CN107188969A - 抗‑表皮生长因子受体变体iii嵌合抗原受体及其用于治疗癌症的用途 - Google Patents
抗‑表皮生长因子受体变体iii嵌合抗原受体及其用于治疗癌症的用途 Download PDFInfo
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Abstract
本发明提供了嵌合抗原受体(CAR),其包含人抗体139的抗原结合结构域、细胞外铰链结构域、跨膜结构域和细胞内结构域T细胞受体信号传导结构域。公开了与CAR有关的核酸、重组表达载体、宿主细胞、细胞群、抗体或其抗原结合部分和药物组合物。也公开检测癌症在宿主中的存在的方法和治疗或预防宿主的癌症的方法。
Description
本申请是国际申请日2012年3月21日,国际申请号PCT/US2012/029861,中国申请日为2013年12月5日,中国申请号201280027682.4,发明名称为“抗-表皮生长因子受体变体III嵌合抗原受体及其用于治疗癌症的用途”的分案申请。
对相关申请的交叉引用
本专利申请要求2011年4月8日提交的美国临时专利申请号61/473,409的权益,其通过引用整体结合于此。
电子递交的材料的通过引用的结合
通过引用完整结合于此的是与本文同时递交并且如下识别的计算机可读的核苷酸/氨基酸序列表:一个24,425字节的ASCII(文本)文件,文件名:“709980_ST25.TXT”,日期:2012年3月5日。
背景技术
美国癌症学会估计,在美国每年出现大约20,500例新的原发性脑和神经系统肿瘤病例,并且大约12,740位患者由于这些癌症而死亡(Jemal等,Cancer J.Clin.,57:43-66(2007))。脑肿瘤占所有中枢神经系统恶性肿瘤的大约85-90%。成胶质细胞瘤是最有侵袭性的和最常见的神经胶质瘤,占所有神经胶质瘤的51%(CBTRUS 2008StatisticalReport:Primary Brain Tumors in the United States-CBTRUS,2000-2004(2008))。尽管在常规治疗(诸如外科手术切除术、放射疗法和化学疗法)方面有所进展,神经胶质瘤以及其它类型的脑和神经系统癌症的预后可能较差。例如,大多数具有多形性成胶质细胞瘤(GBM)的患者从诊断以后存活小于15个月。因此,对癌症、尤其是神经胶质瘤的其它治疗存在未得到满足的需要。
发明内容
本发明的一个实施方案提供了嵌合抗原受体(CAR),其包含人抗体139的抗原结合结构域、细胞外铰链结构域、跨膜结构域和细胞内T细胞信号传导结构域。
本发明的其它实施方案提供了有关的核酸、重组表达载体、宿主细胞、细胞群、抗体或其抗原结合部分、和与本发明的CAR有关的药物组合物。
本发明的其它实施方案提供了检测癌症在宿主中的存在的方法以及治疗或预防宿主中的癌症的方法。
附图说明
图1A的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码绿色荧光蛋白(GFP)(●)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人外周血淋巴细胞(PBL)(效应细胞)对51Cr标记的亲本U87成胶质细胞瘤肿瘤细胞系(“U87”)(靶细胞)的特异性裂解(裂解百分比)。
图1B的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码GFP(●)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的U87-GFP(表达GFP)成胶质细胞瘤肿瘤细胞系(靶细胞)的特异性裂解(裂解百分比)。
图1C的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码GFP(●)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的U87-EGFR成胶质细胞瘤肿瘤细胞系(表达野生型表皮生长因子受体)(靶细胞)的特异性裂解(裂解百分比)。
图1D的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码GFP(●)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的U87-vIII成胶质细胞瘤肿瘤细胞系(表达EGFRvIII)(靶细胞)的特异性裂解(裂解百分比)。
图2A的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码绿色荧光蛋白(GFP)(●)、抗-ERBB2CAR(◆)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的亲本U251成胶质细胞瘤肿瘤细胞系(靶细胞)的特异性裂解(裂解百分比)。
图2B的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码绿色荧光蛋白(GFP)(●)、抗-ERBB2CAR(◆)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的U251-GFP成胶质细胞瘤肿瘤细胞系(表达GFP)(靶细胞)的特异性裂解(裂解百分比)。
图2C的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码绿色荧光蛋白(GFP)(●)、抗-ERBB2CAR(◆)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的U251-EGFR成胶质细胞瘤肿瘤细胞系(表达野生型EGFR)(靶细胞)的特异性裂解(裂解百分比)。
图2D的图显示了在不同效应物:靶标比(E:T比),未转导(UnTd)(■)或转导有编码绿色荧光蛋白(GFP)(●)、抗-ERBB2CAR(◆)、SEQ ID NO:10(h139Ab-hCD828BBZ CAR)(x)或SEQ ID NO:11(h139Ab-hCD28Z)(▲)的载体的人PBL(效应细胞)对51Cr标记的U251-vIII成胶质细胞瘤肿瘤细胞系(表达野生型EGFRvIII)(靶细胞)的特异性裂解(裂解百分比)。
图3A-3C的图显示了在与靶细胞系未转导的NIH-3T3(3T3)(3T3UT,灰色条)、未转导的BHK(BHK UT,带点的条)、未转导的293GP(293GP UT,带方格的条)、EGFR-野生型转导的3T3(3T3 EGFRwt,白色条)、EGFR-野生型转导的BHK(BHK EGFRwt,带条纹的条)、EGFRvIII-转导的3T3(3T3 EGFRvIII,黑色条)、EGFRvIII-转导的BHK(BHK EGFRvIII,带交叉影线的条)或EGFRvIII-转导的293GP(293GP EGFRvIII,带垂直和水平条纹的条)共培养以后,通过ELISA测得的未转导的细胞(UT)或被3C10 CAR(图3A)、L8A4CAR(图3B)、h139Ab-hCD28Z CAR(图3C)转导的人T细胞的干扰素(IFN)-γ分泌(pg/ml,一式三份测定的平均值)。
图4A和4B的图显示了通过ELISA测得的下述T-细胞的IFN-γ分泌(pg/ml,一式三份测定的平均值):被绿色荧光蛋白(GFP)或139-28Z载体(未分选)(139bulk)转导的、得自供体2(图4A)或供体3(图4B)的T-细胞,或被h139Ab-hCD28Z载体转导、然后小珠(bead)分选成CD8和CD4富集的(>96%+)T细胞群(139CD8+和139CD4+)的T细胞。在转导的细胞与BHK靶细胞(黑色条)、EGFR野生型工程改造的BHK细胞(EGFRwt,灰色条)或EGFRvIII工程改造的BHK细胞(EGFRvIII,带交叉影线的条)或培养基(带方格的条)一起共培养过夜以后,测量IFN-γ。
图5A和5B的图显示了被抗-EGFRvIII CAR载体(139-28BBZ)(EGFRvIII)、GFP表达载体(GFP)或CAR载体靶向ERBB2转导的或未转导的(UT)、得自人供体4(图5A)和人供体5(图5B)的T细胞的IFN-γ分泌。将转导的T细胞与培养基(黑色条)、野生型EGFR工程改造的U251细胞(U251-EGFRwt,白色条)、EGFR变体III工程改造的U251细胞(U251-EGFRvIII,灰色条)或神经胶质瘤干细胞系1228(带水平线的条)、308(带点的条)或822(带交叉影线的条)共培养。
具体实施方式
本发明的一个实施方案提供了嵌合抗原受体(CAR),其包含人抗体139(h139Ab)的抗原结合结构域、细胞外铰链结构域、跨膜结构域和细胞内T细胞信号传导结构域。
嵌合抗原受体(CAR)是人工构建的杂合蛋白或多肽,其含有与T-细胞信号传导结构域连接的、抗体的抗原结合结构域(例如,scFv)。CAR的特征包括:它们利用单克隆抗体的抗原结合性质以非-MHC限制的方式改变T-细胞对选定靶标的特异性和反应性的能力。所述非-MHC限制的抗原识别会给表达CAR的T细胞提供不依赖抗原加工而识别抗原的能力,由此绕过肿瘤逃逸的主要机制。此外,当在T-细胞中表达时,CAR有利地不会与内源T细胞受体(TCR)α和β链二聚化。
本文中使用的短语“具有抗原特异性”和“引起抗原-特异性反应”是指,CAR可以特异性地结合并免疫识别抗原,使得CAR与所述抗原的结合会引起免疫反应。
本发明的CAR对表皮生长因子受体变体III(EGFRvIII)具有抗原特异性。EGFRvIII是表皮生长因子受体(EGFR)的变体,其是作为蛋白激酶超家族成员之一的跨膜糖蛋白。EGFRvIII是在人神经胶质瘤中发现的几种EGFR突变中的最普遍的,且在约30%至约50%的多形性成胶质细胞瘤(GBM)(也被称作“成胶质细胞瘤”)中表达。EGFRvIII的表达源自消除EGFR外显子2-7并造成编码序列的外显子1和8的连接的基因内缺失重排。EGFRvIII由不同癌症的肿瘤细胞表达,所述癌症如,例如:成胶质细胞瘤(包括成胶质细胞瘤干细胞);乳腺癌、卵巢癌和非小细胞肺癌;头颈鳞状细胞癌;髓母细胞瘤、结直肠癌、前列腺癌和膀胱癌。不受特定理论或机制的约束,据信,通过引起针对EGFRvIII的抗原-特异性反应,本发明的CAR会提供下述的一项或多项:靶向和破坏表达EGFRvIII的肿瘤细胞,减少或消除肿瘤,促进免疫细胞向肿瘤部位的渗入,和增强/延长抗肿瘤反应。因为EGFRvIII不在正常的(即,非癌性的)组织中表达,预见到,本发明的CAR有利地基本上避免靶向/破坏正常的组织和细胞。
本发明提供了一种包含人抗体139的抗原结合结构域的CAR。抗体139是一种人抗-EGFRvIII抗体。抗体139特异性地结合EGFRvIII。合适的人抗体139序列公开在例如美国专利7,628,986中,所述文献通过引用结合于此。在这点上,本发明的一个优选实施方案提供了包含抗原-结合结构域的CAR,其包含人抗体139的单链可变片段(scFv)、由其组成或基本上由其组成。
