CN105392887A - Cd123特异性嵌合抗原受体重导向性t细胞及其使用方法 - Google Patents
Cd123特异性嵌合抗原受体重导向性t细胞及其使用方法 Download PDFInfo
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Abstract
开发含有CD123特异性scFv的嵌合抗原受体(CAR)家族以靶向CD123上的不同抗原。在一些实施方案中,这类CD123嵌合抗原受体(CD123CAR)基因包含以符合阅读框的方式融合于以下的抗CD123scFv区:经修饰的IgG4铰链区,该经修饰的IgG4铰链区包含S228P取代、L235E取代和任选地N297Q取代;共刺激信号传导域;和T细胞受体(TCR)zeta链信号传导域。当在健康供体T细胞(CD4/CD8)中表达时,CD123CAR重导向T细胞特异性和介导针对CD123+细胞系以及原代AML患者样品的有力的效应器活性。另外,从患有活动性AML的患者获得的T细胞可修饰为表达CD123CAR基因且能体外裂解自体同源AML胚细胞。最后,单剂量的5.0x106个CAR123T细胞在小鼠中导致白血病进展显著延迟。这些结果表明CD123CAR转导的T细胞可用作治疗高风险AML的免疫疗法。
Description
优先权要求
本申请要求对2013年3月15日提交的美国专利申请号13/844,048的优先权,其包括附图在内通过提述完整并入本文。
政府利益
本发明在NIH准予P50CA107399、P01CA030206和M01RR0004下的政府支持下进行。政府对本发明享有某些权益。
发明背景
急性髓性白血病(AML)的特征在于未成熟髓细胞在骨髓中的快速增殖,导致功能障碍性造血作用[1]。急性髓性白血病(AML)的一线治疗几乎50年都保持基本未变,且AML仍是具有不良预后的疾病。尽管标准诱导能诱导完全免除,但许多患者最终复发并死于该疾病[2]。因此,开发AML的新治疗是至关重要的。
同种异源造血细胞移植能在选定的患者中实现该疾病的治愈且突显了AML对供体来源的免疫疗法的易感性。另外,已鉴定白介素3受体alpha链(CD123)是潜在的免疫治疗靶物,因为它在AML上相比于正常造血干细胞过表达。
在AML细胞的免疫表型分析中的最近进展揭示了几种可充当未来治疗的靶物的AML有关的细胞表面抗原[3]。实际上,已描述了使用靶向CD44、CD47、T细胞免疫球蛋白粘蛋白-3(TIM-3)和白介素3受体alpha链(IL-3Rα;CD123)的抗体来治疗AML的临床前研究且在鼠模型中显示出有希望的抗白血病活性[3,4]。CD123在多种恶性肿瘤上表达,包括急性和慢性髓性白血病、毛细胞白血病、B细胞系急性淋巴母细胞白血病、和胚细胞性浆细胞样树突细胞赘生物。另外,CD123通常不在正常造血干细胞上表达,如此使得CD123称为理想的免疫治疗靶物。而且,已完成了CD123特异性治疗的两个1期试验,其中两种药物均展现较好的安全性概况(临床试验政府ID:NCT00401739和NCT00397579)。不幸的是,这些CD123靶向性药物具有有限的功效,表明可能需要其他的且更有力的靶向CD123的治疗来观察抗白血病活性。
用于治疗AML的一种可能更有力的备选疗法是使用表达嵌合抗原受体(CAR)的T细胞,该嵌合抗原受体以不依赖于MHC的方式将T细胞特异性重导向(redirect)到细胞表面肿瘤有关的抗原(TAA)[5]。在大多数情况中,CAR包含来自单克隆抗体的单链可变片段(scFv),其融合于CD3ζ的信号传导域,且可以含有共刺激内在域(endodomain)[5]。几个研究组已开发了靶向多种抗原的CAR用于治疗B细胞恶性[6-10]且许多已进展到在1期临床试验中评估表达CAR的T细胞[11-15]。相比之下,用于治疗AML的CAR工程化的T细胞仍然较少[16,17]。
尽管AML的目前治疗方案能在选定的患者中实现完全的应答,但许多最终会复发,凸显了对可以引起更持久应答的新治疗的需要。目前正开发多种以AML为目标的免疫疗法,包括抗原特异性细胞毒性T淋巴细胞、同种反应性天然杀伤细胞和树突细胞疫苗。例如,Oka和同事显示Wilms的肿瘤1肽疫苗接种能在AML患者中产生临床和免疫应答[33]。然而,这些靶向性疗法是HLA依赖性的。为此,将期望设计一种靶向性治疗物如CAR,其能以不依赖于HLA的方式将T细胞特异性重导向到选择性靶物AML细胞。
发明概述
开发含有CD123特异性scFv的嵌合抗原受体(CAR)的家族来靶向CD123上的不同表位。在一些实施方案中,这类CD123嵌合抗原受体(CD123CAR)基因包含抗CD123scFv区符合阅读框地融合于经修饰的IgG4铰链区,所述经修饰的IgG4铰链区包含IgG4间隔区的改变,其将消除Fc受体结合。在一个实施方案中,经修饰的IgG4铰链区包含S228P取代、L235E取代、和任选地N297Q取代。所述CD123CAR基因还包含至少一个共刺激信号传导域;和T细胞受体(TCR)zeta链信号传导域。在一些实施方案中,所述CD123CAR基因包含选自SEQIDNO:1,SEQIDNO:2,SEQIDNO:3或SEQIDNO:4的核苷酸序列。在其他实施方案中,CD123CAR基因编码包含SEQIDNO:9;SEQIDNO:10,SEQIDNO:11或SEQIDNO:12的氨基酸序列。
根据下文描述的实施方案,CD123CAR基因可以是插入载体(例如病毒载体)中的表达盒的一部分。如此,人T细胞的群体可由该载体转导,导致该T细胞表达CD123CAR基因。当在健康供体T细胞(CD4/CD8)中表达时,CD123CAR重导向T细胞特异性和介导针对CD123+细胞系以及原代AML患者样品的有力的效应器活性。CD123CART细胞不显著改变体外粒细胞/巨噬细胞和红细胞集落形成,表明在AML细胞上与免疫细胞相反的不同效果。
此外,从患有活性AML的患者获得的T细胞可修饰为表达CD123CAR基因且能体外裂解自体同源AML胚细胞。这些结果表明CD123CAR转导的T细胞可用作治疗高风险AML的免疫疗法。因此,根据一些实施方案,提供治疗受试者中AML的方法,其中这类方法包括对所述受试者施用用第一CD123CAR基因转导的第一T细胞群体。该方法可进一步包括另外的步骤即对所述受试者施用用第一CD123CAR基因转导的第一T细胞群体与用第二CD123CAR基因转导的第二T细胞群体的组合。在一些实施方案中,第一CD123CAR基因包含选自SEQIDNO:3或SEQIDNO:4的核苷酸序列。第二CD123CAR基因也可以包含选自SEQIDNO:3或SEQIDNO:4的核苷酸序列,然而,第二CD123CAR基因的核苷酸序列不能与对第一CD123CAR基因选定的核苷酸序列相同。这引起使用用两种或更多种不同CD123CAR转导的T细胞群体的AML组合治疗,其相比于使用单一CD123CAR转导的T细胞群体可导致协同效果。
附图简述
图1显示CD123特异性CAR可在健康供体人T细胞中表达。(A)含有经修饰的IgG4铰链、CD28的经修饰的跨膜和胞内信号传导域、和CD3ζ信号传导域的CAR的示意图。还指示了T2A核糖体跳跃(skip)序列和截短的EGFR(EGFRt)转导标志物。(B)源自单个健康供体的用模拟物和慢病毒转导的T细胞的代表性表型。在免疫磁性选择和一轮扩增后,经CAR修饰的T细胞用生物素化抗Fc或生物素化抗EGFR,接着是缀合有PE的链霉亲合素和抗TCRα/β、抗CD4或抗CD8染色,,并通过流式细胞术分析。象限放置基于用同种型对照的染色,且指示了落入每个象限的细胞百分比。(C)在免疫磁性选择和一轮扩增后来自3个不同健康供体T细胞系的指定细胞表面标志物的表达。数据代表均值±SEM。
图2显示表达CD123特异性CAR的T细胞裂解表达CD123的肿瘤细胞系。(A)对瞬时转染以表达CD123(顶部,黑色线)或CD19(底部,黑色线)的293T细胞的流式计量学(Flowkilometric)分析。将用亲本模拟物转导的293T细胞用抗CD123或抗CD19抗体染色(灰色填充,顶部和底部)来测定背景表达水平。(B)表达CD123-CAR的T细胞(26292和32716)对表达CD123(293T-CD123)或CD19(293T-CD19)的293T细胞的特异性细胞毒性,通过铬释放测定法测量。数据代表一式三份孔的均值+S.D.(C)对AML细胞系KG1a、用EBV转化的LCL细胞系和CML细胞系K562上的CD123的流式计量学分析。在每个柱状图中指示了CD123染色为阳性的细胞(黑色线)对同种型对照(灰色填充)的百分比。(D)CD123-CART细胞(26292和32716)对CD19+CD123+LCL细胞系和CD19-CD123+细胞系KG1a的特异性细胞毒性,通过铬释放测定法测量。分别使用表达LCL的OKT3(LCL-OKT3)和CD19-CD123-K562细胞系作为阳性和阴性对照细胞系。数据代表一式三份孔的均值+S.D。
