CN107709548B - 用于增强治疗性免疫细胞的功效的方法 - Google Patents
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Abstract
本发明涉及使用受体(例如嵌合抗原受体‑CAR)的方法,所述受体在结合癌细胞配体后与靶结合分子一起活化免疫应答,以生成增强的抗癌免疫细胞,所述靶结合分子靶向用于去除或中和的蛋白或分子。本发明还涉及具有增强的治疗功效的工程免疫细胞及其用途。
Description
背景技术
免疫细胞可为强大和特异性的“活药物”。免疫细胞具有靶向肿瘤细胞同时保留正常组织的潜力;几项临床观察指示它们可具有主要的抗癌活性。因此,在接受同种异体造血干细胞移植(HSCT)的患者中,T细胞介导的移植物抗宿主病(GvHD)(Weiden,PL等人,N.Engl.J.Med.1979;300(19):1068-1073;Appelbaum,FR Nature,2001;411(6835):385-389;Porter,DL等人,N.Engl.J.Med.1994;330(2):100-106;Kolb,HJ等人Blood.1995;86(5):2041-2050;Slavin,S.等人,Blood.1996;87(6):2195-2204)、以及供体天然杀伤(NK)细胞同种异体反应性(Ruggeri L等人Science.2002;295(5562):2097-2100;Giebel S等人Blood.2003;102(3):814-819;Cooley S等人Blood.2010;116(14):2411-2419)与白血病复发呈负相关。除HSCT背景之外,施用从抑制信号释放T细胞的抗体(Sharma P等人,Nat RevCancer.2011;11(11):805-812.;Pardoll DM.,Nat Rev Cancer.2012;12(4):252-264)、或将其与肿瘤细胞桥接(Topp MS等人J.Clin.Oncol.2011;29(18):2493-2498)在患有实体瘤或白血病的患者中产生主要临床应答。最后,遗传修饰的自体T淋巴细胞的输注在患有难治性白血病和淋巴瘤的患者中诱导完全和持久的缓解(Maude SL等人N Engl J Med.2014;371(16):1507-1517)。
然而,存在通过拓宽其适用性和增强其功效用于改善免疫细胞疗法的显著需要。
发明内容
本发明涉及对于例如癌症治疗具有增强的治疗功效的工程免疫细胞。在某些实施例中,本发明提供了工程免疫细胞,所述工程免疫细胞包括包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子的核苷酸序列的核酸。
在其他实施例中,本发明提供了工程免疫细胞用于治疗癌症的用途,所述工程免疫细胞包含编码免疫活化受体的基因、以及编码与定位结构域连接的靶结合分子的基因,所述用途包括向有此需要的受试者施用治疗量的工程免疫细胞。
在各个实施例中,本发明还提供了用于产生工程免疫细胞的方法,所述方法包括向免疫细胞内引入包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子的核苷酸序列的核酸,由此产生工程免疫细胞。
在一些实施例中,由于宿主中降低的移植物抗宿主病(GvHD)、由宿主的排斥降低或消除、宿主中的延长存活、宿主中通过肿瘤的抑制降低、宿主中降低的自身杀伤、宿主中降低的炎症级联、或宿主中持续的天然/人工受体介导的(例如CAR介导的)信号转导中的一种或多种,工程免疫细胞具有增强的治疗功效。
附图说明
根据本发明的示例性实施例的下述更具体的描述,前文将是显而易见的,如附图中示出的,在所述附图中相同的附图标记指在不同视图各处的相同部分。附图不一定按比例绘制,而是将重点放在示出本发明的实施例上。
图1A-1B是本发明中采用的策略的图示。图1A是CAR介导的癌细胞杀死的总体机制。图1B显示了CAR与不同形式的区室导向的scFv(与定位结构域连接的靶结合分子的例子)的组合表达和可能靶的例子。CAR可替换为可增强免疫细胞能力的其他受体。
图2是含有scFv的构建体连同将它们定位于特定细胞区室的结构域的示意图。缩写:β2M,β-2微球蛋白;SP,信号肽;VL,可变轻链;VH,可变重链;TM,跨膜结构域;HA,人流感血凝素。图中未列出的另外的构建体包括膜结合(mb)myc EEKKMP、mb myc KKTN、mb mycYQRL、mb TGN38细胞质结构域、mb myc RNIKCD、接头(20个氨基酸)mb EEKKMP、以及不含信号肽且在CD8跨膜结构域中具有不同数目的氨基酸的构建体变体。10个氨基酸的接头的核苷酸序列是GGTGGTGGCGGCAGTGGTGGCGGTGGCTCA(SEQ ID NO:61);氨基酸序列是GGGGSGGGGS(SEQ ID NO:62)。20个氨基酸的接头的核苷酸序列是GGTGGTGGCGGCAGTGGTGGCGGTGGCTCAGGCGGTGGTGGCTCCGGTGGCGGTGGCTCT(SEQ ID NO:63);氨基酸序列是GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:41)。各种定位结构域在标题“定位结构域”下指示,并且在一些例子中描述了接头,如所示的。构建体“myc KDEL”和“PEST KDEL”显示了在单个构建体中使用多于一个定位结构域。
图3A-3C显示了通过CD3ε的scFv靶向下调T细胞中的CD3/TCR。图3A显示了在Jurkat细胞中的表面CD3ε表达,所述Jurkat细胞用仅含有绿色荧光蛋白(GFP)的逆转录病毒载体(“模拟”)、或含有GFP加上不同构建体的载体转导,如所示的。在使用与别藻蓝蛋白缀合的抗CD3抗体(BD Biosciences)转导后1周,在细胞膜上的CD3ε表达与模拟转导的细胞的那种相比较。在对GFP阳性细胞门控后执行所有比较。图3B描述了用外周血T淋巴细胞执行的类似实验,所述外周血T淋巴细胞用抗CD3/CD28珠(Lifesciences)扩增。在转染后1周执行染色。图3C显示了流式细胞术图,其示出了在用所示构建体转导后,在Jurkat细胞中的膜CD3ε的下调。每个图的右上象限上的虚线矩形包围GFP+CD3+细胞。
图4显示了在用抗CD3εscFv-KDEL或–PEST或–mb EEKKMP转导后,在Jurkat T细胞中的细胞膜上的CD3ε和TCRαβ下调。在使用与别藻蓝蛋白缀合的抗CD3抗体(BDBiosciences)或与藻红蛋白缀合的抗TCRαβ(Biolegend)转导后1周,测量膜标记物表达。标记为“对照”的线表示模拟转导细胞的标记。虚线垂直线表示用同种型匹配的非反应性抗体获得的染色的上限。
图5显示了抗scFv和CAR可同时表达。流式细胞计数点图表示用抗-CD3别藻蓝蛋白抗体和山羊抗小鼠Fab2生物素加上与藻红蛋白缀合的链霉抗生物素蛋白(以检测CAR)的Jurkat细胞(顶行)或外周血淋巴细胞(底行)的染色。用抗CD3 scFv-myc KDEL构建体、抗CD19-4-1BB-CD3ζ构建体或两者转导细胞。在对GFP阳性细胞门控后,用抗CD3 scFv-mycKDEL转导的那些下调CD3(左柱,左下象限),并且用抗CD19-4-1BB-CD3ζ构建体转导的那些表达CAR(中间柱,右上象限)。用两种构建体转导的很大比例的细胞是CD3阴性和CAR阳性的(右柱,左上象限)。
图6示出了抗CD19 CAR触发T细胞活化和脱颗粒,与CD3/TCR下调无关。Jurkat细胞用抗CD3 scFv-myc KDEL构建体、抗CD19-4-1BB-CD3ζ构建体或两者进行转导。将T细胞活化和脱颗粒与模拟转导的细胞的那种进行比较。细胞单独或与CD19+白血病细胞系OP-1以1:1的比率共培养。在18小时后,使用特异性抗体(来自BD Biosciences)通过流式细胞术测试CD69和CD25的表达;在6小时后测试CD107a的表达(来自BD Biosciences的抗体)。在OP-1细胞的存在下,无论细胞是否还用抗CD3 scFv-KDEL转导,在CAR表达细胞中的CD69和CD25表达都发生;在模拟或抗CD3 scFv-myc KDEL转导的细胞中、或在不存在OP-1细胞的情况下不发生活化。CAR刺激增强不受CD3/TCR下调影响的CD107表达。
图7显示了在T细胞中表达的抗CD19 CAR引起T细胞增殖,与CD3/TCR下调无关。用抗CD3 scFv-myc KDEL构建体和抗CD19-4-1BB-CD3ζ构建体两者转导外周血T淋巴细胞。经转导的T淋巴细胞与用Streck(Omaha,NE)处理的OP-1细胞共培养,以在所示时间内抑制其增殖。将表达抗CD19 CAR的CD3阳性和CD3阴性T淋巴细胞的扩增与模拟转导的T细胞的扩增进行比较。每个符号显示了两个平行培养物的平均细胞计数。不管CD3/TCR表达,CAR T细胞都相等良好地扩增。
图8显示了在外周血T淋巴细胞的膜上的CD7表达,所述外周血T淋巴细胞用仅含有GFP的逆转录病毒载体(“模拟”)、或含有GFP加上和抗CD7 scFv-myc KDEL构建体的载体转导。在使用与藻红蛋白缀合的抗CD7抗体(BD Biosciences)转导后1周,将细胞膜上的CD7表达与模拟转导细胞的那种进行比较。每个图的右上象限上的虚线矩形包围GFP+CD7+细胞。
图9描绘了通过β2-微粒蛋白的scFv靶向下调T细胞中的HLA I类。用抗-β2M scFv-myc KDEL转导Jurkat T细胞。在使用与藻红蛋白缀合的抗HLA-ABC抗体(BD Biosciences)转导后1周,将细胞膜上的HLA-ABC表达与模拟转导细胞的那种进行比较。还显示了用同种型匹配的对照抗体的染色。在对GFP阳性细胞门控后执行分析。
图10描绘了通过KIR2DL1和KIR2DL2/DL3的scFv靶向,下调人NK细胞中的杀伤细胞免疫球蛋白样受体(KIR)2DL1和KIR2DL2/DL3。用抗KIR2DL1-KIR2DL2/DL3 scFv-接头(20)AEKDEL或–EEKKMP转导NK细胞,所述NK细胞离体扩增并且选择用于KIR2DL1表达。在使用与别藻蓝蛋白缀合的抗KIR2DL1抗体(R&D Systems)或与藻红蛋白缀合的抗KIR2DL2/DL3抗体(BD Biosciences)转导后8天,将细胞膜上的相应KIR表达与模拟转导细胞的那种进行比较。还显示了用同种型匹配的对照抗体的染色。在对GFP阳性细胞门控后执行分析。
图11描述了通过scFv靶向下调人NK细胞中的NKG2A。用抗NKG2A scFv-EEKKMP转导离体扩增的NK细胞。在使用与藻红蛋白缀合的NKG2A抗体(Beckman Coulter)转导后8天,将细胞膜上的NKG2A表达与模拟转导细胞的那种进行比较。还显示了用同种型匹配的对照抗体的染色。在对GFP阳性细胞门控后执行分析。
具体实施方式
下文是本发明的示例实施例的描述。
近年来,关于调节免疫细胞的分子途径的知识中的增长已与通过离体操纵其(包括其扩增和遗传工程)的能力中的显著变化平行。现在能够以及时方式可靠地制备高度复杂的临床级免疫细胞产品。免疫细胞的抗癌活性可如何通过离体细胞工程引导和放大的主要例子是嵌合抗原受体(CAR)T细胞的开发(Eshhar,Z.等人,PNAS.1993;90(2):720-724)。
