凝胺(polybrene)(6μg/ml,Sigma-Aldrich)存在下,在常温以2500rpm离心90分钟来进行转导。使用流式细胞仪(FACS-Aria II,BD Biosciences)对转导的Raji细胞中GFP阳性细胞进行分离纯化并用作Raji-Luc细胞。
实施例1-12:CAR-T细胞的肿瘤杀伤能力及活化测量
将逆转录病毒转导后增殖3天的CAR-T细胞(1.2×103~7.5×105cells/100μl/孔)以不同比例(0.04-25:1)添加到Raji-Luc细胞(3×104cells/50μl/孔)后在96孔板中过夜共培养(co-culture)后,添加50μl的D-荧光素(D-Luciferin)(600μg/ml,Promega)后在37℃培养10分钟,以诱导存活至此时的Raji-Luc细胞中的荧光素酶的酶作用。使用Luminometer(Tecan)测量这些细胞的发光度,并通过与未处理CAR-T细胞的Raji-Luc细胞的发光度进行比较,来计算肿瘤细胞的存活率,从而计算CAR-T细胞的肿瘤杀伤能力。
为了测量CAR-T细胞的活化程度,将CAR-T细胞和Raji细胞等量(3×104cells)混合,在96孔板中共培养24小时后,收获了培养上清液。通过ELISA法(人IFN-γELISA试剂盒,BD Biosciences)测量了分泌到上清液中的IFN-γ的量。
实施例1-13:评价CAR-T细胞的体内功效
对免疫缺陷NSG小鼠静脉注射Raji-Luc细胞(5×105cells/只小鼠),7天后,静脉注射进行逆转录病毒转导后增殖8天的CAR-T细胞(5×106cells/只小鼠)。然后,定期腹腔注射D-荧光素(2mg/只,普洛麦格(Promega))后,通过生物发光成像(bioluminescenceimaging)设备(IVIS,珀金埃尔默(Perkin Elmer))测量体内发光度来观察了肿瘤负荷(tumor burden)的变化。
实施例1-14:评价CAR-T细胞与Raji细胞的免疫突触形成能力
为了观察CAR-T细胞与肿瘤细胞(Raji)之间的免疫突触形成,将使用CMTMR(10μM,英杰(Invitrogen))在37℃染色30分钟的Raji细胞(1×105cells/200μl)和CAR-T细胞(2×105cells/200μl)在包被聚-L-赖氨酸(Poly-L-Lysine)的载玻片上共培养,并在15分钟、30分钟、1小时、3小时时进行固定。以与如上所述的共聚焦显微镜方法相同的方式,对F-肌动蛋白进行染色后使用FlowView3000共聚焦显微镜(Olympus)进行拍摄并使用Image J(NIH)进行了分析。
实施例2:确认CD99缺陷引起的T细胞免疫突触形成障碍
基于T细胞中的CD99刺激使T细胞的活化增加且CD99存在于包含肌动蛋白细胞骨架的脂筏部分(lipid raft fraction)的现有研究(Wingett D等人,Cell Immunol.1999;193(1):17-23),为了验证CD99在免疫突触形成中的作用,对CD99缺陷的T细胞在TCR刺激下的活化及免疫突触形成过程进行了分析。对从CD99敲除小鼠分离的T细胞在抗-CD3/CD28抗体刺激下的细胞分裂进行了分析,结果显示,与正常CD8 T细胞相比,观察到初始细胞分裂显著延长的现象。并且,还确认到与正常T细胞CD99相比,缺陷T细胞的初始细胞因子(cytokine)生成能力也减少。因此,确认到CD99参与TCR刺激下的T细胞活化过程(图2的A部分、B部分)。
为了研究其具体机制,通过T细胞与抗原呈递细胞的共培养(co-culture)观察了免疫突触形成过程,结果确认到,与正常T细胞相比,构成免疫突触的TCR与LFA-1的抗原呈递细胞接触区域的密集现象在CD99缺陷T细胞中显著减少(图3的A部分)。与此相符,观察到为免疫突触形成提供细胞骨架的肌动蛋白的突触密集现象也因CD99缺陷而显著减少(图3的B部分)。为了更详细地观察免疫突触中的肌动蛋白细胞骨架的重排,将包被抗-CD3抗体的玻片表面视为抗原呈递细胞的表面,在假设T细胞的玻片接触部位为免疫突触的实验系统中,通过实时共聚焦显微镜(real-time confocal microscopy)观察随T细胞与玻片表面接触的时间的肌动蛋白重排,结果确认到,由于CD99缺陷,基于肌动蛋白聚合(actinpolymerization)的T细胞接触面形成延迟,T细胞接触面的面积也大大减少(图3的C部分至E部分)。并且,在CD99缺陷T细胞中,也观察到免疫突触的结构异常,例如,与细胞的扩散(spreading)相关的板状伪足部分的厚度大大减少,肌动蛋白微簇的位置位于周围部,而不是免疫突触的近端部(图3的F部分、G部分),从而确认到CD99在免疫突触形成中起关键作用。
实施例3:确认CD99缺陷引起的肌动蛋白-微管(actin-microtubule)相互作用的障碍
尽管最近肌动蛋白细胞骨架重排和微管网络的形成在免疫突触形成中起重要作用备受瞩目,但对肌动蛋白-微管相互作用知之甚少。为此,通过跟踪CD99缺陷时T细胞免疫突触中的微管网络的形成过程,结果观察到微管网络形成的不稳定性。也就是说,当活化T细胞时,微管从微管组织中心(microtubule organizing center)(MTOC)重新生成,且生长的微管朝向细胞膜放射状延伸,但CD99缺陷时,观察到这种放射状微管的形成不顺利,并迅速萎缩(图4的A部分、B部分)。并且,在CD99缺陷的T细胞中也未观察到活化T细胞时所观察到的MTOC移位至免疫突触中心的现象。尤其,在一些微管垂直延伸到富含肌动蛋白的板状伪足(actin-rich lamellipodia)内部,并通过与细胞膜中存在的肌动蛋白的相互作用固定在细胞膜,但CD99缺陷时,进入板状伪足的微管显著减少,由此肌动蛋白-微管相互作用可能受到抑制(图4的C部分、D部分)。以作为对此的依据,观察到在正常细胞的细胞提取液(cell lysate)中肌动蛋白和微管蛋白共免疫沉淀(co-immunoprecipitation)而相互结合,而在CD99缺陷细胞中没有观察到这种共免疫沉淀现象(图4的E部分),由此证明CD99有助于肌动蛋白和微管的物理相互结合。
实施例4:CD99的肌动蛋白和微管的相互作用分析
基于上述结果,为了确认CD99是否位于实际免疫突触并介导肌动蛋白和微管蛋白,使用共聚焦显微镜观察CD99在免疫突触中的存在,结果观察到T细胞活化时CD99迁移到免疫突触区域,尤其,观察到与分布在富含肌动蛋白区域(actin-rich area)的LFA-1的共定位(co-localize)(图5的A部分)。观察与细胞骨架的位置关系,结果观察到存在CD99分别与肌动蛋白和微管共定位的位置(图5的B部分)。并且,CD99在活化的T细胞提取液中与肌动蛋白和微管蛋白均发生共免疫沉淀(图5的C部分)。因此,CD99被解释为长期以来一直没有被发现的起到骨桥分子作用的膜蛋白,其介导肌动蛋白与微管的相互租用。
实施例5:CD99与肌动蛋白和微管相互作用中的CD99跨膜结构域和细胞质结构域的作用
为了鉴定CD99与肌动蛋白和微管的结合部位,设计突变蛋白(mutant proteins)后,其中,CD99的跨膜结构域(transmembrane domain)或细胞质结构域(cytoplasmicdomain)被不相关蛋白质CD4的相应位点取代,将这些蛋白质表达在CD99缺陷T细胞。将CD99跨膜结构域被CD4的相应位点取代的蛋白质称为“CD99 TM突变体”,并将CD99细胞质结构域被CD4的细胞质结构域取代的蛋白质称为“CD99 Cyt突变体”(图6的A部分)。使用共聚焦显微镜观察每个突变蛋白与肌动蛋白和微管是否共定位,结果显示,CD99 Cyt突变体的特征在于,虽与微管共定位,但不伴随微管的生长进入扩大的板状伪足中,也没固定在质膜(plasma membrane),由于其与肌动蛋白不进行共定位,从而可知这种现象是因CD99 Cyt突变体与肌动蛋白之间的相互作用丧失所致。相反,CD99TM突变体的特征在于,与肌动蛋白保持共定位,但生长延伸的微管的张力(tension)和稳定性(stability)降低,没有诱导板状伪足的退缩和灾变(catastrophe),C99 TM突变体与微管之间丧失共定位(图6的B部分)。由此证明,CD99的细胞质结构域对于与肌动蛋白的相互作用是必需的,并且是促进肌动蛋白和微管的共同生长区域,跨膜结构域对于与微管的相互作用是必需的,并且是促进肌动蛋白和微管的共同收缩的区域。为了确认CD99跨膜结构域中特定亚区(subregion)是否对微管结合至关重要,制备了将一部分CD99跨膜结构域再次引入TM突变体的CD4跨膜结构域的突变体并对其进行实验的结果,确认到整个CD99跨膜结构域对于微管结合是必需的。就CD99细胞质结构域而言,通过构建去除细胞膜区域的远膜区(membrane distal region)而保留近膜区(juxtamembrane region)的突变体来进行了实验,结果观察到类似于正常CD99蛋白质,保持与肌动蛋白和微管之间的相互作用,从而确认到近膜区对于与肌动蛋白的相互作用具有决定性(图6的A部分、B部分)。总而言之,CD99因利用跨膜结构域而对肌动蛋白-微管的共收缩很重要,利用胞内近膜区作用于肌动蛋白-微管的共生长,并介导肌动蛋白与微管之间的整体相互作用并有助于动态不稳定性(dynamic instability)