图3显示CD123特异性T细胞释放INF-γ和TNF-α且应答表达CD123的靶细胞而增殖。将来自3个健康供体的CD123CART细胞或对照配对的T细胞与指定的细胞系以10:1的E:T共培养24小时,并通过Luminex多重珠(multiplexbead)技术量化IFN-γ和TNF-α的释放。(B)将配对的用CFSE标记的CD19或CD123特异性T细胞与指定的刺激细胞系以2:1的E:T共培养96小时,并通过流式细胞术分析用于CFSE稀释。将未刺激的T细胞(填充的柱状图)用作基线T细胞增殖对照。
图4显示在与原代AML样品共培养后通过CD123特异性CAR对多种CD4和CD8效应器功能的活化。将配对的CAR工程化的T细胞与3份不同的原代AML患者样品(AML179、373和605)共培养6小时并分析表面CD107a表达和胞内IFN-γ或TNF-α产生。(A,条状图).表达CD107a的DAPI-CD3+CD8+EGFRt+细胞的百分比。数据代表均值+S.D.(A,饼状图).经历脱粒和产生IFN-γ和/或TNF-α的CD3+CD8+EGFRt+细胞的分数在饼状图中绘出。(B)来自同一实验的DAPI-CD3+CD4+EGFRt+群体数据,如A和B中描述的。(C)将配对的用CFSE标记的CD19或CD123特异性T细胞与指定的刺激细胞以2:1的E:T共培养72小时,并通过对于CFSE稀释的流式细胞术在DAPICD3+EGFRt+群体中分析。LCL和K562细胞系分别充当阳性和阴性27对照。PreB-ALL802是对CD19和CD123为双阳性的原代患者样品。象限放置基于未刺激的T细胞。
图5显示原代AML细胞由CD123特异性T细胞特异性靶向。(A)将配对的CD19或CD123特异性T细胞与用51Cr标记的CD34+原代AML样品以25:1的E:T共培养4小时。LCL和K562细胞系分别充当阳性和阴性对照。PreB-ALL802是对CD19和CD123为双阳性的原代患者样品。数据代表一式三份孔的均值+S.D.(B)(A)中来自3份原代AML患者样品的AML胚细胞的特定裂解。数据代表均值±SEM。使用不配对Student’st检验将26292和32716与CD19R比较,*,p<0.05,**,p<0.0005。
图6显示表达CD123CAR的T细胞在体外对正常和白血病祖细胞的作用。(A和B)通过CD34免疫磁性选择选出CD34+脐带血(CB)细胞(n=3)并与CD19或CD123特异性配对的T细胞或仅培养基(未处理)以25:1的E:T共培养4小时。然后,将细胞铺板于半固态甲基纤维素祖细胞培养14-18天并对粒细胞-巨噬细胞集落形成单位(CFU-GM,A)和红系爆发集落形成单位(burstforminguniterythroid)(BFU-E,B)集落的存在打分。将百分比相对于CD19特异性T细胞对照标准化。数据代表3份不同CB样品的均值±SEM。(C)免疫磁性地选择CD34+原代AML患者样品(AML493、519或545)并与CD19或CD123特异性配对的T细胞或仅培养基(未处理)以25:1的E:T共培养4小时。然后,将细胞铺板于半固态甲基纤维素祖细胞培养14-18天并对白血病集落形成单位(CFU-L)的存在打分。将百分比相对于CD19特异性T细胞对照标准化。数据代表3份不同原代AML患者样品的均值±SEM。使用不配对Student’st检验将26292和32716与CD19R比较,*,p<0.05。(D)用任一CD123靶向性CAR构建体(26292或32716)处理的来自(A)的CB或来自(C)的AML细胞的组合的集落形成,相对于CD19R标准化。使用不配对Student’st检验,*,p<0.05。
图7显示源自AML患者的CD123CAR重导向的T细胞在体外特异性裂解自体同源胚细胞。(A)将来自3名AML患者的T细胞慢病毒转导以表达CD19R、26292或32716CAR。显示在转导后19天来自AML722的T细胞系。(B)用于51Cr释放测定法的在靶细胞上的CD123表达。指示每份样品的CD123+细胞百分比和相对荧光指数(RFI)。(C)使用从3份AML患者样品工程化的T细胞作为效应器和51Cr标记的自体同源富集CD34的胚细胞作为靶细胞进行的4小时自体同源杀伤测定法的结果。数据代表一式三份孔的均值+S.D。
图8显示如由对NSG小数的生物发光成像显示的肿瘤大小的变化,该小鼠在注射经修饰以表达萤火虫萤光素酶的AML细胞系KG1后5天(第5天)用含有S228P+L235E突变或S228P+L235E+N297Q突变的CD123CAR转导的T细胞(26292)处理。
图9显示嵌合抗原受体(CAR)的示意图,依照一些实施方案其具有抗原特异性单链Fv、铰链区、共刺激信号传导域、和T细胞受体zeta链信号传导域。(图像来自UrbaWJ和LongoDLNEnglJMed2011;365:754-757)。
图10显示依照一些实施方案具有L235E突变和S228P突变的32716CAR构建体(“32716CAR(S228P+L235E)”)的示意图连同32716CAR(S228P+L235E)构建体的核苷酸序列(SEQIDNO:1–反义链(顶部编号链);SEQIDNO:5–有义链(底部未编号链))和32716CAR(S228P+L235E)构建体的氨基酸序列(SEQIDNO:9)。突变粗体显示。
图11显示依照一些实施方案具有L235E突变和S228P突变的26292CAR构建体(“26292CAR(S228P+L235E)”)的示意图连同26292CAR(S228P+L235E)构建体的核苷酸序列(SEQIDNO:2–反义链(顶部编号链);SEQIDNO:6–有义链(底部未编号链))和26292CAR(S228P+L235E)构建体的氨基酸序列(SEQIDNO:10)。突变粗体显示。
图12显示依照一些实施方案具有L235E突变、S228P突变和N297Q突变的32716CAR构建体(“32716CAR(S228P+L235E+N297Q)”)的示意图连同32716CAR(S228P+L235E+N297Q)构建体的核苷酸序列(SEQIDNO:3–反义链(顶部编号链);SEQIDNO:7–有义链(底部未编号链))和32716CAR(S228P+L235E+N297Q)构建体的氨基酸序列(SEQIDNO:11)。突变高亮、粗体和划线显示。IUPAC碱基编码R对应于A或G,而IUPAC碱基编码Y对应于T或C。
图13显示依照一些实施方案具有L235E突变、S228P突变和N297Q突变的26292CAR构建体(“26292CAR(S228P+L235E+N297Q)”)的示意图连同26292CAR(S228P+L235E+N297Q)构建体的核苷酸序列(SEQIDNO:4–反义链(顶部编号链);SEQIDNO:8–有义链(底部未编号链))和26292CAR(S228P+L235E+N297Q)构建体的氨基酸序列(SEQIDNO:12)。突变粗体显示。IUPAC碱基编码R对应于A或G,而IUPAC碱基编码Y对应于T或C。
图14显示原代AML样品和脐带血上的CD123表达。(A)原代AML细胞上CD123表达的代表性例子。将细胞在DAPI-系-CD34+群体上设门并评估CD123表达(黑色-同种型对照,红色–抗CD123)。(B)在DAPI-系-CD34+群体中表达的CD123阳性细胞的百分比。每个点代表单个样品。(C)DAPI-系-CD34+群体中的CD123相对荧光指数(RFI)。RFI通过将抗CD123细胞的中值除以同种型对照染色细胞的中值来计算。(D)AML605(红色)、AML722(蓝色)和脐带血样品(灰色)上CD123表达的柱状图覆盖。同种型对照以黑色显示。
图15例示了用于研究通过CD123特异性T细胞应答与原代AML患者样品的温育而对多种效应器功能的活化的设门策略。对于CD123CAR(基于26292的)T细胞在与AML373共培养后显示用于多色流式细胞术以鉴定T细胞效应器功能的设门策略。(A)初始门在CD3+细胞上设定。(B)第二门,使用荧光减去一个对照建立,在EGFRt+细胞上设定。(C)对CD4+和CD8+群体设定第三门。(D)最后的门在CD107a+细胞上设定。(E)CD107a+群体内的IFN-γ和TNF-α产生。象限使用同种型对照染色的样品建立。记录每个象限中的百分比。
图16显示在表达CAR的T细胞的CD4和CD8群体两者中稀释的CFSE。显示于图5C的细胞的CD4(A)和CD8(B)子群体在此处显示。在DAPI-CD3+EGFRt+细胞上的初始门后,在与原代AML患者样品共培养后分析CD4和CD8细胞的CFSE稀释。象限放置基于未刺激的T细胞。
发明详述
使用特定的例子、序列和附图详细描述了本发明的某些实施方案。列举的实施方案不意图将本发明限定到那些实施方案,因为本发明意图涵盖所有备选、修饰和等同物,其可包括在本发明的范围内如由权利要求限定的。本领域技术人员将认可许多类似或等同于本文中描述的那些的方法和材料,其可用于实践本发明。