CAR是人工多分子蛋白,其先前已得到描述(Geiger TL等人,J Immunol.1999;162(10):5931-5939;Brentjens RJ等人,NatMed.2003;9(3):279-286;Cooper LJ等人,Blood.2003;101(4):1637-1644)。CAR包含结合特异性靶的细胞外结构域、跨膜结构域和细胞质结构域。细胞外结构域和跨膜结构域可源自用于这种结构域的任何所需源,如例如以引用的方式全文并入本文的美国专利号8,399,645中所述。简言之,可将CAR设计为含有特异性结合靶的抗体的单链可变区(scFv)。scFv可经由跨膜结构域和铰链结构域与T细胞受体(TCR)相关的信号传导分子例如CD3ζ连接。scFv与同源抗原的连接引发信号转导。因此,CAR可瞬时地将细胞毒性T淋巴细胞朝向癌细胞重定向,并且引发肿瘤细胞裂解(Eshhar,Z.等人,PNAS.1993;90(2):720-724;Geiger TL等人,J Immunol.1999;162(10):5931-5939;Brentjens RJ等人,NatMed.2003;9(3):279-286;Cooper LJ等人,Blood.2003;101(4):1637-1644;Imai C等人,Leukemia.2004;18:676-684)。因为单独的CD3ζ信号传导不足以持续活化T细胞(Schwartz RH.Annu Rev Immunol.2003;21:305-334;Zang X和AllisonJP.Clin Cancer Res.2007;13(18Pt 1):5271-5279),已将共刺激分子如CD28和4-1BB(或CD137)掺入CAR构建体内,以促进信号转导。这种双重信号传导设计(“第二代CAR”)可用于引出来自T细胞的有效抗肿瘤活性(Imai C等人,Leukemia.2004;18:676-684;Campana D等人,Cancer J.2014;20(2):134-140)。
美国专利8,399,645中已描述了含有4-1BB和CD3ζ两者的特异性CAR,抗CD19 CAR。表达抗CD19-4-1BB-CD3ζCAR的自体T细胞的输注导致患有慢性淋巴细胞性白血病(CLL)(Porter DL等人,Chimeric antigen receptor-modified T cells in chronic lymphoidleukemia;2011:N Engl J Med.2011;365(8):725-733;Kalos M等人,SciTranslMed.2011;3(95):95ra73)、以及急性成淋巴细胞性白血病(ALL)(Grupp SA等人,N Engl J Med.2013;368(16):1509-1518;Maude SL等人,N Engl J Med.2014;371(16):1507-1517)的患者中的急剧临床应答。这些研究和使用具有不同信号传导模块的CAR的研究(Till BG等人,Blood.2012;119(17):3940-3950;Kochenderfer JN等人,Blood.2012;119(12):2709-2720;Brentjens RJ等人,Blood.2011;118(18):4817-4828;Brentjens RJ等人,SciTransl Med.2013;5(177):177ra138),提供了这种技术的临床潜力和一般而言的免疫治疗的有力证实。
本文描述的方法允许在由天然或人工受体(例如CAR)重定向的免疫细胞中特异性蛋白质的快速去除或失活,因此拓宽了应用潜力并且显著改善工程细胞的功能。该方法部分依赖于单一构建体或多个构建体,其含有免疫活化受体例如CAR(其包含结合特异性靶的细胞外结构域(例如scFv)、跨膜结构域和细胞质结构域)连同靶结合分子,所述靶结合分子结合要去除或中和的靶(例如蛋白质);取决于应用,靶结合分子连接到将其导向特定细胞区室(例如高尔基体或内质网、蛋白酶体或细胞膜)的结构域(即定位结构域)。为了简单起见,连接到定位结构域(LD)的靶结合分子在本文中有时被称为“LD连接的靶结合分子”。
如由本文的教导显而易见的,各种免疫活化受体可适合于本发明的方法。即,可根据本方法使用包含分子的任何受体,在结合(连接)癌细胞上表达的配体(例如肽或抗原)后,所述分子能够活化免疫应答。例如,如上所述,免疫活化受体可为嵌合抗原受体(CAR);用于设计和操纵CAR的方法是本领域已知的(参见,Geiger TL等人,J Immunol.1999;162(10):5931-5939;Brentjens RJ等人,NatMed.2003;9(3):279-286;Cooper LJ等人,Blood.2003;101(4):1637-1644)。另外,可使用具有抗体结合能力的受体(例如CD16-4-1BB-CD3ζ受体–Kudo K等人Cancer Res.2014;74(1):93-103),所述受体与CAR类似,但用抗体结合分子(例如CD16、CD64、CD32)替换scFv。此外,根据本方法,也可使用包含T细胞受体α和β链的T细胞受体,在肿瘤细胞HLA的背景下,所述T细胞受体α和β链结合在肿瘤细胞上表达的肽。另外,还可使用具有分子的其他受体,所述分子通过结合在癌细胞上表达的配体来活化免疫应答–例如NKG2D-DAP10-CD3ζ受体,其结合在肿瘤细胞上表达的NKG2D配体(参见例如Chang YH等人,Cancer Res.2013;73(6):1777-1786)。如本文使用的,所有这些合适的受体统称为“免疫活化受体”或“在结合癌细胞配体后活化免疫应答的受体”。因此,具有由癌细胞配体活化的分子的免疫活化受体可连同根据本方法的LD连接的靶结合分子一起表达。
基于由人工受体重定向的免疫细胞的输注,本方法显著扩展了免疫疗法的潜在应用。所述方法是实用的,并且可容易地掺入临床级细胞处理中。例如,通过在编码CAR和LD连接的靶结合分子的2个cDNA之间插入内部核糖体进入位点(IRES)或2A肽编码区位点,可制备含有例如CAR和LD连接的靶结合分子例如scFv-myc KDEL(或PEST或跨膜)的单个双顺反子构建体。设计三顺反子递送系统以缺失多于一个靶也应该是可行的。可替代地,可执行2个基因的分开转录(同时或序贯)。在癌细胞治疗的背景下,CAR可替换为抗体结合信号传导受体(Kudo K等人,Cancer Res.2014;74(1):93-103)、针对特异性HLA-肽组合的T细胞受体、或通过与癌细胞接触而活化的任何受体(Chang YH等人,Cancer Res.2013;73(6):1777-1786)。使用同时抗CD19-4-1BB-CD3ζCAR和抗CD3εscFv-KDEL的本文所述研究的结果证实CAR的信号传导能力并未受损。
本文测试的两种抗CD3εscFv-KDEL(和–PEST)均稳定地下调CD3以及TCR表达。可使用CD3珠去除残留的CD3+T细胞,这也是临床级别形式中可用的方法。生成响应CAR信号传导的CD3/TCR阴性细胞的能力代表重大进展。使用CAR T细胞的临床研究一般已使用自体T细胞执行。因此,细胞产品的质量因患者而异,并且应答是异质的。由于通过接受者的组织抗原刺激内源性TCR,同种异体T细胞的输注目前是不可能的,因为它具有潜在致命的GvHD的不可接受的高风险。CD3/TCR的下调开放了输注同种异体T细胞的可能性,因为缺乏内源性TCR消除了GvHD的能力。同种异体产物可用最佳的细胞组成(例如富含高度细胞毒性的T细胞、耗尽调节性T细胞等)制备并且选择,使得所输注的细胞具有高CAR表达和功能效力。此外,完全标准化的产品可冷冻保存且可用于使用,不管患者的免疫细胞状态以及他/她对经历单采或大量抽血的适应性。已使用基因编辑工具如核酸酶解决了TCR表达的去除(Torikai H等人Blood,2012;119(24):5697-5705)。虽然这是有效的方法,但它在临床环境中难以实施,因为它需要几轮细胞选择和扩增,伴随延长培养。本文描述的方法具有相当多的实际优点。
另外,LD连接的靶结合分子(例如scFv-myc KDEL、scFv-EEKKMP或scFv-PEST,其中scFv靶向特异性蛋白/分子)可根据本发明用于缺失HLA I类分子,减少同种异体细胞排斥的可能性。虽然同种异体T细胞的输注是CAR T细胞治疗的未来目标,但同种异体天然杀伤(NK)细胞的输注已经用于治疗患有癌症的患者。决定基于NK细胞的治疗成功的关键因素在于NK细胞必须持续足够的数目,以实现可能产生肿瘤细胞减少的效应物:靶比率(MillerJS.Hematology Am Soc Hematol Educ Program.2013;2013:247-253)。然而,当输注同种异体细胞时,其持久性是有限的。给予患者的免疫抑制化学疗法允许所输注的NK细胞的瞬时移植物植入,但这些在输注的2-4周内被排斥(Miller JS等人Blood.2005;105:3051-3057;Rubnitz JE等人,J Clin Oncol.2010;28(6):955-959)。与器官移植相反,继续免疫抑制并非选项,因为免疫抑制药物也抑制NK细胞功能。因为排斥主要由接受者的CD8+T淋巴细胞识别HLA I类分子介导,所以从所输注的NK细胞(或T细胞)中去除HLA I类分子将减小或取消排斥率,延长同种异体细胞的存活,并且因此延长其抗肿瘤能力。
此外,LD连接的靶结合分子可根据本发明用于靶向抑制性受体。具体地,从抑制性信号释放T细胞的抗体如抗PD1或抗CTLA-4的施用已产生了显著的临床应答(Sharma P等人,Nat Rev Cancer.2011;11(11):805-812;Pardoll DM.Nat Rev Cancer.2012;12(4):252-264)。CAR-T细胞,特别是针对实体瘤的那些,可被类似的机制抑制。因此,针对PD1、CTLA-4、Tim3或其他抑制性受体的靶结合分子(例如scFv或配体)的表达将阻止这些分子的表达(如果与例如KDEL(SEQ ID NO:4)、EEKKMP(SEQ ID NO:64)或PEST基序SHGFPPEVEEQDDGTLPMSCAQESGMDRHPAACASARINV(SEQ ID NO:7)连接),或阻止受体与其配体的结合(如果与跨膜结构域连接),并且持续CAR介导的信号转导。在NK细胞中,抑制性受体的例子包括杀伤细胞免疫球蛋白样受体(KIR)和NKG2A(Vivier E等人,Science,2011;331(6013):44-49)。
本发明的方法还使得能够靶向顺应CAR指导的T细胞治疗的更多靶。CAR指导治疗的主要限制之一是由肿瘤细胞表达的特异性抗原的缺乏。在血液恶性肿瘤例如白血病和淋巴瘤的情况下,在非造血细胞中未表达的分子可为潜在的靶,但不能用作CAR靶,因为它们也在T细胞和/或NK细胞上表达。在免疫细胞上表达这种CAR可能导致免疫细胞本身由于“自相残杀”机制的死亡,使其抗癌能力无效。如果靶分子可从免疫细胞中去除而无不利的功能效应,则可表达具有相应特异性的CAR。这开放了靶向血液恶性肿瘤的许多新的机会。可能靶的例子包括在多发性骨髓瘤中表达的CD38、在T细胞白血病和淋巴瘤中表达的CD7、在急性白血病中表达的Tim-3、在霍奇金病中表达的CD30、在所有血液恶性肿瘤中表达的CD45和CD52。这些分子也在很大比例的T细胞和NK细胞中表达。