实施例6:构建移入CD99部分的CAR-T细胞
最近,CAR-T细胞治疗剂因其对CD19阳性急性白血病的高治疗效果(70-80%的完全缓解率)而备受关注,但众所周知,但在生长成实体瘤的CD19阳性淋巴瘤中治疗效率下降(50%左右的完全缓解率)。因此,有必要大幅提高对包括CD19阳性淋巴瘤在内的实体瘤的CAR-T细胞的功能性。
目前主要使用的CAR蛋白的T细胞活化主要依赖于胞内信号转导结构域的活化,作为连接抗体区域和胞内信号转导结构域的骨架的CD8胞外及跨膜结构域仅执行物理连接功能。根据上述实施例2至实施例5,证明了CD99的细胞膜和胞内近膜区通过介导肌动蛋白和微管相互作用,有助于免疫突触形成的稳定化。因此,在向现有CAR蛋白设计中引入CD99的细胞膜和近膜区的情况下,除了现有信号转导功能外,赋予稳定免疫突触的附加功能,从而预计能够构建进一步改善的CAR-T细胞。
因此,在本实施例中,针对靶向CD19抗原的CAR蛋白,设计了几种利用CD99的部分胞外域和跨膜结构域及近膜区的CAR蛋白,并构建了表达这些新CAR蛋白的CAR-T细胞。尤其,分别设计了使用不同长度(分别为58个、45个、35个氨基酸残基)的CD99胞外域(F58BBz、F45BBz、F35BBz、F35BBz-1)或使用现有CAR蛋白的CD8胞外域作为CAR蛋白的胞外域的CAR蛋白(F8TJBBz)(表6及表8、图7的A部分)。然后,通过构建这些蛋白质的基因表达用逆转录病毒,并通过转导至人T细胞来构建了CAR-T细胞。
对这样构建的CAR-T细胞的表型(phenotype)和试管内(in vitro)功能进行分析的结果,通过流式细胞术分析(flow cytometry)确认了每个CAR蛋白在T细胞表面表达(图7的B部分)。就CAR阳性细胞比例测量的转导效率(transduction efficiency)和以平均荧光强度(mean fluorescent intensity,MFI)测量的每个细胞的CAR表达量而言,基于这些CD99骨架的CAR-T细胞,与现有CD8骨架的CAR-T细胞(h19BBz)相比相对低(图7的B部分),但在对CD19阳性淋巴瘤细胞(Raji cell)的细胞杀伤力测试中,基于CD99骨架的CAR-T细胞的杀伤力与现有CAR-T细胞不相上下(图7的C部分)。在在随后进行的T细胞的细胞因子分泌能力实验中,除F8TJBBz CAR-T细胞以外,所有基于CD99骨架的CAR-T细胞均表现出与现有CAR-T细胞类似或进一步提高的IFN-γ分泌能力(图7的D部分)。尤其,就胞外域的长度最短的F35BBz CAR-T细胞而言,与现有CAR-T细胞相比,具有突出的IFN-γ生产能力。因此确认到,尽管基于CD99骨架的CAR-T细胞的CAR表达率低,但具有不次于现有CAR-T细胞的肿瘤杀伤力和活化功能性。但是,就F8TJBBz CAR-T细胞而言,由于具有显著低的CAR表达率和细胞因子(cytokine)分泌能力,因此将其排除在未来的实验之外。
实施例7:确认基于CD99骨架的CAR-T细胞的体内抗癌功效改善效果
为了确认实施例6的基于CD99骨架的CAR-T细胞的体内(in vivo)抗癌功效,对接种淋巴瘤细胞的免疫缺陷小鼠(NSG mice)给药CAR-T细胞后,测量了肿瘤的体内增殖及小鼠的存活率。为了有效追踪肿瘤的体内增殖,静脉注射人工表达荧光素酶的人淋巴瘤细胞(Raji-Luc细胞),并采用测量发光程度的生物发光成像法(Bioluminescence Imaging,BLI)来定期测量了肿瘤细胞群发出的光的强度。
肿瘤接种7天后,以治疗目的注入CAR-T细胞时,观察到现有h19BBz CAR-T细胞显著抑制肿瘤的生长。然而,随着时间的流逝,在给药现有CAR-T细胞的组中观察到肿瘤的再生长,最终所有个体都死亡,因此观察到治疗效果有限。然而,在给药基于CD99骨架的CAR-T细胞的组中,这些肿瘤的再生长显著延迟,尤其,在给药F35BBz CAR-T细胞的组中,所有肿瘤细胞被去除,没有观察到肿瘤复发(图8的A部分、B部分)。结果,就给药现有h19BBz CAR-T细胞的组而言,在接种肿瘤90天内所有个体死亡,但是,就给药F35BBz CAR-T细胞和F45BBzCAR-T细胞的小鼠而言,接种肿瘤140天后也没有出现任何个体的死亡,就F35BBz CAR-T细胞治疗组而言,所有个体生存至实验结束的第153天(图8的C部分)。因此,就基于CD99骨架的CAR-T细胞而言,尤其,就F35BBz CAR-T细胞而言,与现有CAR-T细胞相比,具有显著改善的治疗功效。
实施例8:引入CD99部分的CAR-T细胞的免疫突触形成能力改善
为了测试以上观察到的F35BBz CAR-T细胞的体内抗肿瘤效果是基于通过CD99骨架区域的免疫突触增强效果的可能性,比较了在共培养肿瘤细胞(Raji cell)和CAR-T细胞时与h19BBz CAR-T细胞的免疫突触形成能力。结果观察到,与具有CD8骨架的h19BBz CAR-T细胞处理组相比,CAR-T细胞与形成免疫突触的肿瘤细胞的比例在F35BBz CAR-T细胞处理组中显著增加(图9的A部分、B部分)。并且,特殊地,就F35BBz T细胞而言,与h19BBz CAR-T细胞相比,每个肿瘤细胞结合的CAR-T细胞的数量显著多(图9的C部分、D部分)。因此,就F35BBz CAR-T细胞而言,验证了与肿瘤细胞形成更增强的免疫突触。因此,CD99跨膜结构域和近膜区的免疫突触形成介导效果也在CAR-T细胞中重现,这强烈暗示基于CD99骨架的CAR-T细胞的效力增加是通过免疫突触稳定(stabilization)表现出的效果。
工业实用性
在本发明中,确认了现有T细胞表面蛋白质中CD99的免疫突触稳定功能,并构建了以CD99的跨膜结构域为骨架(backbone)的新型嵌合抗原受体。与具有现有骨架(backbone)的CAR-T细胞相比,基于这种CD99的CAR-T细胞与肿瘤细胞形成更稳定的免疫突触,并显示出提高的肿瘤治疗效率,因此可用于癌症治疗的免疫细胞治疗。
以上对本发明内容的特定部分进行了详细描述,对于本领域的普通技术人员显而易见的是,这些具体描述只是优选实施例,本发明的保护范围不受此限制。因此,本发明的实质范围旨在由所附权利要求及其等同物来定义。
序列目录自由文本
附电子版文档。
<110> 蒂卡洛斯有限公司
<120> 用于稳定免疫突触的嵌合抗原受体(CAR)T细胞
<130> PP-B2661
<150> KR 2020-0094624
<151> 2020-07-29
<160> 44
<170> KoPatentIn 3.0
<210> 1
<211> 185
<212> PRT
<213> 人工序列
<220>
<223> CD99
<400> 1
Met Ala Arg Gly Ala Ala Leu Ala Leu Leu Leu Phe Gly Leu Leu Gly
1 5 10 15
Val Leu Val Ala Ala Pro Asp Gly Gly Phe Asp Leu Ser Asp Ala Leu
20 25 30
Pro Asp Asn Glu Asn Lys Lys Pro Thr Ala Ile Pro Lys Lys Pro Ser
35 40 45
Ala Gly Asp Asp Phe Asp Leu Gly Asp Ala Val Val Asp Gly Glu Asn
50 55 60
Asp Asp Pro Arg Pro Pro Asn Pro Pro Lys Pro Met Pro Asn Pro Asn
65 70 75 80
Pro Asn His Pro Ser Ser Ser Gly Ser Phe Ser Asp Ala Asp Leu Ala
85 90 95
Asp Gly Val Ser Gly Gly Glu Gly Lys Gly Gly Ser Asp Gly Gly Gly
100 105 110
Ser His Arg Lys Glu Gly Glu Glu Ala Asp Ala Pro Gly Val Ile Pro
115 120 125
Gly Ile Val Gly Ala Val Val Val Ala Val Ala Gly Ala Ile Ser Ser
130 135 140
Phe Ile Ala Tyr Gln Lys Lys Lys Leu Cys Phe Lys Glu Asn Ala Glu
145 150 155 160
Gln Gly Glu Val Asp Met Glu Ser His Arg Asn Ala Asn Ala Glu Pro
165 170 175
Ala Val Gln Arg Thr Leu Leu Glu Lys
180 185
<210> 2
<211> 558
<212> DNA
<213> 人工序列
<220>
<223> CD99
<400> 2
atggcccgcg gggctgcgct ggcgctgctg ctcttcggcc tgctgggtgt tctggtcgcc 60
gccccggatg gtggtttcga tttatccgat gcccttcctg acaatgaaaa caagaaaccc 120
actgcaatcc ccaagaaacc cagtgctggg gatgactttg acttaggaga tgctgttgtt 180
