CN107074930A - 嵌合的抗原受体 - Google Patents
嵌合的抗原受体 Download PDFInfo
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- CN107074930A CN107074930A CN201580059769.3A CN201580059769A CN107074930A CN 107074930 A CN107074930 A CN 107074930A CN 201580059769 A CN201580059769 A CN 201580059769A CN 107074930 A CN107074930 A CN 107074930A
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Abstract
一种嵌合的抗原受体(CAR),所述嵌合的抗原受体包含胞外间隔区,所述胞外间隔区包含人低亲和力神经生长因子(LNGFR)或其衍生物胞外域的至少一部分。
Description
发明领域
本发明涉及嵌合的抗原受体(CAR),所述嵌合的抗原受体包含基于低亲和力神经生长因子受体(LNGFR)的间隔区。
背景技术
基于将免疫细胞(例如T细胞)过继转移到患者中的免疫疗法在治疗疾病(特别是癌症)中具有重要作用。在多种不同类型的免疫治疗剂中,最有前景的治疗方法之一包括使用嵌合的抗原受体(CAR)。CAR是被设计为靶向特异性抗原如肿瘤抗原的经基因工程改造的受体(Sadelain等,Cancer Discovery.2013.3(4):388-98)。例如,使用CAR转导T细胞以使得表达CAR的T细胞通过靶抗原杀伤肿瘤。
CAR包含胞外配体结合结构域,最常见的是与胞内信号转导部分连接的单克隆抗体的单链可变片段(scFv),最常见的是单独的或与一个或多个共刺激结构域组合的CD3ζ。在胞外抗原结合结构域与跨膜部分之间通常加入间隔区以优化与靶点之间的相互作用。
最常见的是,将恒定免疫球蛋白IgG1铰链-CH2-CH3Fc结构域作为间隔区结构域。使用这种间隔区以选择和跟踪表达CAR的细胞。然而,IgG1间隔区还可以与在先天免疫细胞(如巨噬细胞和自然杀伤细胞)上表达的表面IgG Fcγ受体结合(Hombach等,Gene Ther2000,Jun;7(12):1067-75)。这种结合同时活化经工程改造的T细胞和先天免疫细胞,其不依赖于CAR结合结构域的特异性,导致不需要的、脱靶的免疫应答。
需要不产生脱靶的免疫应答和不被宿主免疫***过早清除的CAR。还需要包含便于对经基因工程改造以表达CAR的细胞进行选择的间隔区单元的CAR。本发明满足了这些需求。
发明内容
根据本发明的第一个方面,提供了一种嵌合的抗原受体(CAR),所述嵌合的抗原受体包含胞外间隔区,所述胞外间隔区包含人低亲和力神经生长因子受体(LNGFR)或其衍生物胞外域的至少一部分。
CAR可以包含人低亲和力神经生长因子受体(LNGFR)或其衍生物胞外域的至少一个片段。
优选地,LNGFR的至少一部分适于促进对使用所述CAR转导的细胞进行免疫选择。
优选地,间隔区缺乏LNGFR的胞内域。
优选地,胞外间隔区包含LNGFR或者其片段或衍生物的前三个TNFR-Cys结构域。
在一个实施方式中,间隔区包含LNGFR或者其片段或衍生物的全部四个TNFR-Cys结构域。
在另一个实施方式中,间隔区包含第四个TNFR-Cys结构域(TNFR-Cys4),但是其中将下述氨基酸序列:NHVDPCLPCTVCEDTERQLRECTRW从所述结构域中除去。优选地,将NHVDPCLPCTVCEDTERQLRECTRW序列替代为下述氨基酸序列:ARA。
在另一个实施方式中,间隔区包含LNGFR中富含丝氨酸/苏氨酸的茎。
在另一个实施方式中,间隔区缺乏LNGFR中富含丝氨酸/苏氨酸的茎。
间隔区可以包含选自下组的序列SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5或SEQID NO:7或者与其具有至少80、85、90、95、96、97、98或99%同一性的序列。
在另一个实施方式中,间隔区可以由选自下组的序列:SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5或SEQ ID NO:7或者与其具有至少80、85、90、95、96、97、98或99%同一性的序列组成。
SEQ ID NO:1、SEQ ID NO:3和SEQ ID NO:5是优选的间隔区元件。
根据本发明的一个方面,提供了一种嵌合的抗原受体(CAR),所述嵌合的抗原受体包含:
(i)抗原特异性靶向结构域;
(ii)根据本申请所定义的胞外间隔区结构域;
(iii)跨膜结构域;
(iv)任选地至少一个共刺激结构域;以及
(v)胞内信号转导结构域。
优选地,抗原特异性靶向结构域包含抗体或其片段,更优选地,包含单链可变片段。
优选地,抗原特异性靶向结构域靶向肿瘤抗原。此类抗原的实例包括CD44、CD19、CD20、CD22、CD23、CD123、CS-1、ROR1、间皮素、c-Met、PSMA、Her2、GD-2、CEA、MAGE A3 TCR。
优选地,肿瘤抗原是CD44的同种型6(CD44v6)。
跨膜结构域的实例包括T细胞受体复合物、CD28和CD8a的ζ链跨膜结构域。
共刺激结构域的实例包括来自CD28、CD137(4-1BB)、CD134(OX40)、DaplO、CD27、CD2、CD5、ICAM-1、LFA-1、Lck、TNFR-I、TNFR-II、Fas、CD30和CD40的共刺激结构域。
胞内信号转导结构域的实例包括人CD3ζ链、FcyRIII、FcsRI、Fc受体胞质尾和携带胞质受体的免疫受体酪氨酸活化基序(ITAM)。
在一个优选的实施方式中,CAR的抗原特异性靶向结构域靶向CD44v6,CAR的跨膜结构域包括CD28的跨膜结构域,CAR的胞内信号转导结构域包括人CD3ζ链的胞内信号转导结构域和CAR的共刺激结构域包括CD28内共刺激结构域。
在本发明的另一个方面中,提供了一种多核苷酸,所述多核苷酸编码本发明的并且根据本申请所定义的CAR。
优选地,多核苷酸编码间隔区结构域,所述间隔区结构域包含SEQ ID NO:2、SEQID NO:4、SEQ ID NO:6或SEQ ID NO:8所示的序列或与其具有至少80、85、90、95、96、97、98或99%同一性的序列。
在一个实施方式中,多核苷酸编码间隔区结构域,所述间隔区结构域由SEQ IDNO:2、SEQ ID NO:4、SEQ ID NO:6或SEQ ID NO:8所示的序列或与其具有至少80、85、90、95、96、97、98或99%同一性的序列组成。
在本发明的另一个方面中,提供了一种载体,所述载体包含本发明的多核苷酸。
在一个实施方式中,载体是病毒载体。
在本发明的另一个方面中,提供了一种细胞,所述细胞包含本发明的CAR、多核苷酸或载体。优选地,细胞是T细胞。
在本发明的另一个方面中,提供了一种药物组合物,所述药物组合物包含本发明的细胞。
在本发明的另一个方面中,提供了本发明的CAR、多核苷酸、载体或细胞在治疗(优选地,癌症治疗)中的用途。
在本发明的另一个方面中,提供了本发明的CAR在治疗表达CD44的肿瘤中的用途,其中抗原特异性靶向结构域靶向CD44v6。
在本发明的另一个方面中,提供了一种治疗方法,所述方法包括向需要其的对象施用本发明的CAR、多核苷酸、载体或细胞。
示例性的CAR如图10至17所示。
附图说明
图1:产生不同的LNGFR-间隔CD44v6-CAR.28z构建体的原理。A.解释携带IgG1CH2CH3间隔区的CAR T细胞的局限性的示意图。B.低亲和力神经生长因子受体(LNGFR)和已产生的四个新的CAR构建体的胞外部分的结构。还包括了携带野生型或突变的IgG1 CH2CH3(mCH2CH3)间隔区的CD44v6-CAR.28z。CHW:携带野生型CH2CH3间隔区的CD44v6-CAR.28z。CHM:携带突变的CH2CH3间隔区的CD44v6-CAR.28z。NWL:携带LNGFR野生型长间隔区(包括4个TNFR-Cys结构域和茎)的CD44v6-CAR.28z。NWS:携带LNGFR野生型短间隔区(仅包括4个TNFR-Cys结构域)的CD44v6-CAR.28z。NML:携带LNGFR突变的长间隔区(包括在第四个结构域和茎中具有缺失的4个TNFR-Cys结构域)的CD44v6-CAR.28z。NMS:携带LNGFR突变的短间隔区(包括在第四个结构域和茎中具有缺失的4个TNFR-Cys结构域)的CD44v6-CAR.28z。大括号表示以氨基酸表示的间隔区长度。白色:共刺激结构域CD28;黑色:CD3。
图2:LNGFR-间隔CD44v6-CAR.28z T细胞能够使用抗-LNGFR mAb分选,有效地在体外扩增并保持早期分化表型。使用CD3/CD28小珠活化T细胞,使用编码不同LNGFR-间隔CD44v6.CAR28z的逆转录病毒载体(RV)对其进行转导并使用IL-7/IL-15培养。A.使用LNGFR-特异性mAb C40-1457鉴定T-细胞表面上的CAR(上图)。使用LNGFR-特异性mAbME20.4鉴定T-细胞表面上的CAR(下图)。B.左图:使用C40-1457mAb和抗-PE小珠分选后的表达不同LNGFR-间隔CD44v6-CAR.28z的T细胞。右图:分选的CH2CH3-间隔和LNGFR-间隔CD44v6-CAR.28z T细胞的扩增动力学显示出成倍增加。C.活化后15天不同LNGFR-间隔CD44v6-CAR.28z的功能分化表型。CD45RA+/CD62L+记忆干T细胞、CD45RA-/CD62L+中央记忆T细胞、CD45RA-/CD62L-效应物记忆T细胞、CD45RA+/CD62L-效应物记忆T细胞。曲线和图是n=4次独立实验的典型结果。
图3:LNGFR-间隔CD44v6-CAR.28z T细胞在体外特异性识别CD44v6+ve肿瘤细胞。A.分选后,以不同的E:T比使用CD44v6+ve MM1.S骨髓瘤细胞、CD44v6+ve THP-1白血病细胞或CD44v6-ve BV-173淋巴母细胞培养不同的LNGFR-间隔CD44v6-CAR.28z T细胞(NWL、NWS、NML、NMS)、CH2CH3-间隔CD44v6-CAR T细胞(CHW、CHM)和携带无关CAR的T细胞。4天后,计数残留的肿瘤细胞并使用FACS分析。显示了在不同的E:T比下CD44v6-CAR.28z T细胞的消除指数(见实施例的方法)。B.使用CFSE染料将CD44v6-CAR.28z T细胞染色并以E:T比1:5使用经照射的肿瘤细胞系对其进行刺激。6天后,利用FACS对T细胞的增殖进行分析,将其表示为CFSE稀释细胞。图和曲线是n=4次独立实验的典型结果。
图4:LNGFR-间隔CD44v6-CAR.28z T细胞缺乏FcRg-介导的识别。A.分选后,以不同的E:T比使用CD44v6+ve/FcRg+ve THP-1白血病细胞或CD44v6-ve/FcRg+ve HL-60白血病细胞培养不同的LNGFR-间隔CD44v6-CAR.28z T细胞(NWL、NWS、NML、NMS)、CH2CH3-间隔CD44v6-CAR T细胞(CHW、CHM)和来自n=4名健康供体的携带无关CAR的T细胞。4天后,计数残留的肿瘤细胞并使用FACS分析。显示了在不同的E:T比下CD44v6-CAR.28z T细胞的消除指数(见实施例的方法)。B.使用CFSE染料将CD44v6-CAR.28z T细胞染色并使用经照射的THP1、HL60或CD44v6-ve/FcRg-ve BV-173淋巴母细胞对其进行刺激。6天后,利用FACS对T细胞的增殖进行分析,将其表示为CFSE稀释细胞。图和曲线是n=4次独立实验的典型结果。
图5:LNGFR-间隔CD44v6-CAR.28z未被可溶性NGF刺激。A.暴露于不同浓度的人重组NGF 24hrs后,利用光学显微镜分析LNGFR+ve PC-12神经细胞的树突形成情况。B.分选后,使用CFSE染料对不同的LNGFR-间隔CD44v6-CAR.28z T细胞(NWL、NWS、NML、NMS)和CH2CH3-间隔CD44v6-CAR.28z T细胞(CHW、CHM)染色并将其暴露于不同浓度的NGF。4天后,利用FACS对T细胞的增殖进行分析,将其表示为CFSE稀释细胞。显示了与CD44v6+ve MM1.S骨髓瘤细胞或CD44v6-ve BV-173淋巴母细胞共培养后的CFSE稀释用于比较。图片和曲线是n=2次独立实验的典型结果。图表示两次实验的平均值±SD。
图6:在微小残留疾病模型中LNGFR-间隔CD44v6-CAR.28z T细胞很好的扩增、持续并介导优越的抗白血病作用。使用CD44v6+ve THP-1白血病细胞输注NSG小鼠,3天后,使用不同的LNGFR-间隔CD44v6-CAR.28z T细胞(NWL、NWS、NML、NMS)、CH2CH3-间隔CD44v6-CAR T细胞(CHW)或表达无关CAR的T细胞(CTR)对其进行治疗,所有细胞经分选为纯度>95%。A.典型的曲线(左图)和全包括图(右图)显示了输注后3天各只小鼠的循环CD44v6-CAR.28z T细胞。在使用抗-IgG多克隆抗体(CTR和CHW)或LNGFR-特异性mAb(C40-1457mAb)染色后,利用FACS追踪不同的间隔CD44v6-CAR.28z。B.CD44v6-CAR28z T-细胞扩增和持续的动力学随时间的变化情况。C.在处死时(7周)经治疗小鼠的THP1-浸润肝脏重量。虚线区表示年龄/性别匹配的正常NSG小鼠的正常肝脏重量范围。当具有统计学意义时显示单因素ANOVA检验的结果(*P<0.05,**P<0.01,***P<0.001)。
图7:在成熟的疾病模型中LNGFR-间隔CD44v6-CAR.28z T细胞很好的扩增、持续并介导优越的抗骨髓瘤作用。使用CD44v6+ve MM1.S细胞输注NSG小鼠,5周后,使用不同的LNGFR-间隔CD44v6-CAR.28z T细胞(NWL、NWS、NMS)、CH2CH3-间隔CD44v6-CAR.28z T细胞(CHW)或表达无关CAR的T细胞(CTR)对其进行治疗,所有细胞经分选为纯度>95%。A.全包括图(右图)显示了输注后3天各只小鼠的循环CD44v6-CAR.28z T细胞。在使用抗-IgG多克隆抗体(CTR和CHW)或LNGFR-特异性mAb(C40-1457mAb)染色后,利用FACS追踪不同的间隔CD44v6-CAR.28z。B.经治疗小鼠的Kaplan-Meyer生存曲线。显示了对不同条件进行比较的对数-秩检验结果(ns:无显著性,*P<0.05,***P<0.001)。
图7BIS:在成熟的疾病模型中LNGFR-间隔CD44v6-CAR.28z T细胞介导优越的抗骨髓瘤作用。使用表达荧光素酶的CD44v6+MM1.S细胞输注NSG小鼠,26天后,使用LNGFR-间隔CD44v6-CAR.28z T细胞(NMS)、CH2CH3-间隔CD44v6-CAR.28z T细胞(CHW)或表达无关CAR的T细胞(CTR)对其进行治疗,所有细胞经分选为纯度>95%。A.以在所示时间点的相对光单位(RLU)评估循环肿瘤细胞的量。B.经治疗小鼠的Kaplan-Meyer生存曲线。显示了对不同条件进行比较的对数-秩检验结果(**P<0.01)。
图8:人LNGFR的序列。
图9:CD44v6CAR.28z的序列。显示了SCFV、CH2CH3、CD28和ζ链的序列。
图10:具有间隔区LNGFR野生型长(NWL)的CD44v6CAR.28z的示例性序列(SEQ IDNO:21)
图11:具有间隔区LNGFR野生型短(NWS)的CD44v6-CAR28z的示例性序列(SEQ IDNO:22)
图12:具有间隔区LNGFR突变的长(NML)的CD44v6-CAR28z的示例性序列(SEQ IDNO:23)
图13:具有间隔区LNGFR突变的短(NMS)的CD44v6-CAR28z的示例性序列(SEQ IDNO:24)
图14:具有间隔区LNGFR野生型长(NWL)的CD44v6CAR.28z的示例性序列(SEQ IDNO:25)
图15:具有间隔区LNGFR野生型短(NWS)的CD44v6-CAR28z的示例性序列(SEQ IDNO:26)
图16:具有间隔区LNGFR突变的长(NML)的CD44v6-CAR28z的示例性序列(SEQ IDNO:27)
图17:具有间隔区LNGFR突变的短(NMS)的CD44v6-CAR28z的示例性序列(SEQ IDNO:28)
图18:具有间隔区LNGFR野生型长(NWL)的CD44v6-4GS2-CAR28z的示例性序列(SEQID NO:32)
图19:具有间隔区LNGFR野生型短(NWS)的CD44v6-4GS2-CAR28z的示例性序列(SEQID NO:33)
图20:具有间隔区LNGFR突变的长(NML)的CD44v6-4GS2-CAR28z的示例性序列(SEQID NO:34)
图21:具有间隔区LNGFR突变的短(NMS)的CD44v6-4GS2-CAR28z的示例性序列(SEQID NO:35)
图22:不同LNGFR-间隔CAR的产生。低亲和力神经生长因子受体(LNGFR)和已产生的靶向CD19和CEA的不同CAR构建体胞外部分的结构。还包括了携带野生型IgG1 CH2CH3间隔区(CH2CH3)的CD19/CEA-CAR.28z。NWL:携带LNGFR野生型长间隔区(包括4个TNFR-Cys结构域和茎)的CD19/CEA-CAR.28z。NMS:携带LNGFR突变的短间隔区(包括具有在第四个结构域中的缺失的4个TNFR-Cys结构域)的CD19/CEA-CAR.28z。大括号表示以氨基酸表示的间隔区长度。灰色:scFv。
图23.LNGFR-间隔CD19/CEA-CAR.28z T细胞能够被抗-LNGFR mAb染色。使用CD3/CD28小珠活化T细胞,使用编码不同的LNGFR-间隔CD19/CEA.CAR28z的逆转录病毒载体(RV)对其进行转导,使用IL-7/IL-15培养并使用C40-1457 mAb和抗-PE小珠进行选择。使用相同条件生产CD44v6-4GS2.CAR28zT细胞作为阳性对照。显示了使用LNGFR-特异性mAb C40-1457对T细胞表面上的CAR进行鉴定。
图24:LNGFR-间隔CD19/CEA-CAR.28z T细胞在体外特异性识别表达抗原的肿瘤细胞。A.分选后,以1:10的E:T比,使用ALL-CM和HL60白血病细胞、BV-173淋巴母细胞和BXPC3癌细胞培养不同的LNGFR-间隔CD19/CEA/CD44v6-4GS2-CAR.28z T细胞(NWL、NMS)和CH2CH3-间隔CD19/CEA-CAR T细胞(CHW)。4天后,计数残留的肿瘤细胞并使用FACS分析。显示了不同CAR.28z T细胞的消除指数(见实施例的方法)。B.24小时后收集A中所述共培养物的上清液并使用CBA测定(Biolegend)对细胞因子的产生情况进行分析。显示了识别靶细胞后IFNγ、IL-2和TNFα的释放情况。
图25:LNGFR-间隔CD19-CAR.28z T细胞介导的抗白血病作用。使用CD19+ALL-CM白血病细胞输注NSG小鼠,3天后,使用不同的LNGFR-间隔CD19-CAR.28z T细胞(19NWL和19NMS)对其进行治疗。输注表达无关CD44v6-4GS2-CAR.28z的T细胞(v6NWL和v6NMS)作为对照。输注前,所有CAR T细胞均分选至纯度>95%。曲线显示了在处死时各只小鼠骨髓(BM)中ALL-CM肿瘤细胞的存在情况。在使用抗-hCD45和抗-hCD19mAb染色后,利用FACS对肿瘤细胞进行追踪。当具有统计学显著性时,显示T检验的结果(*P<0.05,**P<0.01,***P<0.001)。
图26:具有间隔区LNGFR野生型长(NWL)的CD44v6-4GS2-CAR28z的多核苷酸序列(SEQ ID NO:37)
图27:具有间隔区LNGFR野生型短(NWS)的CD44v6-4GS2-CAR28z的多核苷酸序列(SEQ ID NO:38)
图28:具有间隔区LNGFR突变的长(NML)的CD44v6-4GS2-CAR28z的多核苷酸序列(SEQ ID NO:39)
图29:具有间隔区LNGFR突变的短(NMS)的CD44v6-4GS2-CAR28z的多核苷酸序列(SEQ ID NO:40)
具体实施方式
现在将通过非限制性实施例的方式描述本发明的各种优选特征和实施方式。
除非另有说明,否则本发明的实践将使用在本领域普通技术人员的能力范围内的化学、生物化学、分子生物学、微生物学和免疫学的常规技术。在文献中对此类技术进行了解释。参见例如,Sambrook,J.,Fritsch,E.F.和Maniatis,T.(1989)Molecular Cloning:ALaboratory Manual,第2版,Cold Spring Harbor Laboratory Press;Ausubel,F.M.等,(1995年和定期增刊)Current Protocols in Molecular Biology,第9、13和16章,JohnWiley&Sons;Roe,B.,Crabtree,J.和Kahn,A.(1996)DNA Isolation and Sequencing:Essential Techniques,John Wiley&Sons;Polak,J.M.和McGee,J.O’D.(1990)In SituHybridization:Principles and Practice,Oxford University Press;Gait,M.J.(1984)Oligonucleotide Synthesis:A Practical Approach,IRL Press;以及Lilley,D.M.和Dahlberg,J.E.(1992)Methods in Enzymology:DNA Structures Part A:Synthesis andPhysical Analysis of DNA,Academic Press。每部这些一般的教科书均通过引用并入本申请。
嵌合的抗原受体
如在本申请中所使用的“嵌合的抗原受体”或“CAR”指能够赋予细胞(例如T细胞,如幼稚T细胞、中央记忆T细胞、效应物记忆T细胞或其组合)抗原特异性的经工程改造的受体。CAR也称为人工T-细胞受体、嵌合的T细胞受体或嵌合的免疫受体。优选地,本发明的CAR包含抗原特异性靶向区、胞外域、跨膜结构域、任选地一个或多个共刺激结构域和胞内信号转导结构域。
抗原特异性靶向结构域
抗原特异性靶向结构域使CAR具有与目标靶抗原结合的能力。抗原特异性靶向结构域优选地靶向临床上关注的抗原,期望针对其引发导致肿瘤杀伤的效应物免疫应答。
抗原特异性靶向结构域可以是具有特异性识别和结合至生物分子(例如细胞表面受体或肿瘤蛋白,或其部分)能力的任意蛋白或肽。抗原特异性结构域包括任何天然存在的、合成的、半合成的或重组生产的针对目标生物分子的结合伴侣。
示例性的抗原特异性靶向结构域包括抗体或者抗体片段或衍生物、受体的胞外域、细胞表面分子/受体或其受体结合结构域的配体和肿瘤结合蛋白。
在一个优选的实施方式中,抗原特异性靶向结构域是或者来源于抗体。来源于抗体的靶向结构域可以是抗体的片段或抗体的一个或多个片段的基因工程改造产品,该片段参与与抗原的结合。实例包括可变区(Fv)、互补性决定区(CDR)、Fab、单链抗体(scFv)、重链可变区(VH)、轻链可变区(VL)和骆驼抗体(VHH)。
在一个优选的实施方式中,结合结构域是单链抗体(scFv)。scFv可以是鼠源的、人源的或人源化的scFv。
关于抗体或其抗原结合片段的“互补性决定区”或“CDR”指在抗体的重链或轻链可变区中的高变环。CDR能够与抗原构象相互作用并且很大程度上决定了与抗原的结合(尽管已知一些框架区参与结合)。重链可变区和轻链可变区均含有3个CDR。
“重链可变区”或“VH”指抗体重链的片段,其含有***称为框架区的翼侧延伸之间的3个CDR,其比CDR更加高度保守并且形成支持CDR的支架。
“轻链可变区”或“VL”指抗体的轻链片段,其含有***框架区之间的3个CDR。
“Fv”指携带完整抗原结合位点的最小抗体片段。Fv片段由与单一重链的可变区结合的单一轻链的可变区组成。
“单链Fv抗体”或“scFv”指由彼此之间直接连接或通过肽接头序列连接的轻链可变区和重链可变区组成的经工程改造的抗体。
可以使用本领域熟知的方法制备与肿瘤细胞表面分子特异性结合的抗体。此类方法包括噬菌体展示、产生人源或人源化抗体的方法或者使用转基因动物或经工程改造的植物生产人源抗体的方法。部分或完全合成抗体的噬菌体展示文库是可获得的并且能够筛选能够与靶分子结合的抗体或其片段。人源抗体的噬菌体展示文库也是可获得的。一旦被鉴定,则能够分离和/或确定编码抗体的氨基酸序列或多核苷酸序列。
可以由本发明的CAR靶向的抗原的实例包括但不限于在癌细胞上表达的抗原和在与多种血液疾病、自身免疫性疾病、炎性疾病和感染性疾病相关的细胞上表达的抗原。
对于靶向癌症抗原的靶向结构域而言,靶向结构域的选择取决于所治疗的癌症类型,并且可以靶向肿瘤抗原。可以将来自对象的肿瘤样品表征为存在某些生物标记物或细胞表面标记物。例如,来自对象的乳腺癌细胞可能对于Her2Neu、***受体和/或孕酮受体中的每一个是阳性或阴性的。选择在各对象的肿瘤细胞上发现的肿瘤抗原或细胞表面分子。优选地,抗原特异性靶向结构域靶向在肿瘤细胞上发现的并且在正常组织上基本上不存在的或其表达限制于无生命的正常组织中的细胞表面分子。
可以由本发明的CAR靶向的特异性针对癌症的其他抗原包括但不限于下述中的任意一个或多个:癌胚抗原(CEA)、***特异性抗原、PSMA、Her2/neu、***受体、孕酮受体、ephrinB2、ROR1、间皮素、c-Met、GD-2和MAGE A3 TCR、4-1BB、5T4、腺癌抗原、α-甲胎蛋白、BAFF、B-淋巴瘤细胞、C242抗原、CA-125、碳酸酐酶9(CA-IX)、CCR4、CD152、CD200、CD22、CD19、CD22、CD123、CD221、CD23(IgE受体)、CD28、CD30(TNFRSF8)、CD33、CD4、CD40、CD44、CD44v6、CD51、CD52、CD56、CD74、CD80、CS-1、CEA、CNT0888、CTLA-4、DR5、EGFR、EpCAM、CD3、FAP、纤连蛋白额外结构域-B、叶酸受体1、GD2,GD3神经节苷脂、糖蛋白75、GPNMB、HGF、人分散因子受体激酶、IGF-1受体、IGF-I、IgGl、L1-CAM、IL-13、IL-6、***I受体、整合素α5β1、整合素αvβ3、MORAb-009、MS4A1、MUC1、粘蛋白CanAg、N-羟乙酰神经氨酸、NPC-1C、PDGF-Rα、PDL192、磷脂酰丝氨酸、***癌细胞、RANKL、RON、SCH900105、SDC1、SLAMF7、TAG-72、腱生蛋白C、TGFβ2、TGF-β、TRAIL-R1、TRAIL-R2、肿瘤抗原CTAA16.88、VEGF-A、VEGFR-1、VEGFR2或波形蛋白。
可以由本发明的CAR靶向的特异性针对炎性疾病的抗原包括但不限于下述中的任意一个或多个:AOC3(VAP-1)、CAM-3001、CCL11(eotaxin-1)、CD125、CD147(basigin)、CD154(CD40L)、CD2、CD20、CD23(IgE受体)、CD25(IL-2受体的一条链)、CD3、CD4、CD5、IFN-α、IFN-γ、IgE、IgE Fc区、IL-1、IL-12、IL-23、IL-13、IL-17、IL-17A、IL-22、IL-4、IL-5、IL-5、IL-6、IL-6受体、整合素α4、整合素α4β7、美洲驼、LFA-1(CD11a)、MEDI-528、肌肉抑制素、OX-40、rhuMAbβ7、scleroscin、SOST、TGFβ1、TNF-a或VEGF-A。
可以由本发明的CAR靶向的特异性针对神经元疾病的抗原包括但不限于下述中的任意一个或多个:β淀粉样蛋白或MABT5102A。
可以由本发明的CAR靶向的特异性针对糖尿病的抗原包括但不限于下述中的任意一个或多个:L-1β或CD3。特异性针对糖尿病或其他代谢疾病的其他抗原对本领域技术人员而言将是显而易见的。
可以由本发明的CAR靶向的特异性针对心血管疾病的抗原包括但不限于下述中的任意一个或多个:C5、心肌肌球蛋白、CD41(整合素α-Iib)、纤维蛋白II、β链、ITGB2(CD18)和1-磷酸鞘氨醇。
优选地,抗原特异性结合结构域与肿瘤抗原特异性结合。在一个特定的实施方式中,多核苷酸编码与CD44v6特异性结合的单链Fv。
一个示例性的抗原特异性靶向结构域是CD44v6-特异性单链片段(scFv),如在Casucci M等,Blood,2013,Nov 14;122(20):3461-72中描述的。这样的序列如下所示:
CD44v6-特异性单链片段(scFv)
MEAPAQLLFLLLLWLPDTTGEIVLTQSPATLSLSPGERATLSCSASSSINYIYWLQQKPGQAPRILIYLTSNLASGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCLQWSSNPLTFGGGTKVEIKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISSGGSYTYYLDSIKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQGLDYWGRGTLVTVSS(SEQ ID NO:17)
在一个实施方式中,CD44v6-特异性单链片段包含与SEQ ID NO:17具有至少85、90、95、97、98或99%同一性的序列。
在一个更优选的实施方式中,CD44v6-特异性单链片段的轻链可变区和重链可变区彼此之间通过具有下述序列GGGGSGGGGS(4GS2)的肽接头连接。此类CD44v6-特异性单链片段(CD44v6-4GS2)具有下述序列:
MEAPAQLLFLLLLWLPDTTGEIVLTQSPATLSLSPGERATLSCSASSSINYIYWLQQKPGQAPRILIYLTSNLASGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCLQWSSNPLTFGGGTKVEIKRGGGGSGGGGSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISSGGSYTYYLDSIKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQGLDYWGRGTLVTVSS(SEQ ID NO:31)
共刺激结构域
本发明的CAR还可以包含一个或多个共刺激结构域。这种结构域可以增强细胞增殖、细胞存活和记忆细胞的发育。
每个共刺激结构域包含任意一个或多个下述共刺激结构域:例如TNFR超家族成员、CD28、CD137(4-1BB)、CD134(OX40)、DaplO、CD27、CD2、CD5、ICAM-1、LFA-1、Lck、TNFR-1、TNFR-II、Fas、CD30、CD40或其组合。还可以将来自其他蛋白的共刺激结构域与本发明的CAR一起使用。其他共刺激结构域对本领域技术人员而言将是显而易见的。
在一个实施方式中,跨膜和共刺激结构域均来自CD28。在一个实施方式中,跨膜和胞内共刺激结构域包含下述序列:
人CD28的跨膜和胞内部分(UNIPROT:P10747,CD28_人,位置153-220)
FWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:18)