在一些实施方案中,提供编码肿瘤靶向性嵌合抗原受体(CAR)的基因。依照某些实施方案,该基因编码CD123特异性CAR(CD123CAR)。CD123CAR基因包含抗CD123单链Fv(scFv)区和一个或多个以下域:铰链区、共刺激信号传导域、胞内信号传导域、或其组合。
在一些实施方案中,CD123CAR基因可以包括但不限于,抗CD123单链Fv(scFv)区、铰链区、任选地至少一种共刺激信号传导域、和任选地胞内信号传导域。
在某些实施方案中,CD123CAR基因可以包括但不限于,抗CD123单链Fv(scFv)区、铰链区、至少一种共刺激信号传导域、和胞内信号传导域(图9)。
所述抗CD123scFv区可包含在表达时可结合CD123的表位的核苷酸序列。在一些实施方案中,scFv抗CD123scFv区包含编码重组免疫毒素(RIT)26292和32716的VH和VL域的核苷酸[18]。靶向26292的CD123CAR基因和靶向32716的CD123CAR基因在本文中也分别称为26292CAR和32716CAR。在某些实施方案中,抗CD123scFv区可以包含选自以下的核苷酸序列:
对于32716CAR,SEQIDNO:1或SEQIDNO:3的核苷酸82-814;或
对于26292CAR,SEQIDNO:2或SEQIDNO:4的核苷酸82-792。
所述核苷酸序列编码选自以下的氨基酸序列:
当用于32716CAR时,SEQIDNO:9或SEQIDNO:11的残基23-266;或
当用于26292CAR.时,SEQIDNO:10或SEQIDNO:12的残基23-259。
在某些实施方案中,所述抗CD123scFv区可修饰为增强结合或降低免疫原性。例如,在一个方面,所述抗CD123scFv区可以是人源化的抗CD123scFv区。
铰链区可以包含落入CH2-CH3域之间的免疫球蛋白(例如IgG1,IgG2,IgG3,IgG4)的至少一部分。在一些实施方案中,所述铰链区是经修饰的铰链。经修饰的铰链可具有一个或多个氨基酸取代或修饰,其协助降低CD123CAR的脱靶效应,由此增加其特异性和功效。“氨基酸修饰”或“氨基酸取代”或“取代”如用于本文意指在蛋白质或肽序列中的氨基酸取代、插入和/或缺失。“氨基酸取代”或“取代”如用于本文意指将亲本肽或蛋白质序列中特定位置处的氨基酸用另一种氨基酸替换。例如,取代S228P指变体蛋白质或肽,其中位置228处的丝氨酸用脯氨酸替换。
可通过突变进行氨基酸取代从而使得编码蛋白质或肽的核酸序列中的特定密码子变为编码不同氨基酸的密码子。这类突变一般通过进行尽可能少的核苷酸改变来进行。可进行这类取代突变来以非保守性方式(即通过将属于具有特定大小或特征的氨基酸组的氨基酸的密码子改变为属于另一组的氨基酸)或保守性方式(即通过将属于具有特定大小或特征的氨基酸组的氨基酸的密码子改变为属于相同组的氨基酸)改变所得蛋白质中的氨基酸。这类保守性改变一般导致所得蛋白质的结构和功能的较少变化。
以下是氨基酸的各种分组的例子:
●具有非极性R基团的氨基酸:丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、甲硫氨酸
●具有不带电荷的极性R基团的氨基酸:甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺
●具有带电荷的极性R基团的氨基酸(在Ph6.0带负电荷):天冬氨酸、谷氨酸
●碱性氨基酸(在pH6.0带正电荷):赖氨酸、精氨酸、组氨酸(在pH6.0)
另一种分组可以是具有苯基基团的那些氨基酸:苯丙氨酸、色氨酸、酪氨酸。
另一种分组可以根据分子量(即R基团的大小)如下文显示:
在某些实施方案中,经修饰的铰链源自IgG1、IgG2、IgG3或IgG4,其包含用不同于未经修饰的铰链中存在的氨基酸的氨基酸残基取代的一个或多个氨基酸残基。所述一个或多个经取代的氨基酸残基选自但不限于在以下位置处的一个或多个氨基酸残基:220、226、228、229、230、233、234、235、234、237、238、239、243、247、267、268、280、290、292、297、298、299、300、305、309、218、326、330、331、332、333、334、336、339、或其组合。
在一些实施方案中,经修饰的铰链源自IgG1、IgG2、IgG3、或IgG4,其包含但不限于一个或多个以下氨基酸残基取代:C220S、C226S、S228P、C229S、P230S、E233P、V234A、L234V、L234F、L234A、L235A、L235E、G236A、G237A、P238S、S239D、F243L、P247I、S267E、H268Q、S280H、K290S、K290E、K290N、R292P、N297A、N297Q、S298A、S298G、S298D、S298V、T299A、Y300L、V305I、V309L、E318A、K326A、K326W、K326E、L328F、A330L、A330S、A331S、P331S、I332E、E333A、E333S、E333S、K334A、A339D、A339Q、P396L、或其组合(50)。
在一些实施方案中,经修饰的铰链源自具有以下氨基酸序列的IgG4铰链:
位置219ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWY
位置279VDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK
位置339AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
位置399DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQIDNO:13)
在某些实施方案中,经修饰的铰链源自IgG4,其包含用不同于未经修饰的铰链中存在的氨基酸的氨基酸残基取代的一个或多个氨基酸残基。所述一个或多个经取代的氨基酸残基选自但不限于在以下位置处的一个或多个氨基酸残基:220、226、228、229、230、233、234、235、234、237、238、239、243、247、267、268、280、290、292、297、298、299、300、305、309、218、326、330、331、332、333、334、336、339、或其组合。
在一些实施方案中,经修饰的铰链源自IgG4,其包含但不限于一个或多个以下氨基酸残基取代:220S、226S、228P、229S、230S、233P、234A、234V、234F、234A、235A、235E、236A、237A、238S、239D、243L、247I、267E、268Q、280H、290S、290E、290N、292P、297A、297Q、298A、298G、298D、298V、299A、300L、305I、309L、318A、326A、326W、326E、328F、330L、330S、331S、331S、332E、333A、333S、333S、334A、339D、339Q、396L、或其组合,其中未经修饰的铰链中的氨基酸在指定的位置处被上述鉴定的氨基酸取代。
在一些实施方案中,经修饰的IgG4铰链包含但不限于,在位置228用脯氨酸(P)取代丝氨酸(S)(S228P),在位置235用亮氨酸(L)取代谷氨酸(E)(L235E),在位置297用天冬酰胺(N)取代谷氨酰胺(Q)(N297Q)。在某些实施方案中,经修饰的IgG4铰链区可包含选自以下的核苷酸序列:
对于32716CAR,SEQIDNO:1或SEQIDNO:3的核苷酸814-1500;或对于26292CAR,SEQIDNO:2或SEQIDNO:4的核苷酸793-1479。
所述核苷酸序列编码选自以下的氨基酸序列:
当用于32716CAR时,SEQIDNO:1或SEQIDNO:3的残基267-495;或
当用于26292CAR时,SEQIDNO:2或SEQIDNO:4的残基260-488。
在一个实施方案中,经修饰的IgG4铰链区包含S228P取代和L235E取代(“S228P+L235E”)(见图10和11)。在另一个实施方案中,经修饰的IgG4铰链区包含S228P取代、L235E取代和N297Q取代(“S228P+L235E+N297Q”)(见图12和13)。
在一些实施方案中,所述铰链可经修饰以将C123CAR中的Fc间隔区取代为不具有Fc结合的间隔,如CD8a的铰链区。或者,可以删除铰链的Fc间隔区。这类取代将降低或消除Fc结合。