此外,已显示通过活化的免疫细胞分泌的细胞因子触发细胞因子释放综合征和巨噬细胞活化综合征,呈现免疫细胞治疗的严重不良反应(Lee DW等人,Blood.2014;124(2):188-195)。因此,LD连接的靶结合分子可根据本发明用于阻断细胞因子例如IL-6、IL-2、IL-4、IL-7、IL-10、IL-12、IL-15、IL-18、IL-21、IL-27、IL-35、干扰素(IFN)-γ、IFN-β、IFN-α、肿瘤坏死因子(TNF)-α和转化生长因子(TGF)-β,这可促成这种炎症级联。
相应地,在一个实施例中,本发明涉及工程免疫细胞,所述工程免疫细胞包括包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子的核苷酸序列的核酸。
如本文使用的,“工程”免疫细胞包括与天然存在的免疫细胞相比,已进行遗传修饰的免疫细胞。例如,根据本发明方法生产的工程T细胞携带包含核苷酸序列的核酸,所述核苷酸序列不天然存在于它源自其的T细胞中。在一些实施例中,本发明的工程免疫细胞包括嵌合抗原受体(CAR)和与定位结构域连接的靶结合分子(LD连接的靶结合分子)。在一个特定实施例中,本发明的工程免疫细胞包括抗CD19-4-1BB-CD3ζCAR和与定位结构域连接的抗CD3 scFv。
在某些实施例中,工程免疫细胞是工程T细胞、工程天然杀伤(NK)细胞、工程NK/T细胞、工程单核细胞、工程巨噬细胞或工程树突状细胞。
在某些实施例中,如本文使用的,“免疫活化受体”指在结合癌细胞配体后活化免疫应答的受体。在一些实施例中,免疫活化受体包含这样的分子,在结合(连接)癌细胞上表达的配体(例如肽或抗原)后,所述分子能够活化免疫应答。在一个实施例中,免疫活化受体是嵌合抗原受体(CAR);用于设计和操纵CAR的方法是本领域已知的。在其他实施例中,免疫活化受体是抗体结合受体,其与CAR类似,但用抗体结合分子(例如CD16、CD64、CD32)替换scFv(参见例如CD16-4-1BB-CD3ζ受体–Kudo K等人Cancer Res.2014;74(1):93-103)。在各个实施例中,根据本方法,也可使用包含T细胞受体α和β链的T细胞受体,在肿瘤细胞HLA的背景下,所述T细胞受体α和β链结合在肿瘤细胞上表达的肽。在某些实施例中,还可使用具有分子的其他受体,所述分子通过结合在癌细胞上表达的配体来活化免疫应答–例如NKG2D-DAP10-CD3ζ受体,其结合在肿瘤细胞上表达的NKG2D配体(参见例如Chang YH等人,Cancer Res.2013;73(6):1777-1786)。在结合(连接)癌细胞上表达的配体(例如肽或抗原)后能够活化免疫应答的所有这些合适的受体统称为“免疫活化受体”。如本领域技术人员应了解的,免疫活化受体不需要含有抗体或抗原结合片段(例如scFv);相反,结合靶分子的免疫活化受体的一部分可源自例如受体-配体对中的受体、或受体-配体对中的配体。
在某些方面,免疫活化受体结合在肿瘤细胞的表面上表达的分子,包括但不限于CD20、CD22、CD33、CD2、CD3、CD4、CD5、CD7、CD8、CD45、CD52、CD38、CS-1、TIM3、CD123、间皮素、叶酸盐受体、HER2-neu、表皮-生长因子受体和表皮生长因子受体。在一些实施例中,免疫活化受体是CAR(例如抗CD19-4-1BB-CD3ζCAR)。在某些实施例中,免疫活化受体包含抗体或其抗原结合片段(例如scFv),其结合在肿瘤细胞的表面上表达的分子,包括但不限于CD20、CD22、CD33、CD2、CD3、CD4、CD5、CD7、CD8、CD45、CD52、CD38、CS-1、TIM3、CD123、间皮素、叶酸盐受体、HER2-neu、表皮-生长因子受体和表皮生长因子受体。针对在肿瘤细胞的表面上表达的这些分子的抗体是本领域已知和可获得的。例如,针对CD3和CD7的抗体是商购可得和本领域已知的。这样的抗体以及由其衍生的抗体片段(例如scFv)可用于本发明中,如本文所示。此外,产生针对靶蛋白的抗体和抗体片段的方法是本领域众所周知和常规的。
根据本发明的免疫活化受体(例如CAR)的跨膜结构域可源自单次穿膜蛋白,包括但不限于CD8α、CD8β、4-1BB、CD28、CD34、CD4、FcεRIγ、CD16(例如CD16A或CD16B)、OX40、CD3ζ、CD3ε、CD3γ、CD3δ、TCRα、CD32(例如CD32A或CD32B)、CD64(例如CD64A、CD64B或CD64C)、VEGFR2、FAS和FGFR2B。在一些例子中,膜蛋白不是CD8α。跨膜结构域也可为非天然存在的疏水蛋白区段。
免疫活化受体(例如CAR)的铰链结构域可源自蛋白质例如CD8α或IgG。铰链结构域可为CD8α的跨膜结构域或铰链结构域的片段,或非天然存在的肽,例如由不同长度的亲水残基组成的多肽,或(GGGGS)n(SEQ ID NO:8)多肽,其中n是例如3-12(包括端值)的整数。
免疫活化受体(例如CAR)的信号传导结构域可源自CD3ζ、FcεRIγ、DAP10、DAP12或已知在免疫细胞中递送活化信号的其他分子。受体的至少一个共刺激信号传导结构域可为共刺激分子,例如4-1BB(也称为CD137)、CD28、CD28LL→GG变体、OX40、ICOS、CD27、GITR、HVEM、TIM1、LFA1或CD2。这样的分子是本领域中容易获得和已知的。
如本领域技术人员应了解的,免疫活化受体的组分可进行改造,以包含如本文所述的许多功能组合,以产生所需结果。使用特定的CAR抗CD19-4-1BB-CD3ζ作为例子,结合分子的抗体(例如或其抗原结合片段,例如scFv)可取代结合不同分子的抗体,如本文所述(例如抗CD20、抗CD33、抗CD123等,而不是抗CD19)。在其他实施例中,共刺激分子(该具体例子中的4-1BB)也可用不同的共刺激分子例如CD28来改变。在一些实施例中,刺激分子(该具体例子中的CD3ζ)可被另一种已知的刺激分子取代。在各个实施例中,受体的跨膜结构域也可根据需要而变化。这种免疫活化受体的功能性的设计、生产和测试可由本领域技术人员容易地确定。类似地,编码这种免疫活化受体的核酸的设计、递送到细胞内和表达是本领域容易知道和可获得的。
如本文使用的,术语“核酸”指包含多个核苷酸单体(例如核糖核苷酸单体或脱氧核糖核苷酸单体)的聚合物。“核酸”包括例如基因组DNA、cDNA、RNA和DNA-RNA杂交分子。核酸分子可为天然存在的、重组的或合成的。另外,核酸分子可为单链、双链或三链的。在一些实施例中,核酸分子可为经修饰的。在双链聚合物的情况下,“核酸”可指分子的任一链或两条链。
提及核酸的术语“核苷酸序列”指通过共价键连接的连续系列的核苷酸,例如磷酸键(例如磷酸二酯、烷基和芳基-膦酸酯、硫代磷酸酯、磷酸三酯键)、和/或非磷酸键(例如肽和/或氨基磺酸盐键)。在某些实施例中,编码例如与定位结构域连接的靶结合分子的核苷酸序列是异源序列(例如具有不同物种或细胞类型起源的基因)。
术语“核苷酸”和“核苷酸单体”指天然存在的核糖核苷酸或脱氧核糖核苷酸单体,及其非天然存在的衍生物和类似物。相应地,核苷酸可包括例如包含天然存在的碱基(例如腺苷、胸苷、鸟苷、胞苷、尿苷、肌苷、脱氧腺苷、脱氧胸苷、脱氧鸟苷或脱氧胞苷)的核苷酸、以及包含本领域已知的经修饰的碱基的核苷酸。
如本领域技术人员应了解的,在一些方面,核酸还包含质粒序列。质粒序列可包括例如选自启动子序列、选择标记物序列和基因座靶向序列的一个或多个序列。
如本文使用的,编码与定位结构域连接的靶结合分子的基因有时被称为“LD连接的靶结合分子”。
在某些实施例中,靶结合分子是抗体或其抗原结合片段。如本文使用的,“抗体”指完整抗体或抗体的抗原结合片段,包括已进行修饰或改造、或其为人抗体的完整抗体或抗原结合片段。已进行修饰或改造的抗体的例子是嵌合抗体、人源化抗体、多互补位(multiparatopic)抗体(例如双互补位抗体)和多特异性抗体(例如双特异性抗体)。抗原结合片段的例子包括Fab、Fab'、F(ab')2、Fv、单链抗体(例如scFv)、微型抗体和双抗体。
“Fab片段”包含一条轻链以及一条重链的CH1和可变区。Fab分子的重链不能与另一个重链分子形成二硫键。
“Fc”区含有包含抗体的CH2和CH3结构域的两个重链片段。两个重链片段通过两个或更多个二硫键并且通过CH3结构域的疏水相互作用保持在一起。
“Fab'片段含有一条轻链以及一条重链的一部分,所述部分含有VH结构域和CH1结构域、以及在CH1和CH2结构域之间的区域,使得可在两个Fab'片段的两条重链之间形成链间二硫键,以形成F(ab′)2分子。
“F(ab′)2片段”含有两条轻链和两条重链,含有在CH1和CH 2结构域之间的恒定区的一部分,使得在两条重链之间形成链间二硫键。F(ab′)2片段因此由两个Fab'片段组成,所述两个Fab'片段通过两条重链之间的二硫键保持在一起。
“Fv区”包含来自重链和轻链两者的可变区,但缺少恒定区。
在一个特定实施例中,靶结合分子是单链Fv抗体(“scFv抗体”)。scFv指包含抗体的VH和VL结构域的抗体片段,其中这些结构域存在于单条多肽链中。一般地,Fv多肽还包含VH和VL结构域之间的多肽接头,其使得scFv能够形成用于抗原结合的所需结构。关于scFv的综述,参见Pluckthun(1994)The Pharmacology Of Monoclonal Antibodies,第113卷,Rosenburg和Moore编辑Springer-Verlag,New York,第269-315页。还参见PCT公开号WO88/01649以及美国专利号4,946,778和5,260,203。例如,本文公开的scFv的VH和VL结构域之间的接头包含例如GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:41)或GGGGSGGGGSGGGGS(SEQ IDNO:43)。如本领域技术人员应了解的,可就最佳功能设计和测试各种合适的接头,如本领域中提供的且如本文公开的。
其为LD连接的靶结合分子的部分的scFv不一定与在例如嵌合抗原受体(CAR)或类似的抗体结合信号传导受体的背景下存在的scFv相同。在一些实施例中,其为LD连接的靶结合分子的部分的scFv与在例如嵌合抗原受体(CAR)或类似的抗体结合信号传导受体的背景下存在的scFv相同。
在一些实施例中,包含编码靶结合分子(例如在LD连接的靶结合分子的上下文中的scFv)的核苷酸序列的核酸包含一个或多个序列,其与SEQ ID NO:14、15、18、19、22、23、26、27、30、31、34、35、38或39中的任何一个或多个具有至少80%、至少85%、至少88%、至少90%、至少92%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。