gatggagaaa atgacgaccc acgaccaccg aacccaccca aaccgatgcc aaatccaaac 240
cccaaccacc ctagttcctc cggtagcttt tcagatgctg accttgcgga tggcgtttca 300
ggtggagaag gaaaaggagg cagtgatggt ggaggcagcc acaggaaaga aggggaagag 360
gccgacgccc caggcgtgat ccccgggatt gtgggggctg tcgtggtcgc cgtggctgga 420
gccatctcta gcttcattgc ttaccagaaa aagaagctat gcttcaaaga aaatgcagaa 480
caaggggagg tggacatgga gagccaccgg aatgccaacg cagagccagc tgttcagcgt 540
actcttttag agaaatag 558
<210> 3
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> CD99 TM
<400> 3
Ala Pro Gly Val Ile Pro Gly Ile Val Gly Ala Val Val Val Ala Val
1 5 10 15
Ala Gly Ala Ile Ser Ser Phe Ile Ala
20 25
<210> 4
<211> 75
<212> DNA
<213> 人工序列
<220>
<223> CD99 TM
<400> 4
gccccaggcg tgatccccgg gattgtgggg gctgtcgtgg tcgccgtggc tggagccatc 60
tctagcttca ttgct 75
<210> 5
<211> 100
<212> PRT
<213> 人工序列
<220>
<223> CD99 EC
<400> 5
Asp Gly Gly Phe Asp Leu Ser Asp Ala Leu Pro Asp Asn Glu Asn Lys
1 5 10 15
Lys Pro Thr Ala Ile Pro Lys Lys Pro Ser Ala Gly Asp Asp Phe Asp
20 25 30
Leu Gly Asp Ala Val Val Asp Gly Glu Asn Asp Asp Pro Arg Pro Pro
35 40 45
Asn Pro Pro Lys Pro Met Pro Asn Pro Asn Pro Asn His Pro Ser Ser
50 55 60
Ser Gly Ser Phe Ser Asp Ala Asp Leu Ala Asp Gly Val Ser Gly Gly
65 70 75 80
Glu Gly Lys Gly Gly Ser Asp Gly Gly Gly Ser His Arg Lys Glu Gly
85 90 95
Glu Glu Ala Asp
100
<210> 6
<211> 300
<212> DNA
<213> 人工序列
<220>
<223> CD99 EC
<400> 6
gatggtggtt tcgatttatc cgatgccctt cctgacaatg aaaacaagaa acccactgca 60
atccccaaga aacccagtgc tggggatgac tttgacttag gagatgctgt tgttgatgga 120
gaaaatgacg acccacgacc accgaaccca cccaaaccga tgccaaatcc aaaccccaac 180
caccctagtt cctccggtag cttttcagat gctgaccttg cggatggcgt ttcaggtgga 240
gaaggaaaag gaggcagtga tggtggaggc agccacagga aagaagggga agaggccgac 300
300
<210> 7
<211> 58
<212> PRT
<213> 人工序列
<220>
<223> CD99 58EC
<400> 7
Asp Asp Pro Arg Pro Pro Asn Pro Pro Lys Pro Met Pro Asn Pro Asn
1 5 10 15
Pro Asn His Pro Ser Ser Ser Gly Ser Phe Ser Asp Ala Asp Leu Ala
20 25 30
Asp Gly Val Ser Gly Gly Glu Gly Lys Gly Gly Ser Asp Gly Gly Gly
35 40 45
Ser His Arg Lys Glu Gly Glu Glu Ala Asp
50 55
<210> 8
<211> 174
<212> DNA
<213> 人工序列
<220>
<223> CD99 58EC
<400> 8
gacgacccac gaccaccgaa cccacccaaa ccgatgccaa atccaaaccc caaccaccct 60
agttcctccg gtagcttttc agatgctgac cttgcggatg gcgtttcagg tggagaagga 120
aaaggaggca gtgatggtgg aggcagccac aggaaagaag gggaagaggc cgac 174
<210> 9
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> CD99 45EC
<400> 9
Asn Pro Asn Pro Asn His Pro Ser Ser Ser Gly Ser Phe Ser Asp Ala
1 5 10 15
Asp Leu Ala Asp Gly Val Ser Gly Gly Glu Gly Lys Gly Gly Ser Asp
20 25 30
Gly Gly Gly Ser His Arg Lys Glu Gly Glu Glu Ala Asp
35 40 45
<210> 10
<211> 135
<212> DNA
<213> 人工序列
<220>
<223> CD99 45EC
<400> 10
aatccaaacc ccaaccaccc tagttcctcc ggtagctttt cagatgctga ccttgcggat 60
ggcgtttcag gtggagaagg aaaaggaggc agtgatggtg gaggcagcca caggaaagaa 120
ggggaagagg ccgac 135
<210> 11
<211> 35
<212> PRT
<213> 人工序列
<220>
<223> CD99 35EC
<400> 11
Gly Ser Phe Ser Asp Ala Asp Leu Ala Asp Gly Val Ser Gly Gly Glu
1 5 10 15
Gly Lys Gly Gly Ser Asp Gly Gly Gly Ser His Arg Lys Glu Gly Glu
20 25 30
Glu Ala Asp
35
<210> 12
<211> 105
<212> DNA
<213> 人工序列
<220>
<223> CD99 35EC
<400> 12
ggtagctttt cagatgctga ccttgcggat ggcgtttcag gtggagaagg aaaaggaggc 60
agtgatggtg gaggcagcca caggaaagaa ggggaagagg ccgac 105
<210> 13
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CD99 jTM
<400> 13
Tyr Gln Lys Lys Lys Leu Cys Phe Lys Glu Asn
1 5 10
<210> 14
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> CD99 jTM
<400> 14
taccagaaaa agaagctatg cttcaaagaa aat 33
<210> 15
<211> 41
<212> PRT
<213> 人工序列
<220>
<223> CD8 EC
<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
35 40
<210> 16
<211> 123
<212> DNA
<213> 人工序列
<220>
<223> CD8 EC
<400> 16
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gac 123
<210> 17
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ胞内信号转导结构域(野生型)
<400> 17
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 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> 18