术语“位置”如用于本文,是蛋白质序列中的位置。位置可以连续编号或依照确立的形式,例如Kabat位置或EU位置或如Kabat中的EU索引来编号。对于本文中论述的所有位置,编号依照EU索引或EU编号方案(Kabat等,1991,SequencesofProteinsofImmunologicalInterest,5thEd.,UnitedStatesPublicHealthService,NationalInstitutesofHealth,Bethesda,通过提述完整并入本文)。EU索引或如Kabat中的EU索引或EU编号方案指EU抗体的编号(Edelman等,1969,ProcNatlAcadSciUSA63:78-85,通过提述完整并入本文)。在本领域中也是公知的Kabat位置对于给定的位置可能不同于EU位置。例如,上文描述的S228P和L235E取代指EU位置。然而,这些取代还可以对应于Kabat位置241(S241P)和248(L248E)[21]。
所述共刺激信号传导域可包含任何适宜的共刺激域,包括但不限于4-1BB共刺激域、OX-40共刺激域、CD27共刺激域、或CD28共刺激域。依照本文中描述的实施方案,CD123CAR可包含至少一个共刺激信号传导域。在一个方面,所述CD123CAR具有单个共刺激信号传导域,或它可以包含连个或更多个共刺激信号传导域,如上文描述的那些。在另一个方面,所述共刺激域可由单个共刺激域(如上文描述的那些)构成,或者可由两个或更多个共刺激域的两个或更多个部分构成。或者,在一些实施方案中,CD123CAR不包含共刺激信号传导域。
在一个实施方案中,所述CD123CAR包含共刺激信号传导域,其为CD28共刺激域。CD28信号传导域可包含经修饰的CD28跨膜域。在一个实施方案中,这类经修饰的CD28跨膜域具有一个或多个氨基酸取代或修饰,其包括但不限于以下取代:在SEQIDNO:10或SEQIDNO:12的氨基酸残基530-531处或在SEQIDNO:11或SEQIDNO:13的残基523-524处亮氨酸-亮氨酸(LL)至甘氨酸-甘氨酸(GG)的取代(例如RLLH→RGGH[22])。在某些实施方案中,经修饰的共刺激信号传导域区可包含选自选自以下的核苷酸序列:
对于32716CAR,SEQIDNO:1或SEQIDNO:3的核苷酸1501-1707;或对于26292CAR,SEQIDNO:2或SEQIDNO:4的核苷酸1480-1686。
所述核苷酸序列编码选自以下的氨基酸序列:
当用于32716CAR时,SEQIDNO:1或SEQIDNO:3的残基498-564;或
当用于26292CAR时,SEQIDNO:2或SEQIDNO:4的残基489-557。
胞内信号传导域可以包含任何适宜的T细胞受体(TCR)复合物、其信号传导域部分。在一些实施方案中,胞内信号传导域是TCRzeta链(ζ-链)信号传导域。在某些实施方案中,ζ-链信号传导域可包含选自以下的核苷酸序列:
对于32716CAR,SEQIDNO:1或SEQIDNO:3的核苷酸1717-2052;或对于26292CAR,SEQIDNO:2或SEQIDNO:4的核苷酸1696-2031。
所述核苷酸序列编码选自以下的氨基酸序列:
当用于32716CAR时,SEQIDNO:1或SEQIDNO:3的残基568-679;当用于26292CAR时,SEQIDNO:2或SEQIDNO:4的残基561-672。
因此,依照上文描述的实施方案,CD123CAR基因可以包含选自SEQIDNO:1,SEQIDNO:2,SEQIDNO:3或SEQIDNO:4的核苷酸序列。在其他实施方案中,CD123CAR基因可以编码选自SEQIDNO:9,SEQIDNO:10,SEQIDNO:11或SEQIDNO:12的氨基酸序列。(图10,11,12,13)。
CD123CAR基因的表达和T细胞的转导
在一些实施方案中,CD123CAR基因是表达盒的一部分。在一些实施方案中,表达盒除了CD123CAR基因以外,还可以包含附属基因。当由T细胞表达时,附属基因可充当转导T细胞选择标志物、体内追踪标志物、或转导T细胞的自杀基因。
在一些实施方案中,附属基因是截短的EGFR基因(EGFRt)。EGFRt可用作非免疫原性选择工具(例如,使用生物素化西妥昔单抗(cetuximab)与抗生物素微珠的组合的免疫磁性选择用于富集已用含EGFRt的构建体慢病毒转导T细胞)、追踪标志物(例如流式细胞术分析用于追踪T细胞移入(engraftment))、和自杀基因(例如,经由Cetuximab/介导的抗体依赖性细胞性细胞毒性(ADCC)途径)。可依照本文中描述的实施方案使用的截短的EGFR(EGFRt)基因的一个例子记载于国际申请No.PCT/US2010/055329,其主题通过提述如其在本文完整列出的那些并入本文。在其他实施方案中,附属基因是截短的CD19基因(CD19t)。
在另一个实施方案中,所述附属基因是可诱导的自杀基因。自杀基因是将导致其中表达该基因的细胞在期望的时间经历程序化细胞死亡或抗体介导的清除的重组基因。在一个实施方案中,可用作附属基因的可诱导的自杀基因是可诱导的胱天蛋白酶9基因(参见Straathof等(2005)Aninduciblecaspase9safetyswitchforT-celltherapy.Blood.June1;105(11):4247–4254,其主题通过提述如其在本文完整列出的那些并入本文)。
在一些实施方案中,可将包含上文描述的CD123CAR基因的表达盒插入用于投递(经由转导或转染)到靶细胞的载体中。可以使用任何适宜的载体,例如细菌载体、病毒载体或质粒。在一些实施方案中,载体是选自逆转录病毒载体、慢病毒载体、痘病毒载体、腺病毒载体或腺相关病毒载体的病毒载体。在一些实施方案中,载体可以转导健康T细胞的群体。成功转导或转染的靶细胞表达作为表达盒一部分的一个或多个基因。
如此,可将一个或多个T细胞群体用CD123CAR基因转导。在一些实施方案中,CD123CAR基因包含选自SEQIDNO:1,SEQIDNO:2,SEQIDNO:3或SEQIDNO:4的核苷酸序列。因此,在一些实施方案中,转导的T细胞表达CD123CAR基因,其编码选自SEQIDNO:9,SEQIDNO:10,SEQIDNO:11或SEQIDNO:12的氨基酸序列。(图10,11,12,13)。经转导的T细胞可以来自供体,或可来自患有AML且需要AML治疗的受试者。在一些实施方案中,将经转导的T细胞用于过继性免疫疗法治疗来治疗AML。
此外,所述一个或多个T细胞的群体可以是用于投递以施用给受试者的药学可接受的组合物的一部分。除了CD123CAR转导的T细胞以外,药学有效的组合物还可以包含一种或多种药学有效的载体。“药学可接受的载体”如用于本文指药学可接受的材料、组合物或媒介物,其涉及将目的治疗物从一种组织、器官或身体一部分携带或运输至另一组织、器官或身体的一部分。这类载体可以包含例如,液体、固体或半固体的填充剂、溶剂、表面活性剂、稀释剂、赋形剂、佐剂、结合剂、缓冲剂、分解辅助(dissolutionaid)、溶剂、封装材料、掩蔽剂(sequesteringagent)、分散剂、防腐剂、润滑剂、分解剂、稠化剂、乳化剂、抗微生物剂、抗氧化剂、稳定剂、增色剂或其中一些组合。
载体的每种组分是“药学可接受的”,因为它必须与组合物的其他成分相容且必须适合与它可能遇到的任何组织、器官或身体的部分接触,这意味着它不能带有毒性、刺激、过敏反应、免疫原性或任何其他大量超出其治疗益处的并发症的风向。
一些能充当药学可接受的载体的材料的例子包括:(1)糖,如乳糖、葡萄糖和蔗糖;(2)淀粉,如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和纤维素乙酸;(4)粉化黄芪胶;(5)麦芽;(6)天然聚合物如明胶、胶原、血纤蛋白、血纤蛋白原、核纤层蛋白、核心蛋白多糖(decorin)、透明质烷(hyaluronan)、藻酸盐和壳聚糖;(7)滑石;(8)赋形剂,如可可脂和栓剂蜡;(9)油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,如丙二醇;(11)多元醇,如甘油、山梨糖醇、甘露醇和聚乙二醇;(12)酯,如三亚甲基碳酸酯、乙基油酸酯和乙基月桂酸酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)藻酸(或藻酸盐);(16)无致热原水;(17)等渗盐水;(18)林格氏(Ringer's)溶液;(19)醇,如乙醇和丙醇;(20)磷酸盐缓冲溶液;(21)热塑性塑料,如聚如三、聚羟乙酸,(22)聚酯,如聚己酸内酯;(23)自组装肽;和(24)在药物制剂中采用的其他无毒相容物质如丙酮。
所述药物组合物可按需要含有药学可接受的辅助物质以接近生理学条件,如pH调节剂和缓冲剂、毒性调节剂等,例如醋酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
在一个实施方案中,药学可接受的载体是水性载体,例如缓冲盐水等。在某些实施方案中,药学可接受的载体是极性溶剂,例如丙酮和醇。
用CD123CAR转导的T细胞在这些制剂中的浓度可以广泛变化,且将主要基于流体体积、粘度、器官大小、体重等根据选定的具体施用模式和生物系统的需要来选择。