术语“序列同一性”意指当例如通过程序GAP或BESTFIT使用缺省缺口权重进行最佳比对时,两个核苷酸或氨基酸序列共享例如至少70%序列同一性、或至少80%序列同一性、或至少85%序列同一性、或至少90%序列同一性、或至少95%序列同一性或更多。对于序列比较,通常一个序列充当测试序列与之进行比较的参考序列(例如亲本序列)。当使用序列比较算法时,将测试序列和参考序列输入计算机内,需要时,指定子序列坐标,并且指定序列算法程序参数。基于指定的程序参数,序列比较算法然后计算测试序列相对于参考序列的序列同一性百分比。
用于比较的序列的最佳比对可例如通过下述进行:Smith&Waterman,Adv.Appl.Math.2:482(1981)的局部同源性算法,Needleman&Wunsch,J.Mol.Biol.48:443(1970)的同源性比对算法,Pearson&Lipman,Proc.Nat'l.Acad.Sci.USA 85:2444(1988)的相似性搜索方法,这些算法的计算机化实现(Wisconsin Genetics Software Package,Genetics Computer Group,575Science Dr.,Madison,Wis.中的GAP、BESTFIT、FASTA和TFASTA),或目视检查(一般参见Ausubel等人,Current Protocols in MolecularBiology)。适合于确定序列同一性和序列相似性百分比的算法的一个例子是BLAST算法,其在Altschul等人,J.Mol.Biol.215:403(1990)中描述。用于执行BLAST分析的软件可通过美国国家生物技术信息中心(National Center for Biotechnology Information)公开获得(可通过美国国立卫生研究院(National Institutes of Health)NCBI互联网服务器公开访问)。通常,缺省程序参数可用于执行序列比较,尽管也可使用定制参数。对于氨基酸序列,BLASTP程序使用字长(W)3、期望值(E)10和BLOSUM62评分矩阵作为缺省值(参见Henikoff&Henikoff,Proc.Natl.Acad.Sci.USA 89:10915(1989))。
在某些实施例中,抗体(例如scFv)分别包含具有SEQ ID NO:12和13;SEQ ID NO:16和17;SEQ ID NO:20和21;SEQ ID NO:24和25;SEQ ID NO:28和29;SEQ ID NO:32和33;或SEQ ID NO:36和37中所示的氨基酸序列的VH和VL。在一些实施例中,抗体(例如scFv)包含VH和VL,其具有的序列各自分别与SEQ ID NO:12和13;SEQ ID NO:16和17;SEQ ID NO:20和21;SEQ ID NO:24和25;SEQ ID NO:28和29;SEQ ID NO:32和33;或SEQ ID NO:36和37中所示的VH和VL序列具有至少90%的序列同一性、至少91%的序列同一性、至少92%的序列同一性、至少93%的序列同一性、至少94%的序列同一性、至少95%的序列同一性、至少96%的序列同一性、至少97%的序列同一性、至少98%的序列同一性、至少99%的序列同一性、或100%的序列同一性。
“双抗体”是具有两个抗原结合位点的小抗体片段。该片段包含与相同多肽链中的轻链可变区(VL)连接的重链可变区(VH)(VH-VL或VL-VH)。通过使用太短而不允许同一链上的两个结构域之间的配对的接头,结构域被迫与另一条链的互补结构域配对并且产生两个抗原结合位点。双抗体在例如专利文件EP 404,097;WO 93/11161;和Holliger等人,(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448中描述。
在某些实施例中,抗体是三抗体或四抗体。设计和生产三抗体和四抗体的方法是本领域已知的。参见例如Todorovska等人,J.Immunol.Methods248(1-2):47-66,2001。
“结构域抗体片段”是仅含有重链的可变区或轻链的可变区的免疫功能的免疫球蛋白片段。在一些情况下,两个或更多个VH区与肽接头共价连接,以产生二价结构域抗体片段。二价结构域抗体片段的两个VH区可靶向相同或不同的抗原。
在一些实施例中,抗体进行修饰或改造。进行修饰或改造的抗体的例子包括嵌合抗体、多互补位抗体(例如双互补位抗体)和多特异性抗体(例如双特异性抗体)。
如本文使用的,“多补位抗体”意指包含至少两个单结构域抗体的抗体,其中至少一个单结构域抗体针对抗原上的第一抗原决定簇,并且至少一个其他单结构域抗体针对相同抗原上的第二抗原决定簇。因此,例如,“双互补位”抗体包含针对抗原上的第一抗原决定簇的至少一个单结构域抗体、以及针对相同抗原上的第二抗原决定簇的至少一个进一步的单结构域抗体。
如本文使用的,“多特异性抗体”意指包含至少两个单结构域抗体的抗体,其中至少一个单结构域抗体针对第一抗原,并且至少一个其他单结构域抗体针对第二抗原(不同于第一抗原)。因此,例如,“双特异性”抗体是包含针对第一抗原的至少一个单结构域抗体和针对第二抗原(例如不同于第一抗原)的至少一个进一步的单结构域抗体的“双特异性”抗体。
在一些实施例中,本文公开的抗体是单克隆抗体,例如鼠单克隆抗体。产生单克隆抗体的方法是本领域已知的。参见,例如,Pluckthun(1994)The Pharmacology ofMonoclonal Antibodies,第113卷,Rosenburg和Moore编辑Springer-Verlag,New York,第269-315页。
在各个实施例中,在LD连接的靶结合分子的上下文中的靶结合分子是与靶分子结合的受体或配体。例如,该靶结合分子可为结合PD-1(例如PD-L1或PD-L2)的配体。因此,如本领域技术人员应了解的,靶结合分子可为结合靶分子的抗体或配体/受体。
如本文使用的,在LD连接的靶结合分子的上下文中的“连接”指与编码一个或多个定位结构域的一个或多个基因直接在框中相邻(例如不含接头)的编码靶结合分子的基因。可替代地,如本文所述,编码靶结合分子的基因可通过接头序列与编码一个或多个定位结构域的一个或多个基因连接。本领域已知的各种合适的接头可用于将靶结合分子与定位结构域栓系。例如,可根据本发明使用非天然存在的肽,例如由不同长度的亲水残基组成的多肽,或(GGGGS)n(SEQ ID NO:8)多肽,其中n是例如包括3-12在内的整数。在特定实施例中,接头包含例如GGGGSGGGGS(SEQ ID NO:62)。在一些实施例中,接头包含例如GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:41)。在各个实施例中,具有约5至约100个氨基酸(包括端值)的长度的肽接头可用于本发明。在某些实施例中,具有约20至约40个氨基酸(包括端值)的长度的肽接头可用于本发明中。在一些实施例中,具有至少5个氨基酸、至少10个氨基酸、至少15个氨基酸、至少20个氨基酸、至少25个氨基酸、至少30个氨基酸、至少35个氨基酸、或至少40个氨基酸的长度的肽接头可用于本发明中。如本领域技术人员应了解的,这种接头序列以及这种接头序列的变体是本领域已知的。设计掺入接头序列的构建体的方法以及评价功能性的方法对于本领域技术人员是容易获得的。
在某些实施例中,LD连接的靶结合分子与在免疫细胞的表面上表达的靶结合。在一些实施例中,LD连接的靶结合分子抑制靶分子的活性或功能。例如,如本文公开的,LD连接的靶结合分子可设计为与例如CD3、CD7、CD45、hB2MG、KIR2DL1、KIR2DL2/DL3或NKG2A结合,由此下调这些分子的细胞表面表达。这些分子的下调可通过例如将分子定位/靶向用于降解和/或内化来实现。在其他实施例中,LD连接的靶结合分子致使靶无活性(例如靶可不再与其同源配体或受体相互作用和/或结合)。
在一些实施例中,本发明的工程免疫细胞具有增强的治疗功效。如本文使用的,“增强的治疗功效”指宿主中降低的移植物抗宿主病(GvHD)、由宿主的排斥降低或消除、宿主中的延长存活、宿主中通过肿瘤的抑制降低、宿主中降低的自身杀伤、宿主中降低的炎症级联、或宿主中持续的CAR介导的信号转导中的一种或多种。
在本发明的某些实施例中,在LD连接的靶结合分子的上下文中的靶结合分子结合CD3/T细胞受体(TCR)复合物中的分子、细胞因子、人白细胞抗原(HLA)I类分子或下调免疫应答的受体。
在某些实施例中,CD3/TCR复合物中的分子可为CD3ε、TCRα、TCRβ、TCRγ、TCRδ、CD3δ、CD3γ或CD3ζ。在一个特定实施例中,分子是CD3ε。
在另一个实施例中,HLA I类分子是β-2微球蛋白、α1-微球蛋白、α2-微球蛋白或α3-微球蛋白。
在其他实施例中,下调免疫应答的受体选自例如PD-1、CTLA-4、Tim3、杀伤细胞免疫球蛋白样受体(KIR–例如KIR2DL1(也称为CD158a)、KIR2DL2/DL3(也称为CD158b))、CD94或NKG2A(也称为CD159a)、蛋白酪氨酸磷酸酶如含Src同源性区域2结构域的磷酸酶(SHP)-1和SHP-2。因此,如本文所述,这样的受体可通过部分LD连接的靶结合分子靶向。
在各个实施例中,可用部分LD连接的靶结合分子靶向的细胞因子的例子包括例如白细胞介素(IL)-6、IL-2、IL-4、IL-7、IL-10、IL-12、IL-15、IL-18、IL-21、IL-27、IL-35、干扰素(IFN)-γ、IFN-β、IFN-α、肿瘤坏死因子(TNF)-α、或生长因子(TGF)-β。
在一个进一步的方面,LD连接的靶结合分子结合选自例如CD2、CD4、CD5、CD7、CD8、CD30、CD38、CD45、CD52或CD127的分子。
产生针对任何靶蛋白的抗体及其抗体片段的方法是本领域众所周知和常规的。此外,如本文例示的,针对各种靶例如CD3和CD7的商购可得的抗体可用于生成如本文例示的LD连接的靶结合分子。本领域已知的抗体以及由其衍生的抗体片段(例如scFv)可用于本发明中,如本文例示的。
在其他方面,LD连接的靶结合分子的定位结构域包含内质网(ER)保留序列KDEL(SEQ ID NO:4)、或者其他ER或高尔基体保留序列,例如KKXX(SEQ ID NO:9)、KXD/E(SEQ IDNO:10)(其中X可为任何氨基酸-参见Gao C等人,Trends in Plant Science 19:508-515,2014)和YQRL(SEQ ID NO:11)(参见Zhan J等人,Cancer Immunol Immunother 46:55-60,1998);包含例如“PEST”基序-SHGFPPEVEEQDDGTLPMSCAQESGMDRHPAACASARINV(SEQ ID NO:7)的蛋白酶体靶向序列;和/或将靶结合分子靶向细胞膜的序列,例如CD8α跨膜结构域或另一种单次穿膜蛋白的跨膜,如本文所述(例如CD8α、CD8β、4-1BB、CD28、CD34、CD4、FcεRIγ、CD16(例如CD16A或CD16B)、OX40、CD3ζ、CD3ε、CD3γ、CD3δ、TCRα、CD32(例如CD32A或CD32B)、CD64(例如CD64A、CD64B或CD64C)、VEGFR2、FAS或FGFR2B)。本文例示的特定定位结构域(序列)的例子显示于图2中。各种其他定位序列是本领域已知和可用的。