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> CD3ζ胞内信号转导结构域(野生型)
<400> 18
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc 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
<210> 19
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ胞内信号转导结构域(突变体)
<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
<220>
<223> CD3ζ胞内信号转导结构域(突变体)
<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
<210> 21
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 4-1BB共刺激结构域
<400> 21
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> 22
<211> 126
<212> DNA
<213> 人工序列
<220>
<223> 4-1BB共刺激结构域
<400> 22
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 23
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> αCD19 scFv
<400> 23
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
115 120 125
Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
130 135 140
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
145 150 155 160
Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
165 170 175
Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
195 200 205
Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
210 215 220
Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
225 230 235 240
Ser Ser
<210> 24
<211> 726
<212> DNA
<213> 人工序列
<220>
<223> αCD19 scFv
<400> 24
gacatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacattagt aaatatttaa attggtatca gcagaaacca 120
gatggaactg ttaaactcct gatctaccat acatcaagat tacactcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa 240
gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccgtacac gttcggaggg 300
gggaccaagc tggagatcac aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgaaactgca ggagtcagga cctggcctgg tggcgccctc acagagcctg 420
tccgtcacat gcactgtctc aggggtctca ttacccgact atggtgtaag ctggattcgc 480
cagcctccac gaaagggtct ggagtggctg ggagtaatat ggggtagtga aaccacatac 540
tataattcag ctctcaaatc cagactgacc atcatcaagg acaactccaa gagccaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca tttactactg tgccaaacat 660
tattactacg gtggtagcta tgctatggac tactggggcc aaggaacctc agtcaccgtc 720
tcctca 726
<210> 25
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> hCD8L
<400> 25
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> 26
<211> 63
<212> DNA
<213> 人工序列
<220>
<223> hCD8L
<400> 26
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 27
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> F58BBz
<400> 27
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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Asp Asp Pro Arg Pro Pro Asn Pro Pro
260 265 270
Lys Pro Met Pro Asn Pro Asn Pro Asn His Pro Ser Ser Ser Gly Ser
275 280 285
Phe Ser Asp Ala Asp Leu Ala Asp Gly Val Ser Gly Gly Glu Gly Lys
290 295 300
Gly Gly Ser Asp Gly Gly Gly Ser His Arg Lys Glu Gly Glu Glu Ala
305 310 315 320
Asp Ala Pro Gly Val Ile Pro Gly Ile Val Gly Ala Val Val Val Ala
325 330 335
Val Ala Gly Ala Ile Ser Ser Phe Ile Ala Tyr Gln Lys Lys Lys Leu
340 345 350
Cys Phe Lys Glu Asn Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
355 360 365
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
370 375 380
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
385 390 395 400
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln
405 410 415
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
420 425 430
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
435 440 445
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
450 455 460
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
465 470 475 480
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
485 490 495
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 28
<211> 1536
<212> DNA
<213> 人工序列
<220>
<223> F58BBz
<400> 28
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcag acgacccacg accaccgaac ccacccaaac cgatgccaaa tccaaacccc 840
aaccacccta gttcctccgg tagcttttca gatgctgacc ttgcggatgg cgtttcaggt 900
ggagaaggaa aaggaggcag tgatggtgga ggcagccaca ggaaagaagg ggaagaggcc 960
gacgccccag gcgtgatccc cgggattgtg ggggctgtcg tggtcgccgt ggctggagcc 1020