在一个实施方式中,跨膜和胞内信号结构域包含与SEQ ID NO:18具有至少85、90、95、97、98或99%同一性的序列。
在一个实施方式中,CD28的跨膜结构域包含序列
FWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO:29)。
在一个实施方式中,CD28的胞内共刺激结构域包含序列
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:30)。
胞内信号转导结构域
本发明的CAR还可以包含胞内信号转导结构域。这种结构域可以是细胞质并且可以转导效应物功能信号和引导细胞发挥其特定功能。胞内信号转导结构域的实例包括但不限于T细胞受体的ζ链或其任意同源物(例如η链、FcεR1γ和β链、MB1(Igα)链、B29(Igβ)链等)、CD3多肽(Δ、δ和ε)、syk家族酪氨酸激酶(Syk、ZAP 70等)、src家族酪氨酸激酶(Lck、Fyn、Lyn等)以及参与T细胞转导的其他分子,如CD2、CD5和CD28。胞内信号转导结构域可以是人CD3ζ链、FcyRIII、FcsRI、Fc受体的胞质尾、携带胞质受体的免疫受体酪氨酸活化基序(ITAM)及其组合。
优选地,胞内信号转导结构域包括人CD3ζ链的胞内信号转导结构域。
在一个实施方式中,人CD3ζ链的胞内信号转导结构域包含下述序列:
UNIPROT:P20963,CD3ζ_人,位置31-143
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:20)
在一个实施方式中,胞内信号转导结构域包含与SEQ ID NO:20具有至少85、90、95、97、98或99%同一性的序列。
其他胞内信号转导结构域对本领域技术人员而言将是显而易见的并且可以结合本发明的替代实施方式使用。
跨膜结构域
本发明的CAR还可以包含跨膜结构域。跨膜结构域可以包含来自具有跨膜结构域的任意蛋白的跨膜序列,包括任意的I型、II型或III型跨膜蛋白。本发明CAR的跨膜结构域还可以包含人工疏水序列。可以对本发明CAR的跨膜结构域进行选择以使得其不发生二聚化。其他跨膜结构域对本领域技术人员而言将是显而易见的。在CAR构建体中使用的跨膜(TM)区的实例为:1)CD28TM区(Pule等,Mol Ther,2005,Nov;12(5):933-41;Brentjens等,CCR,2007,Sep 15;13(18Pt 1):5426-35;Casucci等,Blood,2013,Nov 14;122(20):3461-72.);2)OX40TM区(Pule等,Mol Ther,2005,Nov;12(5):933-41);3)41BB TM区(Brentjens等,CCR,2007,Sep 15;13(18Pt1):5426-35);4)CD3ζTM区(Pule等,Mol Ther,2005,Nov;12(5):933-41;Savoldo B,Blood,2009,Jun 18;113(25):6392-402.);5)CD8a TM区(Maher等,Nat Biotechnol,2002,Jan;20(1):70-5.;Imai C,Leukemia,2004,Apr;18(4):676-84;Brentjens等,CCR,2007,Sep 15;13(18Pt 1):5426-35;Milone等,Mol Ther,2009,Aug;17(8):1453-64.)。
在一个实施方式中,跨膜和胞内信号转导结构域均来自CD28。在一个实施方式中,跨膜和胞内信号转导结构域包含下述序列:
人CD28的跨膜和胞内部分(UNIPROT:P10747,CD28_人,位置153-220)
FWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:18)
在一个实施方式中,跨膜和胞内信号转导结构域包含与SEQ ID NO:18具有至少85、90、95、97、98或99%同一性的序列。
间隔区结构域-低亲和力神经生长因子(LNGFR)
本发明的CAR包含胞外间隔区结构域。胞外间隔区结构域与抗原特异性靶向区和跨膜结构域连接。
本发明的CAR包含含有人低亲和力神经生长因子(LNGFR)或其衍生物胞外域的至少一部分的胞外间隔区。
在大多数人造血细胞上不表达LNGFR,因此能够使用具有单细胞分辨率的免疫荧光对转导基因表达情况进行定量分析。因而,可以在转导细胞中进行LNGFR表达的荧光活化细胞分选分析以研究基因表达情况。关于使用LNGFR分析的进一步的细节可以参见Mavilio1994,Blood 83,1988-1997。
人LNGFR的序列如图8中所示(SEQ ID NO:14)。
在一个实施方式中,本发明使用了截短的LNGFR(也称为ΔLNGFR)。优选地,本发明中使用的LNGFR是在其胞质内结构域中截短的。在Mavilio1994中描述了此类截短。
因此,优选地,本发明的LNGFR间隔区包含LNGFR胞外域或其衍生物的至少一部分,但是缺乏其胞内域。胞外域可以包含LNGFR的氨基酸29-250或其衍生物。
人LNGFR的胞外域(UNIPROT#P08138,TNR16_人,位置29-250)
KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDN(SEQ IDNO:19)
优选地,LNGFR缺乏信号肽。
在一个实施方式中,间隔区包含与LNGFR的胞外域(例如SEQ ID NO:19)具有至少85、90、95、96、97、98或99%同一性的蛋白的至少一部分。在一个实施方式中,间隔区包含与LNGFR蛋白的氨基酸29-250具有至少85、90、95、96、97、98或99%同一性的蛋白的至少一部分。
LNGFR包含4个TNFR-Cys结构域(TNFR-Cys 1、TNFR-Cys 2、TNFR-Cys 3和TNFR-Cys4)。以下列举了这些结构域的序列:
TNFR-Cys 1,SEQ ID NO:9
ACPTGLYTHSGECCKACNLGEGVAQPCGANQTVC
TNFR-Cys 2,SEQ ID NO:10
PCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVC
TNFR-Cys 3,SEQ ID NO:11
RCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVC
TNFR-Cys 4,SEQ ID NO:12
ECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAEC
在一个实施方式中,间隔区包含TNFR-Cys 1、2和3结构域或者其片段或衍生物。在另一个实施方式中,间隔区包含TNFR-Cys 1、2、3和4结构域或者其片段或衍生物。
在一个实施方式中,间隔区包含与TNFR-Cys 1(SEQ ID NO:9)具有至少80、85、90、95、96、97、98、99%同一性或100%同一性的序列,与TNFR-Cys 2(SEQ ID NO:10)具有至少80、85、90、95、96、97、98、99%同一性或100%同一性的序列或与TNFR-Cys 3(SEQ ID NO:11)具有至少80、85、90、95、96、97、98、99%同一性或100%同一性的序列。间隔区还可以包含与TNFR-Cys 4(SEQ ID NO:12)具有至少80、85、90、95、96、97、98、99%同一性或100%同一性的序列。
除了包含全长TNFR-Cys 4结构域以外,间隔区可以包含从所述结构域中缺失下述氨基酸的TNFR-Cys 4结构域:
NHVDPCLPCTVCEDTERQLRECTRW。在一个实施方式中,
NHVDPCLPCTVCEDTERQLRECTRW氨基酸被下述氨基酸ARA替代。
在一个实施方式中,间隔区缺乏LNGFR富含丝氨酸/苏氨酸的茎。在另一个实施方式中,间隔区包含LNGFR富含丝氨酸/苏氨酸的茎。
间隔区可以包含或由SEQ ID NO:1所示序列或与SEQ ID NO:1具有至少85%、90%、95%、96%、97%、98%或99%同一性的序列组成。
间隔区可以包含或由SEQ ID NO:3所示序列或与SEQ ID NO:3具有至少85%、90%、95%、96%、97%、98%或99%同一性的序列组成。
间隔区可以包含或由SEQ ID NO:5所示序列或与SEQ ID NO:5具有至少85%、90%、95%、96%、97%、98%或99%同一性的序列组成。
间隔区可以包含或由SEQ ID NO:7所示序列或与SEQ ID NO:7具有至少85%、90%、95%、96%、97%、98%或99%同一性的序列组成。
间隔区可以具有CAR的性质,以使得其能够对细胞(优选地表达所述CAR的T细胞)进行免疫选择。
本发明的CAR(包含本申请所述的间隔区)优选地能够使表达CAR的T-细胞在存在表达抗原的细胞的条件下增殖,CAR是针对抗原进行设计的。
本发明的CAR(包含本申请所述的间隔区)优选地能够使表达CAR的T-细胞介导针对癌症的显著的治疗性抗癌作用,设计CAR以便对癌症进行靶向。
本发明的CAR(包含本申请所述的间隔区)优选适于促进使用所述CAR转导细胞的免疫选择。
本发明的CAR包含基于LNGFR的间隔区以避免活化不需要的和具有潜在毒性的脱靶免疫应答并且使得表达CAR的T细胞在体内持续存在,而不会被宿主的免疫***过早清除。
如下文所述,本发明还包括本申请所述的间隔区元件的变体、衍生物、同源物和片段的用途。
衍生物和片段
除了本申请所述的特定蛋白、肽和核苷酸以外,本发明还包括其衍生物和片段的用途。
如在本申请中所使用的,术语“衍生物”指本发明的蛋白或多肽,包括将一个(或多个)氨基酸残基从序列中取代、改变、修饰、替代、缺失和/或添加,条件是所得到的蛋白或多肽保留所需的功能。
通常地,可以进行氨基酸取代,例如1、2或3个至10或20个取代,条件是经修饰的序列保留所需的活性或能力。氨基酸取代可以包括使用非天然存在的类似物。
在本发明中使用的蛋白或肽还可以具有氨基酸残基的缺失、***或取代,其产生沉默改变并获得功能性等效的蛋白。可以根据残基的极性、电荷、溶解度、疏水性、亲水性和/或两亲性性质的相似性进行有意的氨基酸取代,只要保留内源性功能即可。例如,带负电荷的氨基酸包括天冬氨酸和谷氨酸;带正电的氨基酸包括赖氨酸和精氨酸;以及具有相似亲水性值的不带电极性头基的氨基酸包括天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸和酪氨酸。
例如可以根据下表进行保守性取代。第二列同一区中的氨基酸和优选地第三列同一行中的氨基酸可以互相替代:
衍生物可以是同源物。如在本申请中所使用的术语“同源物”指与野生型氨基酸序列和野生型核苷酸序列具有一定同源性的实体。术语“同源性”可以等同于“同一性”。
同源序列可以包括可能与主题序列具有至少50%、55%、65%、75%、85%或90%同一性(优选地至少95%或97%或99%同一性)的氨基酸序列。通常地,同源物与主题氨基酸序列将包括相同的活性位点等。尽管还可以将同源性认为是相似性(即具有相似的化学性质/功能的氨基酸残基),但是在本发明的背景下同源性优选表示序列的同一性。
同源序列可以包括可能与主题需要具有至少50%、55%、65%、75%、85%或90%同一性(优选地至少95%或97%或99%同一性)的核苷酸序列。尽管还可以将同源性认为是相似性,但是在本发明的背景下同源性优选表示序列的同一性。
可以通过目测或更通常地借助于容易获得的序列比较程序对同源性进行比较。这些市售的计算机程序能够计算两个或多个序列之间的同源性或同一性百分率。
可以在连续序列上计算同源性百分率,即将一个序列与另一个序列比对,并且将一个序列中的每个氨基酸与另一序列中的相应氨基酸直接比较,每次一个残基。将其称为“无缺口”比对。通常地,仅在相对较少数量的残基上进行此类无缺口比对。
尽管这是一个非常简单和一致的方法,但是其没有考虑到例如在另一个相同的序列对中,核苷酸序列中的一个***或缺失可能导致后面的密码子失配,因此可能导致当进行全局比对时同源性百分率大大降低。因此,大多数序列比对方法被设计为产生考虑可能的***和缺失的最佳比对,其不会对总体同源性评分进行过度罚分。这是通过在序列比对中***“缺口”来实现的,以尝试使局部同源性最大化。
然而,这些更复杂的方法为比对中出现的每个缺口分配“缺口罚分”,以使得对于相同数量的相同氨基酸而言,具有反应两个比较序列之间具有更高相关性的尽可能少缺口的序列比对与具有很多缺口的序列比对相比将获得更高评分。通常使用的“仿射缺口成本”针对存在一个缺口产生相对较高的成本并且对于缺口中的每个随后的残基给予较小的罚分。这是最常用的缺口评分***。较高缺口罚分当然将会产生具有较小缺口的优化比对。大部分比对程序允许对缺口罚分进行修改。然而,当使用此类软件进行序列比较时优选使用默认值。例如,当使用GCG Wisconsin Bestfit软件包时,氨基酸序列的默认缺口罚分是-12和每个扩展是-4。
因此,计算同源性百分率的最大值首先需要产生考虑缺口罚分的最佳比对。进行此类比对的适宜计算机程序是GCG Wisconsin Bestfit软件包(University ofWisconsin,U.S.A.;Devereux等,(1984)Nucleic Acids Res.12:387)。能够进行序列比较的其他软件的实例包括但不限于BLAST软件包(参见Ausubel等,(1999)ibid–Ch.18)、FASTA(Atschul等,(1990)J.Mol.Biol.403-410)和GENEWORKS比较工具套装。BLAST和FASTA均能够进行离线和在线检索(参见Ausubel等,(1999)ibid,第7-58至7-60页)。然而,对于一些应用而言,优选使用GCG Bestfit程序。还可以使用称为BLAST 2序列的另一种工具比较蛋白和核苷酸序列(参见FEMS Microbiol.Lett.(1999)174:247-50;FEMS Microbiol.Lett.(1999)177:187-8)。
尽管可以通过同一性衡量最终的同源性百分率,但是比对过程本身通常不是基于全或无的配对比较的。相反,通常使用成比例的相似性评分矩阵,其向基于化学相似性或进化距离的每个配对比较分配评分。常用的此类矩阵的实例是BLOSUM62矩阵–其是BLAST程序套装的默认矩阵。GCG Wisconsin程序通常使用公共默认值或自定义符号比较表(如有提供)(进一步的详情参见用户手册)。对于一些应用而言,优选使用GCG软件包的公共默认值,或者在其他软件的情况下,使用默认矩阵,如BLOSUM62。
一旦软件产生了最佳比对,就可以计算同源性百分率(优选地序列同一性百分率)。软件通常将其作为序列比较的一部分,并产生数值结果。
片段通常指具有目标功能的多肽或核苷酸的选定区域。因此“片段”指作为全长多肽一部分的氨基酸序列或作为全长核苷酸一部分的核酸序列。由于片段具有目标功能(例如保留所需功能),因而其将排除例如单个氨基酸或单个核酸。
可以使用标准DNA重组技术(如位点定向诱变)制备此类衍生物和片段。当进行***时,可以制备编码***物以及与***位点任意一侧天然存在的序列对应的5’和3’翼侧区的合成DNA。翼侧区将含有与天然存在序列中的位点对应的方便的限制性位点,以使得可以使用适宜的酶切割序列并将合成的DNA连接至切割物中。然后根据本发明对DNA进行表达以制备编码蛋白。这些方法仅是本领域用于操纵DNA序列的多种公知的标准技术中的示例性的并且还可以使用其他公知的技术。
多核苷酸
本发明的多核苷酸可以包括DNA或RNA。其可以是单链的或双链的。本领域技术人员将理解,由于遗传密码的简并性,很多不同的多核苷酸能够编码相同的多肽。此外,应当理解,技术人员可以使用常规技术进行不影响由本发明的多核苷酸编码的多肽序列的核苷酸替换,以反映将在其中表达本发明的多肽的任何特定宿主生物的密码子使用。
可以通过本领域可用的任何方法对多核苷酸进行修饰。可以进行此类修饰以增强本发明多核苷酸的体内活性或寿命。
可以通过重组、合成或通过本领域技术人员可用的任何方法生产多核苷酸(如DNA多核苷酸)。也可以通过标准技术对其进行克隆。
通常使用重组方法生产更长的多核苷酸,例如使用聚合酶链式反应(PCR)克隆技术。这将包括制备在所需克隆的靶序列翼侧的引物对(例如约15至30个核苷酸),将引物与从动物或人细胞获得的mRNA或cDNA接触,在使所需区域扩增的条件下进行聚合酶链式反应,分离扩增的片段(例如通过使用琼脂糖凝胶纯化反应混合物)以及回收扩增的DNA。可以将引物设计为含有适宜的限制性酶识别位点,以使得可以将扩增的DNA克隆进入适宜载体中。
密码子优化
在本发明中使用的多核苷酸可以是密码子优化的。此前已在WO 1999/41397和WO2001/79518中对密码子优化进行了描述。不同细胞在其对特定密码子的使用中是不同的。这种密码子偏好对应于在细胞类型中对特定tRNA相对丰度的偏好。通过改变序列中的密码子以使其适于与相应tRNA的相对丰度相匹配,可以增加表达。同样地,可以通过故意选择相应tRNA已知在特定细胞类型中的罕见密码子减少表达。因此,可以进行附加的翻译程度控制。
载体
载体是允许或促进将实体从一个环境转移至另一个环境的工具。根据本发明和举例而言,在重组核酸技术中使用的一些载体能够使实体(如核酸区段,例如异源DNA区段,如异源cDNA区段)转移进入靶细胞。载体可以是非病毒的或病毒的。在重组核酸技术中使用的载体的实例包括但不限于质粒、mRNA分子(例如体外转录的mRNA)、染色体、人工染色体和病毒。载体还可以是例如裸核酸(例如DNA)。在这种最简形式中,载体本身可以是目标核苷酸。
在本发明中使用的载体可以是例如质粒、mRNA或病毒载体并且可以包括用于表达核苷酸的启动子和任选地启动子的调节子。
可以使用本领域公知的多种技术将包含本发明多核苷酸的载体引入细胞中,如转化和转导。本领域公知的几种技术,例如使用重组病毒载体如逆转录病毒、慢病毒、腺病毒、腺相关病毒、杆状病毒和单纯疱疹病毒载体感染;直接注射核酸和基因枪转化。
非病毒递送***包括但不限于DNA转染方法。这里,转染包括使用非病毒载体向靶细胞递送基因的过程。
典型的转染方法包括电穿孔、DNA基因枪、脂质介导的转染、压缩DNA介导的转染、脂质体、免疫脂质体、脂质体(lipofectin)、阳离子剂介导的转染、阳离子面部两亲物(CFA)(Nat.Biotechnol.(1996)14:556)及其组合。
逆转录病毒载体
在一个实施方式中,本发明中使用的载体是基于已经过基因工程改造的逆转录病毒的载体,以使得一旦该病毒进入靶细胞后其不能复制并产生子代感染性病毒颗粒。有多种逆转录病毒被广泛用于在组织培养条件下和在活生物体内递送基因。实例包括且不限于鼠白血病病毒(MLV)、人免疫缺陷病毒(HIV-1)、马感染性贫血病毒(EIAV)、小鼠乳腺肿瘤病毒(MMTV)、劳斯肉瘤病毒(RSV)、藤浪氏肉瘤病毒(FuSV)、莫洛尼鼠白血病病毒(Mo-MLV)、FBR鼠骨肉瘤病毒(FBR MSV)、莫洛尼鼠肉瘤病毒(Mo-MSV)、艾贝尔森鼠白血病病毒(A-MLV),禽类骨髓细胞瘤病毒-29(MC29)和禽类成红细胞增生病毒(AEV)和所有其他包括慢病毒的逆转录病毒。逆转录病毒的详细列表可以参见Coffin等,1997,“retroviruses”,ColdSpring Harbour Laboratory Press Eds:JM Coffin,SM Hughes,HE Varmus pp 758-763。
逆转录病毒基因组的基本结构是5’LTR和3’LTR,在其间或之内具有使基因组能够包装的包装信号、引物结合位点、能够整合进入宿主细胞基因组的整合位点以及编码包装组件(这些多肽是病毒颗粒包装所需的)的gag、pol和env基因。更复杂的逆转录病毒具有其他特征,如在HIV中的rev和RRE序列,其能够将整合的原病毒的RNA转录物有效地从感染靶细胞的细胞核输出至细胞质。
在原病毒中,这些基因翼侧的两端是称为长末端重复(LTR)的区域。LTR负责原病毒的整合和转录。LTR还是增强子启动子序列并且能够控制病毒基因的表达。逆转录病毒RNA通过位于病毒基因组5’端的psi序列封闭。
LTR本身是能够分成三个元件的相同序列,其称为U3、R和U5。U3来源于RNA 3’末端所特有的序列。R来源于在RNA的两个末端重复的序列和U5来源于RNA 5’末端所特有的序列。三种元件的尺寸在不同逆转录病毒之间可能有很大差异。
在有缺陷的逆转录病毒载体基因组中,gag、pol和env可能不存在或无功能。在RNA两个末端的R区是重复序列。U5和U3分别代表RNA基因组5’和3’末端的特有序列。
更优选地,病毒载体是被靶向的载体,即其具有与天然病毒相比改变的组织嗜性,以使得载体被靶向至特定细胞。这可以通过修饰逆转录病毒的Env蛋白实现。优选地,包膜蛋白是无毒的包膜或在主要靶细胞中以无毒量产生的包膜,例如MMLV双嗜性包膜或经修饰的双嗜性包膜。
优选地,包膜允许人细胞转导的包膜。适宜env基因的实例包括但不限于VSV-G、MLV双嗜性env如4070A env、RD114猫白血病病毒env或来自流感病毒的血凝素(HA)。Env蛋白可以是能够结合至有限数量人细胞类型上的受体的并且可以是含有靶向部分的经工程改造的包膜。env和gag-pol编码序列从在所选择的包装细胞中具有活性的启动子和任选地增强子转录并且转录单位被多聚腺苷酸化信号终止。例如,如果包装细胞是人细胞,则可以使用的适宜的启动子-增强子组合是来自人巨细胞病毒主要立即早期(hCMV-MIE)基因的和多聚腺苷酸化信号是来自SV40病毒的。其他适宜的启动子和多聚腺苷酸化信号是本领域公知的。
MLV
优选地,在本发明中使用的逆转录病毒载体是鼠白血病病毒(MLV)载体。来自双嗜性莫洛尼鼠白血病病毒(MLV-A)的逆转录病毒是全世界的临床方案中通常使用的。这些病毒使用细胞表面磷酸转运体受体进入,然后永久整合进入增殖细胞染色体。然后在细胞的寿命中保持这些基因。基于MLV上基因活性的构建体易于控制并且可以长期有效。使用基于这些MLV的***进行的临床试验显示其具有良好的耐受性并且没有不利的副作用。
在本发明中使用的MLV载体的实例是来源于SFCMM-3的载体,其携带***基因HSV-tk和标记物基因ΔLNGFR(Verzeletti 98,Human Gene Therapy 9:2243)。在SFCMM-3的制备中使用的原始载体是LXSN(Miller等,Improved retroviral vectors for genetransfer and expression.BioTechniques 7:980-990,1989)(Genebank登记号#28248)。通过将HSV-tk基因***独特的Hpa I位点(“钝切”),通过使用Hind III和Nae I进行消化除去neo基因并在该位点***编码ΔLNGFR的cDNA对LXSN载体进行修饰。
慢病毒
在一个实施方式中,本发明的载体可以是慢病毒载体。慢病毒载体是更大的逆转录病毒载体组的一部分。慢病毒的详细列表可以参见Coffin等(“Retroviruses”1997ColdSpring Harbour Laboratory Press Eds:JM Coffin,SM Hughes,HE Varmus pp 758-763)。简言之,可以将慢病毒分成灵长类组和非灵长类组。灵长类慢病毒的实例包括但不限于:人免疫缺陷病毒(HIV)、人获得性免疫缺陷综合征(AIDS)的致病因子和猿猴免疫缺陷病毒(SIV)。非灵长类慢病毒组包括原型“慢病毒”visna/maedi病毒(VMV)以及相关的山羊关节炎脑炎病毒(CAEV)、马传染性贫血病毒(EIAV)以及最近描述的猫免疫缺陷病毒(FIV)和牛免疫缺陷病毒(BIV)。
慢病毒家族与其他类型逆转录病毒之间的差异在于慢病毒具有感染***细胞和非***细胞的能力。相比之下,其他逆转录病毒(如MLV)不能感染不***或缓慢***的细胞,如组成例如肌肉、脑、肺和肝组织的那些。由于慢病毒能够转导终末分化/原代细胞,因而使用慢病毒筛选策略能够在原代的不***或缓慢***的宿主靶细胞中进行文库选择。
腺病毒载体
在另一个实施方式中,本发明的载体可以是腺病毒载体。腺病毒是不经过RNA中间体的双链、线形DNA病毒。存在50种以上不同的人腺病毒血清型,根据遗传序列的同源性将其分成6个亚组。腺病毒的天然靶点是呼吸道和胃肠道上皮细胞,通常仅引起轻微的症状。血清型2和5(具有95%的序列同源性)是在腺病毒载体***中最常使用的并且通常与年轻人中的上呼吸道感染相关。
腺病毒是无包膜的规则十二面体。典型的腺病毒包含140nm被壳体包裹的DNA病毒。病毒的十二面体对称型由152个壳粒组成:240个六邻体和12个五邻体。颗粒的核心包含36kb线形双螺旋DNA,其在5’末端与末端蛋白(TP)共价结合,末端蛋白是DNA复制的引物。DNA具有反向末端重复序列(ITR)并且其长度随血清型而改变。
腺病毒是双链DNA无包膜病毒,其能够在体内和体外转导广泛的人源和肺人源细胞类型。这些细胞包括呼吸道上皮细胞、肝细胞、肌细胞、心肌细胞、滑膜细胞、原代乳腺上皮细胞和有丝***后终末分化的细胞如神经元。
腺病毒载体还能够转导非***细胞。这对于疾病如囊性纤维化是非常重要的,在该疾病中肺上皮内的受累细胞具有缓慢的周转速率。事实上,在正在进行中的几项试验中利用腺病毒介导的转移将囊性纤维化转运子(CFTR)导入受影响的成年囊性纤维化患者的肺中。
已将腺病毒作为基因治疗和表达异源基因的载体。其较大(36千碱基)的基因组能够容纳高达8kb的外源性***DNA并且其能够在补体细胞系中有效地复制以产生高达1012的极高滴度。因此,腺病毒是在原代非复制细胞中研究基因表达的最佳***之一。
从腺病毒基因组表达病毒或外源基因不需要复制细胞。腺病毒载体通过受体介导的内吞作用进入细胞。一旦进入细胞,腺病毒载体极少整合进入宿主染色体。而相反的是,其作为宿主细胞核中的线形基因组游离基因(独立于宿主基因组)发挥功能。因此,使用重组腺病毒减少了与随机整合至宿主基因组相关的问题。
痘病毒载体
根据本发明可以使用痘病毒载体,因为较大的DNA片段易于克隆进入其基因组中并且已描述了重组减毒疫苗变体(Meyer等,1991;Smith and Moss,1983)。
痘病毒载体的实例包括但不限于野兔痘病毒:Upton等,1986(兔纤维瘤病毒);山羊痘病毒:Gershon等,1989(肯尼亚绵羊-1);正痘病毒:Weir等,1983(牛痘);Esposito等,1984(猴痘和天花病毒);Hruby等,1983(牛痘);Kilpatrick等,1985(亚巴猴肿瘤病毒);禽痘病毒:Binns等,(1988)(鸡痘);Boyle等,1987(鸡痘);Schnitzlein等,1988(鸡痘,鹌鹑痘);昆虫痘(Lytvyn等,1992)。
痘病毒载体广泛用作真核细胞中目标基因的表达载体。其在多种宿主细胞中易于克隆和增殖,这导致痘病毒载体特别广泛地用于外源蛋白的表达和作为病毒抗原的递送载体。
牛痘病毒载体
本发明的载体可以是牛痘病毒载体如MVA或NYVAC。最优选的牛痘毒株是经修饰的病毒安卡拉(MVA)或由其衍生的毒株。牛痘病毒载体的替代方案包括禽痘病毒载体如鸡痘或称为ALVAC的金丝雀痘及其衍生毒株,其能够在人细胞中感染和表达重组蛋白但不能复制。
细胞
本发明还提供了经基因工程改造的细胞,所述细胞包含和稳定表达本发明的CAR。
抗原特异性靶向结构域可能能够以MHC非限制性的方式特异性结合抗原,T-细胞受体以该方式在正常情况下不与该抗原结合。在一个实施方式中,抗原特异性靶向区包含靶点特异性抗体或者其功能性等价物或片段或衍生物。抗原特异性抗体可以是抗体的Fab片段或抗体的单链可变片段(scFv)。
可以包含和表达本发明的CRA的经基因工程改造的细胞包括但不限于T细胞、幼稚T细胞、干细胞记忆T细胞、中央记忆T细胞、效应物记忆T细胞、自然杀伤细胞、造血干细胞和/或能够产生治疗相关子代的细胞。在一个实施方式中,经基因工程改造的细胞是自体细胞。举例说明,本发明的各T细胞可以是CD4+/CD8-、CD4-/CD8+、CD4-/CD8-或CD4+/CD8+。T细胞可以是CD4+/CD8-和CD4-/CD8+细胞的混合群或单一克隆群。
在通常情况下,基因修饰的细胞可以由具有编码本发明CAR的DNA的稳定转染的细胞生产。
可以采用多种方法生产表达本发明CAR的稳定转染子。在一个实施方式中,一种稳定转染和重新定向细胞的方法是使用裸DNA进行电穿孔。通过使用裸DNA,可以显著缩短生产重新定向细胞所需的时间。使用编码本发明CAR的裸DNA基因工程改造细胞的其他方法包括但不限于化学转化法(例如使用磷酸钙、树枝状大分子、脂质体和/或阳离子聚合物)、非化学转化法(例如电穿孔、光学转化、基因电转移和/或流体力学递送)和/或基于颗粒的方法(例如使用基因枪和/或电磁感应侵染)。转染细胞表明存在单一整合的未经重排载体并且可以离体扩增CAR的表达。在一个实施方式中,选择用于离体扩增的细胞是CD8+并且表明其能够特异性识别和裂解抗原特异性靶细胞。
病毒转导法还可以用于产生表达本发明CAR的重新定向细胞。
在适宜条件下使用抗原刺激T细胞导致细胞增殖(扩增)和/或产生IL-2。包含本发明CAR的细胞将响应于一个或多个抗原与CAR抗原特异性靶向区的结合在数量上扩增。本发明还提供了制备和扩增表达CAR的细胞的方法。该方法可以包括在使用下述物质刺激细胞后使用表达CAR的载体转染或转导细胞:1)多克隆刺激物如无细胞支架,优选地最佳尺寸的小珠,其含有至少一种活化的多肽优选地特异性针对CD3的抗体和活化的多肽优选地特异性针对CD28的抗体;2)表达靶抗原的肿瘤细胞;3)天然人工抗原提呈细胞,以及使用包括IL-2、IL-7、IL-15、IL-21的细胞因子单独或联合对其进行培养。
治疗方法和药物组合物
本申请中提供了在需要其的对象中治疗与由通过本发明的CAR靶向的抗原相关的疾病的方法。该方法包括施用有效量的CAR、编码CAR的多核苷酸或载体或者表达所述CAR的细胞,以便在对象中治疗与抗原相关的疾病。
还提供了包含本发明CAR的药物组合物。在组合物中的本发明CAR可以是编码CAR的多核苷酸、编码CAR的载体、包含CAR的蛋白或包含CAR的经基因工程修饰的细胞中的任意一种或多种。
药物组合物是包含或由治疗有效量的药物活性剂组成的组合物。其优选地包括药学上可接受的载体、稀释剂或赋形剂(包括其组合)。用于治疗用途的可接受的载体或稀释剂是药物领域中熟知的并且在例如Remington's Pharmaceutical Sciences,MackPublishing Co.(A.R.Gennaro edit.1985)中对其进行了描述。可以根据预期给药途径和标准药学实践对药物载体、赋形剂或稀释剂的选择进行选择。药物组合物可以包含或者除了载体、赋形剂或稀释剂还可以包含任意适宜的粘合剂、润滑剂、混悬剂、包衣剂或增溶剂。
药学上可接受的载体的实例包括例如水、盐溶液、醇、硅酮、蜡、凡士林、植物油、聚乙二醇、丙二醇、脂质体、糖、明胶、乳糖、直链淀粉、硬脂酸镁、滑石、表面活性剂、硅酸、粘性石蜡、芳香油、脂肪酸甘油单酯和甘油二酯、石油醚脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮等。
实施例
实施例1-方法
LNGFR-间隔CD44v6-CAR.28z构建体的产生