如图2所示,本发明的LD连接的靶结合分子可包含一个或多个定位结构域。例如,LD连接的靶结合分子可具有连接在一起的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、或至少十个定位结构域。当在给定的LD连接的靶结合分子中使用多于一个定位结构域时,每个定位结构域可用或不用任何间插接头连接。例如,如图2所示,定位结构域CD8TM、PEST基序和EEKKMP可用于单个LD连接的靶结合分子中。虽然这个特定构建体显示了不含任何间插接头的定位结构域,但可在一些或所有定位结构域之间掺入各种间插接头。其他例子显示于图2中。
如本领域技术人员应了解的,免疫活化受体和/或LD连接的靶结合分子可设计为结合本文公开的靶,以及本文公开的靶的变体。例如,免疫活化受体和/或LD连接的靶结合分子可设计为结合CD3/TCR复合物中的分子、或其天然存在的变体分子。这种天然存在的变体可具有与分子的野生型形式相同的功能。在其他实施例中,变体可具有相对于分子的野生型形式改变的功能(例如赋予患病状态)。
如本领域技术人员应了解的,图2所示的LD连接的靶结合分子构建体的各种组分可以不同的组合取代(例如含有不同的接头、不同的定位序列、不同的scFv等),只要该组合产生功能性LD连接的靶结合分子。评价特定构建体的功能性的方法在本领域技术人员的知识范围内,如本文公开的。
在进一步的方面,本发明涉及工程免疫细胞用于治疗癌症的用途,所述工程免疫细胞包括包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子(例如scFv)的核苷酸序列的核酸,所述用途包括向有此需要的受试者施用治疗量的工程免疫细胞。
在另一个方面,本发明涉及工程免疫细胞用于治疗癌症的用途,所述工程免疫细胞包括包含编码嵌合抗原受体(CAR)的核苷酸序列的核酸、以及包含编码与定位结构域连接的单链可变片段(scFv)的核苷酸序列的核酸,所述用途包括向有此需要的受试者施用治疗量的工程免疫细胞。
在其他方面,本发明涉及工程免疫细胞用于治疗自身免疫病症的用途,所述工程免疫细胞包括包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子(例如scFv)的核苷酸序列的核酸,所述用途包括向有此需要的受试者施用治疗量的工程免疫细胞。
在其他方面,本发明还涉及工程免疫细胞用于治疗感染性疾病的用途,所述工程免疫细胞包括包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子(例如scFv)的核苷酸序列的核酸,所述用途包括向有此需要的受试者施用治疗量的工程免疫细胞。
在各个实施例中,免疫活化受体是CAR(例如抗CD19-4-1BB-CD3ζCAR)。
在其他实施例中,与定位结构域连接的单链可变片段(scFv)选自图2所示的任何一种或多种构建体。
在一些方面,通过输注到受试者内来施用工程免疫细胞。输注免疫细胞(例如同种异体或自体免疫细胞)的方法是本领域已知的。向接受者施用足够数目的细胞以便改善疾病的症状。通常,在单个设置中输注107至1010个细胞的剂量,例如109个细胞的剂量。输注以单个109细胞剂量施用或分成几个109细胞剂量。需要或指示时,输注的频率可为每3到30天甚至更长的间隔。输注的数量一般为至少1次输注/受试者,且优选至少3次输注,如耐受的,或直到疾病症状已得到改善。可以50-250ml/小时的速率静脉内输注细胞。其他合适的施用方式包括动脉内输注、直接注射到肿瘤内和/或手术后的肿瘤床灌注、在肿瘤部位处在人工支架中植入、鞘内施用和眼内施用。使本发明适应这种递送方式的方法对于本领域技术人员是容易获得的。
在某些方面,待治疗的癌症是实体瘤或血液恶性肿瘤。血液恶性肿瘤的例子包括急性髓样白血病、慢性骨髓性白血病、骨髓发育不良、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、多发性骨髓瘤、霍奇金淋巴瘤和非霍奇金淋巴瘤。实体瘤的例子包括肺癌、黑素瘤、乳腺癌、前列腺癌、结肠癌、肾细胞癌、卵巢癌、胰腺癌、肝细胞癌、成神经细胞瘤、横纹肌肉瘤、脑肿瘤。
在另一个实施例中,本发明涉及用于产生本发明的工程免疫细胞的方法,所述方法包括向免疫细胞内引入包含编码免疫活化受体的核苷酸序列的核酸、以及包含编码与定位结构域连接的靶结合分子的核苷酸序列的核酸,由此产生工程免疫细胞。
在某些实施例中,将包含核苷酸序列的核酸离体引入免疫细胞内。在其他实施例中,将包含核苷酸序列的核酸在体内引入免疫细胞内。
在一些实施例中,“免疫细胞”包括例如T细胞、天然杀伤(NK)细胞、NK/T细胞、单核细胞、巨噬细胞或树突状细胞。
包含要引入的核苷酸序列的核酸可为单个双顺反子构建体,其含有本文所述的免疫活化受体、以及与定位结构域连接的靶结合分子(例如scFv)。如本文所述,通过在编码如本文所述的免疫活化受体(例如CAR)和靶结合分子(例如scFv)的2个cDNA之间插入内部核糖体进入位点(IRES)或2A肽编码区位点,可制备单个双顺反子构建体。设计三顺反子递送系统以缺失多于一个靶也应该是可行的。可替代地,可执行各个构建体(例如CAR和LD连接的靶结合分子)的分开转录(同时或序贯)。引入外源核酸的方法在本文中例示,并且是本领域众所周知的。
如本文使用的,不定冠词“一个”和“一种”应当理解为意指“至少一个/种”,除非明确指出相反。
示例
方法
来自小鼠抗人CD3杂交瘤的scFv的克隆
将分泌抗人CD3单克隆抗体(IgG2a同种型;Creative Diagnostics,Shirley,NY)的PLU4杂交瘤细胞在IMDM加上GlutaMAX培养基(Life Technologies,Carlsbad,CA)中进行培养,所述培养基具有20%胎牛血清(Thermo Fisher Scientific,Waltham,MA)和抗生素。使用TRIzol试剂(Life Technologies)提取总RNA,并且通过M-MLV逆转录酶(Promega,Madison,WI)和寡核苷酸(dT)15引物(Promega)合成cDNA。IgG Library Primer Set MouseBioGenomics(US Biological,Salem,MA)用于扩增重链(VH)和轻链(VL)的可变区;将PCR产物克隆到TOPO TA克隆试剂盒内用于测序(Life Technologies)。使用通过重叠延伸PCR的剪接,通过编码(Gly4Ser)4的柔性接头序列,将VH和VL基因装配成scFv。使用源自来自健康供体的人活化T细胞的cDNA,通过PCR亚克隆CD8α的信号肽结构域,并且将该信号肽结构域连接到VL片段的5'末端。使用有义引物:5’-ATATATGAATTCGGCTTCCACCATGGCCTTACCAGTGACC-3’(SEQ ID NO:2)和反向引物5’-CAGATCTTCTTCAGAAATAAGTTTTTGTTCGGCTGAGGAGACTGTGA GAG-3’(SEQ ID NO:3),通过PCR将Myc标签(EQKLISEEDL;SEQ ID NO:1)加到VH的C末端'。另外,通过有义引物:5’-ATATATGAATTCGGCTTCCACCATGGCCTTACCAGTGACC-3’(SEQ IDNO:5)和反向引物:5’-TATATACTCGAGTTACAACTCGTCCTTCAGATCTTCTTCAGAAATAAG-3’(SEQ IDNO:6),在Myc标签后生成KDEL(SEQ ID NO:4)编码序列。将由CD8信号肽、针对人CD3的scFv、Myc标签和KDEL(SEQ ID NO:4)序列组成的合成基因亚克隆到MSCV-IRES-GFP载体的EcoRI和XhoI位点内。还制备了其中myc-KDEL替换为其他序列的构建体,如图2中列出的。
从GenBank(登录号NM_013614.2)获得对应于小鼠鸟氨酸脱羧酶的氨基酸422-461的“PEST”-SHGFPPEVEEQDDGTLPMSCAQESGMDRHPAACASARINV(SEQ ID NO:7)基序的序列。密码子优化和基因合成由GenScript(Piscataway,NJ)完成,并且通过PCR亚克隆到VH的3'末端内。将构建体亚克隆到MSCV-IRES-GFP载体的EcoRI和XhoI位点内。
针对人CD7的scFv的克隆
源自鼠TH69(抗CD7)抗体的序列scFv得自文献(Peipp等人,Cancer Res 2002(62):2848-2855)。在密码子优化后,将由CD8信号肽、针对人CD7的scFv、Myc标签和KDEL(SEQ ID NO:4)序列组成的合成基因亚克隆到MSCV-IRES-GFP载体的EcoRI和XhoI位点内。还制备了其中myc-KDEL替换为其他序列的构建体,如图2中列出的。
针对人β-2微球蛋白(hB2MG)的scFv的克隆
源自鼠BBM.1(抗hB2MG)IgG2b抗体的序列scFv得自文献(Grovender,E.A.等人,Kidney Int.2004;65(1):310-322)。在密码子优化后,将由CD8信号肽、针对人B2MG的scFv、Myc标签和KDEL(SEQ ID NO:4)序列组成的合成基因亚克隆到MSCV-IRES-GFP载体的EcoRI和XhoI位点内。
针对人KIR2DL1和KIR2DL2/DL3的scFv的克隆
人单克隆抗体I-7F9(抗KIR2DL1、KIR2DL2和KIR2DL3)的氨基酸序列源自Moretta等人的公开的国际专利申请WO2006003179A2。在密码子优化后,通过用接头序列连接可变轻(VL)区和可变重(VH)区来设计scFv的序列。将由CD8信号肽、针对人KIR(KIR2DL1、KIR2DL2和KIR2DL3)的scFv、CD8铰链和跨膜结构域、以及KKMP序列组成的合成基因亚克隆到MSCV-IRES-GFP载体的EcoRI和XhoI位点内。还制备了其中KKMP替换为其他序列的构建体,如图2中列出的。
针对人NKG2A的scFv的克隆
鼠抗体Z199(抗NKG2A)的序列源自Spee等人的公开的专利(EP2247619 A1)。在密码子优化后,通过用接头序列连接可变轻(VL)区和可变重(VH)区来设计scFv的序列。将由CD8信号肽、针对人NKG2A的scFv、CD8铰链和跨膜、以及KKMP序列组成的合成基因亚克隆到MSCV-IRES-GFP载体的EcoRI和XhoI位点内。还制备了其中KKMP替换为其他序列的构建体,如图2中列出的。本文生成的用于scFv的序列信息显示于表1中。图2中所示的各种组分的序列信息显示于表2中。
抗CD19-4-1BB-CD3ζCAR
如先前所述(Imai,C.等人,Leukemia.2004;18:676-684;Imai,C.等人,Blood.2005;106:376-383)生成该CAR。
表1.scFv序列信息
表2.图2中所示组分的序列信息
基因转导、细胞扩增、流式细胞术分析和功能研究
这些如先前所述执行(Kudo,K等人,Cancer Res.2014;74(1):93-103)。
结果
scFv构建体的生成