人抗体139包含轻链可变区和重链可变区。所述轻链可变区可以包含SEQ ID NO:1、由其组成或基本上由其组成。所述重链可变区可以包含SEQ ID NO:2、由其组成或基本上由其组成。因此,在本发明的一个实施方案中,所述抗原结合结构域包含:包含SEQ ID NO:1的轻链可变区和/或包含SEQ ID NO:2的重链可变区。
在一个实施方案中,所述抗原结合结构域包含接头肽。所述接头肽可以位于轻链可变区和重链可变区之间。在这点上,所述抗原结合结构域可以包含这样的接头肽:其包含SEQ ID NO:3、由其组成或基本上由其组成。
在一个实施方案中,所述抗原结合结构域包含前导序列。所述前导序列可以位于轻链可变区的氨基端。在这点上,所述抗原结合结构域可以包含这样的前导序列:其包含SEQ ID NO:4、由其组成或基本上由其组成。
在一个实施方案中,所述抗原结合结构域可以包含前导序列、轻链可变区、接头肽和重链可变区。在这点上,所述包含前导序列、轻链可变区、接头肽和重链可变区的抗原结合结构域包含SEQ ID NO:5(scFv人抗体139)、由其组成或基本上由其组成。
在本发明的一个实施方案中,所述CAR包含细胞外铰链结构域、跨膜结构域、和任选的含有CD8的细胞内铰链结构域、以及含有CD28、4-1BB和CD3ζ的细胞内T细胞信号传导结构域。CD28是一种在T细胞共刺激中重要的T细胞标志物。CD8也是一种T细胞标志物。4-1BB会将有效的共刺激信号传导至T细胞,从而促进分化和增强T淋巴细胞的长期存活。CD3ζ与TCR结合以产生信号,且含有基于免疫受体酪氨酸的活化基序(ITAM)。在这点上,本发明的一个优选实施方案提供了这样的细胞外铰链结构域和跨膜结构域:其包含SEQ ID NO:6(人CD8细胞外铰链结构域和跨膜结构域)、基本上由其组成或由其组成。所述细胞内T细胞信号传导结构域包含SEQ ID NO:7(人CD28、4-1BB和CD3ζ细胞内T细胞信号传导结构域)、基本上由其组成或由其组成。
在本发明的另一个实施方案中,所述CAR包含细胞外铰链结构域、跨膜结构域、以及含有CD28和CD3ζ的细胞内T细胞信号传导结构域。在这点上,本发明的一个优选实施方案提供了这样的的细胞外铰链结构域、跨膜结构域和细胞内T细胞信号传导结构域,其包含SEQ ID NO:8(人CD28细胞外铰链、跨膜结构域和细胞内T细胞信号传导结构域)和SEQ IDNO:9(人CD3ζ细胞内T细胞信号传导结构域),基本上由其组成或由其组成。
本发明的其它实施方案提供了这样的CAR:其包含显示在表1中的任意氨基酸序列、由其组成或基本上由其组成。
表1
本发明还提供了有关的核酸、重组表达载体、宿主细胞、细胞群、抗体或其抗原结合部分、以及与本发明的CAR有关的药物组合物。
在本发明的范围内包括本文中描述的本发明的CAR的功能部分。当关于CAR使用时,术语“功能部分”表示本发明的CAR的任何这样的部分或片段,所述部分或片段保持CAR(所述部分或片段是所述CAR的部分)(亲本CAR)的生物学活性。功能部分包括,例如,这样的CAR部分:其以与亲本CAR相似、相同或更高的程度保持识别靶细胞或者检测、治疗或预防疾病的能力。关于亲本CAR,功能部分可以包含,例如,亲本CAR的约10%、25%、30%、50%、68%、80%、90%、95%或更多。
所述功能部分可以包含位于所述部分的氨基或羧基端或者两端的额外的氨基酸,所述额外的氨基酸未在亲本CAR的氨基酸序列中发现。理想地,所述额外的氨基酸不干扰功能部分的生物学功能,例如,识别靶细胞、检测癌症、治疗或预防癌症等。更理想的是,与亲本CAR的生物学活性相比,所述额外的氨基酸增强生物学活性。
在本发明的范围内包括本文所述的本发明的CAR的功能变体。本文中使用的术语“功能变体”表示与亲本CAR具有基本或显著序列同一性或者相似性的CAR、多肽或蛋白,所述功能变体保持所述功能变体作为其变体的CAR的生物学活性。功能变体包括,例如,本文所述的CAR(亲本CAR)的那些变体,所述变体以与亲本CAR相似、相同或更高的程度保持识别靶细胞的能力。关于亲本CAR,功能变体可以,例如,在氨基酸序列上与亲本CAR具有至少约30%、50%、75%、80%、90%、98%或更多的的同一性。
功能变体可以,例如,包含具有至少一个保守氨基酸置换的亲本CAR的氨基酸序列。备选地或另外地,功能变体可以包含具有至少一个非保守氨基酸置换的亲本CAR的氨基酸序列。在该情况下,优选的是,所述非保守氨基酸置换不会干扰或抑制功能变体的生物学活性。所述非保守氨基酸置换可能增强功能变体的生物学活性,使得所述功能变体的生物学活性与亲本CAR相比增加。
本发明的CAR的氨基酸置换优选地是保守氨基酸置换。保守氨基酸置换是本领域已知的,并且包括这样的氨基酸置换:其中一个具有特定物理和/或化学性质的氨基酸被交换为另一个具有相同或类似化学或物理性质的氨基酸。例如,保守氨基酸置换可以是一个酸性的/带负电荷的极性氨基酸置换另一个酸性的/带负电荷的极性氨基酸(例如,Asp或Glu),一个具有非极性侧链的氨基酸置换另一个具有非极性侧链的氨基酸(例如,Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Cys、Val等),一个碱性/带正电荷的极性氨基酸置换另一个碱性/带正电荷的极性氨基酸(例如Lys、His、Arg等),一个具有极性侧链的不带电荷的氨基酸置换另一个具有极性侧链的不带电荷的氨基酸(例如,Asn、Gln、Ser、Thr、Tyr等),一个具有β-分支的侧链的氨基酸置换另一个具有β-分支的侧链的氨基酸(例如,Ile、Thr和Val),一个具有芳族侧链的氨基酸置换另一个具有芳族侧链的氨基酸(例如,His、Phe、Trp和Tyr)等。
所述CAR可以基本上由本文所述的一个或多个特定氨基酸序列组成,以致其它组分(例如,其它氨基酸)不实质改变功能变体的生物学活性。
本发明的实施方案的CAR(包括功能部分和功能变体)可以具有任何长度,即,可以包含任何数量的氨基酸,条件是,所述CAR(或其功能部分或功能变体)保持其生物学活性,例如,以下能力:特异性结合抗原,检测宿主中的患病细胞,或者治疗或预防宿主的疾病等。例如,所述CAR的长度可以是50至5000个氨基酸,诸如50、70、75、100、125、150、175、200、300、400、500、600、700、800、900、1000或更多个氨基酸的长度。
本发明的实施方案的CAR(包括本发明的功能部分和功能变体)可以包含代替一个或多个天然存在的氨基酸的合成氨基酸。这样的合成氨基酸在本领域中是已知的,并且包括,例如,氨基环己烷羧酸、正亮氨酸、α-氨基正癸酸、高丝氨酸、S-乙酰氨基甲基-半胱氨酸、反-3-和反-4-羟基脯氨酸、4-氨基苯丙氨酸、4-硝基苯丙氨酸、4-氯苯丙氨酸、4-羧基苯丙氨酸、β-苯基丝氨酸β-羟基苯丙氨酸、苯基甘氨酸、α-萘基丙氨酸、环己基丙氨酸、环己基甘氨酸、二氢吲哚-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸、氨基丙二酸、氨基丙二酸单酰胺、N’-苄基-N’-甲基-赖氨酸、N’,N’-二苄基-赖氨酸、6-羟基赖氨酸、鸟氨酸、α-氨基环戊烷羧酸、α-氨基环己烷羧酸、α-氨基环庚烷羧酸、α-(2-氨基-2-降莰烷)-羧酸、α,γ-二氨基丁酸、α,β-二氨基丙酸、高苯丙氨酸,和α-叔丁基甘氨酸。
本发明的实施方案的CAR(包括功能部分和功能变体)可以被糖基化、酰胺化、羧基化、磷酸化、酯化、N-酰化、经由例如二硫键环化,或者转化为酸加成盐和/或任选地二聚或多聚,或者缀合。
本发明的实施方案的CAR(包括其功能部分和功能变体)可以通过本领域已知的方法得到。所述CAR可以通过任意合适的制备多肽或蛋白的方法来制备。从头合成多肽和蛋白的合适方法描述于文献中,如Chan等,Fmoc Solid Phase Peptide Synthesis(Fmoc固相肽 合成),Oxford University Press,Oxford,United Kingdom,2000;Peptide and Protein Drug Analysis(肽和蛋白药物分析),ed.Reid,R.,Marcel Dekker,Inc.,2000;Epitope Mapping(表位定位),ed.Westwood等,Oxford University Press,Oxford,UnitedKingdom,2001;和美国专利5,449,752。并且,可以使用本文所述的核酸使用标准重组方法重组地生产多肽和蛋白。见,例如,Sambrook等,Molecular Cloning:A Laboratory Manual (分子克隆:实验室手册),3rded.,Cold Spring Harbor Press,Cold Spring Harbor,NY2001;和Ausubel等,Current Protocols in Molecular Biology(当前的分子生物学实验 方案),Greene Publishing Associates and John Wiley&Sons,NY,1994。此外,本发明的一些CAR(包括其功能部分和功能变体)可以从如以下的来源分离和/或纯化:植物、细菌、昆虫、哺乳动物例如大鼠、人等。分离和纯化的方法是本领域中已知的。备选地,本文中描述的CAR(包括其功能部分和功能变体)可以由公司如Synpep(Dublin,CA)、PeptideTechnologies Corp.(Gaithersburg,MD)和Multiple Peptide Systems(San Diego,CA)商业合成。在这点上,本发明的CAR可以是合成的、重组的、分离的和/或纯化的。
本发明的一个实施方案进一步提供了特异性地结合本发明的CAR的表位的抗体或其抗原结合部分。所述抗体可以是本领域已知的任意类型的免疫球蛋白。例如,所述抗体可以是任何同种型,例如,IgA、IgD、IgE、IgG、IgM等。抗体可以是单克隆的或多克隆的。抗体可以是天然抗体,例如,分离和/或纯化自哺乳动物,例如小鼠、兔、山羊、马、鸡、仓鼠、人等的抗体。备选地,抗体可以是遗传改造的抗体,例如,人源化抗体或者嵌合抗体。抗体可以是以单体或多聚体形式。并且,抗体可以具有针对本发明的CAR的功能部分的任何水平的亲和力或亲合力。
检测抗体结合本发明的CAR的任何功能部分的能力的方法是本领域中已知的并且包括任何抗体-抗原结合测定,如,例如,放射免疫测定(RIA)、ELISA、蛋白印迹法、免疫沉淀和竞争性抑制测定(见,例如,Janeway等,如下,和美国专利申请公开号2002/0197266 A1)。