atctctagct tcattgctta ccagaaaaag aagctatgct tcaaagaaaa taaacggggc 1080
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 1140
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgaga 1200
gtgaagttca gcaggagcgc agacgccccc gcgtacaagc agggccagaa ccagctctat 1260
aacgagctca atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg 1320
gaccctgaga tggggggaaa gccgagaagg aagaaccctc aggaaggcct gtacaatgaa 1380
ctgcagaaag ataagatggc ggaggcctac agtgagattg ggatgaaagg cgagcgccgg 1440
aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 1500
gacgcccttc acatgcaggc cctgccccct cgctaa 1536
<210> 29
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> F45BBz
<400> 29
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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Asn Pro Asn Pro Asn His Pro Ser Ser
260 265 270
Ser Gly Ser Phe Ser Asp Ala Asp Leu Ala Asp Gly Val Ser Gly Gly
275 280 285
Glu Gly Lys Gly Gly Ser Asp Gly Gly Gly Ser His Arg Lys Glu Gly
290 295 300
Glu Glu Ala Asp Ala Pro Gly Val Ile Pro Gly Ile Val Gly Ala Val
305 310 315 320
Val Val Ala Val Ala Gly Ala Ile Ser Ser Phe Ile Ala Tyr Gln Lys
325 330 335
Lys Lys Leu Cys Phe Lys Glu Asn Lys Arg Gly Arg Lys Lys Leu Leu
340 345 350
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
355 360 365
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
370 375 380
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
385 390 395 400
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
405 410 415
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
420 425 430
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
435 440 445
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
450 455 460
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
465 470 475 480
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
485 490 495
Pro Arg
<210> 30
<211> 1497
<212> DNA
<213> 人工序列
<220>
<223> F45BBz
<400> 30
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcaa atccaaaccc caaccaccct agttcctccg gtagcttttc agatgctgac 840
cttgcggatg gcgtttcagg tggagaagga aaaggaggca gtgatggtgg aggcagccac 900
aggaaagaag gggaagaggc cgacgcccca ggcgtgatcc ccgggattgt gggggctgtc 960
gtggtcgccg tggctggagc catctctagc ttcattgctt accagaaaaa gaagctatgc 1020
ttcaaagaaa ataaacgggg 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> 488
<212> PRT
<213> 人工序列
<220>
<223> F35BBz
<400> 31
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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Gly Ser Phe Ser Asp Ala Asp Leu Ala
260 265 270
Asp Gly Val Ser Gly Gly Glu Gly Lys Gly Gly Ser Asp Gly Gly Gly
275 280 285
Ser His Arg Lys Glu Gly Glu Glu Ala Asp Ala Pro Gly Val Ile Pro
290 295 300
Gly Ile Val Gly Ala Val Val Val Ala Val Ala Gly Ala Ile Ser Ser
305 310 315 320
Phe Ile Ala Tyr Gln Lys Lys Lys Leu Cys Phe Lys Glu Asn Lys Arg
325 330 335
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
340 345 350
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
355 360 365
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
370 375 380
Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
385 390 395 400
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
405 410 415
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 32
<211> 1467
<212> DNA
<213> 人工序列
<220>
<223> F35BBz
<400> 32
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcag gtagcttttc agatgctgac cttgcggatg gcgtttcagg tggagaagga 840
aaaggaggca gtgatggtgg aggcagccac aggaaagaag gggaagaggc cgacgcccca 900
ggcgtgatcc ccgggattgt gggggctgtc gtggtcgccg tggctggagc catctctagc 960
ttcattgctt accagaaaaa gaagctatgc ttcaaagaaa ataaacgggg cagaaagaaa 1020
ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 1080
ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc 1140
agcaggagcg cagacgcccc cgcgtacaag cagggccaga accagctcta taacgagctc 1200
aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 1260
atggggggaa agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 1320
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 1380
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1440