在某些实施方案中,用CD124CAR基因转导的T细胞(即CD124CAR转导T细胞)的群体如本文中描述的用于靶向和杀伤AML细胞的方法中的那些可在细胞培养基中培养。在该实施方案的某些方面,所述方法可用于体外或研究背景以研究CD123在AML病因学中的作用,或评估新CD123CAR构建体的靶向能力。
使用用CD123CAR转导的T细胞治疗AML
依照一些实施方案,CD123CAR基因和用CD123CAR基因转导的T细胞群体如上文描述的那些可用于治疗受试者中AML的方法中。这类方法可包括对受试者施用治疗有效量的至少一种T细胞群体的步骤,所述T细胞群体用至少一种CD123CAR基因转导。在这些实施方案中,用CD123CAR转导的T细胞的群体表达一种或多种CD123CAR基因,如上文描述的那些。在某些实施方案中,所述T细胞用32716CAR(S228P+L235E+N297Q)基因构建体(图12)或26292CAR(S228P+L235E+N297Q)基因构建体(图13)转导并将其表达。当经由过继性免疫治疗疗法施用这类细胞时,经转导的T细胞在体内特异性靶向和裂解表达CD123的细胞(即AML细胞),由此投递其消除癌细胞的治疗效果。如下文实施例中描述的,在铰链范围内具有S228P和L235E突变的CD123CAR基因构建体提供充足的对脱靶效应的预防以体外生成培养的细胞中的充分应答。然而,该数据不应外推至这些构建体的体内效果。研究者就其将治疗效果到体内数据的可转移性而言极大依赖于体外数据。有时,体外数据确实与体内数据一致。然而,这种相关性是不能预测的,因为如图8显示,在体外显示高度有效的抗肿瘤细胞效果的CD123CAR(S228P+L235E)基因构建体(图10-11)在体内不具有相同效果。因此,在铰链区进行另外的突变(N297Q)以生成CD123CAR(S228P+L235E+N297Q)构建体。与CD123CAR(S228P+L235E)基因构建体相对,施用这些构建体产生白血病负荷的显著降低。
可依照本文中描述的方法使用的用一种或多种CD123CAR基因转导的一种或多种T细胞群体可通过任何适宜的施用路径施用,单独地或作为药物组合物的一部分。施用路径可以指任何本领域中已知的施用途径,包括但不限于,颅内、胃肠外或经皮。“胃肠外”指一般与注射有关的施用路径,包括眶下、输注、动脉内、囊内、心脏内、皮内、肌内、腹膜内、肺内、脊柱内、胸骨内、鞘内、肿瘤内、子宫内、静脉内、蛛网膜下、囊下、皮下、经粘膜或经器官。在某些实施方案中,静脉内或鞘内施用经转导的T细胞。
如用于本文中的,术语“有效量”指产生期望效果的药剂、化合物、治疗或疗法的量。例如,可将细胞群体与有效量的药剂、化合物、治疗或疗法接触以研究其体外效果(例如细胞培养物)或产生期望的离体或体外治疗效果。有效量的药剂、化合物、治疗或疗法可用于在受试者中产生治疗效果,如预防或治疗目标疾患、减轻与疾患有关的病症、或产生期望的生理学效果。在这类情况中,有效量的化合物是“治疗有效的量”、“治疗有效的浓度”或“治疗有效的剂量”。准确的有效量或治疗有效量是将在给定的受试者或细胞群体中得到就治疗功效而言最有效结果的组合物的量。该量将随着多种因素而变化,包括但不限于,化合物的属性(包括活性、药动学、药效学和生物利用度)、受试者或细胞的生理状况(包括年龄、性别、疾病类型和阶段、一般身体状况、对给定剂量的应答性、和药物类型)、制剂中药学可接受的一种或多种载体的性质、和施用路径。另外,有效或治疗有效量可根据化合物是单独施用或与另一种化合物、药物、疗法或其他治疗方法或形式(modality)组合施用而变化。临床和药理学领域的技术人员将能经由常规实验确定有效量或治疗有效量,即通过监测细胞或受试者对化合物施用的应答和相应调整剂量。对于别的指南,参见Remington:TheScienceandPracticeofPharmacy,第21版,Univ.ofSciencesinPhiladelphia(USIP),LippincottWilliams&Wilkins,Philadelphia,PA,2005,其通过提述如其在本文中完整列出的并入本文。可以以有效量或治疗有效量使用以依照本文中描述的实施方案产生期望效果的药剂、化合物治疗或疗法可包括但不限于,CD123CAR基因、包含CD123CAR基因的表达盒、投递包含CD123CAR基因的表达盒至靶细胞如T细胞的载体、和用CD123CAR基因转导的T细胞群体。
术语疾患的“治疗”可以指预防疾患、延缓疾患形成的发作或速率、降低疾患形成的风险、预防或延迟与疾患有关的症状的形成、降低或终止于疾患有关的症状、生成疾患的完全或部分消退、或其一些组合。治疗还可以指对疾患的防护性或预防性处理。
术语“受试者”如用于本文指人或动物,包括所有哺乳动物如灵长类(特别是高等灵长类)、绵羊、犬、啮齿类(例如小鼠或大鼠)、豚鼠、山羊、猪、猫、家兔和牛。在一些实施方案中,受试者是人。
在某些实施方案中,用于治疗AML的方法可包括施用治疗有效量的用第一CD123CAR基因转导的第一T细胞群体与治疗有效量用第二CD123CAR基因转导的第二T细胞群体的组合的步骤。
在其他实施方案中,用CD123CAR转导的T细胞可以与一种或多种另外的抗癌疗法组合。“组合”或“与…组合”如用于本文指在同一受试者中治疗同一癌症的过程中,以任意次序使用两种或更多种药剂、药物、治疗物、规程、治疗方案、治疗形式或其组合。这包括同时施用,以及相隔多达数天的时间间隔次序。这类组合治疗还可以包括任意一种或多种药剂、药物、治疗物、规程、治疗方案、和治疗形式的超过一次施用。此外,两种或更多种药剂、药物、治疗物、规程、治疗方案、治疗形式或其组合的施用可通过相同或不同的施用路径。
可以依照本文中描述的方法使用的另外的抗癌疗法可以包括一种或多种抗癌规程、治疗形式、抗癌治疗或其组合。在一些实施方案中,可将用CD123CAR转导的T细胞与一种或多种抗癌规程或治疗形式组合施用,所述抗癌规程或治疗形式包括但不限于,干细胞移植(例如使用同种异体干细胞、自体同源干细胞的骨髓移植或外周血干细胞移植;或非清髓性移植)、放疗或外科手术。在其他实施方案中,可将用CD123CAR转导的T细胞与一种或多种可用于治疗AML的抗癌治疗或药物组合施用,所述抗癌治疗或药物包括但不限于,化疗物和其他抗癌药物、免疫治疗、靶向治疗或其组合。
依照本文中描述的实施方案可与用CD123CAR转导的T细胞组合施用的化疗物和其他抗癌药物包括但不限于,全反式视黄酸(ATRA)、三氧化二砷、蒽环类抗生素及其药学可接受的盐(例如盐酸多柔比星(doxorubicinhydrochloride)、盐酸道诺霉素(daunorubicinhydrochloride)、去甲氧正定霉素(idarubicin)、米托蒽醌(mitoxantrone))、烷化剂(例如环磷酰胺、laromustine)、抗代谢类似物(阿糖胞苷(cytarabine)、6-硫代鸟嘌呤、6-巯基嘌呤、甲氨蝶呤)、脱甲基剂(例如地西他滨(decitabine)、5-氮胞苷(azacytidine))、核酸合成抑制剂(例如羟脲)、拓扑异构酶抑制剂(例如依托泊苷(etoposide))、长春花生物碱(例如硫酸长春新碱(vincristinesulfate))、或其组合(例如“ADE”,其为包含阿糖胞苷(Ara-C)、盐酸道诺霉素和依托泊苷的组合治疗)。
依照本文中描述的实施方案可与用CD123CAR转导的T细胞组合施用的免疫治疗包括但不限于,免疫调控剂(例如STAT3抑制剂,Lenalidomide)和治疗性单克隆抗体。所述治疗性单克隆抗体可设计为(i)靶向一种或多种AML抗原,包括但不限于CD33(例如gemtuzumab、lintuzumab)、MUC1(例如cantuzumabravtansine、clivatuzumabtetraxetan、pemtumomab);(i)B细胞抗原(例如利妥昔单抗(rituximab)、ofatumumab)或血管系统调控物如VEGF或VEGFR(例如alacizumabpegol、贝伐单抗(bevacizumab)、icrucumab、ramucirumab、ranibizumab)。
依照本文中描述的实施方案可与用CD123CAR转导的T细胞组合施用的靶向治疗包括但不限于,酪氨酸激酶抑制剂(imatinib、dasatinib、nilotinib、sunitinib)、法尼基(farnesyl)转移酶抑制剂(例如tipifarnib)、FLT抑制剂和c-Kit(或CD117)抑制剂(imatinib、dasatinib、nilotinib)。
实施例
实施例1:用CD123CAR转导的T细胞体外展现针对AML的有力的细胞裂解活性和多种效应器功能
材料和方法