制备抗体的合适的方法是本领域中已知的。例如,标准杂交瘤方法被描述于,例如,和Milstein,Eur.J.Immunol.,5,511-519(1976),Harlow和Lane(编),Antibodies:A Laboratory Manual(抗体:实验手册),CSH Press(1988),和C.A.Janeway等(编),Immunobiology,第5版,Garland Publishing,New York,NY(2001))。备选地,其它方法,如EBV-杂交瘤法(Haskard和Archer,J.Immunol.Methods,74(2),361-67(1984),和Roder等,Methods Enzymol.,121,140-67(1986)),和噬菌体载体表达系统(见,例如,Huse等,Science,246,1275-81(1989))是本领域中已知的。此外,在非人动物中制备抗体的方法被描述于,例如,美国专利5,545,806、5,569,825和5,714,352,以及美国专利申请公开号2002/0197266 A1)。
此外,噬菌体展示可以用于生产抗体。在这点上,可以使用标准分子生物学和重组DNA技术(见,例如,Sambrook等,出处同上,和Ausubel等,出处同上),生产编码抗体的抗原结合可变(V)结构域的噬菌体文库。选择编码具有所需特异性的可变区的噬菌体用于与所需抗原的特异性结合,并且重建包含所选的可变结构域的完全或部分抗体。将编码重建的抗体的核酸序列引入合适的细胞系中,如用于杂交瘤制备的骨髓瘤细胞,以致由所述细胞分泌具有单克隆抗体特性的抗体(见,例如,Janeway等,出处同上,Huse等,出处同上,和美国专利6,265,150)。
抗体可以由转有特定的重链和轻链免疫球蛋白基因的转基因小鼠制备。所述方法是本领域中已知的并且描述于,例如美国专利5,545,806和5,569,825,以及Janeway等,出处同上。
制备人源化抗体的方法是本领域中已知的,并且详细描述于,例如,Janewaγ等,出处同上,美国专利5,225,539、5,585,089和5,693,761,欧洲专利号0239400 B1,和英国专利号2188638。也可以使用描述于美国专利5,639,641和Pedersen等,J.Mol.Biol.,235,959-973(1994)中的抗体表面重建(resurfacing)技术制备人源化抗体。
本发明的一个实施方案还提供本文所述任何抗体的抗原结合部分。抗原结合部分可以是具有至少一个抗原结合位点的任何部分,如Fab、F(ab’)2、dsFv、sFv、双抗体(diabodies)和三抗体(triabodies)。
可以使用常规重组DNA技术(见,例如,Janeway等,出处同上)制备单链可变区片段(sFv)抗体片段,所述片段是截短的Fab片段,其包括经由合成肽与轻抗体链的V结构域相连的抗体重链的可变(V)结构域。类似地,可以通过重组DNA技术(见,例如,Reiter等,ProteinEngineering,7,697-704(1994))制备二硫键稳定的可变区片段(dsFv)。然而,本发明的抗体片段不限于这些示例类型的抗体片段。
并且,抗体或其抗原结合部分可以被修饰成包含可检测的标记,如,例如,放射性同位素、荧光团(例如,荧光素异硫氰酸酯(FITC),藻红蛋白(PE)),酶(例如,碱性磷酸酶、辣根过氧化酶),和元素颗粒(例如,金颗粒)。
本发明的一个实施方案进一步提供了核酸,其包含编码本文中描述的任意CAR(包括其功能部分和功能变体)的核苷酸序列。本发明的一个实施方案提供了一种核酸,其包含编码人抗体139的抗原结合结构域的核苷酸序列,所述核苷酸序列包含SEQ ID NO:12(其编码前导序列、人抗体139的轻链可变区、接头肽、和人抗体139的重链可变区)。在这点上,本发明的一个实施方案提供了这样的核酸,其包含表2的核苷酸序列、由其组成或基本上由其组成:
表2
本文中使用的“核酸”包括“多核苷酸”、“寡核苷酸”、和“核酸分子”,并且通常表示DNA或RNA的聚合物,其可以是单链的或双链的、合成的或从天然源获得的(例如,分离的和/或纯化的),其可以包含天然、非天然或改变的核苷酸,并且其可以包含天然、非天然或改变的核苷酸间键合,如氨基磷酸酯键合或硫代磷酸酯键合,而不是在未修饰的寡核苷酸的核苷酸之间发现的磷酸二酯。在某些实施方案中,所述核酸不包含任何插入、缺失、倒位和/或置换。然而,如本文所述,在某些情况下,对于核酸可能合适的是包含一个或多个插入、缺失、倒位和/或置换。
本发明的一个实施方案的核酸可以是重组体。本文中使用的术语“重组体”表示:(i)在活细胞外通过将天然或合成的核酸片段与可以在活细胞中复制的核酸分子连接构建的分子,或者(ii)由以上(i)中所述的那些分子的复制产生的分子。对于本文,复制可以是体外复制或体内复制。
重组核酸可以是这样的核酸:其具有非天然存在的序列,或者具有通过2个否则分开的序列区段的人工组合而制备的序列。该人工组合经常通过化学合成来实现,或者更常见地,通过分离的核酸区段的人工操作来实现,例如,通过基因工程技术,诸如在Sambrook等(出处同上)中描述的那些。可以基于化学合成和/或酶连反应使用本领域中已知的方法构建核酸。见,例如,Sambrook等,出处同上,和Ausubel等,出处同上。例如,可以使用被设计用来增加分子的生物学稳定性或增加杂交后形成的双链体的物理稳定性的天然核苷酸或不同修饰的核苷酸(例如,硫代磷酸酯衍生物和吖啶取代的核苷酸)来化学合成核酸。可以用于生产核酸的修饰的核苷酸的实例包括但不限于:5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、次黄嘌呤、黄嘌呤、4-乙酰胞嘧啶、5-(羧基羟基甲基)尿嘧啶、5-羧基甲基氨基甲基-2-硫尿苷、5-羧基甲基氨基甲基尿嘧啶、二氢尿嘧啶、β-D-galactosylqueosine、肌苷、N6-异戊烯腺嘌呤、1-甲基鸟嘌呤、1-甲基肌苷、2、2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、N6-取代腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基氨基甲基-2-硫尿嘧啶、β-D-mannosylqueosine、5′-甲氧基羧基甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲基硫代-N6-异戊烯腺嘌呤、尿嘧啶-5-氧基乙酸(v)、怀丁氧苷(wybutoxosine)、假尿嘧啶、Q核苷(queosine)、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、尿嘧啶-5-氧基乙酸甲酯、3-(3-氨基-3-N-2-羧基丙基)尿嘧啶和2,6-二氨基嘌呤。备选地,本发明的一种或多种核酸可以购买自公司,如Macromolecular Resources(Fort Collins,CO)和Synthegen(Houston,TX)。
核酸可以包含编码任何CAR或其功能部分或功能变体的任何分离的或纯化的核苷酸序列。备选地,核苷酸序列可以包含简并为任意序列或简并序列的组合的核苷酸序列。
本发明的一个实施方案还提供分离或纯化的核酸,所述核酸包含与本文所述的任何核酸的核苷酸序列互补的核苷酸序列,或者在严格条件下与本文所述的任何核酸的核苷酸序列杂交的核苷酸序列。
在严格条件下杂交的核苷酸序列可以在高严格性条件下杂交。“高度严格条件”是指核苷酸序列以相比于非特异性杂交的可检测地更强的量与靶序列(本文所述的任何核酸的核苷酸序列)特异性地杂交。高度严格条件包括将区别具有正确互补序列的多核苷酸的条件,或者仅包含少量分散错配的条件,所述错配来自正好具有少量匹配所述核苷酸序列的小区域(例如,3-10个碱基)的随机序列。这样的互补性小区域比14-17个以上碱基的全长补体更容易解链,并且高度严格杂交使得它们可以容易地区分。相对的高度严格条件包括,例如,低盐和/或高温条件,如由约0.02-0.1M NaCl或等价物,在约50-70℃的温度提供的。这样的高度严格条件几乎不允许(即使有)核苷酸序列与模板或靶链之间的错配,并且尤其适于检测任何本发明的CAR的表达。通常被理解的是,可以通过添加增加量的甲酰胺使得条件更严格。
本发明还提供了一种核酸,其包含与本文中描述的任意核酸具有至少约70%或更多(例如,约80%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%)同一性的核苷酸序列。
在一个实施方案中,本发明的核酸可以结合到重组表达载体中。在这点上,本发明的一个实施方案提供了包含本发明的任何核酸的重组表达载体。当用于本文时,术语″重组表达载体″表示遗传修饰的寡核苷酸或多核苷酸构建体,当所述构建体包含编码mRNA、蛋白、多肽或肽的核苷酸序列,并且将载体在足以使mRNA、蛋白、多肽或肽在细胞内表达的条件下与细胞接触时,所述遗传修饰的寡核苷酸或多核苷酸构建体允许宿主细胞表达mRNA、蛋白、多肽或肽。本发明的载体整体上不是天然存在的。然而,所述载体的部分可以是天然存在的。本发明的重组表达载体可以包含任何类型的核苷酸,包括但不限于DNA和RNA,其可以是单链的或双链的,合成的或部分从天然来源获得的,并且其可以包含天然存在或非天然存在或改变的核苷酸。重组表达载体可以包含天然存在、非天然存在的核苷酸间键合,或上述两种类型的键合。优选地,非天然或改变的核苷酸或核苷酸间键合不妨碍载体的转录或复制。
在一个实施方案中,本发明的重组表达载体可以是任何合适的重组表达载体,并且可以用于转化或转染任何合适的宿主。合适的载体包括那些载体,所述载体被设计成用于增殖和扩大或表达或两者,如质粒和病毒。载体可以选自由以下组成的组:pUC系列(Fermentas Life Sciences,Glen Burnie,MD),pBluescript系列(Stratagene,LaJolla,CA),pET系列(Novagen,Madison,WI),pGEX系列(Pharmacia Biotech,Uppsala,Sweden)和pEX系列(Clontech,Palo Alto,CA)。也可以使用噬菌体载体,如λGT10,λGT11,λZapII(Stratagene),λEMBL4和λNM1149。植物表达载体的实例包括pBI01,pBI101.2,pBI101.3,pBI121和pBIN19(Clontech)。动物表达载体的实例包括pEUK-Cl,pMAM和pMAMneo(Clontech)。重组表达载体可以是病毒载体,例如,反转录病毒载体。