cacatgcagg ccctgccccc tcgctaa 1467
<210> 33
<211> 488
<212> PRT
<213> 人工序列
<220>
<223> F35BBz-1
<400> 33
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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Gly Ser Phe Ser Asp Ala Asp Leu Ala
260 265 270
Asp Gly Val Ser Gly Gly Glu Gly Lys Gly Gly Ser Asp Gly Gly Gly
275 280 285
Ser His Arg Lys Glu Gly Glu Glu Ala Asp Ala Pro Gly Val Ile Pro
290 295 300
Gly Ile Val Gly Ala Val Val Val Ala Val Ala Gly Ala Ile Ser Ser
305 310 315 320
Phe Ile Ala Tyr Gln Lys Lys Lys Leu Cys Phe Lys Glu Asn Lys Arg
325 330 335
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
340 345 350
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
355 360 365
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
370 375 380
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
385 390 395 400
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
405 410 415
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 34
<211> 1467
<212> DNA
<213> 人工序列
<220>
<223> F35BBz-1
<400> 34
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcag gtagcttttc agatgctgac cttgcggatg gcgtttcagg tggagaagga 840
aaaggaggca gtgatggtgg aggcagccac aggaaagaag gggaagaggc cgacgcccca 900
ggcgtgatcc ccgggattgt gggggctgtc gtggtcgccg tggctggagc catctctagc 960
ttcattgctt accagaaaaa gaagctatgc ttcaaagaaa ataaacgggg cagaaagaaa 1020
ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 1080
ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc 1140
agcaggagcg cagacgcccc cgcgtaccag cagggccaga accagctcta taacgagctc 1200
aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 1260
atggggggaa agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 1320
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 1380
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1440
cacatgcagg ccctgccccc tcgctaa 1467
<210> 35
<211> 186
<212> PRT
<213> 人工序列
<220>
<223> CD99 WT
<400> 35
Met Ala Arg Ala Ala Met Glu Ala Ala Ala Thr Val Val Leu Ala Leu
1 5 10 15
Ala Leu Leu Gly Ala Ala Ala Arg Gly Ala Ala Glu Gln Lys Leu Ile
20 25 30
Ser Glu Glu Asp Leu Asn Ser Asp Asp Phe Asn Leu Gly Asp Ala Leu
35 40 45
Glu Asp Pro Asn Met Lys Pro Thr Pro Lys Ala Pro Thr Pro Lys Lys
50 55 60
Pro Ser Gly Gly Phe Asp Leu Glu Asp Ala Leu Pro Gly Gly Gly Gly
65 70 75 80
Gly Gly Ala Gly Glu Lys Pro Gly Asn Arg Pro Gln Pro Asp Pro Lys
85 90 95
Pro Pro Arg Pro His Gly Asp Ser Gly Gly Ile Ser Asp Ser Asp Leu
100 105 110
Ala Asp Ala Ala Gly Gln Gly Gly Gly Gly Ala Gly Arg Arg Gly Ser
115 120 125
Gly Asp Glu Gly Gly His Gly Gly Ala Gly Gly Ala Glu Pro Glu Gly
130 135 140
Thr Pro Gln Gly Leu Val Pro Gly Val Val Ala Ala Val Val Ala Ala
145 150 155 160
Val Ala Gly Ala Val Ser Ser Phe Val Ala Tyr Gln Arg Arg Arg Leu
165 170 175
Cys Phe Arg Glu Gly Gly Ser Ala Pro Val
180 185
<210> 36
<211> 187
<212> PRT
<213> 人工序列
<220>
<223> CD99 TM突变体
<400> 36
Met Ala Arg Ala Ala Met Glu Ala Ala Ala Thr Val Val Leu Ala Leu
1 5 10 15
Ala Leu Leu Gly Ala Ala Ala Arg Gly Ala Ala Glu Gln Lys Leu Ile
20 25 30
Ser Glu Glu Asp Leu Asn Ser Asp Asp Phe Asn Leu Gly Asp Ala Leu
35 40 45
Glu Asp Pro Asn Met Lys Pro Thr Pro Lys Ala Pro Thr Pro Lys Lys
50 55 60
Pro Ser Gly Gly Phe Asp Leu Glu Asp Ala Leu Pro Gly Gly Gly Gly
65 70 75 80
Gly Gly Ala Gly Glu Lys Pro Gly Asn Arg Pro Gln Pro Asp Pro Lys
85 90 95
Pro Pro Arg Pro His Gly Asp Ser Gly Gly Ile Ser Asp Ser Asp Leu
100 105 110
Ala Asp Ala Ala Gly Gln Gly Gly Gly Gly Ala Gly Arg Arg Gly Ser
115 120 125
Gly Asp Glu Gly Gly His Gly Gly Ala Gly Gly Ala Glu Pro Glu Gly
130 135 140
Thr Pro Gln Gly Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu
145 150 155 160
Leu Phe Ile Gly Leu Gly Ile Phe Phe Cys Ala Tyr Gln Arg Arg Arg
165 170 175
Leu Cys Phe Arg Glu Gly Gly Ser Ala Pro Val
180 185
<210> 37
<211> 177
<212> PRT
<213> 人工序列
<220>
<223> CD99 Cyt突变体
<400> 37
Met Ala Arg Ala Ala Met Glu Ala Ala Ala Thr Val Val Leu Ala Leu
1 5 10 15
Ala Leu Leu Gly Ala Ala Ala Arg Gly Ala Ala Glu Gln Lys Leu Ile
20 25 30
Ser Glu Glu Asp Leu Asn Ser Asp Asp Phe Asn Leu Gly Asp Ala Leu
35 40 45