细胞系.除非另外说明,所有细胞系均在用2mML-谷氨酰胺、25mMHEPES和10%热灭活FCS(Hyclone)补充的RPMI1640(IrvineScientific)(下文称为完全培养基(CM))中维持。如先前描述的,将外周血单核细胞(PBMC)用Epstein-Barr病毒转化以生成淋巴母细胞细胞系(LCL)[19]。LCL-OKT3细胞表达膜结合型OKT3且在补充有0.4mg/ml潮霉素的CM中生长[20]。K562细胞获自ATCC并如推荐的培养。KG1a细胞(由RaviBhatia博士热心提供)在补充有25mMHEPES,4mML-谷氨酰胺(IrvineScientific)和20%FCS的IMDM(IrvineScientific)中维持。293T细胞(来自希望之城(CityofHope)的生物医学和遗传学中心(CenterforBiomedicineandGenetics)的善意礼物)在DMEM+10%热灭活的FCS中维持。
原代AML样品.原代AML样品获自患者的外周血(本文中称为AML样品IDNo.179.373,493,519,545,559,605,722和813)。样品的特征在下表1中汇总。
[表1在另一页]
表1.原代AML样品的特征。
a相对荧光指数(RFI)是CD34+群体中9F5染色的信号的中值对同种型匹配的对照染色的比率
b在CD34+群体上设门
ND-未测定
PB-外周血
流式细胞术.缀合有荧光染料的同种型对照,抗CD4,抗CD8,抗T细胞受体αβ(TCRαβ),抗CD123(9F5),抗CD34(8G12)和抗CD38(HIT2)购自BDBiosciences。生物素化的抗Fc购自JacksonImmunoResearchLaboratories。生物素化的西妥昔单抗(Erbitux)购自COH药房且先前已描述过[20]。生物素化的抗CD2,抗CD3,抗CD7,抗CD10,抗CD11b,抗CD19,抗CD33和抗CD235A购自eBioscience。数据采集在FACSCalibur,LSRII(BDBiosciences)或MACSQuantAnalyzer(MiltenyiBiotec)上进行并使用FCSExpress版本3(DeNovoSoftware)分析。
用CD123转染293T细胞.使用聚合酶链式反应和引物(CD123-F:5’-ATAAGGCCTGCCGCCACCATGGTCCTCCTTTGGCTCACG-3’和CD123-R5’-ATAGCTAGCTCAAGTTTTCTGCACGACCTGTACTTC-3’),从CD123-pMD18-T(SinoBiologicalInc.)扩增CD123cDNA。使用StuI和NheI限制位点将PCR产物克隆到pMGPac中。使用Lipofectamine2000(LifeTechnologies)按照制造商的用法说明转染293T细胞。转染后24小时,通过流式细胞术确认CD123的表达。
慢病毒载体的生成.为了生成本研究中使用的CAR构建体,合成密码子优化的DNA序列(GENEART)并使用NheI和RsrII位点克隆到CD19RCAR-T2AEGFRt_epHIV7[20]中代替CD19RCAR,所述DNA序列编码VH和VL链、经修饰的IgG4铰链和经修饰的CD28跨膜域(RLLH→RGGH[22])。慢病毒通过使用CalPhosTM哺乳动物细胞转染试剂盒(Clontech)用慢病毒载体和包装载体pCMV-Rev2、pCHGP-2和pCMV-G转染293T细胞产生。这些26292和32716CAR构建体在本文中也称为26292CAR(S228P+L235E)或26292CAR(S228P+L235E+N297Q)(图11和13)和32716CAR(S228P+L235E)或32716CAR(S228P+L235E+N297Q)(图10和12)。在转染后24、48和72小时收获慢病毒上清液并通过超滤浓缩。
转导健康供体和AML患者PBMC.去识别的(deidentified)PBMC按照机构审查委员会批准的方案获自知情同意健康供体和患者。对于健康供体,T细胞使用OKT3(30ng/ml)在每周3次用25U/mlIL-2和0.5ng/mlIL-15补充的CM(本文中称为T细胞培养基)中活化。活化后72小时,将T细胞用慢病毒以MOI=3旋转接种(spinoculate),其通过以800g在32℃离心30分钟。在慢病毒转导后12-14天通过流式细胞术分析CAR表达。如先前描述的[20],富集表达EGFRt的T细胞。通过快速扩增方法[23]在T细胞培养基中扩增T细胞。
对于来自AML患者的T细胞的遗传修饰,使用HumanT-ExpanderCD3/CD28(LifeTechnologies)以3:1的珠:CD3+细胞比在T细胞培养基中刺激融化的外周血或血浆分离置换产物(apheresisproduct)。珠刺激后72小时,将细胞以MOI=3用慢病毒旋转接种。初始刺激后9-14天使用DynaMagTM-50磁体(LifeTechnologies)除去珠,并在T细胞培养基中维持T细胞。在杀伤测定法中使用之前,未对表达CAR的AML患者来源的T细胞系进行免疫磁性选择。
CFSE增殖测定法.将T细胞用0.5μM羧基萤光素琥珀酰亚胺酯(CFSE;MolecularProbes)按制造商用法说明标记。将经标记的T细胞与或不与刺激细胞(E:T比为2:1)在补充有10U/mlIL-2的CM中共培养。在72-96小时后,收获细胞并用生物素化西妥昔单抗以及碘化丙啶或DAPI染色以从分析排除死细胞。通过流式细胞术分析样品以通过CFSE稀释评估活EGFRt阳性细胞的增殖。
铬释放测定和细胞因子分泌测定.将靶细胞用51Cr(PerkinElmer)标记1小时,清洗5次,并与效应细胞一起以多种效应器对靶物(E:T)比以5X103细胞/孔一式三份等分取样。在4小时共培养后,收获上清液并使用gamma计数器或Topcount(PerkinElmer)测量放射性。如先前描述的[24],计算百分比特异性裂解。如先前描述的[25],在以10:1E:T比共培养24小时之后测量细胞因子产生。
CD107a脱粒和胞内细胞因子产生.将T细胞以2:1的E:T与靶细胞在37℃在存在GolgiStopTM(BDBiosciences)和抗CD107a克隆H4A3或同种型匹配的对照抗体的情况下共培养6小时。在完成6小时温育时,收获细胞,清洗并用抗CD3、CD4、CD8和生物素化西妥昔单抗染色,接着使用缀合有PE的链霉亲合素蛋白次级染色。然后,固定细胞和按照制造商用法说明渗透化(Cytofix/CytopermTMBDBiosciences)并用抗IFN-_(BDBiosciences克隆B27)和抗TNF-α(BDBiosciences克隆MAb11)染色。数据采集使用MACSQuant分析仪(MiltenyiBiotec)进行并使用FCSExpress版本3(DeNovoSoftware)完成分析。
集落形成细胞测定法.使用免疫磁性柱分离(MiltenyiBiotech)从脐带血(CB)单核细胞或原代AML样品选择CD34+细胞。将103个CD34+CB细胞与25X103效应细胞共培养4小时,接着铺板于双份孔中的半固体甲基纤维素祖细胞培养基中[26]。14至18天后,计算集落形成单位粒细胞-巨噬细胞(CFU-GM)和红系爆发形成单位(burst-forminguniterythroid,BFUE)集落。对于AML样品,将5X103CD34+AML细胞与125X103效应细胞共培养4小时,接着铺板于双份孔中的半固体甲基纤维素祖细胞培养基中。
统计学分析.使用GraphpadPrismv5.04实施统计学分析。使用非配对Student'st检验来鉴定治疗组之间的显著差异。
结果
表达CD123CAR的T细胞的生成
为了重导向T细胞特异性,开发编码CD123CAR的慢病毒载体。每种CAR包含密码子优化的序列,其分别编码两种CD123特异性scFv之一,26292和32716[18]。将scFv符合阅读框地融合至人IgG4Fc区、CD28共刺激域和CD3ζ信号传导域。就在CAR序列下游是T2A核糖体跳跃(skip)序列和截短的人EGFR(EGFRt)转导标志物(图1A)。将来自健康供体的用OKT3刺激的PBMC用慢病毒转导并通过免疫磁性选择分离表达CAR的T细胞,其使用生物素化的Erbitux抗体接着是用抗生物素磁珠的次级染色。在一个REM循环后,通过流式细胞术分析分离的细胞的CAR表面表达和T细胞表型。在来自3名健康供体的生成的T细胞系中Fc和EGFRt表达两者均大于90%,且最终T细胞产物由CD4和CD8阳性T细胞的混合物组成(图1B、1C)。
CD123CART细胞特异性靶向表达CD123的肿瘤细胞系
为了确认CD123CART细胞的特异性,检查经遗传修饰的T细胞裂解瞬时转染以表达CD123的293T细胞的能力(293T-CD123;图2A)。生成的两种CD123CART细胞均有效裂解293T-CD123,而非瞬时转染以表达CD19的293T细胞,表明对CD123的特异性识别(图2B)。接着,研究CD123特异性T细胞对于内源表达CD123的肿瘤细胞系的体外细胞裂解能力。通过流式细胞术确认CD123在细胞系LCL和KG1a上的表达(图2C)。两种CD123特异性T细胞系均有效地裂解LCL和KG1a靶系,而非CD123-K562细胞系(图2C)。配对的CD19特异性T细胞有效裂解CD19+LCL靶物,而非CD19-KG1a或K562靶物(图2D)。模拟转导的亲本细胞仅裂解阳性对照LCL-OKT3细胞系(图2D)。