许多转染技术通常是本领域已知的(见,例如,Graham等人,Virology,52:456-467(1973);Sambrook等人,出处同上;Davis等人,Basic Methods in Molecular Biology,Elsevier(1986);和Chu等人,Gene,13:97(1981)。转染方法包括磷酸钙共沉淀(见,例如,Graham等,出处同上)、直接显微注射进培养的细胞中(见,例如,Capecchi,Cell,22:479-488(1980))、电穿孔(见,例如,Shigekawa等人,BioTechniques,6:742-751(1988))、脂质体介导的基因转移(见,例如,Mannino等人,BioTechniques,6:682-690(1988))、脂质介导的转导(见,例如,Felgner等,Proc.Natl.Acad.Sci.USA,84:7413-7417(1987))和使用高速微射弹的核酸递送(见,例如,Klein等,Nature,327:70-73(1987))。
在一个实施方案中,可以使用标准重组DNA技术制备本发明的重组表达载体,所述技术描述于例如,Sambrook等,同上,和Ausubel等,同上。环形或线形的表达载体的构建体可被制备成包含在原核或真核宿主细胞中起作用的复制系统。复制系统可以来源自,例如,ColE1、2μ质粒、λ病毒、SV40病毒、牛乳头瘤病毒等。
重组表达载体可以包含调节序列,如转录和翻译起始和终止密码子,其对其中将要引入所述载体的宿主(例如,细菌、真菌、植物或动物)是特异的,适当地并且考虑载体是基于DNA的还是基于RNA的。
重组表达载体可以包括一种或多种标记物基因,这允许选择转化的或转染的宿主。标记物基因包括杀菌剂抗性,例如,对抗生素、重金属等的的抗性,在营养缺陷型宿主中的互补以提供原营养,等。适用于本发明的表达载体的标记物基因包括,例如,新霉素/G418抗性基因,潮霉素抗性基因,组胺醇抗性基因,四环素抗性基因和氨苄青霉素抗性基因。
重组表达载体可以包含天然或者非天然启动子,所述启动子可操作地连接至编码CAR(包括其功能部分和功能变体)的核苷酸序列、或连接至这样的核苷酸序列:其与编码CAR的核苷酸序列互补或杂交。选择例如,强的、弱的、可诱导的、组织特异性的和发育特异性的启动子属于技术人员的常规技术。类似地,将核苷酸序列与启动子结合也在技术人员的技术内。启动子可以是非病毒启动子或病毒启动子,例如,巨细胞病毒(CMV)启动子、SV40启动子、RSV启动子或发现于鼠干细胞病毒的长末端重复中的启动子。
本发明的重组表达载体可以被设计成用于瞬时表达、稳定表达或两者。并且,重组表达载体可以被制成用于组成型表达或可诱导表达。
此外,重组表达载体可以被制成包括自杀基因。当在本文中使用时,术语″自杀基因″是指导致表达自杀基因的细胞死亡的基因。自杀基因可以是这样的基因,其将对药剂例如药物的敏感性给予表达该基因的细胞,并且当细胞与所述药剂接触或暴露于所述药剂时导致所述细胞死亡。自杀基因是本领域中已知的(见,例如,Suicide Gene Therapy: Methods and Reviews(自杀基因疗法:方法和综述),Springer,Caroline J.(CancerResearch UK Centre for Cancer Therapeutics at the Institute of CancerResearch,Sutton,Surrey,UK),Humana Press,2004),并且包括,例如,单纯疱疹病毒(HSV)胸腺嘧啶激酶(TK)基因,胞嘧啶脱氨酶(daminase),嘌呤核苷磷酸化酶,和硝基还原酶。
在本发明的范围内包括缀合物,例如,生物缀合物,其包含任何本发明的CAR(包括其任何功能部分或变体)、核酸、重组表达载体、宿主细胞、宿主细胞群或抗体或其抗原结合部分。缀合物,以及通常用于合成缀合物的方法在本领域中是已知的(见,例如,Hudecz,F.,Methods Mol.Biol.298:209-223(2005)和Kirin等,Inorg Chem.44(15):5405-5415(2005))。
本发明的一个实施方案还提供包含本文所述的任何重组表达载体的宿主细胞。当在本文中使用时,术语″宿主细胞″是指可以包含本发明的重组表达载体的任何类型的细胞。宿主细胞可以是真核细胞,例如,植物、动物、真菌或藻类,或者可以是原核细胞,例如,细菌或原生动物。宿主细胞可以是培养的细胞或原代细胞,即,直接分离自生物例如人的细胞。宿主细胞可以是粘附细胞或悬浮细胞,即,在悬浮液中生长的细胞。合适的宿主细胞是本领域中已知的并且包括,例如,DH5α大肠杆菌细胞,中国仓鼠卵巢细胞,猴VERO细胞,COS细胞,HEK293细胞等。为了扩增或复制重组表达载体,宿主细胞可以是原核细胞,例如,DH5α细胞。为了制备重组CAR,宿主细胞可以是哺乳动物细胞。宿主细胞可以是人细胞。虽然宿主细胞可以是任何细胞类型,可以来源于任何类型的组织,并且可以处于任何发育阶段,但是宿主细胞可以是外周血淋巴细胞(PBL)或者外周血单核细胞(PBMC)。宿主细胞可以是T细胞。
当用于本文时,T细胞可以是任何T细胞,如培养的T细胞,例如,原代T细胞,或者来自培养的T细胞系例如Jurkat、SupT1等的T细胞,或获得自哺乳动物的T细胞。如果获得自哺乳动物,T细胞可以获得自多个来源,包括但不限于血液、骨髓、淋巴结、胸腺或其他组织或流体。T细胞也可以被浓缩或纯化。T细胞可以是人T细胞。T细胞可以是分离自人的T细胞。T细胞可以是任何类型的T细胞并且可以处于任何发育阶段,包括但不限于,CD4+/CD8+双阳性T细胞,CD4+辅助T细胞,例如,Th1和Th2细胞,CD8+T细胞(例如,细胞毒性T细胞),肿瘤浸润细胞,记忆T细胞,幼稚T细胞等。T细胞可以是CD8+T细胞或CD4+T细胞。
本发明的一个实施方案还提供包含至少一种本文所述的宿主细胞的细胞群。细胞群可以是异种群,其包含含有所述任何重组表达载体的宿主细胞,此外还包含至少一种其他细胞,例如,不含有任何重组表达载体的宿主细胞(例如,T细胞),或者除T细胞以外的细胞,例如,B细胞、巨噬细胞、嗜中性粒细胞、红细胞、肝细胞、内皮细胞、上皮细胞、肌细胞、脑细胞等。备选地,细胞群可以是基本同种的群,其中该群主要包含含有重组表达载体的宿主细胞(例如,基本由其组成)。所述群也可以是克隆的细胞群,其中该群的所有细胞都是含有重组表达载体的单个宿主细胞的克隆,以致该群的所有细胞都含有重组表达载体。在本发明的一个实施方案中,细胞群是克隆的群,其包含宿主细胞,所述宿主细胞包含如本文所述的重组表达载体。
CAR(包括其功能部分和变体)、核酸、重组表达载体、宿主细胞(包括其群)和抗体(包括其抗原结合部分)(它们在下文中被统称为“本发明的CAR材料”)可以是分离的和/或纯化的。本文中使用的术语“分离的”表示已经从其天然环境中取出。本文中使用的术语“纯化的”或“分离的”不要求绝对纯度或分离;相反,它是指相对术语。因而,例如,纯化的(或分离的)宿主细胞制品是这样的:其中宿主细胞比处于其在体内天然环境中的细胞更纯。这样的宿主细胞可以通过例如标准纯化技术来生产。在某些实施方案中,纯化宿主细胞制品,使得宿主细胞占所述制品的总细胞含量的至少约50%,例如至少约70%。例如,所述纯度可以是至少约50%,可以是大于约60%、约70%或约80%,或可以是约100%。
本发明的CAR材料可以被制成组合物,如药物组合物。在这点上,本发明的一个实施方案提供了一种药物组合物,其包含任意的CAR、功能部分、功能变体、核酸、表达载体、宿主细胞(包括其群)和抗体(包括其抗原结合部分)和药用载体。含有任何本发明的CAR材料的本发明的药物组合物可以包含超过一种本发明的CAR材料,例如,CAR和核酸,或者2种或更多种不同的CAR。备选地,药物组合物可以包含本发明的CAR材料以及其他药物活性试剂或药物,如化疗剂,例如,天冬酰胺酶、白消安(busulfan)、卡铂(carboplatin)、顺铂、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、氟尿嘧啶、吉西他滨(gemcitabine)、羟基脲、甲胺蝶呤、紫杉醇(paclitaxel)、利妥昔单抗(rituximab)、长春碱(vinblastine)、长春新碱(vincristine)等。在一个优选的实施方案中,所述药物组合物包含本发明的宿主细胞或其群体。
本发明的CAR材料可以以盐(例如,药用盐)的形式提供。合适的药用酸加成盐包括源自无机酸(诸如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸)和有机酸(诸如酒石酸、乙酸、柠檬酸、苹果酸、乳酸、富马酸、苯甲酸、羟乙酸、葡糖酸、琥珀酸和芳基磺酸,例如,对甲苯磺酸)的那些盐。
关于药物组合物,药用载体可以是任何常规使用的那些载体并且仅受化学-物理考虑,如溶解性和缺少与活性剂的反应性,和给药路径的限制。本文所述的药用载体,例如,运载体(vehicle)、佐剂、赋形剂和稀释剂对于本领域中的技术人员是已知的,并且公众可以容易地获得。优选地,药用载体是在化学上对活性试剂为惰性的载体和在使用条件下没有有害副作用或毒性的载体。
载体的选择将部分由特定的本发明的CAR材料以及用于给药本发明的CAR材料的特定方法确定。因此,存在多种本发明的药物组合物的合适制剂。可以使用防腐剂。合适的防腐剂可以包括,例如,对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸钠和苯扎氯铵。可以任选地使用2种或更多种防腐剂的混合物。防腐剂或其混合物通常以总组合物的约0.0001重量%至约2重量%的量存在。
合适的缓冲剂可以包括,例如,柠檬酸、柠檬酸钠、磷酸、磷酸钾、和多种其它酸和盐。可以任选地使用2种或更多种缓冲剂的混合物。所述缓冲剂或其混合物通常以总组合物的约0.001重量%至约4重量%的量存在。
本发明的CAR材料在药物制剂中的浓度可以变化,例如,按重量计,从小于约1%(通常在或至少约10%)到多达约20%至约50%或更多,且可以主要根据选择的特定给药模式通过流体体积和粘度来选择。
用于制备可施用的(例如,可胃肠外施用的)组合物的方法是本领域技术人员已知的或显而易见的,且更详细地描述在,例如,Remington:The Science and Practice ofPharmacy,Lippincott Williams&Wilkins;第21版(2005年5月1日)。
以下用于口服给药、气溶胶给药、肠胃外给药(例如,皮下、静脉内、动脉内、肌肉内、真皮内、腹膜间和鞘内)和局部给药的制剂仅仅是示例性的并且决不是限制性的。超过一种路径可以用于施用本发明的CAR材料,并且在某些情况下,特定途径可以提供比另一种途径更快速和更有效的反应。