Glu Asp Pro Asn Met Lys Pro Thr Pro Lys Ala Pro Thr Pro Lys Lys
50 55 60
Pro Ser Gly Gly Phe Asp Leu Glu Asp Ala Leu Pro Gly Gly Gly Gly
65 70 75 80
Gly Gly Ala Gly Glu Lys Pro Gly Asn Arg Pro Gln Pro Asp Pro Lys
85 90 95
Pro Pro Arg Pro His Gly Asp Ser Gly Gly Ile Ser Asp Ser Asp Leu
100 105 110
Ala Asp Ala Ala Gly Gln Gly Gly Gly Gly Ala Gly Arg Arg Gly Ser
115 120 125
Gly Asp Glu Gly Gly His Gly Gly Ala Gly Gly Ala Glu Pro Glu Gly
130 135 140
Thr Pro Gln Gly Leu Val Pro Gly Val Val Ala Ala Val Val Ala Ala
145 150 155 160
Val Ala Gly Ala Val Ser Ser Phe Val Val Arg Cys Arg His Arg Arg
165 170 175
Arg
<210> 38
<211> 189
<212> PRT
<213> 人工序列
<220>
<223> CD99 TMrst-S突变体
<400> 38
Met Ala Arg Ala Ala Met Glu Ala Ala Ala Thr Val Val Leu Ala Leu
1 5 10 15
Ala Leu Leu Gly Ala Ala Ala Arg Gly Ala Ala Glu Gln Lys Leu Ile
20 25 30
Ser Glu Glu Asp Leu Asn Ser Asp Asp Phe Asn Leu Gly Asp Ala Leu
35 40 45
Glu Asp Pro Asn Met Lys Pro Thr Pro Lys Ala Pro Thr Pro Lys Lys
50 55 60
Pro Ser Gly Gly Phe Asp Leu Glu Asp Ala Leu Pro Gly Gly Gly Gly
65 70 75 80
Gly Gly Ala Gly Glu Lys Pro Gly Asn Arg Pro Gln Pro Asp Pro Lys
85 90 95
Pro Pro Arg Pro His Gly Asp Ser Gly Gly Ile Ser Asp Ser Asp Leu
100 105 110
Ala Asp Ala Ala Gly Gln Gly Gly Gly Gly Ala Gly Arg Arg Gly Ser
115 120 125
Gly Asp Glu Gly Gly His Gly Gly Ala Gly Gly Ala Glu Pro Glu Gly
130 135 140
Thr Pro Gln Gly Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Leu
145 150 155 160
Leu Phe Ile Gly Leu Gly Ala Val Ser Ser Phe Val Ala Tyr Gln Arg
165 170 175
Arg Arg Leu Cys Phe Arg Glu Gly Gly Ser Ala Pro Val
180 185
<210> 39
<211> 188
<212> PRT
<213> 人工序列
<220>
<223> CD99 TMrst-L突变体
<400> 39
Met Ala Arg Ala Ala Met Glu Ala Ala Ala Thr Val Val Leu Ala Leu
1 5 10 15
Ala Leu Leu Gly Ala Ala Ala Arg Gly Ala Ala Glu Gln Lys Leu Ile
20 25 30
Ser Glu Glu Asp Leu Asn Ser Asp Asp Phe Asn Leu Gly Asp Ala Leu
35 40 45
Glu Asp Pro Asn Met Lys Pro Thr Pro Lys Ala Pro Thr Pro Lys Lys
50 55 60
Pro Ser Gly Gly Phe Asp Leu Glu Asp Ala Leu Pro Gly Gly Gly Gly
65 70 75 80
Gly Gly Ala Gly Glu Lys Pro Gly Asn Arg Pro Gln Pro Asp Pro Lys
85 90 95
Pro Pro Arg Pro His Gly Asp Ser Gly Gly Ile Ser Asp Ser Asp Leu
100 105 110
Ala Asp Ala Ala Gly Gln Gly Gly Gly Gly Ala Gly Arg Arg Gly Ser
115 120 125
Gly Asp Glu Gly Gly His Gly Gly Ala Gly Gly Ala Glu Pro Glu Gly
130 135 140
Thr Pro Gln Gly Ala Leu Ile Val Leu Gly Gly Val Ala Gly Leu Val
145 150 155 160
Ala Ala Val Ala Gly Ala Val Ser Ser Phe Val Ala Tyr Gln Arg Arg
165 170 175
Arg Leu Cys Phe Arg Glu Gly Gly Ser Ala Pro Val
180 185
<210> 40
<211> 180
<212> PRT
<213> 人工序列
<220>
<223> CD99 CytJuxt突变体
<400> 40
Met Ala Arg Ala Ala Met Glu Ala Ala Ala Thr Val Val Leu Ala Leu
1 5 10 15
Ala Leu Leu Gly Ala Ala Ala Arg Gly Ala Ala Glu Gln Lys Leu Ile
20 25 30
Ser Glu Glu Asp Leu Asn Ser Asp Asp Phe Asn Leu Gly Asp Ala Leu
35 40 45
Glu Asp Pro Asn Met Lys Pro Thr Pro Lys Ala Pro Thr Pro Lys Lys
50 55 60
Pro Ser Gly Gly Phe Asp Leu Glu Asp Ala Leu Pro Gly Gly Gly Gly
65 70 75 80
Gly Gly Ala Gly Glu Lys Pro Gly Asn Arg Pro Gln Pro Asp Pro Lys
85 90 95
Pro Pro Arg Pro His Gly Asp Ser Gly Gly Ile Ser Asp Ser Asp Leu
100 105 110
Ala Asp Ala Ala Gly Gln Gly Gly Gly Gly Ala Gly Arg Arg Gly Ser
115 120 125
Gly Asp Glu Gly Gly His Gly Gly Ala Gly Gly Ala Glu Pro Glu Gly
130 135 140
Thr Pro Gln Gly Leu Val Pro Gly Val Val Ala Ala Val Val Ala Ala
145 150 155 160
Val Ala Gly Ala Val Ser Ser Phe Val Ala Tyr Gln Arg Arg Arg Leu
165 170 175
Cys Phe Arg Glu
180
<210> 41
<211> 486
<212> PRT
<213> 人工序列
<220>
<223> hCD19BBz
<400> 41
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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
340 345 350
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
355 360 365
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg
485
<210> 42
<211> 1461
<212> DNA
<213> 人工序列
<220>
<223> hCD19BBz
<400> 42
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140
agcgcagacg cccccgcgta caagcagggc cagaaccagc tctataacga gctcaatcta 1200
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1260