图1中概述了该技术的示意图。我们生成的抑制性构建体的图示显示于图2中。可通过从产生抗体的杂交瘤细胞系或相应的公开序列中克隆编码可变轻(VL)和可变重(VH)免疫球蛋白链区的cDNA而衍生scFv部分。根据标准技术,将VL和VH与短肽序列(“接头”)连接以制备完整的scFv。为了表达,将scFv与在N末端处的信号肽连接;如在初步实验中证实的,需要信号肽用于表达scFv。含有scFv加上信号肽的蛋白质一般被释放到细胞的环境内。例如,在初步实验(未示出)中,在细胞的培养上清液中检测到在Jurkat T细胞中表达的抗CD3εscFv加信号肽。通过将scFv导向特定区室并且阻止其分泌,会阻止对其他细胞的可能作用。为了将其导向内质网(ER),利用KDEL(SEQ ID NO:4)基序(其将蛋白质保留在ER中)(Strebe N.等人,J Immunol Methods.2009;341(1-2):30-40)。为了促进被靶向的蛋白质的降解,我们将其与蛋白酶体靶向PEST基序连接(Joshi,S.N.等人,MAbs.2012;4(6):686-693)。通过将scFv连接到CD8α或另一种跨膜蛋白的跨膜结构域和铰链,也可将scFv导向细胞膜。
表达抗CD19-BB-ζCAR的T淋巴细胞中的T细胞受体的下调
为了确定所提出的策略是否可应用于产生表达CAR并且缺乏一种或多种标记物的免疫细胞,T细胞受体(TCR)表达在抗CD19 CAR T细胞中被下调。
为了在细胞膜上表达,CD3/TCR复合物需要其所有组分(TCRα、TCRβ、CD3δ、CD3ε、CD3γ、CD3ζ)的装配。一种组分的缺少阻止CD3/TCR表达,并且因此阻止抗原识别。在初步研究中,克隆来自抗CD3ε杂交瘤(购自Creative Diagnostics,Shirley,NY)的scFv,并且生成含有KDEL(SEQ ID NO:4)、PEST、CD8α跨膜结构域或其他的构建体,如图2所示。
使用含有绿色荧光蛋白(GFP)的鼠干细胞病毒(MSCV)逆转录病毒载体,在CD3/TCR+Jurkat细胞系中转导本文公开的构建体。在转导后GFP+细胞的百分比在所有实验中都>90%。图3A显示了如通过流式细胞术测量的,GFP+细胞中用抗CD3ε抗体染色的结果。CD3ε的抗体染色在用所列出的构建体转导的细胞中降低到不同程度。用人外周血T淋巴细胞获得CD3ε的类似下调(图3B)。图3C显示了与用含有单独GFP的载体转导的细胞相比,在用不同基因构建体转导后,GFP阳性Jurkat细胞中的CD3ε表达的举例说明性流式细胞术点图。CD3的下调不影响Jurkat细胞的生长或测试的所有其他细胞标记物(包括CD2、CD4、CD8、CD45、CD25、CD69)的表达。CD3表达的抑制持续超过3个月。CD3阴性细胞的进一步富集可通过用抗-CD3磁珠(Dynal,Life Technologies,Carlsbad,CA)的CD3+T细胞耗尽来实现。
用抗TCRαβ抗体染色Jurkat细胞或人外周血T淋巴细胞显示CD3ε表达的下调与TCRαβ表达的下调相关(图4)。
接下来,确定抗CD3 scFv-myc KDEL是否可与抗CD19-4-1BB-CD3ζCAR同时表达。如图5所示,这导致T细胞缺乏CD3表达,同时表达抗CD19CAR。这些细胞上也不存在TCR(未示出)。
为了评价CAR是否可在具有下调的CD3/TCR的Jurkat细胞中发信号,测试了活化标记物CD69和CD25的表达,并且通过与CD19+白血病细胞系OP-1共培养的Jurkat细胞中的CD107a表达来测量裂解性颗粒的胞吐作用。如图6所示,用抗CD3 scFv-myc KDEL构建体下调CD3/TCR并未降低抗CD19-4-1BB-CD3ζCAR活化Jurkat细胞的能力。为了进一步探索CD3/TCR缺失对CAR信号传导的作用,确定是否可通过其连接刺激表达CAR的CD3阴性T淋巴细胞。如图7所示,表达抗CD19 CAR的T淋巴细胞与CD19+白血病细胞的共培养导致T细胞增殖,与CD3是否下调无关,这指示CD3/TCR下调并未降低CAR增殖刺激。
相应地,可使用抗CD3 scFv-myc KDEL构建体在CAR-T细胞中有效下调CD3/TCR,而不影响由CAR驱动的T细胞活化、脱颗粒和增殖。
CD7的下调
确定成功调节CD3/TCR表达的策略是否可应用于其他表面分子。为此,调节CD7表达。scFv序列源自通过Peipp等人公开的那种(Cancer Res 2002(62):2848-2855),所述scFv序列与CD8信号肽和myc-KDEL序列连接,如图2所示。使用MSCV逆转录病毒载体,在外周血淋巴细胞中转导抗CD7-myc KDEL构建体,如通过与藻红蛋白缀合的抗CD7抗体(BDBioscience)检测的,所述外周血淋巴细胞具有CD7的高表达。如图8所示,用构建体转导的T淋巴细胞中的CD7事实上被取消。
HLA-I类的下调
然后将该策略应用于下调另一种表面分子,HLA I类。
HLA I类由多态性α链和称为β2-微球蛋白的非多态性链组成。后一亚基的击倒导致HLA(小鼠中的MHC)I类表达的取消(Koller,BH等人,Science.1990;248(4960):1227-1230)。与β2-微球蛋白反应的scFv用于抑制免疫细胞中的HLA I类的表达。
scFv序列源自通过Grovender等人公开的那种(Kidney Int.2004;65(1):310-322),所述scFv序列与CD8信号肽和myc KDEL序列连接,如图2所示。使用MSCV逆转录病毒载体,在Jurkat细胞中转导抗β2M-myc KDEL构建体,如通过与藻红蛋白缀合的抗HLA-ABC抗体(BD Pharmingen)检测的,所述Jurkat细胞具有HLA I类的高表达。如图9所示,用构建体转导的Jurkat细胞具有HLA-ABC表达的显著下调。细胞维持其形态和生长能力。
NK细胞中的抑制性受体的下调
为了确定上述策略是否也适用于在其他免疫细胞中表达的表面分子,在NK细胞中测试了抑制性受体KIR2DL1、KIR2DL2/DL3和NKG2A的功能下调。
为了下调KIR受体,与KIR2DL1和KIR2DL2/DL3反应的scFv用于抑制其在NK细胞中的表达。scFv序列源自通过Moretta等人公开的那种(专利WO2006003179 A2),所述scFv序列与CD8信号肽和ER保留序列连接,如图2所示。使用MSCV逆转录病毒载体,将构建体在从人外周血扩增的NK细胞中转导,并且选择用于KIR2DL1表达。如通过与别藻蓝蛋白缀合的抗KIR2DL1抗体(R&D Systems)检测的,这些细胞具有高KIR2DL1表达,并且如通过与藻红蛋白缀合的抗KIR2DL2/DL3抗体(BD Bioscience)检测的,这些细胞还具有高KIR2DL2/DL3表达。图10显示了使用scFv-接头(20)AEKEDL和scFv-EEKKMP获得的结果,具有被靶向的KIR的显著下调。
为了下调NKG2A,与NKG2A反应的scFv用于抑制其在NK细胞中的表达。源自Scee等人的公开的欧洲专利申请号EP2247619 A1的scFv序列与CD8信号肽和ER保留序列连接,如图2所示。使用MSCV逆转录病毒载体,将构建体在从人外周血扩增的NK细胞中转导,所述NK细胞具有高NKG2A表达,如通过与藻红蛋白缀合的抗NKG2A抗体(Beckman Coulter)检测的。图11显示了用scFv-EEKKMP获得的NKG2A的显著下调。
本文引用的所有专利、公开的专利申请和参考文献的教导以引用的方式全文并入。
虽然已参考本发明的示例性实施例具体显示和描述了本发明,但本领域技术人员应理解,可在其中作出形式和细节中的各种改变,而不背离由所附权利要求涵盖的本发明的范围。
序列表
<110> 新加坡国立大学
<120> 用于增强治疗性免疫细胞的功效的方法
<130> 4459.1116-002
<140> PCT/SG2016/050063
<141> 2016-02-05
<150> 62/112,765
<151> 2015-02-06
<150> 62/130,970
<151> 2015-03-10
<160> 64
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> Myc标签
<400> 1
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
<210> 2
<211> 40
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 有义引物
<400> 2
atatatgaat tcggcttcca ccatggcctt accagtgacc 40
<210> 3
<211> 50
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 反向引物
<400> 3
cagatcttct tcagaaataa gtttttgttc ggctgaggag actgtgagag 50
<210> 4
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> KDEL编码序列
<400> 4
Lys Asp Glu Leu
1
<210> 5
<211> 40
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 有义引物
<400> 5
atatatgaat tcggcttcca ccatggcctt accagtgacc 40
<210> 6
<211> 48
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 反向引物
<400> 6
tatatactcg agttacaact cgtccttcag atcttcttca gaaataag 48
<210> 7
<211> 40
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> PEST基序
<400> 7
Ser His Gly Phe Pro Pro Glu Val Glu Glu Gln Asp Asp Gly Thr Leu
1 5 10 15
Pro Met Ser Cys Ala Gln Glu Ser Gly Met Asp Arg His Pro Ala Ala
20 25 30
Cys Ala Ser Ala Arg Ile Asn Val
35 40
<210> 8
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 亲水性肽
<400> 8
Gly Gly Gly Gly Ser
1 5
<210> 9
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> ER或高尔基体保留序列
<220>
<221> VARIANT
<222> (3, 4)
<223> Xaa = 任何氨基酸
<220>
<221> UNSURE
<222> (3)..(3)
<223> The 'Xaa' at location 3 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (4)..(4)
<223> The 'Xaa' at location 4 stands for Gln, Arg, Pro, or Leu.