适于口服给药的制剂可以包含以下或者由以下组成:(a)液体溶液,如溶解在稀释剂如水、盐水或橙汁中的有效量的本发明的CAR材料;(b)胶囊、囊剂、片剂、锭剂(lozenge)和锭剂(troche),其各自含有预定量的为固体或颗粒的活性成分;(c)粉剂;(d)在合适液体中的混悬剂;和(e)合适的乳状剂。液体制剂可以包括稀释剂,如水和醇,例如,乙醇、苄醇和聚乙烯醇,同时添加或不添加药用表面活性剂。胶囊形式可以是常规的硬壳明胶类型或软壳明胶类型,其含有,例如,表面活性剂、润滑剂和惰性填料,如乳糖、蔗糖、磷酸钙和玉米淀粉。片剂形式可以包括以下各项中的一种更多种:乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、藻酸、微晶纤维素、阿拉伯树胶、明胶、瓜尔胶、胶体二氧化硅、交联羧甲纤维素钠、滑石、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸和其他赋形剂、着色剂、稀释剂、缓冲剂、崩解剂、润湿剂、防腐剂、调味剂和其他药用赋形剂。锭剂(lozenge)形式可以包含具有风味的本发明的CAR材料,通常是蔗糖和阿拉伯树胶或黄蓍胶,以及在惰性基质中包含本发明的CAR材料的软锭剂(pastille),所述惰性基质如明胶和甘油,或蔗糖和阿拉伯树胶,包含除此之外的赋形剂的乳剂,凝胶等,其是本领域中已知的。
适用于肠胃外给药的制剂包括水性和非水性的、等渗无菌注射液,其可以含有抗氧化剂、缓冲剂、抑菌剂和使制剂与目标受体的血液等渗的溶质,以及水性和非水性的无菌混悬剂,其可以包括助悬剂、增溶剂、增稠剂、稳定剂和防腐剂。本发明的CAR材料可以在药物载体中在生理用稀释剂中被施用,所述稀释剂如无菌液体或液体的混合物,包括水、盐水、葡萄糖水溶液和相关糖溶液,醇,如乙醇或十六醇,二醇,如丙二醇或聚乙二醇,二甲亚砜,甘油,缩酮如2,2-二甲基-1,3-二氧戊环-4-甲醇,醚,聚(乙二醇)400,油剂,脂肪酸,脂肪酸酯或甘油酯,或乙酰化脂肪酸甘油酯(在添加或不添加药用表面活性剂的情况下,所述药用表面活性剂如脂肪酸盐(soap)或去垢剂),助悬剂,如果胶,卡波姆,甲基纤维素,羟基丙基甲基纤维素,或羧基甲基纤维素,或乳化剂和其他药物佐剂。
可以用于肠胃外制剂中的油包括石油、动物油、植物油或合成油。油的具体实例包括花生、大豆、芝麻、棉籽、玉米、橄榄、矿脂和矿物油。适用于肠胃外制剂的脂肪酸包括油酸、硬脂酸和异硬脂酸。油酸乙酯和豆蔻酸异丙酯是合适的脂肪酸酯的实例。
适用于肠胃外制剂中的脂肪酸盐(soap)包括脂肪碱金属盐、铵盐和三乙醇胺盐,而合适的去垢剂包括(a)阳离子去垢剂如,例如,二甲基二烷基卤化铵和烷基卤化吡啶,(b)阴离子去垢剂如,例如,烷基,芳基,和烯烃磺酸酯(或盐),烷基,烯烃,醚,和单甘油酯硫酸酯,和磺基琥珀酸酯(或盐),(c)非离子去垢剂如,例如,脂肪胺氧化物,脂肪酸链烷醇酰胺,和聚乙烯聚丙烯共聚物,(d)两性去垢剂如,例如,烷基-β-氨基丙酸酯(或盐),和2-烷基-咪唑啉季铵盐,和(e)它们的混合物。
肠胃外制剂将典型地包含例如约0.5重量%至约25重量%的溶液中的本发明的CAR材料。可以使用防腐剂和缓冲剂。为了最小化或消除注射位点处的刺激,所述组合物可以包含一种或多种非离子表面活性剂,所述非离子表面活性剂具有例如约12至约17的亲水亲油平衡值(HLB)。表面活性剂在所述制剂中的量典型地为例如约5重量%至约15重量%。合适的表面活性剂包括聚乙二醇脱水山梨醇脂肪酸酯,如单油酸脱水山梨醇酯和环氧乙烷与通过缩合环氧丙烷和丙二醇形成的疏水基质的高分子量加合物。肠胃外制剂可以被提供在单位剂量或多剂量的密封容器如安瓿和小药瓶中,并且可以存储在冷冻干燥(冻干)条件中,其仅需要在使用前的即刻添加注射用无菌液体赋形剂,例如,水。临时注射溶液和混悬剂可以制备自之前所述类型的无菌粉剂、粒剂和片剂。
可注射制剂是根据本发明的一个实施方案。对用于可注射组合物的有效药物载体的需要是本领域技术人员已知的(见,例如,Pharmaceutics and Pharmacy Practice(药物和药学实践),J.B.Lippincott Company,Philadelphia,PA,Banker和Chalmers编辑,238-250页(1982),以及ASHP Handbook on Injectable Drugs(关于可注射药物的ASHP手册),Toissel,第4版,622-630页(1986))。
局部制剂(包括可用于透皮药物释放的那些)是本领域技术人员众所周知的,且在本发明的实施方案的背景下适合施用于皮肤。本发明的CAR材料(单独地或者与其它合适的组分组合地)可以被制成经由吸入给药的气溶胶制剂。这些气溶胶制剂可以被置于加压可用的推进剂(诸如二氯二氟甲烷、丙烷、氮气等)中。它们也可以被制成用于非加压制剂的药物,如在喷雾器或雾化器中。所述喷雾制剂也可以用于粘膜喷雾。
“有效量”或“治疗……的有效量”表示,足以预防或治疗个体中的癌症的剂量。对于治疗或预防用途而言,有效量将取决于,例如,要治疗的疾病或障碍的阶段和严重程度,患者的年龄、重量和一般健康情况,以及处方医师的判断。剂量的大小也将取决于:选择的活性剂,施用方法,施用时机和频率,可能伴随特定活性剂的施用的任何不利副作用的存在、性质和程度,以及期望的生理效应。本领域技术人员会明白,不同的疾病或障碍可能需要包括多次施用的长期治疗,可能在每轮或不同轮施用中使用本发明的CAR材料。作为示例且无意限制本发明,本发明的CAR材料的剂量可以是约0.001至约1000mg/kg要治疗的受试者的体重/天,约0.01至约10mg/kg体重/天,约0.01mg至约1mg/kg体重/天。当本发明的CAR材料是宿主细胞时,宿主细胞的一种示例性剂量可以是约100万个细胞(1mg细胞/剂)的最小值。当本发明的CAR材料是被包装在病毒中的核酸时,病毒的一种示例性剂量可以是约1ng/剂。
就本发明的目的而言,施用的本发明的CAR材料的量或剂量应当足以在合理的时间范围内,在受试者或动物中产生治疗或预防反应。例如,本发明的CAR材料的剂量应当足以在自给药起的约2小时以上例如约12小时至约24个小时以上的时间中结合抗原,或检测、治疗或预防疾病。在某些实施方案中,时间可以更长。剂量将取决于具体的本发明的CAR材料的效力和动物(例如,人)的状态,以及待治疗的动物(例如,人)的体重。
就本发明的目的而言,这样的测定可以用于确定向哺乳动物施用的起始剂量:所述测定包含例如,在各自被施用不同剂量的T细胞的一组哺乳动物之间,比较在向所述哺乳动物施用给定剂量的所述T细胞后,靶细胞被溶解的程度和/或表达本发明的CAR的T细胞分泌IFN-γ的程度。施用特定剂量后靶细胞溶解的程度和/或IFN-γ分泌的程度可以通过本领域中已知的方法测定。
除了前述药物组合物以外,本发明的CAR材料可以被配制为包合络合物,诸如环糊精包合络合物或脂质体。脂质体可以用于将本发明的CAR材料靶向特定组织。脂质体也可以用于增加本发明的CAR材料的半衰期。许多方法可用于制备脂质体,如在例如下述文献中所述:Szoka等,Ann.Rev.Biophys.Bioeng.,9,467(1980)和美国专利4,235,871、4,501,728、4,837,028和5,019,369。
在本发明的实施方案的背景下有用的递送系统可以包括定时释放、延迟释放和持续释放递送系统,使得本发明的组合物的递送提前发生,且具有足够的时间以造成要治疗的部位的致敏。本发明的组合物可以与其它治疗剂或疗法结合使用。这样的系统可以避免本发明的组合物的重复施用,由此增加受试者和医师的便利,且可以特别适合用于本发明的某些组合物实施方案。
许多类型的释放递送系统是本领域普通技术人员可利用的和已知的。它们包括基于聚合物的系统,诸如聚(丙交酯-乙交酯)、共聚草酸酯、聚己内酯、聚酯酰胺、聚原酸酯、聚羟基丁酸和聚酸酐。含有药物的前述聚合物的微胶囊描述于,例如,美国专利5,075,109。递送系统也包括非聚合物系统,其为:脂质,包括甾醇诸如胆固醇、胆固醇酯和脂肪酸或者中性脂肪如甘油一酯、甘油二脂和甘油三酯;水凝胶释放系统;硅橡胶(sylastic)系统;基于肽的系统;蜡包被物;使用常规粘合剂和赋形剂的压制片剂;部分融合的植入物;等。具体例子包括但不限于:(a)侵蚀系统,其中活性组合物以在基质内的形式被包含,诸如在美国专利4,452,775、4,667,014、4,748,034和5,239,660中描述的那些,以及(b)扩散系统,其中活性组分以受控速率从聚合物渗透,例如在美国专利3,832,253和3,854,480中描述的那些。另外,可以使用基于泵的硬件递送系统,其中的一些适合用于植入。
本领域技术人员将容易理解,本发明的CAR材料可以以任何数量的方式修饰,以致本发明的CAR材料的治疗或预防效力通过所述修饰而增加。例如,本发明的CAR材料可以通过接头直接或间接与靶向部分缀合。将化合物(例如本发明的CAR材料)缀合到靶向部分的实践是本领域中已知的。见,例如,Wadwa等,J.Drug Targeting 3:111(1995)和美国专利号5,087,616。
备选地,本发明的CAR材料可以被改变成贮库(depot)形式,以致本发明的CAR材料释放到其被给药于的身体中的方式关于时间和体内的位置被控制(见,例如,美国专利4,450,150)。本发明的CAR材料的贮库形式可以是,例如,可植入组合物,所述可植入组合物包含本发明的CAR材料和多孔或非多孔材料,如聚合物,其中本发明的CAR材料被所述材料包封或通过所述材料和/或非多孔材料的分解扩散。然后贮库被植入到所需的体内位置中,并且本发明的CAR材料以预定的速率从所述植入物释放。
当本发明的CAR材料与一种或多种其他治疗剂一起施用时,可以将一种或多种其他治疗剂共同施用给哺乳动物。“共同施用”是指,在时间上足够靠近地施用一种或多种其他治疗剂和本发明的CAR材料,使得本发明的CAR材料可以增强一种或多种其他治疗剂的作用,或反之亦然。在这点上,可以首先施用本发明的CAR材料,并可以然后施用一种或多种其他治疗剂,或反之亦然。备选地,可以同时地施用本发明的CAR材料和一种或多种其他治疗剂。可以与CAR材料共同施用的一种示例性的治疗剂是IL-2。据信,IL-2会增强本发明的CAR材料的治疗效果。为了本发明的方法(其中将宿主细胞或细胞群施用给宿主)的目的,所述细胞可以是与宿主同种异源的细胞或宿主的自体细胞。
预见到,本发明的药物组合物、CAR、核酸、重组表达载体、宿主细胞或细胞群可以用于治疗或预防宿主的疾病的方法。不受特定理论或机制的约束,本发明的CAR具有生物学活性,例如,识别抗原(例如,EGFRvIII)的能力,使得当被细胞表达时,CAR能够介导针对表达所述CAR对其具有特异性的抗原(例如,EGFRvIII)的细胞的免疫反应。在这点上,本发明的一个实施方案提供了一种治疗或预防宿主的癌症的方法,所述方法包括:以有效地治疗或预防宿主的癌症的量,给所述宿主施用本发明的CAR、核酸、重组表达载体、宿主细胞、细胞群、抗体和/或其抗原结合部分和/或药物组合物。
本发明的一个实施方案进一步包括,在施用本发明的CAR材料之前,使宿主淋巴细胞耗竭。淋巴细胞耗竭(lymphodepletion)的例子包括、但是可以不限于:非骨髓根除的(nonmyeloablative)淋巴细胞耗竭化学疗法、骨髓根除的淋巴细胞耗竭化学疗法、全身辐照等。