基于LNGFR的间隔区序列来源于低亲和力神经生长因子受体(LNGFR)的除去信号肽(P08138,TNR16_人)的胞外部分。野生型长(NWL)设计含有4个富含TNFR半胱氨酸的结构域和富含丝氨酸/苏氨酸的茎两者。野生型短(NWS)设计仅含有4个富含TNFR半胱氨酸的结构域。突变的长(NWL)设计含有4个富含TNFR半胱氨酸的结构域、富含丝氨酸/苏氨酸的茎并且在第四个结构域中包含特定的修饰以避免与NGF结合(Yan等,J Biol Chem,1991,Jun25;266(18):12099-104)。突变的短(NMS)设计仅含有4个富含TNFR半胱氨酸的结构域,在第四个结构域中包含特定的修饰。该间区由GENEART合成,其翼侧为特异性的限制性位点(BamH1和PflMI),以使得其能够克隆进入我们原始的CD44v6-特异性、第二代CAR构建体(图9;SEQ ID NO:15)IgG1 CH2CH3间隔区的位置。所有构建体已针对在人中的表达进行过密码子优化。所有构建体在SFG-RV骨架(常用的剪接的基于MoNLV的逆转录病毒构建体(Riviere等,PNAS,1995,Jul 18;92(15):6733-7))中表达。
间隔区LNGFR野生型长(NWL):
蛋白序列(SEQ ID NO:1):
核苷酸序列(SEQ ID NO:2):
间隔区LNGFR野生型短(NWS):
蛋白序列(SEQ ID NO:3):
核苷酸序列(SEQ ID NO:4):
间隔区LNGFR突变的长(NML):
蛋白序列(SEQ ID NO:5):
核苷酸序列(SEQ ID NO:6):
间隔区LNGFR突变的短(NMS):
蛋白序列(SEQ ID NO:7):
核苷酸序列(SEQ ID NO:8):
注释:
下划线:1号富含TNFR半胱氨酸的结构域。
粗体:2号富含TNFR半胱氨酸的结构域。
粗体和下划线:3号富含TNFR半胱氨酸的结构域。
斜体:4号富含TNFR半胱氨酸的结构域。
斜体和下划线:富含丝氨酸/苏氨酸的茎。
转导和培养条件:
使用细胞尺寸的CD3/CD28-小珠(ClinExVivo,Invitrogen)和IL-7/IL-15(5 ng/ml,Peprotech)活化T细胞并且在刺激后第2天和第3天通过两轮优化离心感染细胞法(spinoculation)进行RV转导。在第6天时,除去小珠并且在存在IL-7和IL-15的条件下在含10%FBS(BioWhittaker)的RPMI 1640(Gibco-Brl)中培养T细胞。使用特异性针对IgG1CH2CH3间隔区的mAb(Jackson Laboratories)检测CH2CH3-间隔、CD44v6-特异性CAR构建体(CHW和CHM)的表面表达,同时使用来自BD Bioscience(克隆:C40-14579)或来自Miltenyi(克隆:ME20.4)的LNGFR-特异性mAb分析LNGFR-间隔CD44v6-特异性CAR构建体(NWL、NWS、NML和NMS)的表面表达。在活化第9天至第15天之间,使用多克隆IgG1 CH2CH3-特异性mAbFACS-分选CH2CH3-间隔CD44v6-CAR.28z T细胞,同时使用PE-缀合的、LNGFR-特异性mAbC40-14579对LNGFR-间隔CD44v6-CAR.28z T细胞染色并利用使用抗-PE顺磁性小珠(Miltenyi)的柱子对其进行分选。以增加倍数表示分选后的T-细胞扩增情况:在第x天的T细胞数/分选后的T细胞数。
分析特异性识别的体外测定
在共培养测定中,以不同的E:T比使用靶细胞培养CAR分选的T细胞。4天后,计数存活的细胞并使用FACS分析。一直使用转导无关CAR(CD19)的T细胞作为对照。消除指数的计算方法如下:1-(在存在CD44v6.CAR28z+T细胞时的残留靶细胞数)/(在存在CTR.CAR28z+T细胞时的残留靶细胞数)。在CFSE-稀释测定中,使用CFSE对CAR分选的T细胞染色并使用经照射(10’000rad)的肿瘤细胞以E:S比1:5或具有生物活性浓度的NGF对其进行刺激。6天后,利用FACS检测T细胞的增殖情况,并分析具有被稀释的CFSE染料的细胞百分比。
评价抗肿瘤作用的移植瘤模型
实验方案经实验动物管理和使用委员会(IACUC)批准。对于微小残留疾病模型而言,输注i.v.给予NSG小鼠(Jackson)1,5x106个THP1白血病细胞/小鼠。3天后,i.v给予小鼠5x106个分选的LNGFR-间隔CD44v6-CAR.28z T细胞、CH2CH3-间隔CD44v6-CAR.28z T细胞或携带无关CAR(CD19)的T细胞对其进行治疗。每周一次通过取血和FACS分析监测T细胞移植情况。7周后,处死小鼠并对其肝脏进行组织病理学分析和利用FACS检测THP-1细胞的存在情况。对于成熟的疾病模型而言,输注i.v.给予NSG小鼠2x106个MM1.S骨髓瘤细胞/小鼠。5周后,i.v给予小鼠5x106个分选的LNGFR-间隔CD44v6-CAR.28z T细胞、CH2CH3-间隔CD44v6-CAR.28z T细胞或携带无关CAR(CD19)的T细胞对其进行治疗。每周一次通过取血和FACS分析监测T细胞移植和骨髓瘤进展情况(根据不同的人CD45/CD3表型对骨髓瘤细胞和T细胞进行鉴别)。当循环MM1.S细胞超过30个细胞/l和/或小鼠表现出明显的与肿瘤相关的痛苦体征(麻痹或体重减轻>10%)时,将小鼠安乐死。
流式细胞术
对于FACS分析而言,我们使用针对人CD44v6、CD4(e-Bioscience)、CD123、CD19、CD14、CD3、CD8、CD45RA、CD62L、CXCR4、CD127、CD33、CD38、CD45、LNGFR、小鼠CD45、7AAD(BDBiosciences)和IgG1CH2CH3(Jackson laboratories)的与FITC-、PE-、PerCP-、PE-Cy7-、APC-、APC-Cy7和太平洋蓝缀合的抗体。将细胞(2×105)与抗体在4℃下孵育15分钟并使用含1%FBS的PBS洗涤。在FACS Canto II流式细胞仪(BD Biosciences)上检测样品并使用Flow Jo软件(Tree star Inc)进行数据分析。相对荧光强度(RFI)的计算方法如下:样品的平均荧光强度/相应同种型对照的平均荧光强度。
实施例2-LNGFR-间隔CD44v6-CAR.28z构建体
我们最近基于CD3ζ链和CD28内共刺激结构域(Casucci等,Blood 2013,Nov 14;122(20):3461-72)构建了CD44v6-特异性CAR。在该CAR的胞外间隔区中,***IgG1 CH2CH3间隔区以更好地靶向CD44v6抗原并能够选择和在体内追踪转导的T细胞。然而,CH2CH3-间隔CAR的严重不足是其与Fcγ受体(FcγR)相互作用(Hombach等,Gene Ther 2000,Jun;7(12):1067-75),可能导致非特异性靶向表达这些受体的细胞(例如单核细胞/巨噬细胞)和/或转导T细胞的体内清除(图1A)。为了解决这个问题,我们使用来自低亲和力神经生长因子受体(LNGFR)的不同胞外域代替原始的CH2CH3间隔区。缺乏胞内信号部分的截短型LNGFR已在临床中用于T细胞的基因标记(Bonini等,Nat Med,2003,Apr;9(4):367-9;Ciceri等,Lancet Oncol,2009,May;10(5):489-500)。LNGFR的胞外部分由4个富含TNFR半胱氨酸的区域和富含丝氨酸/苏氨酸的茎组成(图1B)。首先,我们产生了两个CD44v6-CAR.28z构建体:一个使用LNGFR的整个胞外部分(LNGFR野生型长或NWL)间隔,另一个仅使用4个富含TNFR半胱氨酸的区域(LNGFR野生型短或NWS)间隔。为了排除通过天然配体NGF的LNGFR-间隔构建体的抗原依赖性活化的可能性,我们产生了携带第四个富含TNFR半胱氨酸结构域特异性缺失的两个附加的CD44v6-CAR.28z构建体,已知其消除NGF的信号转导(Yan等,J Biol Chem,1991,Jun 25;266(18):12099-104),分别形成了LNGFR-突变的长同种型或NML和LNGFR-突变的短同种型或NMS。作为对照,我们还产生了包含原始CH2CH3间隔区的突变型(CHM)的CD44v6-CAR.28z构建体,其不能识别FcγRI(Hombach等,Gene Ther 2000,Jun;7(12):1067-75)。值得注意的是,FcγRII和FcγRIII两者均能够使用这个共同集合以外的残基,表明这个突变不能完全消除结合(Shields等,J Biol Chem,2001,Mar 2;276(9):6591-604.;Armour等,Mol Immunol,2003,Dec;40(9):585-93)。
实施例3-LNGFR-间隔CD44v6-CAR.28z构建体能够用于选择和追踪转导的T细胞
将不同的LNGFR-间隔CD44v6-CAR.28z构建体克隆进入逆转录病毒载体(RV)用于转导原代T细胞。对于转导而言,根据更好地保留其具有功能的表型的方案(Kaneko等,Blood,2009,Jan 29;113(5):1006-15;Bondanza等,Blood 2011,Jun 16;117(24):6469-78;Cieri等,Blood,2013,Jan 24;121(4):573-84),使用CD3/CD28-小珠和IL-7/IL-15活化T细胞。转导后,能够使用抗-LNGFR mAb C40-1457在T细胞表面上鉴定得到所有构建体(图2A),表明其被正确地加工,安装在细胞膜上并且最重要的是被抗-NGFR mAb所识别。因此,能够使用免疫磁珠分选不同的LNGFR-间隔CD44v6-CAR.28z T细胞(图2B)。更加仔细观察时,我们发现仅NWL间隔同种型与另一种抗LNGFR mAb ME20.4结合,表明由不同长度LNGFR间隔区支配的构象改变可以控制ME20.4表位的可接近性。重要的是,不同LNGFR-间隔细胞的扩增动力学与CH2CH3-间隔CD44v6-CAR.28z T细胞类似(图2B),排除了由安装在CAR上的胞外LNGFR序列诱导的潜在增殖优势。在培养结束时,所得到的群富含早期分化T细胞(图2C),表明在存在IL-7/IL-15时对小珠活化T细胞的功能性分化路径没有干扰。
实施例4-LNGFR-间隔CD44v6-CAR.28z T细胞保留CD44v6-特异性识别,同时丧失由与FcγR的相互作用介导的非特异性识别
为了验证使用LNGFR间隔取代原始CH2CH3间隔后保留CD44v6-特异性识别,在与表达CD44v6的肿瘤细胞的共培养实验中,对LNGFR-间隔CD44v6-CAR.28z T细胞进行了测试。与CH2CH3间隔区类似,LNGFR-间隔CD44v6-CAR.28z T细胞有效消除CD44v6+ve(MM1S和THP-1细胞系)而非CD44v6-ve(BV173细胞系)肿瘤细胞(图3A)。而且,CD44v6-特异性识别与剧烈的T细胞扩增相关(图3B),表明其完全保留了LNGFR-间隔CD44v6-CAR.28z T细胞的治疗潜能。因此,本发明的LNGFR-间隔CAR针对表达其靶向的特异性抗原的肿瘤模型是有效的。
为了证明缺乏由FcRγ介导的非特异性识别,将LNGFR-间隔CD44v6-CAR.28z T细胞与CD44v6+ve/FcγRs+ve THP1白血病细胞或与CD44v6-ve/FcγRs+veHL-60白血病细胞共培养。在这个***中,CH2CH3-间隔CD44v6-CAR.28z T细胞同时消除CD44v6+ve THP1和CD44v6-ve HL-60细胞,而LNGFR-间隔CD44v6-CAR.28z CAR T细胞特异性消除CD44v6+veTHP-1而非CD44v6-ve HL-60细胞(图4A)。相应地,LNGFR-间隔CD44v6-CAR.28z CAR T细胞响应于CD44v6+ve THP-1而非CD44v6-ve HL-60细胞增殖(图4B)。在这两个***中,LNGFR-间隔细胞的行为与突变的CH2CH3-间隔CD44v6-CAR.28z CAR T细胞重叠,表明消除了FcγR-介导的作用。
因此,因为不存在恒定的免疫球蛋白IgG1铰链-CH2-CH3Fc结构域作为间隔区,所以根据本发明的含有来源于LNGFR间隔区的CAR不与IgG Fcγ受体结合,从而避免了不需要的活化和具有潜在毒性的脱靶免疫应答。因而,LNGFR-间隔CAR比含有IgG铰链-CH2-CH3的那些更加安全。
最后,为了排除通过可溶性NGF的抗原依赖性刺激,将LNGFR-间隔CD44v6-CAR28.zT细胞在体外与NGF共培养。即使在已知迫使表达LNGFR的神经元细胞系PC12分化(图5A)的超生理NGF浓度下,也未诱导LNGFR-间隔CD44v6-CAR.28z CAR T细胞增殖(图5B),表明缺乏通过可溶性NGF的信号转导。
实施例5-LNGFR-间隔CD44v6-CAR.28z T细胞在体内更好地持续并介导优越的抗肿瘤作用
在体外证明有效和特异性识别后,首先在微小残留疾病和随后在成熟疾病(WED)模型中,考察了LNGFR-间隔CD44v6-CAR.28z T细胞的体内抗肿瘤活性。在第一个模型中,输注给予NSG小鼠THP-1白血病细胞并且3天后使用CH2CH3-间隔或不同的LNGFR-间隔CD44v6-CAR.28z T细胞对其进行治疗。与CH2CH3-间隔CD44v6-CAR.28z T细胞相比,不同的LNGFR-间隔CD44v6-CAR.28z T细胞更好地扩增(图6A)和持续(图6B)。因此,LNGFR-间隔CD44v6-CAR.28zT细胞似乎介导了更好的抗肿瘤作用,其被与输注CH2CH3-间隔CD44v6-CAR.28z T细胞的小鼠相比其具有更正常的THP1浸润肝脏重量所证明(图6C)。在第二个成熟疾病模型中,使用表达CD44v6的MM1.S骨髓瘤细胞输注NSG小鼠,并且在5周后,当肿瘤已经在骨髓中定殖时,使用CH2CH3-间隔或不同的LNGFR-间隔CD44v6-CAR.28z T细胞对其进行治疗。未包括携带NML同种型的CD44v6-CAR.28z T细胞。在这个更加严重的模型中,CH2CH3-间隔CD44v6-CAR.28z T细胞几乎没有移植并且没有介导任何显著的抗肿瘤作用,而不同的LNGFR-间隔CD44v6-CAR.28z T细胞扩增(图7A)、持续并产生了显著的抗肿瘤活性(图7B)。
使用利用表达分泌的荧光素酶的CD44v6+MM1.S细胞的成熟的骨髓瘤模型进一步确证了LNGFR-间隔CD44v6-CAR.28z T细胞介导优越的抗肿瘤活性的能力。存在这种荧光素酶能够每天对使用CH2CH3-间隔(v6CHW)或使用NMS LNGFR-间隔(v6NMS)CD44v6-CAR.28z T细胞治疗小鼠的循环MM1.S肿瘤细胞的量进行监测。在这个具有挑战性的模型中,CH2CH3-间隔CD44v6-CAR.28z T细胞显示出与无关CAR T细胞(CTR)相同的抗肿瘤活性,而NMS-间隔CD44v6-CAR.28z T细胞能够保持对循环肿瘤细胞数量的控制达21天(图7BIS A)并且显著延长总生存期(图7BIS B)。
实施例6-方法
LNGFR-间隔CD19-CAR.28z和CEA-CAR.28z构建体的产生
使用与实施例1中所述的类似策略产生CD19-特异性和CEA-特异性CAR构建体(图22)。产生了下述构建体:
CD19-CAR.28z:携带CD19特异性靶向结构域、CD3ζ链与CD28内共刺激结构域的组合和野生型IgG1 CH2CH3间隔区(CH2CH3)
NWL:携带LNGFR野生型长间隔区(包含4个TNFR-Cys结构域和茎)的CD19-CAR.28z
NMS:携带LNGFR突变的短间隔区(包含第四个结构域缺失的4个TNFR-Cys结构域)的CD19-CAR.28z
CEA-CAR.28z:携带CEA特异性靶向结构域、CD3ζ链与CD28内共刺激结构域的组合和野生型IgG1 CH2CH3间隔区(CH2CH3)
NWL:携带LNGFR野生型长间隔区(包含4个TNFR-Cys结构域和茎)的CEA-CAR.28z
NMS:携带LNGFR突变的短间隔区(包含第四个结构域缺失的4个TNFR-Cys结构域)的CEA-CAR.28z
转导和培养条件
使用细胞尺寸的CD3/CD28-小珠(ClinExVivo,Invitrogen)和IL-7/IL-15(5ng/ml,Peprotech)活化T细胞并且在刺激后第2天和第3天通过两轮优化离心感染细胞法(spinoculation)进行RV转导。在第6天时,除去小珠并且在存在IL-7和IL-15的条件下在含10%FBS(BioWhittaker)的RPMI 1640(Gibco-Brl)中培养T细胞。使用特异性针对IgG1CH2CH3间隔区的mAb(Jackson Laboratories)检测CH2CH3-间隔、CD19和CEA特异性CAR构建体(CHW)的表面表达,同时使用来自BD Bioscience(克隆:C40-14579)的LNGFR-特异性mAb分析LNGFR-间隔CAR构建体(NWL和NMS)的表面表达。在活化第9天至第15天之间,使用多克隆IgG1 CH2CH3-特异性mAb FACS-分选CH2CH3-间隔CAR.28z T细胞,同时使用PE-缀合的、LNGFR-特异性mAb C40-14579对LNGFR-间隔CAR.28z T细胞染色并利用使用抗-PE顺磁性小珠(Miltenyi)的柱子对其进行分选。
分析特异性识别的体外测定
在共培养测定中,以E:T比1:10使用靶细胞培养CAR分选的T细胞。4天后,计数存活的细胞并使用FACS分析。消除指数的计算方法如下:1-(在存在CD44v6-4GS2.CAR28z+T细胞时的残留靶细胞数)/(在存在CTR.CAR28z+T细胞时的残留靶细胞数)。孵育24小时后收集共培养物的上清液并使用CBA测定(BD Biolegend)对细胞因子的产生情况(IFNγ、IL-2和TNFα)进行分析。
评价抗肿瘤作用的移植瘤模型
对于微小残留疾病模型而言,输注i.v.给予NSG小鼠(Jackson)1,5x106个ALL-CM白血病细胞/小鼠。3天后,i.v5x106个分选的LNGFR-间隔(NWL,NMS)CD19-CAR.28z或CD44v6-4GS2.CAR.28z T细胞对小鼠进行治疗。每周一次通过取血和FACS分析监测T细胞移植情况。7周后,处死小鼠并使用抗-hCD45和抗-hCD19mAb针对ALL-CM细胞的存在情况通过FACS对其骨髓(BM)进行分析。
实施例7-The LNGFR-间隔-CAR.28z构建体能够用于选择和追踪转导的T细胞
将不同的LNGFR-间隔CAR.28z构建体克隆进入逆转录病毒载体(RV)用于转导原代T细胞。对于转导而言,根据更好地保留其具有功能的表型的方案(Kaneko等,Blood,2009,Jan 29;113(5):1006-15;Bondanza等,Blood 2011,Jun 16;117(24):6469-78;Cieri等,Blood,2013,Jan 24;121(4):573-84),使用CD3/CD28-小珠和IL-7/IL-15活化T细胞。转导后,能够使用免疫磁珠分选T细胞(图23),表明如CAR靶向至CD44v6抗原所示,来源于LNGFR的间隔区被正确地加工并安装在细胞膜上,使用特异性针对CD19和CEA抗原的两个其他CAR的情况下也是这样的。
实施例8-LNGFR-间隔CD19-CAR.28z T细胞、CEA-CAR.28z T细胞和CD44v6-4GS2.CAR.28z T细胞保留抗原特异性识别,同时丧失由与FcγR的相互作用介导的非特异性识别
为了验证使用LNGFR间隔取代原始CH2CH3间隔后保留CD19和CEA-特异性识别,在与表达抗原的肿瘤细胞的共培养实验中,对LNGFR-间隔CD19-CAR.28z和CEA-CAR.28z T细胞进行了测试。与CH2CH3-间隔类似,LNGFR-间隔CD19-CAR.28z、CEA-CAR.28z T细胞和CD44v6-4GS2.CAR.28z T细胞分别有效地消除了CD19+、CEA+和CD44v6+肿瘤细胞,但对抗原阴性肿瘤细胞消除较少(图24A)。特别地,LNGFR-间隔CD19-CAR.28z CAR T细胞特异性消除CD19+ALL-CM和BV-173细胞,而非CD19-HL-60和BXPC3细胞(图24A)。类似地,LNGFR-间隔CEA-CAR.28z T细胞特异性消除CEA+BXPC3细胞,而非CEA-HL-60、ALL-CM和BV-173细胞(图24A)以及CD44v6-4GS2.CAR.28z T细胞特异性消除CD44v6+BXPC3细胞,而非CD44v6-ALL-CM、BV173和HL-60细胞(图24A)。当对抗原特异性细胞因子的释放(IFNγ、IL-2和TNFα)进行评估时观察到了类似结果(图24B)。
根据本发明的含有LNGFR作为间隔区的CAR使用不同的抗原特异性靶向结构域时
保留了特异性和抗肿瘤作用。
为了证明缺乏由与FcRγ的相互作用介导的非特异性识别,将LNGFR-间隔CD19-CAR.28z T细胞、CEA-CAR.28z T细胞和CD44v6-4GS2.CAR.28z T细胞与FcγR+、CD19-CEA-HL-60细胞共培养。在这个***中,仅CH2CH3-间隔CD19-CAR.28z和CEA-CAR.28z T细胞能够消除HL-60靶细胞,从而确证了使用基于LNGFR的间隔区避免了不需要的先天性免疫应答的活化。
实施例12-LNGFR-间隔CD19-CAR.28z T细胞介导的体内抗肿瘤作用
在体外证明有效和特异性识别后,在微小残留疾病模型中考察了LNGFR-间隔CD19-CAR.28z T细胞的体内抗肿瘤活性。使用ALL-CM白血病细胞输注NSG小鼠并且3天后使用不同的LNGFR-间隔(NWL和NMS)CD19-CAR.28z T细胞对其进行治疗。在这种情况下,使用LNGFR-间隔(NWL和NMS)CD44v6-4GS2.CAR.28z T细胞作为阴性对照,因为ALL-CM白血病细胞不表达CD44v6抗原(图25)。两种LNGFR-间隔CD19-CAR.28z T细胞均显示出介导抗肿瘤作用,因为与使用CD44v6-CAR.28z T细胞输注的小鼠相比,其显示出较低浓度的ALL-CM细胞的骨髓浸润(图25)。
在上述说明书中提及的所有出版物均通过引用并入本申请。在不脱离本发明的范围和精神的前提下,本发明所述的CARS、多核苷酸、载体、细胞和组合物的各种修饰和变化对于本领域技术人员而言是显而易见的。尽管已经结合特定的优选实施方式对本发明进行了描述,但是应当理解不应不适宜地将所要求保护的发明限制为这些特定的实施方式。事实上,对生化和生物技术或相关领域的技术人员是显而易见的用于实施本发明所述模式的各种修订均旨在包括在下述权利要求的范围内。
序列表
<110> 莫尔梅德股份有限公司
<120> 嵌合的抗原受体
<130> P105739PCT
<150> EP 14184838.2
<151> 2014-09-15
<160> 40
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<400> 6
aaagaggcct gccccaccgg cctgtacacc cacagcggag agtgctgcaa ggcctgcaac 60
ctgggagagg gcgtggccca gccttgcggc gccaatcaga ccgtgtgcga gccctgcctg 120
gacagcgtga ccttcagcga cgtggtgtcc gccaccgagc cctgcaagcc ttgcaccgag 180
tgtgtgggcc tgcagagcat gagcgccccc tgcgtggaag ccgacgacgc cgtgtgtaga 240
tgcgcctacg gctactacca ggacgagaca accggcagat gcgaggcctg tagagtgtgc 300
gaggccggca gcggcctggt gttcagttgt caagacaagc agaataccgt gtgtgaagag 360
tgccccgacg gcacctacag cgacgaagcc gccagagccg ccgacgccga gtgcgaagag 420
atccccggca gatggatcac cagaagcacc ccccctgagg gcagcgacag caccgcccct 480
agcacccagg aacctgaggc ccctcccgag caggacctga tcgcctctac agtggccggc 540
gtggtgacaa ccgtgatggg cagctctcag cccgtggtga cacggggcac caccgacaat 600
<210> 7
<211> 140
<212> PRT
<213> 人工序列
<220>
<223> 间隔LNGFR 突变的短 (NMS)
<400> 7
Lys Glu Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys
1 5 10 15
Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn
20 25 30
Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val
35 40 45
Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu
50 55 60
Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg
65 70 75 80
Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala
85 90 95
Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp
100 105 110
Lys Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp
115 120 125
Glu Ala Ala Arg Ala Ala Asp Ala Glu Cys Glu Glu
130 135 140
<210> 8
<211> 420
<212> DNA
<213> 人工序列
<220>
<223> 间隔LNGFR 突变的短 (NMS)
<400> 8
aaagaggcct gccccaccgg cctgtacacc cacagcggag agtgctgcaa ggcctgcaac 60
ctgggagagg gcgtggccca gccttgcggc gccaatcaga ccgtgtgcga gccctgcctg 120
gacagcgtga ccttcagcga cgtggtgtcc gccaccgagc cctgcaagcc ttgcaccgag 180
tgtgtgggcc tgcagagcat gagcgccccc tgcgtggaag ccgacgacgc cgtgtgtaga 240
tgcgcctacg gctactacca ggacgagaca accggcagat gcgaggcctg tagagtgtgc 300
gaggccggca gcggcctggt gttcagttgt caggacaagc agaacaccgt gtgtgaagag 360
tgccccgacg gcacctacag cgacgaggcc gcccgggccg ccgacgccga gtgcgaggaa 420
<210> 9
<211> 34
<212> PRT
<213> 智人
<400> 9
Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala
1 5 10 15
Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr
20 25 30
Val Cys
<210> 10
<211> 42
<212> PRT
<213> 智人
<400> 10
Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu
1 5 10 15
Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala
20 25 30
Pro Cys Val Glu Ala Asp Asp Ala Val Cys
35 40
<210> 11
<211> 39
<212> PRT
<213> 智人
<400> 11
Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu
1 5 10 15
Ala Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln
20 25 30
Asp Lys Gln Asn Thr Val Cys
35
<210> 12
<211> 41
<212> PRT
<213> 智人
<400> 12
Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro
1 5 10 15
Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu
20 25 30
Cys Thr Arg Trp Ala Asp Ala Glu Cys
35 40
<210> 13
<211> 25
<212> PRT
<213> 智人
<400> 13
Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu
1 5 10 15
Arg Gln Leu Arg Glu Cys Thr Arg Trp
20 25
<210> 14
<211> 427
<212> PRT
<213> 智人
<400> 14
Met Gly Ala Gly Ala Thr Gly Arg Ala Met Asp Gly Pro Arg Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Gly Val Ser Leu Gly Gly Ala Lys Glu Ala Cys
20 25 30
Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn
35 40 45
Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys
50 55 60
Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr
65 70 75 80
Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser
85 90 95
Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly
100 105 110
Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys
115 120 125
Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr
130 135 140
Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His
145 150 155 160
Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln
165 170 175
Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu Ile Pro