CD123CART细胞在与CD123阳性靶细胞共培养时活化多种效应器功
能
为了检查CD123特异性T细胞的效应器功能,在与多种肿瘤细胞系共培养后测量IFN-γ和TNF-α的分泌。表达任一CD123CAR的T细胞产物在与CD123+靶细胞共培养时产生IFN-γ和TNF-α两者,而配对的CD19特异性T细胞仅在与CD19+LCL或LCL-OKT3细胞系共培养时分泌这些细胞因子(图3A)。另外,两种CD123特异性T细胞系在与CD123+细胞系LCL、LCL-OKT3或KG1a而非与CD123-K562细胞系共培养时增殖(图3B)。相比之下,配对的表达CD19CAR的T细胞仅在与LCL或LCL-OKT3共培养时增殖(图3B)。
CD123CART细胞在与原代AML样品共培养时激活多种效应器功能
CD123在原代AML样品上的过表达得到充分证明[27-29],且在本研究中确认(图14)。多面性(multifaceted)T细胞应答对于对感染和疫苗的强有力免疫应答是关键的且还可能在CAR重导向T细胞的抗肿瘤活性中起作用[30]。为了研究CD123CART细胞激活针对原代AML样品的多种效应器途径的能力,将工程化的T细胞与3种不同的AML患者样品(179、373和605)共培养6小时并使用多色流式细胞术(设门策略显示于图15)评估CD107a的上调和IFN-γ和TNF-α的产生。CD107a的细胞表面动员(mobilization)在CD123特异性T细胞的CD4和CD8区室两者中观察到,而配对的CD19RT细胞没有可感知的针对原代AML样品的脱粒(图4A,条形图)。另外,CD107a+CD123CART细胞的子群体也产生IFN-γ、TNF-α或这两种细胞因子(图4A,饼状图)。这种多功能应答对于CD4和CD8群体两者观察到(图4A和4B)。另外,检查了CAR工程化的T细胞应答与原代AML样品共培养而增殖的能力。两种CD123特异性T细胞系均能在与AML813或preB-ALL802样品共培养后增殖(图4C)。在CD4和CD8群体两者中均观察到增殖(图16)。配对的CD19特异性T细胞在与CD19+preB-ALL802共培养而非与AML813共培养时增殖。
表达CD123CAR的T细胞体外靶向原代AML细胞
CD123特异性T细胞在体外不消除脐带血细胞的集落形成
鉴于CD123在常见的髓性祖细胞(CMP)上表达[31],研究了工程化的T细胞对富集CD34的正常脐带血(CB)样品的集落形成能力的作用。在与表达CD123-CAR的T细胞以25:1的E:T共培养4小时后,CB样品的髓性和红系集落形成相比于配对的CD19RCART细胞没有显著降低(图6A&B)。接着,在体外检查了CD123特异性T细胞抑制原代克隆形成性(clonogenic)AML细胞的生长的能力。两种CD123CART细胞系相比于配对的CD19RT细胞均显著降低了白血病集落的形成(图6C)。显著地,CD123特异性T细胞对白血病集落形成比正常髓性集落形成具有更大的影响(图6D,分别为69%降低相对于31%降低)。
来自AML患者的T细胞可经遗传修饰以表达CD123CAR和特异性靶向
自体同源的肿瘤细胞
已知AML患者来源的T细胞较差地再极化肌动蛋白和与自体同源胚细胞形成缺陷性免疫突触[32]。另外,据我们所知,源自AML患者的表达CAR的T细胞还有待描述。因此,确定来自AML患者的T细胞是否能经遗传修饰以表达CD123CAR。将冷藏保存的PBMC(AML605和AML722)或血浆分离置换产物(AML559)用CD3/CD28珠刺激,并慢病毒转导以表达CD123CAR或CD19R对照CAR。所有3种患者样品来源的T细胞均表达26292CAR(40-65%转导效率)、32716CAR(46-70%转导效率)和CD19RCAR。为了评估CD123特异性T细胞杀伤原代AML细胞的能力,将配对的CD19RCAR或CD123CAR表达性T细胞与富集CD34的原代AML患者样品在4小时51Cr释放测定法中共培养。与配对的CD19RT细胞相比,两种CD123CART细胞系均有力地裂解所有测试的原代AML患者样品(图5A)。另外,尽管在表达CD123CAR的T细胞的细胞裂解能力之间没有注意到统计学差异,但两种CD123特异性T细胞相比于配对的CD19R-CART细胞展现显著增强的细胞毒性(图5B)。
23-37%转导效率。AML患者来源的CART细胞的表型的代表性例子显示于图7A。接着,在4小时51Cr释放测定法中检查AML患者来源的CART细胞对于自体同源的富集CD34的靶细胞的细胞裂解潜力。所有自体同源的富集CD34的细胞均表达CD123,尽管以不同的百分比和强度(图7B)。源自AML605和722的T细胞有效地裂解自体同源胚细胞而源自AML559的T细胞展现出低水平的自体同源胚细胞裂解,可能是由于AML559胚细胞上CD123的较低且异质性的表达(图7C)。
论述
本文中描述的实施方案包括使用来自重组免疫毒素(RIT)的scFv生成两种新的CD123靶向性CAR,26292和32716,其结合不同的表位且对于CD123具有相似的结合亲和力[18]。当由T细胞的群体表达时,这些CD123靶向性CAR重导向针对表达CD123的细胞的T细胞特异性。使用标准的4小时铬51(51Cr)释放测定法,工程化为表达CD123CAR的健康的供体T细胞有效裂解CD123+细胞系和原代AML患者样品。另外,两种CD123CART细胞在与CD123+细胞系和原代AML患者样品共培养后均激活多种效应器功能。此外,靶向CD123的T细胞相比于CD19CART细胞未显著降低来自脐带血(CB)的集落形成单位粒细胞-巨噬细胞(CFU-GM)或红系爆发形成单位(BFU-E)集落的数目。显著地,虽然CD19特异性T细胞对于原代AML样品的白血病集落形成具有极小影响,但CD123靶向性T细胞在体外显著降低白血病集落形成。还显示AML患者来源的T细胞能表达CD123CAR和体外裂解自体同源胚细胞。
表达两种CD123特异性CAR的任一种的T细胞能特异性裂解表达CD123的细胞系和原代AML患者样品,并以抗原特异性方式体外激活多种效应器功能,显示两种表位均为治疗的潜在靶物。在CD123CAR工程化的T细胞系之间就与CD123+细胞共培养时的靶细胞杀伤、细胞因子分泌或增殖而言没有观察到主要差异。对此一个可能的解释是CD123-CAR中使用的CD123特异性scFv的结合亲和力在纳摩级范围且相差不到3倍,如此在任一scFv赋予的靶抗原结合中没有提供显著优势[18]。
AML细胞上多种细胞表面抗原的表达已经得到充分证明[4,27,34]。经由表达CAR的T细胞靶向其中一些抗原可能不可行。例如,AML有关的抗原TIM-3在耗尽性T细胞(exhaustedTcell)的子集上表达[35,36]且使用CAR工程化的T细胞靶向TIM-3可导致该经遗传修饰的细胞的自溶。另外,CD47遍在表达[37]且如此不太可能由CAR工程化的T细胞靶向。CD33分化抗原主要在髓样细胞上表达,而且靶向CD33的免疫治疗物如Gemtuzumabozogamicin、CD33/CD3双特异性T细胞衔接抗体、和CD33CAR目前在在临床和预临床背景中使用[17,38,39]。与TIM-3相似,CD33在T细胞的子集上表达,使得其称为基于CAR的治疗的非理想靶物[40]。另外,CD33靶向疗法的抗白血病活性经常伴随有造血作用的缓慢恢复和血球减少(tytopenias),可能是长期自我更新的正常造血干细胞(HSC)上CD33表达的结果[41]。另外,肝中毒是CD33靶向性治疗的常见副作用,且可能是由于无意靶向CD33+Kupffer细胞[42]。
在T细胞上没有CD123的表达,其主要局限于髓系的细胞[43],且在很大程度上不存在于HSC上[27]。总之,这些观察结果使得CD123成为CAR介导的T细胞疗法的有吸引力的靶物。特异于CD123的治疗剂已在I期试验中展现出有利的安全性概况(profile)(临床试验政府ID:NCT00401739和NCT00397579)。不幸的是,这些疗法不能在绝大多数治疗的患者中诱导应答。本文生成的CD123-CAR表达性T细胞针对CD123+细胞系和原代AML样品在体外展现出有力的细胞裂解能力。下文描述的研究显示来自患有较差风险AML的患者的原代样品易感于CD123CART细胞介导的细胞毒性。总之,在用于短期细胞毒性测定的原代样品的小分组中,在诊断和/或化疗抗性时展现出高风险特征的AML患者样品对CD123CAR杀伤敏感,类似于在使用CD123+细胞系的实验中观察到的。将需要完成进一步的分析以确认这些结果是否适用样品的更大分组。