为了本发明的方法(其中施用宿主细胞或细胞群)的目的,所述细胞可以是与宿主同种异源的细胞或宿主的自体细胞。优选地,所述细胞是宿主自体细胞。
在本文中提及的宿主可以是任何宿主。所述宿主可以是哺乳动物。本文中使用的术语“哺乳动物”表示任何哺乳动物,包括、但不限于,啮齿目(order Rodentia)的哺乳动物,如小鼠和仓鼠,和兔形目(order Logomorpha)的哺乳动物,如兔子。所述哺乳动物可以来自食肉目(order Carnivora),包括猫科(猫)和犬科(狗)。所述哺乳动物可以来自偶蹄目(order Artiodactyla),包括牛科(牛)和猪科(猪),或奇蹄目(order Perssodactyla),包括马科(马)。所述哺乳动物可以是灵长目(order Primates)、Ceboids或Simoids(猴),或类人目(order Anthropoids)(人和猿)。优选地,所述哺乳动物是人。
关于本发明的方法,所述癌症可以是任何癌症,包括下述的任一种:急性淋巴细胞癌,急性髓性白血病,小泡型横纹肌肉瘤,膀胱癌(例如,膀胱恶性肿瘤),骨癌,脑癌(例如,髓母细胞瘤),乳腺癌,肛门、肛管或肛门直肠的癌症,眼睛的癌症,肝内胆管的癌症,关节的癌症,颈、胆囊或胸膜的癌症,鼻、鼻腔或中耳的癌症,口腔的癌症,外阴的癌症,慢性淋巴细胞白血病,慢性骨髓癌,结肠癌,食管癌,宫颈癌,纤维肉瘤,胃肠类癌瘤,头颈癌(例如,头颈鳞状细胞癌),霍奇金淋巴瘤,下咽癌,肾癌,喉癌,白血病,液体肿瘤,肝癌,肺癌(例如,非小细胞肺癌),淋巴瘤,恶性间皮瘤,肥大细胞瘤,黑素瘤,多发性骨髓瘤,鼻咽癌,非霍奇金淋巴瘤,卵巢癌,胰腺癌,腹膜、网膜和肠系膜癌,咽癌,前列腺癌,直肠癌,肾癌,皮肤癌,小肠癌,软组织癌,实体瘤,胃癌,睾丸癌,甲状腺癌,和输尿管癌。优选地,所述癌症是神经胶质瘤(例如,室管膜瘤、星形细胞瘤、少突神经胶质瘤和寡星状细胞瘤),更优选多形性成胶质细胞瘤(GBM)(也被称作成胶质细胞瘤、星形细胞瘤IV级和IV级星形细胞瘤)。优选地,所述癌症的特征在于EGFRvIII的表达。
术语″治疗″和″预防″以及从其衍生的词语,当在本文中使用时,不一定意味100%或完全的治疗或预防。而是,有不同程度的治疗或预防,本领域技术人员承认其具有潜在的有利或治疗效果。在这点上,本发明的方法可以提供任何量的任何水平的对哺乳动物癌症的治疗或预防。此外,本发明的方法提供的治疗或预防可以包括治疗或预防被治疗或预防的疾病(例如癌症)的一种或多种病症或症状。同样,当用于本文的目的时,“预防”可以包括延迟疾病或其症状或病症的发作。
本发明的另一个实施方案提供了本发明的CAR、核酸、重组表达载体、宿主细胞、细胞群、抗体或其抗原结合部分、或药物组合物用于治疗或预防宿主的癌症的用途。
本发明的另一个实施方案提供了一种检测癌症在宿主中的存在的方法,所述方法包括:(a)使包含一个或多个得自宿主的细胞的样品与本发明的CAR、核酸、重组表达载体、宿主细胞、细胞群、抗体和/或其抗原结合部分接触,由此形成复合物,(b)和检测所述复合物,其中检测到所述复合物指示癌症在宿主中的存在。
所述样品可以通过任意合适的方法得到,例如,活组织检查或尸检。活组织检查是从个体取出组织和/或细胞。这样的取出可以是从个体收集组织和/或细胞,以便对取出的组织和/或细胞进行实验。该实验可以包括确定个体是否具有和/或正在遭受某种病症或疾病状态的实验。所述病症或疾病可以是例如癌症。
关于本发明的检测癌症在宿主中的存在的方法的一个实施方案,包含宿主细胞的样品可以是含有全细胞、其裂解物或全细胞裂解物的级分(例如,细胞核或细胞质级分、全蛋白级分、或核酸级分)的样品。如果样品包含全细胞,所述细胞可以是宿主的任意细胞,例如,任意器官或组织的细胞,包括血细胞或内皮细胞。
对本发明的检测方法来说,所述接触可以发生在相对于宿主的体外或体内。优选地,接触是在体外。
并且,对复合物的检测可以通过本领域中已知的任何数量的方式发生。例如,本文所述的本发明的TCR、多肽、蛋白、核酸、重组表达载体、宿主细胞、细胞群或抗体或其抗原结合部分,可以被标记以可检测的标记物如,例如,放射性同位素,荧光团(例如,荧光素异硫氰酸酯(FITC),藻红蛋白(PE)),酶(例如,碱性磷酸酶、辣根过氧化酶),和元素颗粒(例如,金颗粒)。
针对识别靶细胞的能力和抗原特异性来测试CAR的方法是本领域已知的。例如,Clay等人,J.Immunol.,163:507-513(1999)教导了测量细胞因子(例如,干扰素-γ、粒细胞/单核细胞集落刺激因子(GM-CSF)、肿瘤坏死因子α(TNF-α)或白介素2(IL-2))的释放的方法。另外,如在Zhao等,J.Immunol.,174:4415-4423(2005)中所述,可以通过测量细胞的细胞毒性来评价CAR功能。
下述实施例进一步举例说明本发明,但是,当然不应该解释为以任何方式限制本发明的范围。
实施例1
本实施例证实,包含SEQ ID NO:10(h139Ab-hCD828BBZ)或SEQ ID NO:11(h139Ab-hCD28Z)的CAR在与EGFRvIII工程改造的靶细胞系共培养以后产生IFN-γ。
通过将得自7种不同的抗-EGFRvIII抗体的单链抗体序列与CD28和CD3ζ的T细胞信号传导结构域结合,生产靶向EGFRvIII的嵌合抗原受体。基于鼠抗体3C10、MR-1、Y10、L8A4和人抗体131、139和13.1.2(它们插入在γ-逆转录病毒载体MSGV1中),装配了共计9种不同的构建体(在2种构建体中,转换VL和VH的次序)。通过转导外周血淋巴细胞(PBL)和使用抗-Fab特异性试剂(或在以后的实验中,蛋白L)的荧光激活细胞分选(FACS)分析,试验了每种构建体的表达。9种构建的载体中的3种在转导的PBL中可再现地表现出CAR表达,特别是基于抗体3C10、L8A4和139(SEQ ID NO:11)的那些CAR被证实在转导的PBL中具有细胞表面染色。
为了试验这3种抗-EGFRvIII CAR构建体的生物学活性,生产了γ-逆转录病毒载体上清液并用于转导PBL,将所述PBL与表达EGFRvIII的靶细胞系共培养。为了开发体外系统以评价潜在的EGFRvIII靶向载体,建立了适当的靶细胞系,因为没有已知的成胶质细胞瘤细胞系表达EGFRvIII。从商业来源得到野生型EGFR基因,并通过聚合酶链式反应(PCR)构建vIII形式并将其插入逆转录病毒载体中,所述载体共表达NeoR基因。转导和选择几个细胞系(NIH-3T3、BHK、HEK-293GP、U87和U251),并通过vIII特异性抗体确定EGFRvIII表达。
通过与EGFRvIII工程改造的建立的细胞系一起的共培养,证实了所有3种构建体的特异性IFN-γ生产(图3A、3B和3C,与NIH-3T3、BHK和293GP来源的系的共培养的代表性数据)。将BHK细胞(BHK)、EGFR转导的BHK(BHK-EGFRwt)、EGFRvIII转导的BHK(BHK-EGFRvIII)、3T3细胞(3T3UT)、EGFR转导的3T3(3T3-EGFRwt)、EGFRvIII转导的3T3(3T3-EGFRvIII)、293GP细胞(293GPUT)或EGFRvIII转导的293GP(293GP-EGFRvIII)与指定的CAR-转导的PBL(或作为对照的未转导的(UT)PBL)共培养,并确定IFN-γ水平(值为共培养过夜以后以pg/ml计的IFN-γ)。在这些共培养测定中,当暴露于表达EGFRvIII的靶细胞而不是被工程改造成过表达野生型EGFR基因的细胞时,所有3种CAR 3C10、L8A4和139产生了特异性的IFN-γ生产。基于下述发现使用基于139scFv的CAR构建体(SEQ ID NO:11)进行所有随后测定:139CAR具有稍微更高的反应性,且是人起源的,并且因此在患者中可能具有更低的免疫原性。将得自2种被139-CAR转导的供体的T细胞分类成CD8和CD4T细胞群,并针对反应性独立地进行试验(图4A(供体2)和4B(供体3))。CD4和CD8T细胞在与EGFRvIII靶细胞的共培养中特异性地产生了IFN-γ。
得自41BB共刺激分子的T细胞信号传导元件的添加可以增强CAR工程改造的T细胞的存活。使用得自CD28-41BB-CD3ξ的信号传导结构域装配了新构建体(SEQ ID NO:13),并与原始CD28-CD3ζ构建体(SEQ ID NO:14)进行了对比。尽管通过FACS对28BBZ CAR载体构建的检测小于28Z构建体,转导的T细胞对表达EGFRvIII的靶标具有同样的反应性。用这些载体和对照载体(GFP或Her2/neu CAR)转导T细胞,并与工程改造的成胶质细胞瘤细胞系和多形性成胶质细胞瘤肿瘤干细胞(GBM-TSC)系一起共培养(表3A和3B)。对建立的成胶质细胞瘤系U87和U251工程改造以表达对照GFP基因、野生型EGFR基因(EGFRwt)或EGFRvIII基因(,EGFRvIII)。将这些靶细胞或GBM-TSC系308、822和1228与被含有CD28-CD3ζ(139-28Z)(SEQID NO:14)或CD28-41BB-CD3ζ(139-BBZ;h139Ab-hCD828BBZ)(SEQ ID NO:13)信号传导结构域的EGFRvIII-CAR载体转导的T细胞一起共培养。确定IFN-γ水平(值为与工程改造成表达EGFRvIII的成胶质细胞瘤细胞系共培养过夜以后以pg/ml计的IFN-γ)。其他T细胞对照包括UT-未转导的PBL、GFP-GFP载体转导的PBL和Her2/neu特异性的CAR。通过IFN-γ释放确定的生物学活性(表3A和3B)证实,所述2种不同的载体转导的T细胞对表达EGFRvIII的神经胶质瘤细胞系U87和U251具有同样的反应性。
表3A
表3B
UT | GFP | 139-28Z | 139-BBZ | HER2/Neu | |
GBM-TSC 308 | 0 | 35 | 987 | 1123 | 578 |
GBM-TSC 822 | 0 | 95 | 1683 | 2267 | 372 |
GBM-TSC 1228 | 0 | 0 | 1387 | 1493 | 371 |
实施例2
本实施例证实,包含SEQ ID NO:10(h139Ab-hCD828BBZ)或SEQ ID NO:11(h139Ab-hCD28Z)的CAR特异性地裂解被工程改造成表达突变体EGFRvIII的细胞系。
接下来在标准51Cr-释放测定中确定了EGFRvIII CAR工程改造的T细胞裂解靶细胞的能力(图1A-D和2A-D)。
将未转导的(UnTd)PBL或被对照GFP载体(GFP)、139-28Z CAR(vIII-28Z)(编码SEQID NO:11)或139-28BBZ(vIII-BBZ)(编码SEQ ID NO:10)转导的PBL与51Cr标记的靶肿瘤细胞系一起共培养4小时(图1A-1D:亲本U87,GFP,野生型EGFR,或EGFRvIII工程改造的)。