<400> 9
Lys Lys Xaa Xaa
1
<210> 10
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> ER或高尔基体保留序列
<220>
<221> VARIANT
<222> (2)
<223> Xaa = 任何氨基酸
<220>
<221> VARIANT
<222> (3)
<223> Xaa = ASP或GLU
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (3)..(3)
<223> The 'Xaa' at location 3 stands for Gln, Arg, Pro, or Leu.
<400> 10
Lys Xaa Xaa
1
<210> 11
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> ER或高尔基体保留序列
<400> 11
Tyr Gln Arg Leu
1
<210> 12
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD3的scFv的可变重区
<400> 12
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala
115 120
<210> 13
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD3的scFv的可变轻区
<400> 13
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg
100 105
<210> 14
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD3的scFv的可变重区
<400> 14
gaggtccagc tgcagcagtc tggggctgaa ctggcaagac ctggggcctc agtgaagatg 60
tcctgcaagg cttctggcta cacctttact aggtacacga tgcactgggt aaaacagagg 120
cctggacagg gtctggaatg gattggatac attaatccta gccgtggtta tactaattac 180
aatcagaagt tcaaggacaa ggccacattg actacagaca aatcctccag cacagcctac 240
atgcaactga gcagcctgac atctgaggac tctgcagtct attactgtgc aagatattat 300
gatgatcatt actgccttga ctactggggc caaggcacca ctctcacagt ctcctcagcc 360
<210> 15
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD3的scFv的可变轻区
<400> 15
caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60
atgacctgca gtgccagctc aagtgtaagt tacatgaact ggtaccagca gaagtcaggc 120
acctccccca aaagatggat ttatgacaca tccaaactgg cttctggagt ccctgctcac 180
ttcaggggca gtgggtctgg gacctcttac tctctcacaa tcagcggcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtaacc cattcacgtt cggctcgggg 300
acaaagttgg aaataaaccg g 321
<210> 16
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD7的scFv的可变重区 (TH69)
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Phe Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asp Glu Val Arg Gly Tyr Leu Asp Val Trp Gly Ala Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 17
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD7的scFv的可变轻区 (TH69)
<400> 17
Ala Ala Tyr Lys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
1 5 10 15
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly
20 25 30
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
35 40 45
Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
65 70 75 80
Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser
85 90 95
Lys Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 18
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD7的scFv的可变重区 (TH69)
<400> 18
gaggtgcagc tggtcgaatc tggaggagga ctggtgaagc caggaggatc tctgaaactg 60
agttgtgccg cttcaggcct gaccttctca agctacgcca tgagctgggt gcgacagaca 120
cctgagaagc ggctggaatg ggtcgctagc atctcctctg gcgggttcac atactatcca 180
gactccgtga aaggcagatt tactatctct cgggataacg caagaaatat tctgtacctg 240
cagatgagtt cactgaggag cgaggacacc gcaatgtact attgtgccag ggacgaagtg 300
cgcggctatc tggatgtctg gggagctggc actaccgtca ccgtctccag c 351
<210> 19
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD7的scFv的可变轻区 (TH69)
<400> 19
gccgcataca aggatattca gatgactcag accacaagct ccctgagcgc ctccctggga 60
gaccgagtga caatctcttg cagtgcatca cagggaatta gcaactacct gaattggtat 120
cagcagaagc cagatggcac tgtgaaactg ctgatctact atacctctag tctgcacagt 180
ggggtcccct cacgattcag cggatccggc tctgggacag actacagcct gactatctcc 240
aacctggagc ccgaagatat tgccacctac tattgccagc agtactccaa gctgccttat 300
acctttggcg ggggaacaaa gctggagatt aaaagg 336
<210> 20
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD7的scFv的可变重区 (3a1f)
<400> 20
Gln Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Val Tyr Tyr Asp Leu Tyr Tyr Tyr Ala Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 21
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD7的scFv的可变轻区 (3a1f)
<400> 21
Asp Ile Glu Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Ser Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Thr
65 70 75 80
Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 22
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD7的scFv的可变重区 (3a1f)
<400> 22
caggtccagc tgcaggagtc aggggcagag ctggtgaaac ccggagccag tgtcaaactg 60
tcctgtaagg ccagcggcta tactttcacc agctactgga tgcactgggt gaaacagagg 120
ccaggacagg gcctggagtg gatcggcaag attaacccca gcaatgggcg caccaactac 180
aacgaaaagt ttaaatccaa ggctacactg actgtggaca agagctcctc taccgcatac 240
atgcagctga gttcactgac atctgaagat agtgccgtgt actattgcgc cagaggcggg 300
gtctactatg acctgtacta ttacgcactg gattattggg ggcagggaac cacagtgact 360
gtcagctcc 369
<210> 23
<211> 324
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD7的scFv的可变轻区 (3a1f)
<400> 23
gacatcgagc tgacacagtc tccagccact ctgagcgtga cccctggcga ttctgtcagt 60
ctgtcatgta gagctagcca gtccatctct aacaatctgc actggtacca gcagaaatca 120
catgaaagcc ctcggctgct gattaagagt gcttcacaga gcatctccgg gattccaagc 180
agattctctg gcagtgggtc aggaaccgac tttacactgt ccattaactc tgtggagacc 240
gaagatttcg gcatgtattt ttgccagcag agcaattcct ggccttacac attcggaggc 300
gggactaaac tggagattaa gagg 324
<210> 24
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD45的scFv的可变重区
<400> 24
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Thr Ser Ser Thr Ile Asn Phe Thr Pro Ser Leu
50 55 60
Lys Asp Lys Val Phe Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Tyr Tyr Arg Tyr Gly Asp Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser
115 120
<210> 25
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向CD45的scFv的可变轻区
<400> 25
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Arg
85 90 95
Glu Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 26
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD45的scFv的可变重区
<400> 26
caggtgcagc tggtcgagtc tggaggagga ctggtgcagc ctggaggaag tctgaagctg 60
tcatgtgcag ccagcgggtt cgacttttct cgatactgga tgagttgggt gcggcaggca 120
ccaggaaaag gactggaatg gatcggcgag attaacccaa ctagctccac catcaatttc 180
acacccagcc tgaaggacaa agtgtttatt tccagagata acgccaagaa tactctgtat 240
ctgcagatgt ccaaagtcag gtctgaagat accgccctgt actattgtgc tcggggcaac 300
tactatagat acggggacgc tatggattat tgggggcagg gaactagcgt gaccgtgagt 360
<210> 27
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向CD45的scFv的可变轻区
<400> 27
gacattgtgc tgacccagtc ccctgcttca ctggcagtga gcctgggaca gagggcaacc 60
atcagctgcc gagcctctaa gagtgtctca acaagcggat actcctatct gcactggtac 120
cagcagaagc caggacagcc acctaaactg ctgatctatc tggcttccaa cctggaatct 180
ggagtgcctg cacgcttctc cggatctgga agtggaaccg actttacact gaatattcac 240
ccagtcgagg aagaggatgc cgctacctac tattgccagc acagccggga gctgcccttc 300
acatttggca gcgggactaa gctggagatc aag 333
<210> 28
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向B2MG的scFv的可变重区
<400> 28
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Pro Ser Gly Phe Asn Val Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Lys Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ser Asp Gly Asp Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Val Ser
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Phe Gly Asp Tyr Gly Ala Met Asn Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 29
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向B2MG的scFv的可变轻区
<400> 29
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Glu Ser Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Ala Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Lys Phe Ser Leu Lys Ile Arg Thr Leu Gln Ala
65 70 75 80
Glu Asp Phe Val Ser Tyr Tyr Cys Gln Gln Leu Tyr Ser Lys Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp
100 105 110
<210> 30
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向B2MG的scFv的可变重区
<400> 30
gaggtgcagc tgcagcagag cggagcagaa ctggtgaaac ctggagccag cgtcaagctg 60
tcctgtactc catctggctt caacgtgaag gacacataca ttcactgggt caagcagcgg 120
cccaaacagg gactggagtg gatcggcaga attgacccat ccgacggcga tatcaagtat 180
gatcccaaat tccaggggaa ggctactatt accgcagata ccagctccaa cacagtgagt 240
ctgcagctgt ctagtctgac cgaagacacc gccgtctact attgtgcatg gtttggcgat 300
tacggggcca tgaattattg ggggcaggga accagcgtca ccgtgtccag c 351
<210> 31
<211> 330
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向B2MG的scFv的可变轻区
<400> 31
gatattcaga tgacccagtc ccctgcatca cagagcgcct ccctgggcga gtcagtgacc 60
atcacatgcc tggctagcca gacaattggc acttggctgg catggtacca gcagaagccc 120
ggcaaatccc ctcagctgct gatctatgca gctacctctc tggcagacgg agtgcccagt 180
aggttctctg ggagtggatc aggcaccaag ttttctctga aaattcgcac actgcaggct 240
gaggatttcg tctcctacta ttgccagcag ctgtactcta aaccttatac atttggcggg 300
ggaactaagc tggaaatcaa acgagcagac 330
<210> 32
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向NKG2A的scFv的可变重区