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1440
caggccctgc cccctcgcta a 1461
<210> 43
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> F8TJBBz
<400> 43
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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Ala Asp Ala Pro Gly Val Ile Pro Gly Ile Val Gly Ala Val Val Val
305 310 315 320
Ala Val Ala Gly Ala Ile Ser Ser Phe Ile Ala Tyr Gln Lys Lys Lys
325 330 335
Leu Cys Phe Lys Glu Asn Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
340 345 350
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
355 360 365
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
370 375 380
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
385 390 395 400
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
405 410 415
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
420 425 430
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
435 440 445
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
450 455 460
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
465 470 475 480
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490 495
<210> 44
<211> 1491
<212> DNA
<213> 人工序列
<220>
<223> F8TJBBz
<400> 44
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120
accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180
ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240
tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300
caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360
ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480
ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540
cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600
tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660
gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720
cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780
gtctcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900
agggggctgg acgccgacgc cccaggcgtg atccccggga ttgtgggggc tgtcgtggtc 960
gccgtggctg gagccatctc tagcttcatt gcttaccaga aaaagaagct atgcttcaaa 1020
gaaaataaac 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
Claims (14)
1.一种嵌合抗原受体,其包含:
(a)抗原结合结构域;
(b)骨架,其包含胞外连接部和跨膜结构域,以及
(c)胞内信号转导结构域;
其中所述嵌合抗原受体还包含CD99衍生的胞内近膜结构域,其包含由SEQID NO:13表示的氨基酸序列,
其中所述胞外连接部包含CD99衍生的胞外域,其包含由SEQ ID NO:7、SEQ ID NO:9或SEQ ID NO:11表示的氨基酸序列,并且
其中所述跨膜结构域包含CD99衍生的跨膜结构域,其包含由SEQ ID NO:3表示的氨基酸序列。
2.根据权利要求1所述的嵌合抗原受体,其中,所述胞内信号转导结构域包含:
选自由CD3截塔(ζ)、CD3伽马(γ)、CD3德尔塔(δ)、CD3伊普西龙(ε)、FcR伽马、FcR贝塔、CD5、CD22、CD79a、CD79b和CD66d组成的组中的胞内信号转导结构域;和/或
选自由与CD2、CD7、CD27、CD28、CD30、CD40、4-1BB(CD137)、OX40(CD134)、ICOS、LFA-1、GITR、MyD88、DAP1、PD-1、LIGHT、NKG2C、B7-H3和与CD83特异性结合的配体组成的组中的共刺激结构域。
3.根据权利要求2所述的嵌合抗原受体,其中,所述CD3截塔(ζ)的胞内信号转导结构域包含SEQ ID NO:17或SEQ ID NO:19的氨基酸序列。
4.根据权利要求1所述的嵌合抗原受体,其中,所述抗原结合结构域包含特异性结合于选自由以下组成的组中的抗原的抗体或其抗原结合片段:
4-1BB、BCMA、BAFF、B7-H3、B7-H6、CA9、CTAG1B、CEA、细胞周期蛋白、细胞周期蛋白A2、细胞周期蛋白B1、CCL-l、CCR4、CD3、CD4、CD19、CD20、CD22、CD23、CD24、CD30、CD33、CD38、CD40、CD44、CD44v6、CD44v7/8、CD52、CD58、CD62、CD79A、CD79B、CD80、CD123、CD133、CD138、CD171、CSPG4、CLDN18、CLDN6、CTLA-4、c-Met、DLL3、EGFR、tEGFR、EGFRvIII、EPG-2、EPG-40、EprinB2、EPHA2、雌激素受体、Fc受体、FCRL5、FGF23、FBP、FOLR1、FOLR2、GD2、神经节苷脂GD3、gp100、GPC3、GPCR5D、GM-CSF、Her2/neu、Her3、Her4、erbB二聚体、HMW-MAA、HBsAg、HLA-A1、HLA-A2、IL-22Ra、IL-13Ra2、ICOS、IGF-1受体、整合素αvβ6、干扰素受体、IFNγ、IL-2R、IL-4R、IL-5R、IL-6R、IL-17RA、IL-31R、IL-36R、kdr、L1-CAM、L1-CAM的CE7表位、LRRC8A、LewisY、LAG3、MAGEAl、MAGEA3、MAGEA6、MAGEAlO、MSLN、CMV、MUC1、NKG2D配体、MART-l、NGF、NCAM、NRP-1、NRP-2、癌胚抗原、PD-L1、PRAME、黄体酮受体、前列腺特异性抗原、PSCA、PSMA、RANKL、ROR1、SLAMF7、存活素、TPBG、TAG72、TRP1、TRP2及威尔姆氏瘤1(WT1)。
5.根据权利要求4所述的嵌合抗原受体,其中,所述抗原结合片段为抗体的单链可变片段(scFv)或纳米抗体。
6.根据权利要求1所述的嵌合抗原受体,其在抗原结合结构域的N-末端还包含信号肽。
7.根据权利要求6所述的嵌合抗原受体,其中,所述信号肽为包含SEQ ID NO:25的氨基酸序列的CD8α信号肽。
8.根据权利要求1所述的嵌合抗原受体,其中,所述嵌合抗原受体包含由SEQ ID NO:27、SEQ ID NO:29、SEQ ID NO:31或SEQ ID NO:33表示的氨基酸序列。
9.一种编码根据权利要求1所述的嵌合抗原受体的核酸。
10.一种包含根据权利要求9所述的核酸的表达载体。
11.一种包含根据权利要求10所述的表达载体的病毒。
12.一种在表面表达根据权利要求1至8中任一项所述的嵌合抗原受体的免疫细胞。
13.根据权利要求12所述的免疫细胞,其中,所述免疫细胞为T细胞、NK细胞、NKT细胞或巨噬细胞。
14.一种包含根据权利要求13所述的免疫细胞的癌治疗用组合物。
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