将未转导的(UnTd)PBL或被对照GFP载体(GFP)、抗-ERBB2CAR(ERBB2)、139-28ZCAR(vIII-28Z)(编码SEQ ID NO:11)或139-28BBZ(vIII-BBZ)(编码SEQ ID NO:10)转导的PBL与51Cr标记的靶肿瘤细胞系一起共培养4小时(图2A-2D:亲本U251,GFP,野生型EGFR,或EGFRvIII工程改造的)。
在图1A-1D和2A-2D的实验中,使用公式:[(特异性释放-自发释放)/总释放-自发释放)],在给定的E∶T比,测量肿瘤细胞的特异性裂解。如图1A-1D和2A-D所示,两种载体仅特异性地裂解被工程改造成表达突变体EGFRvIII的细胞系,而没有裂解对照或野生型EGFR工程改造的细胞系。
实施例3
本实施例证实,抗-EGFRvIII CAR(SEQ ID NO:10(h139Ab-hCD828BBZ))在与肿瘤干细胞(TSC)系一起共培养后产生IFN-γ。
通过对许多不同种类的癌细胞系的详细分子分析,已证实,建立的癌细胞系经常不会反映原发性人癌症的分子特征,对于神经胶质瘤系也是如此。使用建立的神经胶质瘤细胞系的一种替代方案是,分析肿瘤干细胞(TSC)系。TSC范例提议,在癌症中存在这样的细胞亚群,其产生分化的肿瘤中的所有细胞。已经证实,原位神经胶质瘤细胞具有在神经胶质瘤细胞系中未发现的性质,并且具有与肿瘤干细胞一致的特征。进一步证实,在原发性人肿瘤来源的TSC及其匹配的神经胶质瘤细胞系之间存在显著的表型和基因型差异。直接来源于原发性成胶质细胞瘤的TSC具有与正常神经干细胞的极大相似性,并重现了人成胶质细胞瘤的基因型、基因表达谱和体内生物学。这些发现提示,对于理解原发性人肿瘤的生物学来说,来源于神经胶质瘤的TSC可以是比许多常用的神经胶质瘤细胞系更可靠的模型。
因此,针对EGFRvIII的存在分析了3个TSC系,并通过RT-PCR证实,EGFRvIII在这些系中表达。然后用抗-EGFRvIII CAR载体(表达SEQ ID NO:10(h139Ab-hCD828BBZ))工程改造得自2种供体(效应物I和效应物II)的PBL,将其与神经胶质瘤TSC系和对照表达EGFRvIII的细胞系共培养。将5种转导后的PBL与神经胶质瘤TSC系或已经被工程改造成表达野生型EGFR或EGFRvIII的细胞系U251共培养。在所有共培养物中,未转导的(UT)细胞和GFP转导的细胞充当阴性对照,且抗-ERBB2 CAR充当阳性对照。如图5A和5B所示,EGFRvIII CAR工程改造的T细胞显示了U251 EGFRvIII的特异性识别(当与U251 EGFR野生型基因工程改造的细胞相比时),并识别试验的所有3种神经胶质瘤TSC系(308、822和1228)。这些结果进一步支持了EGFRvIII CAR工程改造的T细胞作为神经胶质瘤患者的潜在免疫疗法的用途。
实施例4
本实施例证实,CAR-工程改造的T-细胞在T细胞数目扩大后保持反应性。
使用139-28BBZ(h139Ab-hCD828BBZ)载体转导得自2位成胶质细胞瘤患者、以及1位健康供体的PBL,并针对表达和反应性进行试验。将转导的细胞与EGFRvIII-工程改造的U87细胞共培养,然后通过细胞内细胞因子染色进行测定。得自患者和健康供体的工程改造的T细胞在CD8+和CD8-(推测是CD4+)CD3+T细胞中都表现出的特异性IFN-γ生产(7.8%-16.2%IFN-γ+,相对于,针对对照U87系的>0.36%)。在成胶质细胞瘤患者T细胞和健康供体之间的转导效率也是类似的。如果将来的临床应用需要大量T细胞(>1X 109),这些可以通过例如14-天快速扩增方案(REP)得到(Riddell等,J.Immunol.Methods,128:189-201(1990))获得。为了证实139-28BBZ(h139Ab-hCD828BBZ)CAR转导的T细胞可以扩增至足够用于患者治疗的数目且仍然保持反应性,对这些T细胞进行REP和再试验。139-CAR转导的T细胞保持它们特异性生产IFN-γ的能力,如表4所示。
表4
实施例5
本实施例证实了可用于生产转导细胞所用的病毒载体上清液的生产细胞克隆的生产。
使用139-28BBZ(h139Ab-hCD828BBZ)EGFRvIII CAR构建体,在满足美国食品和药品管理局(FDA)关于人基因治疗临床试验的指南的条件下,生产PG13γ-逆转录病毒载体生产细胞克隆。使用1个细胞克隆(克隆F10)在经历4天收集的6批收获物中生产18L病毒载体上清液。使用每批收获物转导供体PBL,并确定基因转移效率和生物学活性。基于转导的T细胞表达CAR和特异性识别表达EGFRvIII的细胞系的能力,所有收获物产生了具有生物学活性的上清液。在该测定中,收获物1的反应性稍微低于收获物2-6。为了试验对正常人组织的可能毒性,使用收获物3和4的混合物(pool)来转导不同的供体,并将这些转导的T细胞与7种不同的原代人成年和新生儿细胞培养物(来源于上皮、内皮和成纤维细胞)一起共培养。如通过IFN-γ生产所确定的,EGFRvIII CAR转导的T细胞与试验的任何原代人细胞培养物没有反应性。
实施例6
本实施例证实了治疗或预防人患者的癌症的方法,所述方法包括:给所述患者施用包含SEQ ID NO:10(h139Ab-hCD828BBZ)的CAR。
合格中选条件
合格的患者具有在组织学上证实的通过免疫组织化学(IHC)确定表达EGFRvIII的成胶质细胞瘤;先前用放射疗法(用或不用化学疗法)进行的标准治疗失败;Karnofsky评分大于或等于60%;心脏、肺和实验室参数在可接受的限度内。
研究设计:
使用I/II期设计进行本研究。将患者以2组进行试验的I期和II期部分两者:1)在治疗开始时需要使用类固醇的、具有复发性恶性神经胶质瘤的患者,或2)在治疗开始时不需要使用类固醇的、具有复发性恶性神经胶质瘤的患者。在试验的I期部分中确定每个单个组的最高耐受剂量以后,研究进入II期部分。再次将患者分成相同的2组。对于评价的2个组中的每个组,使用单阶段II期设计进行研究。
患者接受非骨髓根除的、但是淋巴细胞耗竭的预处理方案,包括环磷酰胺和氟达拉滨和随后静脉内输注离体肿瘤反应性的EGFRvIII CAR基因转导的PBMC,加上静脉内(IV)阿地白介素(aldesleukin)(720,000IU/kg,每8小时1次,最多15次给药)。在治疗结束后4周(±7天),患者经历完全肿瘤评价(身体和神经学的检查、使用和不使用钆的脑MRI)和临床实验室评价。如果患者具有稳定的疾病或肿瘤收缩,每1个月(±7天)进行重复的完全评价。第一年以后,在适当时每2个月(±7天)继续用该评价跟踪持续反应的患者。
细胞制备:
通过白细胞除去术得到PBMC(大约1X 1010个细胞)。在有抗-CD3(OKT3)和阿地白介素存在下培养全PBMC,以便刺激T细胞生长。通过将大约1X107至5X 108个细胞暴露于含有抗-EGFRvIII CAR逆转录病毒载体的上清液,开始转导。扩增这些转导的细胞,并测试其抗肿瘤活性。通过针对CAR蛋白的FACS分析,确定成功的CAR基因转移,并通过在表达EGFRvIII的细胞上测量的细胞因子释放,测试抗肿瘤反应性。将每个转导的PBL群体的成功CAR基因转移定义为>10%CAR阳性细胞,并且对于生物学活性而言,γ-干扰素分泌必须是至少200pg/ml并且是背景水平的2倍。
抗-EGVRvIII CAR转导的PBL:
用含有嵌合抗-EGFRvIII CAR的逆转录病毒上清液转导PBL。按照目前的良好生产操作规程(cGMP)条件,制备和保存编码针对抗原EGFRvIII的嵌合抗原受体(CAR)的逆转录病毒载体上清液(PG13-139-F10)。所述逆转录病毒载体利用MSGV1逆转录病毒载体主链,且包括4,032个碱基对,包括得自鼠干细胞病毒的5′LTR(启动子)、包含剪接供体(SD)和剪接受体位点的包装信号、含有信号肽信号的基于人抗-EGFRvIII scFv(mAb 139)的CAR蛋白(人GM-CSFR)、139轻链可变区、接头肽、139重链可变区、CD8(铰链,跨膜)、CD28(细胞质区域)、4-1BB(细胞质区域)和TCRζ(细胞质区域),继之以鼠干细胞病毒3′LTR。所述载体包含核苷酸序列SEQ ID NO:13,其编码氨基酸序列SEQ ID NO:10。根据发起人的证书,通过RNA斑点印迹确定物理滴度。在生产结束后,将上清液在-80℃保存在SBVPF,连续不断地监测温度。根据请求,将上清液在干冰上递送以用于体外转导。对于不同的患者,不重复使用相同单位的上清液。已经证实逆转录病毒滴度在立即融化和立即施用(包被预先用Retronectin包被的组织培养孔)以后是稳定的。载体的操作遵循Biosafety Level-2(BSL-2)的指南。
I期-剂量逐步增加:
该方案以1期剂量逐步增加设计开始,使用8个组群(cohort)和2个不同组(一组是在治疗时接受类固醇的患者,一组是没有接受类固醇的患者)。将每个组处理为完全单独的剂量逐步增加试验。
首先,该方案在前3个剂量组群中的每一个中招募1位患者,直到该患者经历剂量限制毒性(DLT)。在组群3以后,所有随后的组群进入1期剂量逐步增加设计,5个组群,n=3。
对于每个组群,EGFRvIII工程改造的细胞的总数是根据表5:
表5
顺序地招募患者,因此招募不进入更高的剂量水平,直至患者已经在前一个组群中被治疗。但是,将患者剂量逐步增加至给定组内的下一个组群,而不依赖于在其他组中发生什么。如果不能培养足够的细胞来满足分配的组群的标准,针对输入的细胞的数目在适当组群中招募患者。
在组群1-3中,如果患者经历DLT,那么以该剂量治疗另外5位患者,以保证不超过1/6的患者在进入下一个更高水平之前具有DLT。如果已经在3-6位患者中鉴别出具有2例或更多例DLT的水平,则以次低剂量处理另外5位患者,以致总数为6,以便在开始II期部分之前进一步表征最高耐受剂量的安全性。如果在第一组群中存在1例或更少的DLT,则研究进入第二组群。如果剂量限制毒性发生在第一组群,将该组群扩大至n=6位患者。如果2例DLT发生在第一组群,则终止研究。
在组群4-8中,由于特定剂量水平的细胞输注,单个患者将经历剂量限制毒性,应当以该剂量治疗另外3位患者,以保证不超过1/6的患者在进入下一个更高水平之前具有DLT。如果已经在3-6位患者中鉴别出具有2例或更多例DLT的水平,则以次低剂量处理另外3位患者,总数为6,以便在开始II期部分之前进一步表征最高耐受剂量的安全性。
最大耐受细胞剂量是6位患者中≤1位患者经历DLT时的最高剂量,或在3个剂量水平中的任一个处没有观察到DLT时研究的最高剂量水平。
在接受工程改造的PBL细胞之前,所有患者接受非骨髓根除的、但是淋巴细胞耗竭的预处理方案,包括环磷酰胺和氟达拉滨(fludarabine)和随后在1-4天中静脉内输注体外肿瘤反应性、EGFRvIII CAR基因转导的PBL加IV阿地白介素(720,000IU/kg,每8小时1次,最多15剂)。