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Glu Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Ile Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Arg His Gly Asp Tyr Pro Arg Phe Phe Asp Val Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 33
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向NKG2A的scFv的可变轻区
<400> 33
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 34
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向NKG2A的scFv的可变重区
<400> 34
gaggtgcagc tggtggagag cggaggagga ctggtgaagc caggaggaag cctgaagctg 60
tcctgtgccg cctctggctt cacattttcc tcttatgcaa tgagctgggt gcggcagtcc 120
ccagagaaga gactggagtg ggtggcagag atcagctccg gaggatccta cacctactat 180
cctgacacag tgaccggccg gttcacaatc tctagagata acgccaagaa taccctgtat 240
ctggagatct ctagcctgag atccgaggat acagccatgt actattgcac caggcacggc 300
gactacccac gcttctttga cgtgtgggga gcaggaacca cagtgaccgt gtcctct 357
<210> 35
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向NKG2A的scFv的可变轻区
<400> 35
cagattgtcc tgacccagtc tccagccctg atgagcgcct cccctggcga gaaggtgaca 60
atgacctgct ctgccagctc ctctgtgagc tacatctatt ggtaccagca gaagcctcgg 120
agctccccaa agccctggat ctatctgaca tccaacctgg cctctggcgt gccagccaga 180
ttctctggca gcggctccgg cacatcttac agcctgacca tctctagcat ggaggccgag 240
gacgccgcca cctactattg ccagcagtgg tccggcaatc catatacatt tggcggcggc 300
accaagctgg agatcaagag g 321
<210> 36
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向KIR2DL1和2/3的scFv的可变重区
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Ile Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 37
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 靶向KIR2DL1和2/3的scFv的可变轻区
<400> 37
Glu Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr
100 105
<210> 38
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向KIR2DL1和2/3的scFv的可变重区
<400> 38
caggtccagc tggtgcagtc tggagctgaa gtgaagaaac cagggagctc cgtcaaggtg 60
tcatgcaaag caagcggcgg gactttctcc ttttatgcaa tctcttgggt gagacaggca 120
cctggacagg gactggagtg gatgggaggc ttcatcccaa tttttggagc cgctaactat 180
gcccagaagt tccagggcag ggtgaccatc acagctgatg agtctactag taccgcatac 240
atggaactgt ctagtctgag gagcgacgat accgccgtgt actattgtgc tcgcattcca 300
tcaggcagct actattacga ctatgatatg gacgtgtggg gccaggggac cacagtcacc 360
gtgagcagc 369
<210> 39
<211> 327
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 靶向KIR2DL1和2/3的scFv的可变轻区
<400> 39
gagatcgtgc tgacccagtc tcctgtcaca ctgagtctgt caccagggga acgggctaca 60
ctgtcttgca gagcaagcca gtccgtgagc tcctacctgg cctggtatca gcagaagcca 120
ggccaggctc ccaggctgct gatctacgat gcaagcaaca gggccactgg gattcccgcc 180
cgcttctctg gcagtgggtc aggaaccgac tttactctga ccatttctag tctggagcct 240
gaagatttcg ccgtgtacta ttgccagcag cgatccaatt ggatgtatac ttttggccag 300
gggaccaagc tggagatcaa acggaca 327
<210> 40
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> CD8信号肽
<400> 40
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 41
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 可变重-可变轻接头
<400> 41
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 42
<211> 70
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> CD8铰链和跨膜
<400> 42
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
35 40 45
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
50 55 60
Leu Val Ile Thr Leu Tyr
65 70
<210> 43
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 可变重-可变轻接头
<400> 43
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 44
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8信号肽
<400> 44
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 45
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8信号肽
<400> 45
atggctctgc ctgtgaccgc actgctgctg cccctggctc tgctgctgca cgccgcaaga 60
cct 63
<210> 46
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8信号肽
<400> 46
atggctctgc ccgtcaccgc tctgctgctg cctctggctc tgctgctgca cgctgctcga 60
cca 63
<210> 47
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8信号肽
<400> 47
atggctctgc ccgtgaccgc tctgctgctg cctctggctc tgctgctgca tgctgctcga 60
cct 63
<210> 48
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8信号肽
<400> 48
atggccctgc ccgtcaccgc cctgctgctg cccctggctc tgctgctgca cgccgcaaga 60
ccc 63
<210> 49
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8信号肽
<400> 49
atggctctgc ccgtgaccgc cctgctgctg cctctggctc tgctgctgca cgctgcccgc 60
cca 63
<210> 50
<211> 68
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> CD8铰链和跨膜
<400> 50
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
35 40 45
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
50 55 60
Ile Thr Leu Tyr
65
<210> 51
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 51
ggtggtggtg gttctggtgg tggtggttct ggcggcggcg gctccggtgg tggtggatcc 60
<210> 52
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 52
ggaggaggag gaagcggagg aggaggatcc ggaggcgggg gatctggagg aggaggaagt 60
<210> 53
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 53
ggaggaggag gatccggcgg aggaggctct gggggaggcg ggagt 45
<210> 54
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 54
ggaggaggag gaagtggagg aggaggatca ggaggcgggg gaagcggcgg gggaggctcc 60
<210> 55
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 55
ggaggaggag gaagtggagg aggagggtca ggaggcgggg gaagcggcgg gggaggatcc 60
<210> 56
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 56
ggaggaggag gatctggagg aggaggcagc ggcggcggcg gctccggcgg cggcggctct 60
<210> 57
<211> 210
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8铰链和跨膜
<400> 57
aagcccacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 60
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 120
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 180
cttctcctgt cactggttat caccctttac 210
<210> 58
<211> 201
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8铰链和跨膜
<400> 58
accactacac ctgcaccaag gcctcccaca cccgctccca ctatcgcttc ccagccactg 60
tccctgaggc ccgaggcctg caggccagca gctggcggag ccgtgcatac ggggctggac 120
ttcgcttgcg acatctacat ctgggcccca ctggcaggga catgcggagt cctgctgctg 180
tccctggtca tcacacttta c 201
<210> 59
<211> 201
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8铰链和跨膜
<400> 59
actaccacac cagctccaag accacctacc cctgcaccaa caattgctag tcagccactg 60
tcactgagac cagaagcatg gcctgcagct ggaggagctg tgcacaccag aggcctggac 120
tttgcctgcg atatctacat ttgggctcct ctggcaggaa cctgtggcgt gctgctgctg 180
tctctggtca tcacacttta c 201
<210> 60
<211> 210
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> CD8铰链和跨膜
<400> 60
aagccaacca caacccctgc accaaggcca cctacaccag cacctaccat cgcaagccag 60
ccactgtccc tgaggccaga ggcatgtagg cctgcagcag gaggcgccgt gcacacacgc 120
ggcctggact ttgcctgcga tatctacatc tgggcaccac tggcaggaac ctgtggcgtg 180
ctgctgctga gcctggtgat taccctgtat 210
<210> 61
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 61
ggtggtggcg gcagtggtgg cggtggctca 30
<210> 62
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 可变重-可变轻接头
<400> 62
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 63
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> unsure
<223> 可变重-可变轻接头
<400> 63
ggtggtggcg gcagtggtgg cggtggctca ggcggtggtg gctccggtgg cggtggctct 60
<210> 64
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> 可变重-可变轻接头
<400> 64
Glu Glu Lys Lys Met Pro
1 5
Claims (13)
1.一种工程T细胞,所述工程T细胞是CD3/TCRαβ阴性T细胞,所述CD3/TCRαβ阴性T细胞包含第一多肽和第二多肽,所述第一多肽包含嵌合抗原受体(CAR),所述第二多肽包含与定位结构域连接的靶结合分子,
其中,所述靶结合分子包含结合CD3ε的单链可变片段(scFv),
其中,所述scFv包含分别具有SEQ ID NO:12和13中所示的氨基酸序列的VH和VL,
其中,所述定位结构域包含保留信号传导结构域,所述保留信号传导结构域包含内质网(ER)保留序列、高尔基体保留序列或蛋白酶体定位序列,所述ER保留序列包含氨基酸序列KDEL(SEQ ID NO:4)、KKXX(SEQ ID NO:9)或KXD/E(SEQ ID NO:10),所述高尔基体保留序列包含氨基酸序列YQRL(SEQ ID NO:11),其中,X是任何氨基酸,所述蛋白酶体定位序列包含PEST基序SEQ ID NO:7,并且
其中,所述与定位结构域连接的靶结合分子下调CD3/TCRαβ复合物的细胞表面表达。
2.根据权利要求1所述的工程T细胞,其中所述工程T细胞是同种异体T细胞。
3.根据权利要求1或2所述的工程T细胞,其中所述工程T细胞是自体T细胞。
4.根据权利要求1或2所述的工程T细胞,其中所述定位结构域进一步包含源自CD8α、CD8β、4-1BB、CD28、CD34、CD4、FcεRIγ、CD16、OX40、CD3ζ、CD3ε、CD3γ、CD3δ、TCRα、CD32、CD64、VEGFR2、FAS或FGFR2B的跨膜结构域。
5.根据权利要求1所述的工程T细胞,其中所述CAR包含抗CD19 scFv结构域、4-1BB刺激信号传导结构域和CD3ζ信号传导结构域。
6.根据权利要求5所述的工程T细胞,其中所述工程T细胞诱导CD19+癌细胞的细胞毒性。
7.根据权利要求1所述的工程T细胞,其中所述CAR包含抗CD3 scFv结构域、4-1BB刺激信号传导结构域和CD3ζ信号传导结构域。
8.根据权利要求7所述的工程T细胞,其中所述工程T细胞诱导CD3+癌细胞的细胞毒性。
9.一种包含根据权利要求1至8中任一项所述的工程T细胞的药物组合物在制备用于治疗有需要的患者的自身免疫性疾病或病毒性疾病的药物中的用途。
10.一种包含根据权利要求1至8中任一项所述的工程T细胞的药物组合物在制备用于降低或消除患者的移植物抗宿主病的可能性的药物中的用途。
11.一种包含根据权利要求1至8中任一项所述的工程T细胞的药物组合物在制备用于治疗有需要的患者的癌症的药物中的用途。
12.根据权利要求11所述的用途,其中所述癌症是CD3+癌症、CD19+癌症、或B细胞恶性肿瘤。
13.根据权利要求12所述的用途,其中所述B细胞恶性肿瘤选自由以下组成的组:复发性或难治性急性成淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、B细胞非霍奇金淋巴瘤(B-NHL)和大B细胞淋巴瘤。
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