180 185 190
Gly Arg Trp Ile Thr Arg Ser Thr Pro Pro Glu Gly Ser Asp Ser Thr
195 200 205
Ala Pro Ser Thr Gln Glu Pro Glu Ala Pro Pro Glu Gln Asp Leu Ile
210 215 220
Ala Ser Thr Val Ala Gly Val Val Thr Thr Val Met Gly Ser Ser Gln
225 230 235 240
Pro Val Val Thr Arg Gly Thr Thr Asp Asn Leu Ile Pro Val Tyr Cys
245 250 255
Ser Ile Leu Ala Ala Val Val Val Gly Leu Val Ala Tyr Ile Ala Phe
260 265 270
Lys Arg Trp Asn Ser Cys Lys Gln Asn Lys Gln Gly Ala Asn Ser Arg
275 280 285
Pro Val Asn Gln Thr Pro Pro Pro Glu Gly Glu Lys Leu His Ser Asp
290 295 300
Ser Gly Ile Ser Val Asp Ser Gln Ser Leu His Asp Gln Gln Pro His
305 310 315 320
Thr Gln Thr Ala Ser Gly Gln Ala Leu Lys Gly Asp Gly Gly Leu Tyr
325 330 335
Ser Ser Leu Pro Pro Ala Lys Arg Glu Glu Val Glu Lys Leu Leu Asn
340 345 350
Gly Ser Ala Gly Asp Thr Trp Arg His Leu Ala Gly Glu Leu Gly Tyr
355 360 365
Gln Pro Glu His Ile Asp Ser Phe Thr His Glu Ala Cys Pro Val Arg
370 375 380
Ala Leu Leu Ala Ser Trp Ala Thr Gln Asp Ser Ala Thr Leu Asp Ala
385 390 395 400
Leu Leu Ala Ala Leu Arg Arg Ile Gln Arg Ala Asp Leu Val Glu Ser
405 410 415
Leu Cys Ser Glu Ser Thr Ala Thr Ser Pro Val
420 425
<210> 15
<211> 2046
<212> DNA
<213> 人工序列
<220>
<223> CD44v6-特异性第二代CAR构建体序列,
CD44v6-CAR.28z
<400> 15
atggaagccc ctgcccagct gctgttcctg ctgctgctgt ggctgcccga caccaccggc 60
gagatcgtgc tgacacagag ccccgccacc ctgtctctga gccctggcga gagagccacc 120
ctgagctgta gcgccagcag cagcatcaac tacatctact ggctgcagca gaagcccggc 180
caggccccca gaatcctgat ctacctgacc agcaacctgg ccagcggcgt gcccgccaga 240
ttttctggca gcggcagcgg caccgacttc accctgacca tcagcagcct ggaacccgag 300
gacttcgccg tgtactactg cctgcagtgg tccagcaacc ccctgacctt cggcggaggc 360
accaaggtgg aaatcaagcg gggtggtggt ggttctggtg gtggtggttc tggcggcggc 420
ggctccggtg gtggtggatc tgaggtgcag ctggtggaaa gcggcggagg cctggtcaag 480
cctggcggca gcctgagact gagctgtgcc gccagcggct tcaccttcag cagctacgac 540
atgagctggg tccgacaggc tccaggcaag ggactggaat gggtgtccac catcagcagc 600
ggcggcagct acacctacta cctggacagc atcaagggcc ggttcaccat cagccgggac 660
aacgccaaga acagcctgta cctgcagatg aacagcctgc gggccgagga caccgccgtc 720
tactactgtg cccggcaggg cctcgactac tggggcagag gcaccctggt caccgtgtcc 780
agcggggatc ccgccgagcc caaatctcct gacaaaactc acacatgccc accgtgccca 840
gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900
ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 960
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020
ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1200
ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 1260
ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcaacc ggagaacaac 1320
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1380
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1440
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa aaaagatccc 1500
aaattttggg tgctggtggt ggttggtgga gtcctggctt gctatagctt gctagtaaca 1560
gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 1620
atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1680
ccacgcgact tcgcagccta tcgctccaga gtgaagttca gcaggagcgc agacgccccc 1740
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1800
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1860
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1920
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1980
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 2040
cgctaa 2046
<210> 16
<211> 681
<212> PRT
<213> 人工序列
<220>
<223> CD44v6-CAR.28z蛋白
<400> 16
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Ala Glu Pro Lys Ser Pro Asp Lys
260 265 270
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
275 280 285
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
290 295 300
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
305 310 315 320
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
325 330 335
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
340 345 350
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
355 360 365
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
370 375 380
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
385 390 395 400
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
405 410 415
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
420 425 430
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
435 440 445
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
450 455 460
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
465 470 475 480
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
485 490 495
Lys Lys Asp Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val Leu
500 505 510
Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
515 520 525
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
530 535 540
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
545 550 555 560
Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser
565 570 575
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
580 585 590
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
595 600 605
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
610 615 620
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
625 630 635 640
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
645 650 655
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
660 665 670
Leu His Met Gln Ala Leu Pro Pro Arg
675 680
<210> 17
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> CD44v6-特异性单链片段
<400> 17
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser
260
<210> 18
<211> 68
<212> PRT
<213> 智人
<400> 18
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
20 25 30
Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly
35 40 45
Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala
50 55 60
Ala Tyr Arg Ser
65
<210> 19
<211> 222
<212> PRT
<213> 智人
<400> 19
Lys Glu Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys
1 5 10 15
Lys Ala Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn
20 25 30
Gln Thr Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val
35 40 45
Val Ser Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu
50 55 60
Gln Ser Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg
65 70 75 80
Cys Ala Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala
85 90 95
Cys Arg Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp
100 105 110
Lys Gln Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp
115 120 125
Glu Ala Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp
130 135 140
Thr Glu Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys
145 150 155 160
Glu Glu Ile Pro Gly Arg Trp Ile Thr Arg Ser Thr Pro Pro Glu Gly
165 170 175
Ser Asp Ser Thr Ala Pro Ser Thr Gln Glu Pro Glu Ala Pro Pro Glu
180 185 190
Gln Asp Leu Ile Ala Ser Thr Val Ala Gly Val Val Thr Thr Val Met
195 200 205
Gly Ser Ser Gln Pro Val Val Thr Arg Gly Thr Thr Asp Asn
210 215 220
<210> 20
<211> 113
<212> PRT
<213> 智人
<400> 20
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 Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 21
<211> 669
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR野生型长(NWL)CD44v6-CAR28z
<400> 21
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro Cys
385 390 395 400
Leu Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu Cys
405 410 415
Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu Ile Pro Gly Arg Trp Ile
420 425 430
Thr Arg Ser Thr Pro Pro Glu Gly Ser Asp Ser Thr Ala Pro Ser Thr
435 440 445
Gln Glu Pro Glu Ala Pro Pro Glu Gln Asp Leu Ile Ala Ser Thr Val
450 455 460
Ala Gly Val Val Thr Thr Val Met Gly Ser Ser Gln Pro Val Val Thr
465 470 475 480
Arg Gly Thr Thr Asp Asn Pro Lys Phe Trp Val Leu Val Val Val Gly
485 490 495
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
500 505 510
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
515 520 525
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
530 535 540
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe
545 550 555 560
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
565 570 575
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
580 585 590
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
595 600 605
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
610 615 620
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
625 630 635 640
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
645 650 655
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665
<210> 22
<211> 609
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR野生型短(NWS)的CD44v6-CAR28z
<400> 22
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro Cys
385 390 395 400
Leu Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu Cys
405 410 415
Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu Pro Lys Phe Trp Val Leu
420 425 430
Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val
435 440 445
Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His
450 455 460
Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys
465 470 475 480
His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
485 490 495
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
500 505 510
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
515 520 525
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
530 535 540
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
545 550 555 560
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
565 570 575
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
580 585 590
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
595 600 605
Arg
<210> 23
<211> 647
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR 突变的长 (NML)的CD44v6-CAR28z
<400> 23
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Ala Arg Ala Ala Asp Ala
385 390 395 400
Glu Cys Glu Glu Ile Pro Gly Arg Trp Ile Thr Arg Ser Thr Pro Pro
405 410 415
Glu Gly Ser Asp Ser Thr Ala Pro Ser Thr Gln Glu Pro Glu Ala Pro
420 425 430
Pro Glu Gln Asp Leu Ile Ala Ser Thr Val Ala Gly Val Val Thr Thr
435 440 445
Val Met Gly Ser Ser Gln Pro Val Val Thr Arg Gly Thr Thr Asp Asn
450 455 460
Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
465 470 475 480
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys
485 490 495
Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg
500 505 510
Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp
515 520 525
Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
530 535 540
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
545 550 555 560
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
565 570 575
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
580 585 590
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
595 600 605
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
610 615 620
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
625 630 635 640
Met Gln Ala Leu Pro Pro Arg
645
<210> 24
<211> 587
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR 突变的短 (NMS)的CD44v6-CAR28z
<400> 24
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Ala Arg Ala Ala Asp Ala
385 390 395 400
Glu Cys Glu Glu Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val
405 410 415
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
420 425 430
Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
435 440 445
Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
450 455 460
Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg
465 470 475 480
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
485 490 495
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
500 505 510
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn
515 520 525
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
530 535 540
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
545 550 555 560
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
565 570 575
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
580 585
<210> 25
<211> 668
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR野生型长(NWL)的CD44v6-CAR28z
<400> 25
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro Cys
385 390 395 400
Leu Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu Cys
405 410 415
Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu Ile Pro Gly Arg Trp Ile
420 425 430
Thr Arg Ser Thr Pro Pro Glu Gly Ser Asp Ser Thr Ala Pro Ser Thr
435 440 445
Gln Glu Pro Glu Ala Pro Pro Glu Gln Asp Leu Ile Ala Ser Thr Val
450 455 460
Ala Gly Val Val Thr Thr Val Met Gly Ser Ser Gln Pro Val Val Thr
465 470 475 480
Arg Gly Thr Thr Asp Asn Pro Lys Phe Trp Val Leu Val Val Val Gly
485 490 495
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
500 505 510
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
515 520 525
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
530 535 540
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe
545 550 555 560
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
565 570 575
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
580 585 590
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
595 600 605
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
610 615 620
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
625 630 635 640
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
645 650 655
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
660 665
<210> 26
<211> 608
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR野生型短(NWS)的CD44v6-CAR28z
<400> 26
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Asn His Val Asp Pro Cys
385 390 395 400
Leu Pro Cys Thr Val Cys Glu Asp Thr Glu Arg Gln Leu Arg Glu Cys
405 410 415
Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu Pro Lys Phe Trp Val Leu
420 425 430
Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val
435 440 445
Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His
450 455 460
Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys
465 470 475 480