多功能T细胞应答与病毒感染的控制相关且在抗肿瘤CART细胞应答中可能是重要的[44]。实际上,对CD19CART细胞疗法应答的患者具有在疗法后离体应答CD19+靶物的可检测的T细胞应答(即脱粒、细胞因子分泌或增殖)[11,12,14]。在下文实施例中,证明了表达CD123-CAR的T细胞的功能性,其通过分析应答CD123+细胞系和原代AML样品两者的CD107a的上调、炎性细胞因子的产生和CD123特异性T细胞的增殖。另外,在CD4+和CD8+区室两者中观察到多功能性,这可能促进持续的抗白血病活性和加强肿瘤微环境内的抗白血病活性[45,46]。其他共刺激域如4-1BB的纳入,和“更年轻的”较少分化的T细胞的使用可以进一步增加CD123CAR应答且是在积极探索中的领域[9,47]。
另外,CD123特异性T细胞不抑制正常祖细胞集落形成-即使以25:1的E:T。谱系CD34+CD38-细胞上CD123的表达是常见髓系祖细胞的标志,如此是CD123CART细胞的可能靶物[31]。尽管当CB细胞与CD123特异性T细胞温育时观察到髓系来源的集落的相对百分比降低,但该降低不显著低于配对的CD19RCART细胞。可能有限的样本量归因于该结果且进一步的实验可能揭示用CD123CART细胞处理的脐带血样品中CFU-GM形成的显著降低。另外,在铺板前T细胞与CB细胞的4小时共培养可能不是足够长以观察到对正常髓系祖细胞集落形成的作用的时间段,且更长的温育时间可能降低观察到的髓系来源的集落的数目。然而,使用与用于CB细胞的相同的方法学,当将富集CD34的原代AML患者样品与CD123CART细胞温育时观察到形成的白血病集落数目中的实质性降低,表明4小时温育时间足以观察到白血病性和正常集落形成之间的作用。或者,CB细胞上相比于AML细胞的相对更低的CD123表达可能部分导致CD123CART细胞不能在体外改变髓系来源的集落形成。尽管他人已显示CD123仅在小部分的谱系CD34+CD38-HSC中表达,但使用靶向CD123的药剂的两项I期试验揭示无长期骨髓抑制,需要进一步的研究来评估CD123CART细胞疗法对造血作用的影响。为了控制不想要的脱靶毒性,在慢病毒构建体中纳入EGFRt以允许表达CAR的T细胞的消融。鉴于杀伤表达CD123的正常细胞的潜力,对调控CART细胞活性如可诱导的胱天蛋白酶9凋亡转换[48]或CARmRNA的电穿孔[49]的策略也具有较大兴趣。
进一步地,显示来自患有活动性疾病的AML患者的冷藏保存的PBMC可经遗传修饰以表达CD123CAR且在2/3的样品中展现出针对自体同源白血病胚细胞的有力细胞裂解活性。尽管来自AML559的表达CD123CAR的T细胞不能裂解表达低水平CD123的自体同源胚细胞,但这些CART细胞确实裂解CD123+LCL和KG1a细胞系(数据未显示),表明生成的T细胞具有靶向表达CD123的靶细胞的潜力。据我们所知,这是首次证明AML患者来源的T细胞可工程化以表达CAR且显示针对自体同源胚细胞的重导向性抗原特异性细胞毒性。
总之,下文实施例中描述的研究的结果证明CD123CART细胞能区分CD123+和CD123-细胞,且能激活针对一组较差风险的原代AML患者样品的多种T细胞效应器功能。注意到CD123特异性T细胞未显著改变正常祖细胞集落形成,但在体外相当大地降低克隆形成性髓性白血病祖细胞的生长。还证明源自AML患者的T细胞可经遗传修饰以表达CD123特异性CAR和体外裂解自体同源胚细胞。因此,CD123CART细胞是用于AML免疫疗法的有希望的候选物。
实施例2:用CD123CAR转导的T细胞在体内延迟白血病进展
CD123CAR构建体.如上文实施例1中描述的生成26292CAR(S228P+L235E)和32716CAR(S228P+L235E)构建体。还生成两种另外的CD123CAR构建体,其包含对于每个scFv在IgG4铰链中在位置297处的另外的突变(N297Q)(“26292CAR(S228P+L235E+N297Q)”和“32716CAR(S228P+L235E+N297Q)”)(图12和13,突变粗体和划线)。
将NSG小鼠移植有AML肿瘤细胞(第0天),并在第5天用表达26292CAR(S228P+L235E)或26292CAR(S228P+L235E+N297Q)的5.0x106CAR+T细胞处理,并通过生物发光成像监测白血病进展。如图8中显示的,与用26292CAR(S228P+L235E)转导的T细胞处理的小鼠的处理日相比,在第8天白血病负担进展,指示用在位置S228P和L235E具有铰链区突变的CD123CAR构建体转导的细胞在体内无效果。相比之下,用26292CAR(S228P+L235E+N297Q)转导的T细胞处理的小鼠显示与处理日相比在肿瘤大小中的降低,表明在位置297处的铰链区突变(N297Q)的添加产生能在体内延迟白血病进展的CD123CAR构建体。
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Claims (18)
1.CD123嵌合抗原受体(CD123CAR)基因,其包含以符合阅读框方式融合于以下的抗CD123scFv区:
经修饰的IgG4铰链区,其包含编码S228P氨基酸取代和L235E氨基酸取代的核苷酸序列;和
T细胞受体(TCR)zeta链信号传导域。
2.权利要求1的CD123CAR基因,其中所述经修饰的IgG4铰链区还包含编码N297Q取代的核苷酸序列。
3.权利要求1的CD123CAR基因,其中所述抗CD123scFv区编码重组免疫毒素26292或32716的VH和VL域。
4.权利要求1的CD123CAR基因,其中所述抗CD123scFv区是人源化的。
5.权利要求1的CD123CAR基因,其还包含选自以下的至少一种共刺激信号传导域:CD27共刺激信号传导域、CD28共刺激信号传导域、4-1BB共刺激信号传导域、OX40共刺激信号传导域、或其任意组合。
6.权利要求1的CD123CAR基因,其包含选自SEQIDNO:1,SEQIDNO:2,SEQIDNO:3或SEQIDNO:4的核苷酸序列。
7.权利要求1的CD123CAR基因,其中所述基因编码包含SEQIDNO:9,SEQIDNO:10,SEQIDNO:11或SEQIDNO:12的氨基酸序列。
8.权利要求1的CD123CAR基因,其中所述基因是插入病毒载体内的表达盒的部分。
9.权利要求7的CD123CAR基因,其中所述表达盒还包含选自下组的附属基因:截短的表皮生长因子受体(EGFRt)、截短的CD19(CD19t)基因或诱导的胱天蛋白酶9基因。
10.由包含以下表达盒的病毒载体转导的人T细胞的群体,该表达盒包含CD123CAR基因,所述基因包含以符合阅读框方式融合于以下的抗CD123scFv区:
经修饰的IgG4铰链区,其包含编码S228P氨基酸取代和L235E氨基酸取代的核苷酸序列;
至少一种共刺激信号传导域;和
T细胞受体(TCR)zeta链信号传导域;
其中所述人T细胞的群体表达所述CD123CAR基因。
11.权利要求10的人T细胞的群体,其中所述经修饰的IgG4铰链区还包含编码N297Q氨基酸取代的核苷酸序列。
12.权利要求10的人T细胞的群体,其中所述CD123CAR基因包含选自SEQIDNO:1,SEQIDNO:2,SEQIDNO:3或SEQIDNO:4的核苷酸序列。
13.权利要求9的人T细胞的群体,其中所述基因编码包含SEQIDNO:9;SEQIDNO:10,SEQIDNO:11或SEQIDNO:12的氨基酸序列。
16.一种在受试者中治疗AML的方法,包括对所述受试者施用用第一CD123CAR基因转导的第一T细胞群体;其中所述第一CD123CAR基因包含以符合阅读框方式融合于以下的抗CD123scFv区:
经修饰的IgG4铰链区,其包含编码S228P取代、L235E取代和N297Q取代的核苷酸序列;
至少一种共刺激信号传导域;和
T细胞受体(TCR)zeta链信号传导域。
17.权利要求16的方法,其中所述第一CD123CAR基因包含选自SEQIDNO:3或SEQIDNO:4的核苷酸序列。
18.权利要求17的方法,其还包括对所述受试者施用用第一CD123CAR基因转导的第一T细胞群体与用第二CD123CAR基因转导的第二T细胞群体的组合;其中所述第二CD123CAR基因包含以符合阅读框方式融合于以下的抗CD123scFv区:
经修饰的IgG4铰链区,其包含S228P取代、L235E取代和N297Q取代;
至少一种共刺激信号传导域;和
T细胞受体(TCR)zeta链信号传导域。
19.权利要求18的方法,其中所述第二CD123CAR基因包含选自SEQIDNO:3或SEQIDNO:4的核苷酸序列,其中所述第二CD123CAR基因的核苷酸序列不同于权利要求17中选择的核苷酸序列。
20.权利要求16的方法,其进一步包括施用用第一CD123CAR基因转导的第一T细胞群体与选自以下的一种或多种抗癌疗法的组合:干细胞移植、放射疗法、手术切除、化疗、免疫治疗、靶向疗法或其组合。
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