His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
485 490 495
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
500 505 510
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
515 520 525
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
530 535 540
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
545 550 555 560
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
565 570 575
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
580 585 590
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
595 600 605
<210> 27
<211> 646
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR 突变的长 (NWL)的CD44v6-CAR28z
<400> 27
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Ala Arg Ala Ala Asp Ala
385 390 395 400
Glu Cys Glu Glu Ile Pro Gly Arg Trp Ile Thr Arg Ser Thr Pro Pro
405 410 415
Glu Gly Ser Asp Ser Thr Ala Pro Ser Thr Gln Glu Pro Glu Ala Pro
420 425 430
Pro Glu Gln Asp Leu Ile Ala Ser Thr Val Ala Gly Val Val Thr Thr
435 440 445
Val Met Gly Ser Ser Gln Pro Val Val Thr Arg Gly Thr Thr Asp Asn
450 455 460
Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
465 470 475 480
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys
485 490 495
Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg
500 505 510
Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp
515 520 525
Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
530 535 540
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
545 550 555 560
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
565 570 575
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
580 585 590
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
595 600 605
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
610 615 620
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
625 630 635 640
Gln Ala Leu Pro Pro Arg
645
<210> 28
<211> 586
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR 突变的短 (NWL)的CD44v6-CAR28z
<400> 28
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
165 170 175
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Leu
195 200 205
Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr Trp Gly Arg Gly Thr Leu
245 250 255
Val Thr Val Ser Ser Gly Asp Pro Lys Glu Ala Cys Pro Thr Gly Leu
260 265 270
Tyr Thr His Ser Gly Glu Cys Cys Lys Ala Cys Asn Leu Gly Glu Gly
275 280 285
Val Ala Gln Pro Cys Gly Ala Asn Gln Thr Val Cys Glu Pro Cys Leu
290 295 300
Asp Ser Val Thr Phe Ser Asp Val Val Ser Ala Thr Glu Pro Cys Lys
305 310 315 320
Pro Cys Thr Glu Cys Val Gly Leu Gln Ser Met Ser Ala Pro Cys Val
325 330 335
Glu Ala Asp Asp Ala Val Cys Arg Cys Ala Tyr Gly Tyr Tyr Gln Asp
340 345 350
Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg Val Cys Glu Ala Gly Ser
355 360 365
Gly Leu Val Phe Ser Cys Gln Asp Lys Gln Asn Thr Val Cys Glu Glu
370 375 380
Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala Ala Arg Ala Ala Asp Ala
385 390 395 400
Glu Cys Glu Glu Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val
405 410 415
Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp
420 425 430
Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
435 440 445
Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
450 455 460
Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg
465 470 475 480
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
485 490 495
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
500 505 510
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
515 520 525
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
530 535 540
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
545 550 555 560
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
565 570 575
Ala Leu His Met Gln Ala Leu Pro Pro Arg
580 585
<210> 29
<211> 27
<212> PRT
<213> 智人
<400> 29
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> 30
<211> 41
<212> PRT
<213> 智人
<400> 30
Arg Ser Lys Arg Ser Arg Leu Leu 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
35 40
<210> 31
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD44v6-4GS2, CD44v6-特异性单链片段
<400> 31
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
130 135 140
Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln
165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Ser Gly Gly
180 185 190
Ser Tyr Thr Tyr Tyr Leu Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser
195 200 205
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr
225 230 235 240
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 32
<211> 658
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR野生型长(NWL)的CD44v6-4GS2-CAR28z
<400> 32
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
130 135 140
Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln
165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Ser Gly Gly
180 185 190
Ser Tyr Thr Tyr Tyr Leu Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser
195 200 205
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr
225 230 235 240
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Asp Pro Lys Glu
245 250 255
Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala
260 265 270
Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr
275 280 285
Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser
290 295 300
Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser
305 310 315 320
Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala
325 330 335
Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg
340 345 350
Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Lys Gln
355 360 365
Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala
370 375 380
Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu
385 390 395 400
Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu
405 410 415
Ile Pro Gly Arg Trp Ile Thr Arg Ser Thr Pro Pro Glu Gly Ser Asp
420 425 430
Ser Thr Ala Pro Ser Thr Gln Glu Pro Glu Ala Pro Pro Glu Gln Asp
435 440 445
Leu Ile Ala Ser Thr Val Ala Gly Val Val Thr Thr Val Met Gly Ser
450 455 460
Ser Gln Pro Val Val Thr Arg Gly Thr Thr Asp Asn Pro Lys Phe Trp
465 470 475 480
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
485 490 495
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu
500 505 510
Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr
515 520 525
Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr
530 535 540
Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
545 550 555 560
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
565 570 575
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
580 585 590
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
595 600 605
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
610 615 620
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
625 630 635 640
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
645 650 655
Pro Arg
<210> 33
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR野生型的短(NWS)的CD44v6-4GS2-CAR28z
<400> 33
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
130 135 140
Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln
165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Ser Gly Gly
180 185 190
Ser Tyr Thr Tyr Tyr Leu Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser
195 200 205
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr
225 230 235 240
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Asp Pro Lys Glu
245 250 255
Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala
260 265 270
Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr
275 280 285
Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser
290 295 300
Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser
305 310 315 320
Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala
325 330 335
Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg
340 345 350
Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Lys Gln
355 360 365
Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala
370 375 380
Asn His Val Asp Pro Cys Leu Pro Cys Thr Val Cys Glu Asp Thr Glu
385 390 395 400
Arg Gln Leu Arg Glu Cys Thr Arg Trp Ala Asp Ala Glu Cys Glu Glu
405 410 415
Pro Lys Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
420 425 430
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys
435 440 445
Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg
450 455 460
Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp
465 470 475 480
Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
485 490 495
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
500 505 510
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
515 520 525
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
530 535 540
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
545 550 555 560
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
565 570 575
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
580 585 590
Gln Ala Leu Pro Pro Arg
595
<210> 34
<211> 636
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR 突变的长 (NML)的CD44v6-4GS2-CAR28z
<400> 34
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
130 135 140
Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln
165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Ser Gly Gly
180 185 190
Ser Tyr Thr Tyr Tyr Leu Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser
195 200 205
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr
225 230 235 240
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Asp Pro Lys Glu
245 250 255
Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala
260 265 270
Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr
275 280 285
Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser
290 295 300
Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser
305 310 315 320
Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala
325 330 335
Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg
340 345 350
Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Lys Gln
355 360 365
Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala
370 375 380
Ala Arg Ala Ala Asp Ala Glu Cys Glu Glu Ile Pro Gly Arg Trp Ile
385 390 395 400
Thr Arg Ser Thr Pro Pro Glu Gly Ser Asp Ser Thr Ala Pro Ser Thr
405 410 415
Gln Glu Pro Glu Ala Pro Pro Glu Gln Asp Leu Ile Ala Ser Thr Val
420 425 430
Ala Gly Val Val Thr Thr Val Met Gly Ser Ser Gln Pro Val Val Thr
435 440 445
Arg Gly Thr Thr Asp Asn Pro Lys Phe Trp Val Leu Val Val Val Gly
450 455 460
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
465 470 475 480
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
485 490 495
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
500 505 510
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe
515 520 525
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
530 535 540
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
545 550 555 560
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
565 570 575
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
580 585 590
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
595 600 605
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
610 615 620
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
625 630 635
<210> 35
<211> 576
<212> PRT
<213> 人工序列
<220>
<223> 具有间隔LNGFR突变的短 (NMS)的CD44v6-4GS2-CAR28z
<400> 35
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser
35 40 45
Ile Asn Tyr Ile Tyr Trp Leu Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Ile Leu Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Trp Ser Ser
100 105 110
Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
130 135 140
Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln
165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Ser Gly Gly
180 185 190
Ser Tyr Thr Tyr Tyr Leu Asp Ser Ile Lys Gly Arg Phe Thr Ile Ser
195 200 205
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gln Gly Leu Asp Tyr
225 230 235 240
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Asp Pro Lys Glu
245 250 255
Ala Cys Pro Thr Gly Leu Tyr Thr His Ser Gly Glu Cys Cys Lys Ala
260 265 270
Cys Asn Leu Gly Glu Gly Val Ala Gln Pro Cys Gly Ala Asn Gln Thr
275 280 285
Val Cys Glu Pro Cys Leu Asp Ser Val Thr Phe Ser Asp Val Val Ser
290 295 300
Ala Thr Glu Pro Cys Lys Pro Cys Thr Glu Cys Val Gly Leu Gln Ser
305 310 315 320
Met Ser Ala Pro Cys Val Glu Ala Asp Asp Ala Val Cys Arg Cys Ala
325 330 335
Tyr Gly Tyr Tyr Gln Asp Glu Thr Thr Gly Arg Cys Glu Ala Cys Arg
340 345 350
Val Cys Glu Ala Gly Ser Gly Leu Val Phe Ser Cys Gln Asp Lys Gln
355 360 365
Asn Thr Val Cys Glu Glu Cys Pro Asp Gly Thr Tyr Ser Asp Glu Ala
370 375 380
Ala Arg Ala Ala Asp Ala Glu Cys Glu Glu Pro Lys Phe Trp Val Leu
385 390 395 400
Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val
405 410 415
Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His
420 425 430
Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys
435 440 445
His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
450 455 460
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
465 470 475 480
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
485 490 495
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
500 505 510
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
515 520 525
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
530 535 540
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
545 550 555 560
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
565 570 575
<210> 36
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽接头
<400> 36
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 37
<211> 8331
<212> DNA
<213> 人工序列
<220>
<223> CD44v6-4GS2-CAR.28Z NGFR野生型长(V6 NWL)
<400> 37
aagctttgct cttaggagtt tcctaataca tcccaaactc aaatatataa agcatttgac 60
ttgttctatg ccctaggggg cggggggaag ctaagccagc tttttttaac atttaaaatg 120
ttaattccat tttaaatgca cagatgtttt tatttcataa gggtttcaat gtgcatgaat 180
gctgcaatat tcctgttacc aaagctagta taaataaaaa tagataaacg tggaaattac 240
ttagagtttc tgtcattaac gtttccttcc tcagttgaca acataaatgc gctgctgagc 300
aagccagttt gcatctgtca ggatcaattt cccattatgc cagtcatatt aattactagt 360
caattagttg atttttattt ttgacatata catgtgaatg aaagacccca cctgtaggtt 420
tggcaagcta gcttaagtaa cgccattttg caaggcatgg aaaaatacat aactgagaat 480
agaaaagttc agatcaaggt caggaacaga tggaacagct gaatatgggc caaacaggat 540
atctgtggta agcagttcct gccccggctc agggccaaga acagatggaa cagctgaata 600
tgggccaaac aggatatctg tggtaagcag ttcctgcccc ggctcagggc caagaacaga 660
tggtccccag atgcggtcca gccctcagca gtttctagag aaccatcaga tgtttccagg 720
gtgccccaag gacctgaaat gaccctgtgc cttatttgaa ctaaccaatc agttcgcttc 780
tcgcttctgt tcgcgcgctt atgctccccg agctcaataa aagagcccac aacccctcac 840
tcggggcgcc agtcctccga ttgactgagt cgcccgggta cccgtgtatc caataaaccc 900
tcttgcagtt gcatccgact tgtggtctcg ctgttccttg ggagggtctc ctctgagtga 960
ttgactaccc gtcagcgggg gtctttcatt tgggggctcg tccgggatcg ggagacccct 1020
gcccagggac caccgaccca ccaccgggag gtaagctggc cagcaactta tctgtgtctg 1080
tccgattgtc tagtgtctat gactgatttt atgcgcctgc gtcggtacta gttagctaac 1140
tagctctgta tctggcggac ccgtggtgga actgacgagt tcggaacacc cggccgcaac 1200
cctgggagac gtcccaggga cttcgggggc cgtttttgtg gcccgacctg agtcctaaaa 1260
tcccgatcgt ttaggactct ttggtgcacc ccccttagag gagggatatg tggttctggt 1320
aggagacgag aacctaaaac agttcccgcc tccgtctgaa tttttgcttt cggtttggga 1380
ccgaagccgc gccgcgcgtc ttgtctgctg cagcatcgtt ctgtgttgtc tctgtctgac 1440
tgtgtttctg tatttgtctg aaaatatggg cccgggctag cctgttacca ctcccttaag 1500
tttgacctta ggtcactgga aagatgtcga gcggatcgct cacaaccagt cggtagatgt 1560
caagaagaga cgttgggtta ccttctgctc tgcagaatgg ccaaccttta acgtcggatg 1620
gccgcgagac ggcaccttta accgagacct catcacccag gttaagatca aggtcttttc 1680
acctggcccg catggacacc cagaccaggt ggggtacatc gtgacctggg aagccttggc 1740
ttttgacccc cctccctggg tcaagccctt tgtacaccct aagcctccgc ctcctcttcc 1800
tccatccgcc ccgtctctcc cccttgaacc tcctcgttcg accccgcctc gatcctccct 1860
ttatccagcc ctcactcctt ctctaggcgc ccccatatgg ccatatgaga tcttatatgg 1920
ggcacccccg ccccttgtaa acttccctga ccctgacatg acaagagtta ctaacagccc 1980
ctctctccaa gctcacttac aggctctcta cttagtccag cacgaagtct ggagacctct 2040
ggcggcagcc taccaagaac aactggaccg accggtggta cctcaccctt accgagtcgg 2100
cgacacagtg tgggtccgcc gacaccagac taagaaccta gaacctcgct ggaaaggacc 2160
ttacacagtc ctgctgacca cccccaccgc cctcaaagta gacggcatcg cagcttggat 2220
acacgccgcc cacgtgaagg ctgccgaccc cgggggtgga ccatcctcta gactgccatg 2280
gaagcccctg cccagctgct gttcctgctg ctgctgtggc tgcccgacac caccggcgag 2340
atcgtgctga cacagagccc cgccaccctg tctctgagcc ctggcgagag agccaccctg 2400
agctgtagcg ccagcagcag catcaactac atctactggc tgcagcagaa gcccggccag 2460
gcccccagaa tcctgatcta cctgaccagc aacctggcca gcggcgtgcc cgccagattt 2520
tctggcagcg gcagcggcac cgacttcacc ctgaccatca gcagcctgga acccgaggac 2580
ttcgccgtgt actactgcct gcagtggtcc agcaaccccc tgaccttcgg cggaggcacc 2640
aaggtggaaa tcaagcgggg tggtggtggt tctggtggtg gtggttctga ggtgcagctg 2700
gtggaaagcg gcggaggcct ggtcaagcct ggcggcagcc tgagactgag ctgtgccgcc 2760
agcggcttca ccttcagcag ctacgacatg agctgggtcc gacaggctcc aggcaaggga 2820
ctggaatggg tgtccaccat cagcagcggc ggcagctaca cctactacct ggacagcatc 2880
aagggccggt tcaccatcag ccgggacaac gccaagaaca gcctgtacct gcagatgaac 2940
agcctgcggg ccgaggacac cgccgtctac tactgtgccc ggcagggcct cgactactgg 3000
ggcagaggca ccctggtcac cgtgtccagc ggggatccca aagaggcctg ccccaccggc 3060
ctgtacaccc acagcggaga gtgctgcaag gcctgcaacc tgggagaggg cgtggcccag 3120
ccttgcggcg ccaatcagac cgtgtgcgag ccctgcctgg acagcgtgac cttcagcgac 3180
gtggtgtccg ccaccgagcc ctgcaagcct tgcaccgagt gtgtgggcct gcagagcatg 3240
agcgccccct gcgtggaagc cgacgacgcc gtgtgtagat gcgcctacgg ctactaccag 3300
gacgagacaa ccggcagatg cgaggcctgt agagtgtgcg aggccggcag cggcctggtg 3360
ttcagttgtc aagacaagca gaataccgtg tgtgaagagt gccccgacgg cacctacagc 3420
gacgaggcca accacgtgga cccctgcctg ccctgcactg tgtgcgagga caccgagcgg 3480
cagctgcgcg agtgcacaag atgggccgac gccgagtgcg aagagatccc cggcagatgg 3540
atcaccagaa gcaccccccc tgagggcagc gacagcaccg cccctagcac ccaggaacct 3600
gaggcccctc ccgagcagga cctgatcgcc tctacagtgg ccggcgtggt gacaaccgtg 3660
atgggcagct ctcagcccgt ggtgacacgg ggcaccaccg acaatcccaa attttgggtg 3720
ctggtggtgg ttggtggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 3780
attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 3840
ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 3900
gcagcctatc gctccagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 3960
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 4020
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 4080
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 4140
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 4200
gccaccaagg acacctacga cgcccttcac atgcaggccc tgcctcctcg ctaagcatgc 4260
aacctcgatc cggattagtc caatttgtta aagacaggat atcagtggtc caggctctag 4320
ttttgactca acaatatcac cagctgaagc ctatagagta cgagccatag ataaaataaa 4380
agattttatt tagtctccag aaaaaggggg gaatgaaaga ccccacctgt aggtttggca 4440
agctagctta agtaacgcca ttttgcaagg catggaaaaa tacataactg agaatagaga 4500
agttcagatc aaggtcagga acagatggaa cagctgaata tgggccaaac aggatatctg 4560
tggtaagcag ttcctgcccc ggctcagggc caagaacaga tggaacagct gaatatgggc 4620
caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga acagatggtc 4680
cccagatgcg gtccagccct cagcagtttc tagagaacca tcagatgttt ccagggtgcc 4740
ccaaggacct gaaatgaccc tgtgccttat ttgaactaac caatcagttc gcttctcgct 4800
tctgttcgcg cgcttctgct ccccgagctc aataaaagag cccacaaccc ctcactcggg 4860
gcgccagtcc tccgattgac tgagtcgccc gggtacccgt gtatccaata aaccctcttg 4920
cagttgcatc cgacttgtgg tctcgctgtt ccttgggagg gtctcctctg agtgattgac 4980
tacccgtcag cgggggtctt tcacacatgc agcatgtatc aaaattaatt tggttttttt 5040
tcttaagtat ttacattaaa tggccatagt acttaaagtt acattggctt ccttgaaata 5100
aacatggagt attcagaatg tgtcataaat atttctaatt ttaagatagt atctccattg 5160
gctttctact ttttctttta tttttttttg tcctctgtct tccatttgtt gttgttgttg 5220
tttgtttgtt tgtttgttgg ttggttggtt aatttttttt taaagatcct acactatagt 5280
tcaagctaga ctattagcta ctctgtaacc cagggtgacc ttgaagtcat gggtagcctg 5340
ctgttttagc cttcccacat ctaagattac aggtatgagc tatcattttt ggtatattga 5400
ttgattgatt gattgatgtg tgtgtgtgtg attgtgtttg tgtgtgtgac tgtgaaaatg 5460
tgtgtatggg tgtgtgtgaa tgtgtgtatg tatgtgtgtg tgtgagtgtg tgtgtgtgtg 5520
tgtgcatgtg tgtgtgtgtg actgtgtcta tgtgtatgac tgtgtgtgtg tgtgtgtgtg 5580
tgtgtgtgtg tgtgtgtgtg tgtgtgttgt gaaaaaatat tctatggtag tgagagccaa 5640
cgctccggct caggtgtcag gttggttttt gagacagagt ctttcactta gcttggaatt 5700
cactggccgt cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc caacttaatc 5760
gccttgcagc acatccccct ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc 5820
gcccttccca acagttgcgc agcctgaatg gcgaatggcg cctgatgcgg tattttctcc 5880
ttacgcatct gtgcggtatt tcacaccgca tatggtgcac tctcagtaca atctgctctg 5940
atgccgcata gttaagccag ccccgacacc cgccaacacc cgctgacgcg ccctgacggg 6000
cttgtctgct cccggcatcc gcttacagac aagctgtgac cgtctccggg agctgcatgt 6060
gtcagaggtt ttcaccgtca tcaccgaaac gcgcgatgac gaaagggcct cgtgatacgc 6120
ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg tggcactttt 6180
cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc aaatatgtat 6240
ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag gaagagtatg 6300
agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg ccttcctgtt 6360
tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt gggtgcacga 6420
gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt tcgccccgaa 6480
gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt attatcccgt 6540
attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa tgacttggtt 6600
gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag agaattatgc 6660
agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac aacgatcgga 6720
ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac tcgccttgat 6780
cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac cacgatgcct 6840
gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac tctagcttcc 6900
cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact tctgcgctcg 6960
gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg tgggtctcgc 7020
ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg 7080
acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca 7140
ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta gattgattta 7200
aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc 7260
aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa 7320
ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca 7380
ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta 7440
actggcttca gcagagcgca gataccaaat actgtccttc tagtgtagcc gtagttaggc 7500
caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca 7560
gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta 7620
ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag 7680
cgaacgacct acaccgaact gagataccta cagcgtgagc attgagaaag cgccacgctt 7740
cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc 7800
acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac 7860
ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac 7920
gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc 7980
tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga gtgagctgat 8040
accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga agcggaagag 8100
cgcccaatac gcaaaccgcc tctccccgcg cgttggccga ttcattaatg cagctggcac 8160
gacaggtttc ccgactggaa agcgggcagt gagcgcaacg caattaatgt gagttagctc 8220
actcattagg caccccaggc tttacacttt atgcttccgg ctcgtatgtt gtgtggaatt 8280
gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc c 8331
<210> 38
<211> 8151
<212> DNA
<213> 人工序列
<220>
<223> CD44V6-4GS2-CAR.28Z NGFR野生型短 (V6 NWS)
<400> 38
aagctttgct cttaggagtt tcctaataca tcccaaactc aaatatataa agcatttgac 60
ttgttctatg ccctaggggg cggggggaag ctaagccagc tttttttaac atttaaaatg 120
ttaattccat tttaaatgca cagatgtttt tatttcataa gggtttcaat gtgcatgaat 180
gctgcaatat tcctgttacc aaagctagta taaataaaaa tagataaacg tggaaattac 240
ttagagtttc tgtcattaac gtttccttcc tcagttgaca acataaatgc gctgctgagc 300
aagccagttt gcatctgtca ggatcaattt cccattatgc cagtcatatt aattactagt 360
caattagttg atttttattt ttgacatata catgtgaatg aaagacccca cctgtaggtt 420
tggcaagcta gcttaagtaa cgccattttg caaggcatgg aaaaatacat aactgagaat 480
agaaaagttc agatcaaggt caggaacaga tggaacagct gaatatgggc caaacaggat 540
atctgtggta agcagttcct gccccggctc agggccaaga acagatggaa cagctgaata 600
tgggccaaac aggatatctg tggtaagcag ttcctgcccc ggctcagggc caagaacaga 660
tggtccccag atgcggtcca gccctcagca gtttctagag aaccatcaga tgtttccagg 720
gtgccccaag gacctgaaat gaccctgtgc cttatttgaa ctaaccaatc agttcgcttc 780
tcgcttctgt tcgcgcgctt atgctccccg agctcaataa aagagcccac aacccctcac 840
tcggggcgcc agtcctccga ttgactgagt cgcccgggta cccgtgtatc caataaaccc 900
tcttgcagtt gcatccgact tgtggtctcg ctgttccttg ggagggtctc ctctgagtga 960
ttgactaccc gtcagcgggg gtctttcatt tgggggctcg tccgggatcg ggagacccct 1020
gcccagggac caccgaccca ccaccgggag gtaagctggc cagcaactta tctgtgtctg 1080
tccgattgtc tagtgtctat gactgatttt atgcgcctgc gtcggtacta gttagctaac 1140
tagctctgta tctggcggac ccgtggtgga actgacgagt tcggaacacc cggccgcaac 1200
cctgggagac gtcccaggga cttcgggggc cgtttttgtg gcccgacctg agtcctaaaa 1260
tcccgatcgt ttaggactct ttggtgcacc ccccttagag gagggatatg tggttctggt 1320
aggagacgag aacctaaaac agttcccgcc tccgtctgaa tttttgcttt cggtttggga 1380
ccgaagccgc gccgcgcgtc ttgtctgctg cagcatcgtt ctgtgttgtc tctgtctgac 1440
tgtgtttctg tatttgtctg aaaatatggg cccgggctag cctgttacca ctcccttaag 1500
tttgacctta ggtcactgga aagatgtcga gcggatcgct cacaaccagt cggtagatgt 1560
caagaagaga cgttgggtta ccttctgctc tgcagaatgg ccaaccttta acgtcggatg 1620
gccgcgagac ggcaccttta accgagacct catcacccag gttaagatca aggtcttttc 1680
acctggcccg catggacacc cagaccaggt ggggtacatc gtgacctggg aagccttggc 1740
ttttgacccc cctccctggg tcaagccctt tgtacaccct aagcctccgc ctcctcttcc 1800
tccatccgcc ccgtctctcc cccttgaacc tcctcgttcg accccgcctc gatcctccct 1860
ttatccagcc ctcactcctt ctctaggcgc ccccatatgg ccatatgaga tcttatatgg 1920
ggcacccccg ccccttgtaa acttccctga ccctgacatg acaagagtta ctaacagccc 1980
ctctctccaa gctcacttac aggctctcta cttagtccag cacgaagtct ggagacctct 2040
ggcggcagcc taccaagaac aactggaccg accggtggta cctcaccctt accgagtcgg 2100
cgacacagtg tgggtccgcc gacaccagac taagaaccta gaacctcgct ggaaaggacc 2160
ttacacagtc ctgctgacca cccccaccgc cctcaaagta gacggcatcg cagcttggat 2220
acacgccgcc cacgtgaagg ctgccgaccc cgggggtgga ccatcctcta gactgccatg 2280
gaagcccctg cccagctgct gttcctgctg ctgctgtggc tgcccgacac caccggcgag 2340
atcgtgctga cacagagccc cgccaccctg tctctgagcc ctggcgagag agccaccctg 2400
agctgtagcg ccagcagcag catcaactac atctactggc tgcagcagaa gcccggccag 2460
gcccccagaa tcctgatcta cctgaccagc aacctggcca gcggcgtgcc cgccagattt 2520
tctggcagcg gcagcggcac cgacttcacc ctgaccatca gcagcctgga acccgaggac 2580
ttcgccgtgt actactgcct gcagtggtcc agcaaccccc tgaccttcgg cggaggcacc 2640
aaggtggaaa tcaagcgggg tggtggtggt tctggtggtg gtggttctga ggtgcagctg 2700
gtggaaagcg gcggaggcct ggtcaagcct ggcggcagcc tgagactgag ctgtgccgcc 2760
agcggcttca ccttcagcag ctacgacatg agctgggtcc gacaggctcc aggcaaggga 2820
ctggaatggg tgtccaccat cagcagcggc ggcagctaca cctactacct ggacagcatc 2880
aagggccggt tcaccatcag ccgggacaac gccaagaaca gcctgtacct gcagatgaac 2940
agcctgcggg ccgaggacac cgccgtctac tactgtgccc ggcagggcct cgactactgg 3000
ggcagaggca ccctggtcac cgtgtccagc ggggatccca aagaggcctg ccccaccggc 3060
ctgtacaccc acagcggaga gtgctgcaag gcctgcaacc tgggagaggg cgtggcccag 3120
ccttgcggcg ccaatcagac cgtgtgcgag ccctgcctgg acagcgtgac cttcagcgac 3180
gtggtgtccg ccaccgagcc ctgcaagcct tgcaccgagt gtgtgggcct gcagagcatg 3240
agcgccccct gcgtggaagc cgacgacgcc gtgtgtagat gcgcctacgg ctactaccag 3300
gacgagacaa ccggcagatg cgaggcctgt agagtgtgcg aggccggcag cggcctggtg 3360
ttcagttgtc aggacaagca gaacaccgtg tgtgaagagt gccccgacgg cacctacagc 3420
gacgaggcca accacgtgga cccctgcctg ccctgcactg tgtgcgagga caccgagcgg 3480
cagctgcgcg agtgcacaag atgggccgac gccgagtgcg aggaacccaa attttgggtg 3540
ctggtggtgg ttggtggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 3600
attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 3660
ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 3720
gcagcctatc gctccagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 3780
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 3840
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 3900
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 3960
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 4020
gccaccaagg acacctacga cgcccttcac atgcaggccc tgcctcctcg ctaagcatgc 4080
aacctcgatc cggattagtc caatttgtta aagacaggat atcagtggtc caggctctag 4140
ttttgactca acaatatcac cagctgaagc ctatagagta cgagccatag ataaaataaa 4200
agattttatt tagtctccag aaaaaggggg gaatgaaaga ccccacctgt aggtttggca 4260
agctagctta agtaacgcca ttttgcaagg catggaaaaa tacataactg agaatagaga 4320
agttcagatc aaggtcagga acagatggaa cagctgaata tgggccaaac aggatatctg 4380
tggtaagcag ttcctgcccc ggctcagggc caagaacaga tggaacagct gaatatgggc 4440
caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga acagatggtc 4500
cccagatgcg gtccagccct cagcagtttc tagagaacca tcagatgttt ccagggtgcc 4560
ccaaggacct gaaatgaccc tgtgccttat ttgaactaac caatcagttc gcttctcgct 4620
tctgttcgcg cgcttctgct ccccgagctc aataaaagag cccacaaccc ctcactcggg 4680
gcgccagtcc tccgattgac tgagtcgccc gggtacccgt gtatccaata aaccctcttg 4740
cagttgcatc cgacttgtgg tctcgctgtt ccttgggagg gtctcctctg agtgattgac 4800
tacccgtcag cgggggtctt tcacacatgc agcatgtatc aaaattaatt tggttttttt 4860
tcttaagtat ttacattaaa tggccatagt acttaaagtt acattggctt ccttgaaata 4920
aacatggagt attcagaatg tgtcataaat atttctaatt ttaagatagt atctccattg 4980
gctttctact ttttctttta tttttttttg tcctctgtct tccatttgtt gttgttgttg 5040
tttgtttgtt tgtttgttgg ttggttggtt aatttttttt taaagatcct acactatagt 5100
tcaagctaga ctattagcta ctctgtaacc cagggtgacc ttgaagtcat gggtagcctg 5160
ctgttttagc cttcccacat ctaagattac aggtatgagc tatcattttt ggtatattga 5220
ttgattgatt gattgatgtg tgtgtgtgtg attgtgtttg tgtgtgtgac tgtgaaaatg 5280
tgtgtatggg tgtgtgtgaa tgtgtgtatg tatgtgtgtg tgtgagtgtg tgtgtgtgtg 5340
tgtgcatgtg tgtgtgtgtg actgtgtcta tgtgtatgac tgtgtgtgtg tgtgtgtgtg 5400
tgtgtgtgtg tgtgtgtgtg tgtgtgttgt gaaaaaatat tctatggtag tgagagccaa 5460
cgctccggct caggtgtcag gttggttttt gagacagagt ctttcactta gcttggaatt 5520
cactggccgt cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc caacttaatc 5580
gccttgcagc acatccccct ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc 5640
gcccttccca acagttgcgc agcctgaatg gcgaatggcg cctgatgcgg tattttctcc 5700
ttacgcatct gtgcggtatt tcacaccgca tatggtgcac tctcagtaca atctgctctg 5760
atgccgcata gttaagccag ccccgacacc cgccaacacc cgctgacgcg ccctgacggg 5820
cttgtctgct cccggcatcc gcttacagac aagctgtgac cgtctccggg agctgcatgt 5880
gtcagaggtt ttcaccgtca tcaccgaaac gcgcgatgac gaaagggcct cgtgatacgc 5940
ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg tggcactttt 6000
cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc aaatatgtat 6060
ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag gaagagtatg 6120
agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg ccttcctgtt 6180
tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt gggtgcacga 6240
gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt tcgccccgaa 6300
gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt attatcccgt 6360
attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa tgacttggtt 6420
gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag agaattatgc 6480
agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac aacgatcgga 6540
ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac tcgccttgat 6600
cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac cacgatgcct 6660
gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac tctagcttcc 6720
cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact tctgcgctcg 6780
gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg tgggtctcgc 6840
ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg 6900
acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca 6960
ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta gattgattta 7020
aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc 7080
aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa 7140
ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca 7200
ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta 7260
actggcttca gcagagcgca gataccaaat actgtccttc tagtgtagcc gtagttaggc 7320
caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca 7380
gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta 7440
ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag 7500
cgaacgacct acaccgaact gagataccta cagcgtgagc attgagaaag cgccacgctt 7560
cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc 7620
acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac 7680
ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac 7740
gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc 7800
tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga gtgagctgat 7860
accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga agcggaagag 7920
cgcccaatac gcaaaccgcc tctccccgcg cgttggccga ttcattaatg cagctggcac 7980
gacaggtttc ccgactggaa agcgggcagt gagcgcaacg caattaatgt gagttagctc 8040
actcattagg caccccaggc tttacacttt atgcttccgg ctcgtatgtt gtgtggaatt 8100
gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc c 8151
<210> 39
<211> 8265
<212> DNA
<213> 人工序列
<220>
<223> CD44v6-4GS2-CAR.28Z NGFR 突变的长 (V6 NML)
<400> 39
aagctttgct cttaggagtt tcctaataca tcccaaactc aaatatataa agcatttgac 60
ttgttctatg ccctaggggg cggggggaag ctaagccagc tttttttaac atttaaaatg 120
ttaattccat tttaaatgca cagatgtttt tatttcataa gggtttcaat gtgcatgaat 180
gctgcaatat tcctgttacc aaagctagta taaataaaaa tagataaacg tggaaattac 240
ttagagtttc tgtcattaac gtttccttcc tcagttgaca acataaatgc gctgctgagc 300
aagccagttt gcatctgtca ggatcaattt cccattatgc cagtcatatt aattactagt 360
caattagttg atttttattt ttgacatata catgtgaatg aaagacccca cctgtaggtt 420
tggcaagcta gcttaagtaa cgccattttg caaggcatgg aaaaatacat aactgagaat 480
agaaaagttc agatcaaggt caggaacaga tggaacagct gaatatgggc caaacaggat 540
atctgtggta agcagttcct gccccggctc agggccaaga acagatggaa cagctgaata 600
tgggccaaac aggatatctg tggtaagcag ttcctgcccc ggctcagggc caagaacaga 660
tggtccccag atgcggtcca gccctcagca gtttctagag aaccatcaga tgtttccagg 720
gtgccccaag gacctgaaat gaccctgtgc cttatttgaa ctaaccaatc agttcgcttc 780
tcgcttctgt tcgcgcgctt atgctccccg agctcaataa aagagcccac aacccctcac 840
tcggggcgcc agtcctccga ttgactgagt cgcccgggta cccgtgtatc caataaaccc 900
tcttgcagtt gcatccgact tgtggtctcg ctgttccttg ggagggtctc ctctgagtga 960
ttgactaccc gtcagcgggg gtctttcatt tgggggctcg tccgggatcg ggagacccct 1020
gcccagggac caccgaccca ccaccgggag gtaagctggc cagcaactta tctgtgtctg 1080
tccgattgtc tagtgtctat gactgatttt atgcgcctgc gtcggtacta gttagctaac 1140
tagctctgta tctggcggac ccgtggtgga actgacgagt tcggaacacc cggccgcaac 1200
cctgggagac gtcccaggga cttcgggggc cgtttttgtg gcccgacctg agtcctaaaa 1260
tcccgatcgt ttaggactct ttggtgcacc ccccttagag gagggatatg tggttctggt 1320
aggagacgag aacctaaaac agttcccgcc tccgtctgaa tttttgcttt cggtttggga 1380
ccgaagccgc gccgcgcgtc ttgtctgctg cagcatcgtt ctgtgttgtc tctgtctgac 1440
tgtgtttctg tatttgtctg aaaatatggg cccgggctag cctgttacca ctcccttaag 1500
tttgacctta ggtcactgga aagatgtcga gcggatcgct cacaaccagt cggtagatgt 1560
caagaagaga cgttgggtta ccttctgctc tgcagaatgg ccaaccttta acgtcggatg 1620
gccgcgagac ggcaccttta accgagacct catcacccag gttaagatca aggtcttttc 1680
acctggcccg catggacacc cagaccaggt ggggtacatc gtgacctggg aagccttggc 1740
ttttgacccc cctccctggg tcaagccctt tgtacaccct aagcctccgc ctcctcttcc 1800
tccatccgcc ccgtctctcc cccttgaacc tcctcgttcg accccgcctc gatcctccct 1860
ttatccagcc ctcactcctt ctctaggcgc ccccatatgg ccatatgaga tcttatatgg 1920
ggcacccccg ccccttgtaa acttccctga ccctgacatg acaagagtta ctaacagccc 1980
ctctctccaa gctcacttac aggctctcta cttagtccag cacgaagtct ggagacctct 2040
ggcggcagcc taccaagaac aactggaccg accggtggta cctcaccctt accgagtcgg 2100
cgacacagtg tgggtccgcc gacaccagac taagaaccta gaacctcgct ggaaaggacc 2160
ttacacagtc ctgctgacca cccccaccgc cctcaaagta gacggcatcg cagcttggat 2220
acacgccgcc cacgtgaagg ctgccgaccc cgggggtgga ccatcctcta gactgccatg 2280
gaagcccctg cccagctgct gttcctgctg ctgctgtggc tgcccgacac caccggcgag 2340
atcgtgctga cacagagccc cgccaccctg tctctgagcc ctggcgagag agccaccctg 2400
agctgtagcg ccagcagcag catcaactac atctactggc tgcagcagaa gcccggccag 2460
gcccccagaa tcctgatcta cctgaccagc aacctggcca gcggcgtgcc cgccagattt 2520
tctggcagcg gcagcggcac cgacttcacc ctgaccatca gcagcctgga acccgaggac 2580
ttcgccgtgt actactgcct gcagtggtcc agcaaccccc tgaccttcgg cggaggcacc 2640
aaggtggaaa tcaagcgggg tggtggtggt tctggtggtg gtggttctga ggtgcagctg 2700
gtggaaagcg gcggaggcct ggtcaagcct ggcggcagcc tgagactgag ctgtgccgcc 2760
agcggcttca ccttcagcag ctacgacatg agctgggtcc gacaggctcc aggcaaggga 2820
ctggaatggg tgtccaccat cagcagcggc ggcagctaca cctactacct ggacagcatc 2880
aagggccggt tcaccatcag ccgggacaac gccaagaaca gcctgtacct gcagatgaac 2940
agcctgcggg ccgaggacac cgccgtctac tactgtgccc ggcagggcct cgactactgg 3000
ggcagaggca ccctggtcac cgtgtccagc ggggatccca aagaggcctg ccccaccggc 3060
ctgtacaccc acagcggaga gtgctgcaag gcctgcaacc tgggagaggg cgtggcccag 3120
ccttgcggcg ccaatcagac cgtgtgcgag ccctgcctgg acagcgtgac cttcagcgac 3180
gtggtgtccg ccaccgagcc ctgcaagcct tgcaccgagt gtgtgggcct gcagagcatg 3240
agcgccccct gcgtggaagc cgacgacgcc gtgtgtagat gcgcctacgg ctactaccag 3300
gacgagacaa ccggcagatg cgaggcctgt agagtgtgcg aggccggcag cggcctggtg 3360
ttcagttgtc aagacaagca gaataccgtg tgtgaagagt gccccgacgg cacctacagc 3420
gacgaagccg ccagagccgc cgacgccgag tgcgaagaga tccccggcag atggatcacc 3480
agaagcaccc cccctgaggg cagcgacagc accgccccta gcacccagga acctgaggcc 3540
cctcccgagc aggacctgat cgcctctaca gtggccggcg tggtgacaac cgtgatgggc 3600
agctctcagc ccgtggtgac acggggcacc accgacaatc ccaaattttg ggtgctggtg 3660
gtggttggtg gagtcctggc ttgctatagc ttgctagtaa cagtggcctt tattattttc 3720
tgggtgagga gtaagaggag caggctcctg cacagtgact acatgaacat gactccccgc 3780
cgccccgggc ccacccgcaa gcattaccag ccctatgccc caccacgcga cttcgcagcc 3840
tatcgctcca gagtgaagtt cagcaggagc gcagacgccc ccgcgtacca gcagggccag 3900
aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag 3960
agacgtggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc tcaggaaggc 4020
ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat tgggatgaaa 4080
ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggtctcag tacagccacc 4140
aaggacacct acgacgccct tcacatgcag gccctgcctc ctcgctaagc atgcaacctc 4200
gatccggatt agtccaattt gttaaagaca ggatatcagt ggtccaggct ctagttttga 4260
ctcaacaata tcaccagctg aagcctatag agtacgagcc atagataaaa taaaagattt 4320
tatttagtct ccagaaaaag gggggaatga aagaccccac ctgtaggttt ggcaagctag 4380
cttaagtaac gccattttgc aaggcatgga aaaatacata actgagaata gagaagttca 4440
gatcaaggtc aggaacagat ggaacagctg aatatgggcc aaacaggata tctgtggtaa 4500
gcagttcctg ccccggctca gggccaagaa cagatggaac agctgaatat gggccaaaca 4560
ggatatctgt ggtaagcagt tcctgccccg gctcagggcc aagaacagat ggtccccaga 4620
tgcggtccag ccctcagcag tttctagaga accatcagat gtttccaggg tgccccaagg 4680
acctgaaatg accctgtgcc ttatttgaac taaccaatca gttcgcttct cgcttctgtt 4740
cgcgcgcttc tgctccccga gctcaataaa agagcccaca acccctcact cggggcgcca 4800
gtcctccgat tgactgagtc gcccgggtac ccgtgtatcc aataaaccct cttgcagttg 4860
catccgactt gtggtctcgc tgttccttgg gagggtctcc tctgagtgat tgactacccg 4920
tcagcggggg tctttcacac atgcagcatg tatcaaaatt aatttggttt tttttcttaa 4980
gtatttacat taaatggcca tagtacttaa agttacattg gcttccttga aataaacatg 5040
gagtattcag aatgtgtcat aaatatttct aattttaaga tagtatctcc attggctttc 5100
tactttttct tttatttttt tttgtcctct gtcttccatt tgttgttgtt gttgtttgtt 5160
tgtttgtttg ttggttggtt ggttaatttt tttttaaaga tcctacacta tagttcaagc 5220
tagactatta gctactctgt aacccagggt gaccttgaag tcatgggtag cctgctgttt 5280
tagccttccc acatctaaga ttacaggtat gagctatcat ttttggtata ttgattgatt 5340
gattgattga tgtgtgtgtg tgtgattgtg tttgtgtgtg tgactgtgaa aatgtgtgta 5400
tgggtgtgtg tgaatgtgtg tatgtatgtg tgtgtgtgag tgtgtgtgtg tgtgtgtgca 5460
tgtgtgtgtg tgtgactgtg tctatgtgta tgactgtgtg tgtgtgtgtg tgtgtgtgtg 5520
tgtgtgtgtg tgtgtgtgtg ttgtgaaaaa atattctatg gtagtgagag ccaacgctcc 5580
ggctcaggtg tcaggttggt ttttgagaca gagtctttca cttagcttgg aattcactgg 5640
ccgtcgtttt acaacgtcgt gactgggaaa accctggcgt tacccaactt aatcgccttg 5700
cagcacatcc ccctttcgcc agctggcgta atagcgaaga ggcccgcacc gatcgccctt 5760
cccaacagtt gcgcagcctg aatggcgaat ggcgcctgat gcggtatttt ctccttacgc 5820
atctgtgcgg tatttcacac cgcatatggt gcactctcag tacaatctgc tctgatgccg 5880
catagttaag ccagccccga cacccgccaa cacccgctga cgcgccctga cgggcttgtc 5940
tgctcccggc atccgcttac agacaagctg tgaccgtctc cgggagctgc atgtgtcaga 6000
ggttttcacc gtcatcaccg aaacgcgcga tgacgaaagg gcctcgtgat acgcctattt 6060
ttataggtta atgtcatgat aataatggtt tcttagacgt caggtggcac ttttcgggga 6120
aatgtgcgcg gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc 6180
atgagacaat aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt 6240
caacatttcc gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct 6300
cacccagaaa cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt 6360
tacatcgaac tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt 6420
tttccaatga tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac 6480
gccgggcaag agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac 6540
tcaccagtca cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct 6600
gccataacca tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg 6660
aaggagctaa ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg 6720
gaaccggagc tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagca 6780
atggcaacaa cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa 6840
caattaatag actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt 6900
ccggctggct ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc 6960
attgcagcac tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg 7020
agtcaggcaa ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt 7080
aagcattggt aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt 7140
catttttaat ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc 7200
ccttaacgtg agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct 7260
tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta 7320
ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc 7380
ttcagcagag cgcagatacc aaatactgtc cttctagtgt agccgtagtt aggccaccac 7440
ttcaagaact ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct 7500
gctgccagtg gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat 7560
aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg 7620
acctacaccg aactgagata cctacagcgt gagcattgag aaagcgccac gcttcccgaa 7680
gggagaaagg cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg 7740
gagcttccag ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga 7800
cttgagcgtc gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc 7860
aacgcggcct ttttacggtt cctggccttt tgctggcctt ttgctcacat gttctttcct 7920
gcgttatccc ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct 7980
cgccgcagcc gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga agagcgccca 8040
atacgcaaac cgcctctccc cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg 8100
tttcccgact ggaaagcggg cagtgagcgc aacgcaatta atgtgagtta gctcactcat 8160
taggcacccc aggctttaca ctttatgctt ccggctcgta tgttgtgtgg aattgtgagc 8220
ggataacaat ttcacacagg aaacagctat gaccatgatt acgcc 8265
<210> 40
<211> 8085
<212> DNA
<213> 人工序列
<220>
<223> CD44v6-4GS2-CAR.28Z NGFR 突变的短 (V6 NMS)
<400> 40
aagctttgct cttaggagtt tcctaataca tcccaaactc aaatatataa agcatttgac 60
ttgttctatg ccctaggggg cggggggaag ctaagccagc tttttttaac atttaaaatg 120
ttaattccat tttaaatgca cagatgtttt tatttcataa gggtttcaat gtgcatgaat 180
gctgcaatat tcctgttacc aaagctagta taaataaaaa tagataaacg tggaaattac 240
ttagagtttc tgtcattaac gtttccttcc tcagttgaca acataaatgc gctgctgagc 300
aagccagttt gcatctgtca ggatcaattt cccattatgc cagtcatatt aattactagt 360
caattagttg atttttattt ttgacatata catgtgaatg aaagacccca cctgtaggtt 420
tggcaagcta gcttaagtaa cgccattttg caaggcatgg aaaaatacat aactgagaat 480
agaaaagttc agatcaaggt caggaacaga tggaacagct gaatatgggc caaacaggat 540
atctgtggta agcagttcct gccccggctc agggccaaga acagatggaa cagctgaata 600
tgggccaaac aggatatctg tggtaagcag ttcctgcccc ggctcagggc caagaacaga 660
tggtccccag atgcggtcca gccctcagca gtttctagag aaccatcaga tgtttccagg 720
gtgccccaag gacctgaaat gaccctgtgc cttatttgaa ctaaccaatc agttcgcttc 780
tcgcttctgt tcgcgcgctt atgctccccg agctcaataa aagagcccac aacccctcac 840
tcggggcgcc agtcctccga ttgactgagt cgcccgggta cccgtgtatc caataaaccc 900
tcttgcagtt gcatccgact tgtggtctcg ctgttccttg ggagggtctc ctctgagtga 960
ttgactaccc gtcagcgggg gtctttcatt tgggggctcg tccgggatcg ggagacccct 1020
gcccagggac caccgaccca ccaccgggag gtaagctggc cagcaactta tctgtgtctg 1080
tccgattgtc tagtgtctat gactgatttt atgcgcctgc gtcggtacta gttagctaac 1140
tagctctgta tctggcggac ccgtggtgga actgacgagt tcggaacacc cggccgcaac 1200
cctgggagac gtcccaggga cttcgggggc cgtttttgtg gcccgacctg agtcctaaaa 1260
tcccgatcgt ttaggactct ttggtgcacc ccccttagag gagggatatg tggttctggt 1320
aggagacgag aacctaaaac agttcccgcc tccgtctgaa tttttgcttt cggtttggga 1380
ccgaagccgc gccgcgcgtc ttgtctgctg cagcatcgtt ctgtgttgtc tctgtctgac 1440
tgtgtttctg tatttgtctg aaaatatggg cccgggctag cctgttacca ctcccttaag 1500
tttgacctta ggtcactgga aagatgtcga gcggatcgct cacaaccagt cggtagatgt 1560
caagaagaga cgttgggtta ccttctgctc tgcagaatgg ccaaccttta acgtcggatg 1620
gccgcgagac ggcaccttta accgagacct catcacccag gttaagatca aggtcttttc 1680
acctggcccg catggacacc cagaccaggt ggggtacatc gtgacctggg aagccttggc 1740
ttttgacccc cctccctggg tcaagccctt tgtacaccct aagcctccgc ctcctcttcc 1800
tccatccgcc ccgtctctcc cccttgaacc tcctcgttcg accccgcctc gatcctccct 1860
ttatccagcc ctcactcctt ctctaggcgc ccccatatgg ccatatgaga tcttatatgg 1920
ggcacccccg ccccttgtaa acttccctga ccctgacatg acaagagtta ctaacagccc 1980
ctctctccaa gctcacttac aggctctcta cttagtccag cacgaagtct ggagacctct 2040
ggcggcagcc taccaagaac aactggaccg accggtggta cctcaccctt accgagtcgg 2100
cgacacagtg tgggtccgcc gacaccagac taagaaccta gaacctcgct ggaaaggacc 2160
ttacacagtc ctgctgacca cccccaccgc cctcaaagta gacggcatcg cagcttggat 2220
acacgccgcc cacgtgaagg ctgccgaccc cgggggtgga ccatcctcta gactgccatg 2280
gaagcccctg cccagctgct gttcctgctg ctgctgtggc tgcccgacac caccggcgag 2340
atcgtgctga cacagagccc cgccaccctg tctctgagcc ctggcgagag agccaccctg 2400
agctgtagcg ccagcagcag catcaactac atctactggc tgcagcagaa gcccggccag 2460
gcccccagaa tcctgatcta cctgaccagc aacctggcca gcggcgtgcc cgccagattt 2520
tctggcagcg gcagcggcac cgacttcacc ctgaccatca gcagcctgga acccgaggac 2580
ttcgccgtgt actactgcct gcagtggtcc agcaaccccc tgaccttcgg cggaggcacc 2640
aaggtggaaa tcaagcgggg tggtggtggt tctggtggtg gtggttctga ggtgcagctg 2700
gtggaaagcg gcggaggcct ggtcaagcct ggcggcagcc tgagactgag ctgtgccgcc 2760
agcggcttca ccttcagcag ctacgacatg agctgggtcc gacaggctcc aggcaaggga 2820
ctggaatggg tgtccaccat cagcagcggc ggcagctaca cctactacct ggacagcatc 2880
aagggccggt tcaccatcag ccgggacaac gccaagaaca gcctgtacct gcagatgaac 2940
agcctgcggg ccgaggacac cgccgtctac tactgtgccc ggcagggcct cgactactgg 3000
ggcagaggca ccctggtcac cgtgtccagc ggggatccca aagaggcctg ccccaccggc 3060
ctgtacaccc acagcggaga gtgctgcaag gcctgcaacc tgggagaggg cgtggcccag 3120
ccttgcggcg ccaatcagac cgtgtgcgag ccctgcctgg acagcgtgac cttcagcgac 3180
gtggtgtccg ccaccgagcc ctgcaagcct tgcaccgagt gtgtgggcct gcagagcatg 3240
agcgccccct gcgtggaagc cgacgacgcc gtgtgtagat gcgcctacgg ctactaccag 3300
gacgagacaa ccggcagatg cgaggcctgt agagtgtgcg aggccggcag cggcctggtg 3360
ttcagttgtc aggacaagca gaacaccgtg tgtgaagagt gccccgacgg cacctacagc 3420
gacgaggccg cccgggccgc cgacgccgag tgcgaggaac ccaaattttg ggtgctggtg 3480
gtggttggtg gagtcctggc ttgctatagc ttgctagtaa cagtggcctt tattattttc 3540
tgggtgagga gtaagaggag caggctcctg cacagtgact acatgaacat gactccccgc 3600
cgccccgggc ccacccgcaa gcattaccag ccctatgccc caccacgcga cttcgcagcc 3660
tatcgctcca gagtgaagtt cagcaggagc gcagacgccc ccgcgtacca gcagggccag 3720
aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag 3780
agacgtggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc tcaggaaggc 3840
ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat tgggatgaaa 3900
ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggtctcag tacagccacc 3960
aaggacacct acgacgccct tcacatgcag gccctgcctc ctcgctaagc atgcaacctc 4020
gatccggatt agtccaattt gttaaagaca ggatatcagt ggtccaggct ctagttttga 4080
ctcaacaata tcaccagctg aagcctatag agtacgagcc atagataaaa taaaagattt 4140
tatttagtct ccagaaaaag gggggaatga aagaccccac ctgtaggttt ggcaagctag 4200
cttaagtaac gccattttgc aaggcatgga aaaatacata actgagaata gagaagttca 4260
gatcaaggtc aggaacagat ggaacagctg aatatgggcc aaacaggata tctgtggtaa 4320
gcagttcctg ccccggctca gggccaagaa cagatggaac agctgaatat gggccaaaca 4380
ggatatctgt ggtaagcagt tcctgccccg gctcagggcc aagaacagat ggtccccaga 4440
tgcggtccag ccctcagcag tttctagaga accatcagat gtttccaggg tgccccaagg 4500
acctgaaatg accctgtgcc ttatttgaac taaccaatca gttcgcttct cgcttctgtt 4560
cgcgcgcttc tgctccccga gctcaataaa agagcccaca acccctcact cggggcgcca 4620
gtcctccgat tgactgagtc gcccgggtac ccgtgtatcc aataaaccct cttgcagttg 4680
catccgactt gtggtctcgc tgttccttgg gagggtctcc tctgagtgat tgactacccg 4740
tcagcggggg tctttcacac atgcagcatg tatcaaaatt aatttggttt tttttcttaa 4800
gtatttacat taaatggcca tagtacttaa agttacattg gcttccttga aataaacatg 4860
gagtattcag aatgtgtcat aaatatttct aattttaaga tagtatctcc attggctttc 4920
tactttttct tttatttttt tttgtcctct gtcttccatt tgttgttgtt gttgtttgtt 4980
tgtttgtttg ttggttggtt ggttaatttt tttttaaaga tcctacacta tagttcaagc 5040
tagactatta gctactctgt aacccagggt gaccttgaag tcatgggtag cctgctgttt 5100
tagccttccc acatctaaga ttacaggtat gagctatcat ttttggtata ttgattgatt 5160
gattgattga tgtgtgtgtg tgtgattgtg tttgtgtgtg tgactgtgaa aatgtgtgta 5220
tgggtgtgtg tgaatgtgtg tatgtatgtg tgtgtgtgag tgtgtgtgtg tgtgtgtgca 5280
tgtgtgtgtg tgtgactgtg tctatgtgta tgactgtgtg tgtgtgtgtg tgtgtgtgtg 5340
tgtgtgtgtg tgtgtgtgtg ttgtgaaaaa atattctatg gtagtgagag ccaacgctcc 5400
ggctcaggtg tcaggttggt ttttgagaca gagtctttca cttagcttgg aattcactgg 5460
ccgtcgtttt acaacgtcgt gactgggaaa accctggcgt tacccaactt aatcgccttg 5520
cagcacatcc ccctttcgcc agctggcgta atagcgaaga ggcccgcacc gatcgccctt 5580
cccaacagtt gcgcagcctg aatggcgaat ggcgcctgat gcggtatttt ctccttacgc 5640
atctgtgcgg tatttcacac cgcatatggt gcactctcag tacaatctgc tctgatgccg 5700
catagttaag ccagccccga cacccgccaa cacccgctga cgcgccctga cgggcttgtc 5760
tgctcccggc atccgcttac agacaagctg tgaccgtctc cgggagctgc atgtgtcaga 5820
ggttttcacc gtcatcaccg aaacgcgcga tgacgaaagg gcctcgtgat acgcctattt 5880
ttataggtta atgtcatgat aataatggtt tcttagacgt caggtggcac ttttcgggga 5940
aatgtgcgcg gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc 6000
atgagacaat aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt 6060
caacatttcc gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct 6120
cacccagaaa cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt 6180
tacatcgaac tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt 6240
tttccaatga tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac 6300
gccgggcaag agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac 6360
tcaccagtca cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct 6420
gccataacca tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg 6480
aaggagctaa ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg 6540
gaaccggagc tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagca 6600
atggcaacaa cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa 6660
caattaatag actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt 6720
ccggctggct ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc 6780
attgcagcac tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg 6840
agtcaggcaa ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt 6900
aagcattggt aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt 6960
catttttaat ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc 7020
ccttaacgtg agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct 7080
tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta 7140
ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc 7200
ttcagcagag cgcagatacc aaatactgtc cttctagtgt agccgtagtt aggccaccac 7260
ttcaagaact ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct 7320
gctgccagtg gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat 7380
aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg 7440
acctacaccg aactgagata cctacagcgt gagcattgag aaagcgccac gcttcccgaa 7500
gggagaaagg cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg 7560
gagcttccag ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga 7620
cttgagcgtc gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc 7680
aacgcggcct ttttacggtt cctggccttt tgctggcctt ttgctcacat gttctttcct 7740
gcgttatccc ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct 7800
cgccgcagcc gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga agagcgccca 7860
atacgcaaac cgcctctccc cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg 7920
tttcccgact ggaaagcggg cagtgagcgc aacgcaatta atgtgagtta gctcactcat 7980
taggcacccc aggctttaca ctttatgctt ccggctcgta tgttgtgtgg aattgtgagc 8040
ggataacaat ttcacacagg aaacagctat gaccatgatt acgcc 8085
Claims (30)
1.一种嵌合的抗原受体(CAR),所述嵌合的抗原受体包含胞外间隔区,所述胞外间隔区包含人低亲和力神经生长因子(LNGFR)或其衍生物胞外域的至少一部分。
2.根据权利要求1所述的CAR,其中所述LNGFR的至少一部分适于促进使用所述CAR转导细胞的免疫选择和鉴定。
3.根据权利要求1或2所述的CAR,其中所述间隔区缺乏LNGFR的胞内域。
4.根据前述任意一项权利要求所述的CAR,其中所述胞外间隔区包含LNGFR或者其片段或衍生物的前三个TNFR-Cys结构域。
5.根据权利要求4所述的CAR,其中间隔区包含LNGFR或者其片段或衍生物的全部四个TNFR-Cys结构域。
6.根据前述任意一项权利要求所述的CAR,其中所述间隔区包含第四个TNFR-Cys结构域(TNFR-Cys 4),但是其中将下述氨基酸序列:NHVDPCLPCTVCEDTERQLRECTRW从所述结构域中除去并替代为下述氨基酸序列:ARA。
7.根据前述任意一项权利要求所述的CAR,其中所述间隔区包含LNGFR中富含丝氨酸/苏氨酸的茎。
8.根据权利要求1至6所述的CAR,其中所述间隔区缺乏LNGFR中富含丝氨酸/苏氨酸的茎。
9.根据权利要求1至3中任意一项所述的CAR,其中所述间隔区包含LNGFR的整个胞外域。
10.根据权利要求1至3中任意一项所述的CAR,其中所述间隔区包含除所述结构域富含丝氨酸/苏氨酸的茎之外的LNGFR的胞外域。
11.根据权利要求1至3中任意一项所述的CAR,其中所述间隔区包含选自下组的序列:SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5或SEQ ID NO:7或者与其具有至少90%同一性的序列。
12.根据权利要求1至3中任意一项所述的CAR,其中所述间隔区由选自下组的序列:SEQID NO:1、SEQ ID NO:3、SEQ ID NO:5或SEQ ID NO:7或者与其具有至少90%同一性的序列组成。
13.一种嵌合的抗原受体(CAR),所述嵌合的抗原受体包含:
(i)抗原特异性靶向结构域;
(ii)根据权利要求1至12中任意一项所定义的胞外间隔区结构域;
(iii)跨膜结构域;
(iv)任选地至少一个共刺激结构域;以及
(v)胞内信号转导结构域。
14.根据权利要求13所述的CAR,其中所述抗原特异性靶向结构域包括抗体或其片段。
15.根据权利要求14所述的CAR,其中所述抗原特异性靶向结构域是单链可变片段。
16.根据权利要求13至15中任意一项所述的CAR,其中所述抗原特异性靶向结构域靶向肿瘤抗原。
17.根据权利要求16所述的CAR,其中所述肿瘤抗原选自下组:CD44、CD19、CD20、CD22、CD23、CD123、CS-1、ROR1、间皮素、c-Met、PSMA、Her2、GD-2、CEA、MAGE A3TCR及其组合。
18.根据权利要求16所述的CAR,其中所述肿瘤抗原是CD44的同种型6(CD44v6)。
19.根据权利要求13至18中任意一项所述的CAR,其中所述跨膜结构域包括T细胞受体复合物、CD28、CD8a及其组合的ζ链跨膜结构域的任意一个或多个。
20.根据权利要求13或19所述的CAR,其中所述共刺激结构域包括来自CD28、CD137(4-1BB)、CD134(OX40)、DaplO、CD27、CD2、CD5、ICAM-1、LFA-1、Lck、TNFR-I、TNFR-II、Fas、CD30、CD40及其组合的任意一个或多个的共刺激结构域。
21.根据权利要求13至20中任意一项所述的CAR,其中所述胞内信号转导结构域包括人CD3ζ链、FcyRIII、FcsRI、Fc受体胞质尾、携带胞质受体的免疫受体酪氨酸活化基序(ITAM)及其组合的一个或多个的胞质信号转导结构域。
22.根据权利要求13至21中任意一项所述的CAR,其中所述抗原特异性靶向结构域靶向CD44v6,所述跨膜结构域包括CD28的跨膜结构域,所述胞内信号转导结构域包括人CD3ζ链的胞内信号转导结构域和所述共刺激结构域包括CD28内共刺激结构域。
23.一种多核苷酸,所述多核苷酸编码权利要求1至22中任意一项所述的CAR。
24.一种载体,所述载体包含权利要求23所述的多核苷酸。
25.根据权利要求24所述的载体,其中所述载体是病毒载体。
26.一种细胞,所述细胞包含根据权利要求1至22中任意一项所述的CAR,根据权利要求23所述的多核苷酸或根据权利要求24或25所述的载体。
27.根据权利要求26所述的细胞,其中所述细胞是T细胞。
28.一种药物组合物,所述药物组合物包含权利要求26或27所述的细胞。
29.根据权利要求13至22中任意一项所述的CAR,或根据权利要求23所述的多核苷酸,或根据权利要求24或25所述的载体或根据权利要求26或27所述的细胞在治疗癌症中的用途。
30.根据权利要求22所述的CAR,编码所述CAR的多核苷酸,包含所述多核苷酸的载体或者包含所述CAR、多核苷酸或载体的宿主细胞在治疗表达CD44的肿瘤中的用途。
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