最大耐受细胞剂量是6位患者中≤1位患者经历DLT时的最高剂量,或在3个剂量水平中的任一个处没有观察到DLT时研究的最高剂量水平。
如下定义剂量限制毒性:2级或更大变应性反应,或包括支气管痉挛或全身性荨麻疹的反应;所有3级和4级毒性,除了骨髓抑制,将其定义为淋巴细胞减少症、嗜中性粒细胞减少症和血小板减少症;IL-2预期的毒性;在细胞输注后24小时内发生的毒性(与细胞输注有关),利用两剂对乙酰氨基酚(650mg)或两剂苯海拉明(25mg),其在8小时内可逆转至2级或以下。
治疗计划
治疗计划阐述在表6中:
表6
1最后1剂氟达拉滨后1-4天
2在细胞输注后24小时内开始
3继续至嗜中性粒细胞计数>1x109/L持续连续3天或>5x109/L。
4 TMP/SMX计划应当调节至QD每周3次(星期一、星期三、星期五),并持续至少6个月且直到CD4>200X2
5继续至ANC>1000/mm3
6在HSV阳性的患者中,继续至ANC大于1000/mm3
免疫学试验:
在治疗之前和治疗之后4-6周,进行单采血液成分术(apheresis)。在其他时间点,通过使用在Ficoll垫上的离心的纯化,从全血得到患者外周血淋巴细胞(PBL)。将这些PBMC的等分试样1)冷冻保存,用于细胞功能的免疫学监测,2)进行DNA和RNA提取,用于CAR的PCR分析和载体拷贝数估测,和3)直接测试淋巴细胞和进行体外培养。直接免疫学监测包括:使用CAR特异性的染色,通过FACS分析定量可与EGFRvIII反应的T细胞。离体免疫学测定包括,通过大量PBL(±抗原刺激)和通过其他实验研究(诸如细胞裂解,如果可得到足够的细胞的话)的细胞因子释放。如果细胞数目是有限的,优选的是,直接分析免疫学活性。通过包括1)输注前PBMC和2)在输注时冷冻保存的工程改造的PBL的等分试样,将免疫学测定标准化。一般而言,这些测定中的2-3倍的差异指示真实的生物学差异。
监测基因治疗试验:持久性和有能力复制的逆转录病毒(RCR):
工程改造的细胞存活:使用现有的PCR技术,在PBMC样品中定量CAR和载体存在。将使用CAR-特异性的染色的免疫学监测用于增强基于PCR的分析。这会提供数据来估测源自输入的细胞的淋巴细胞的体内存活。另外,进行了CD4和CD8T-细胞的测量,并且通过使用特异性的PCR测定来确定循环中的这些T-细胞子集的研究,所述PCR测定能够检测每种逆转录病毒载体工程改造的T-细胞的独特DNA序列。
在细胞输注之前,得到患者的血液样品,并通过PCR进行分析以检测RCR,并且在细胞施用后3和6个月时以及1年时,进行RCR PCR。如果所有以前的试验已经是阴性的且具有简要病历,此后每年保存血液样品。如果患者在该试验期间死亡或发展肿瘤,努力测定用于RCR的活组织检查样品。如果任何治疗后样品是阳性的,进一步分析RCR并咨询FDA采取更广泛的患者随访。RCR PCR测定会检测GaLV壳基因(envelop gene),并在合同下由位于Indiana大学的Naional Gene Vector Laboratory进行。这些试验的结果由执行RCR试验的承包方和国家癌症研究所(Naional Cancer Institute,NCI)Surgery Branch研究团队维护。
由于这些研究的性质,可能观察到特定T-细胞克隆的扩增作为响应于肿瘤抗原的肿瘤反应性T-细胞增殖。因此,在免疫学上和在分子上小心地跟踪T-细胞持久性。在细胞输注后1个月,然后在3、6、12个月,此后每年,得到血液样品(5-10mL),用于确定CAR转导的细胞的持久性。如果任何患者在第6个月显示出CAR基因转导的细胞的高持久性水平(通过半定量DNA-PCR,使用对载体序列特异的引物),对以前保存的样品进行这样的技术:所述技术允许鉴别持久的CAR基因转导的细胞的克隆性(clonality)。这样的技术可以包括T细胞克隆或LAM-PCR 30。如果在随访过程中鉴别出源自CAR基因转导的细胞的优势或单克隆T细胞克隆,则鉴别出整合位点和序列,并随后针对人基因组数据库进行分析,以确定所述序列是否与任何已知的人癌症有关。如果观察到优势的整合位点,则在首次观察以后以不超过3个月的间隔使用T细胞克隆或LAM-PCR试验,以观察所述克隆是否持续或是暂时的。在单克隆性为持续的所有情况下,且特别是在存在克隆扩增的情况下,不论是否已知该序列与已知的人癌症有关,应当密切监测该受试者的恶性肿瘤征象,从而可以在早期开始治疗(如果可用的话)。
治疗后评价(随访)
常规随访:在初次治疗方案(定义为最后一剂阿地白介素后)以后4周(±7天),评价患者。如果患者具有SD或肿瘤缩小,则每月(±7天)进行重复完全评价持续12个月,然后在适当时每1-2个月(±7天)进行评价。
在每次评价时,执行下述评价I)身体检查,包括神经学检查和Karnofsky评分;II)Chem 20:(钠(Na)、钾(K)、氯(Cl)、总CO2(碳酸氢盐)、肌酸酐、葡萄糖、尿素氮(BUN)、白蛋白、总钙、总镁(Mg)、无机磷、碱性磷酸酶、ALT/GPT、AST/GOT、总胆红素、直接胆红素、LD、总蛋白、总CK、尿酸)、完全血细胞计数和甲状腺板;III)CBC;IV)毒性评估;V)使用和不用钆的脑MRI;和VI)检测RCR和CAR基因转导的细胞的持久性:(如上所述)。
仅在第一次随访时,进行5升单采血液成分术。随后,在随访(大约每个月)时得到60ml血液,达至少3个月。冷冻保存外周血单核细胞,使得免疫学试验可以进行。
接受基因转移的患者的长期随访:
在细胞输注后,每年进行身体检查并记录,持续5年,以评价长期安全性。5年后,通过电话联系或邮寄的问卷调查从存活患者得到的健康状况数据。逆转录病毒载体的长期随访期是15年。
反应标准:
作为该试验的一部分,以及为了辅助确定肿瘤进展,做出所有努力来观察患者肿瘤随时间的放射照相变化。
可测量的疾病:通过MRI扫描,具有清楚限定的边缘的二维对比增强病变(2个至少10mm的垂直直径)在2个或更多个轴向切片上可见。测量胞囊或外科手术腔周围的肿瘤是特别困难的挑战。一般而言,这样的病变应当视作不可测量的,除非存在测量直径≥10mm的结节组分。在确定反应时,不应当测量胞囊或外科手术腔。
不可测量、但是可评价的疾病:单维可测量的病变,边缘未清楚限定的团块,或具有多个胞囊组分的病变。
不可评价的疾病:没有确定的、可测量的或可评价的肿瘤。
可测量的病变:
完全反应(CR):完全反应要求所有以下各项:持续至少4周的所有增强的可测量的和不可测量的疾病的完全消失;没有新病变;稳定的或改善的非增强(T2/FLAIR)病变;和患者必须停用皮质类固醇或仅仅处于生理学替换剂量,且在临床上是稳定的或改善的。在没有4周后的确认扫描的情况下,该反应仅仅视作稳定的疾病。
部分反应(PR):部分反应要求所有以下各项:与基线相比,持续至少4周的所有可测量的增强病变的垂直直径的积和减小≥50%;没有不可测量的疾病的进展;没有新病变;与基线扫描相比,在相同或更低剂量的皮质类固醇,稳定的或改善的非增强(T2/FLAIR)病变;和患者所用的皮质类固醇剂量必须不大于在基线扫描处的剂量,且在临床上是稳定的或改善的。在没有4周后的确认扫描的情况下,该反应仅仅视作稳定疾病。
稳定的:如果患者不符合完全反应、部分反应或进展,则发生稳定的疾病,并且其要求以下各项:与基线扫描相比,在相同或更低的皮质类固醇剂量上,稳定的非增强(T2/FLAIR)病变,和临床上稳定的状态。在以下事件中被认为显示稳定疾病的最后一次扫描是当皮质类固醇剂量等同于基线剂量时得到的扫描:由于新征状和征象而增加皮质类固醇剂量,而在神经成像上没有确认疾病进展,且随后的随访成像显示由于疾病进展而需要该皮质类固醇增加。
进展:进展由下述的任一项来定义:在稳定或增加的皮质类固醇剂量上,增强病变的垂直直径的积和具有≥25%增加(相对于最佳反应,或如果没有减小,则相对于基线);在稳定或增加的皮质类固醇剂量上,相对于基线扫描或治疗开始以后的最佳反应,并非由于共病事件的T2/FLAIR非增强病变的显著增加;任何新病变的出现;不可测量的病变的清楚进展;或不可归因于除了肿瘤以外的其他原因或皮质类固醇剂量减小的确定的临床恶化。由于死亡或情况恶化而不能返回以进行评价也应视作进展。具有不可测量的增强疾病的患者如果其病变的尺寸显著增加,且变为可测量的(最小双向直径≥10mm,且在至少2个轴向切片上可见),也被认为已经经历进展。导致进展的从不可测量的病变向可测量的病变的转变,在理论上可以在肿瘤尺寸具有相对较小的增加的情况下发生(例如,9x 9mm病变[不可测量]增加至10x 11mm病变[可测量])。理想地,所述变化应当是显著的(最大直径增加>5mm,或增强病变的垂直直径的积和增加≥25%)。一般而言,如果存在关于病变是否已经进展的疑惑,继续治疗和密切随访评价有助于澄清是否存在真实进展。
可评价的病变:
在每次评价时记录可评价的病变。如果合适的话,也应当评估FLAIR或T2-加权图像作为可评价的疾病。
使用下述量表来表示MRI扫描的相对变化:
+3=肿瘤消失(CR)
+2=明确更好(PR)
+1=可能更好
0=无变化
-1=可能更差
-2=明确更差(PD)
-3=新病变的发展(PD)。
可评价的病变的反应的定义
完全反应(CR):定义为这样的情况:MRI扫描评级为+3,且通过神经成像不再看到肿瘤,并且患者不再需要类固醇用于控制肿瘤诱导的脑水肿。
部分反应(PR):定义为,MRI扫描评级为+2,前提条件是,自最近一个评价时段以来,患者没有增加他/她的类固醇剂量。
进展(P):定义为这样的情况:MRI扫描评级为-2或-3,或者存在新病变。
稳定疾病(SD):定义为这样的情况:MRI扫描显示没有变化或可能(-1或+1)变化。患者应当正在接受稳定或减小剂量的类固醇。
本文引用的所有的参考文献,包括出版物、专利申请和专利,通过引用以如同每一参考文献单独且特别表示通过引用结合的相同程度结合于此,并且在本文中完全阐述。
术语“一个”和”一种”和”所述”以及相似指示词在描述本发明的上下文中(特别是在后附权利要求中)的使用应该解释为涵盖单数和复数,除非另外在本文中指明或者明显与上下文相抵触。术语“包括”,“具有”,“包含”,和“含有”应该被解释为开放的术语(即,意指“包括,但不限于”),除非另外指明。本文中数值范围的引用仅意欲作为单独引用落入该范围的每个独立值的速记方法,除非本文中另外指明,并且每个独立值结合在本说明书中,如同其在本文中独立地引用那样。本文所述的所有方法可以以任何适当的顺序进行,除非本文另外指明或者明显与上下文相抵触。本文提供的任何和全部实例或示例性语言(例如,“诸如”)的使用仅意欲更好地举例说明本发明,并且不产生对本发明范围的限制,除非另外要求。在本说明书中没有任何语言应该被解释为指示对实施本发明是重要的任何未要求的元件。
本文记述了本发明的优选的实施方案,包括本发明人已知的用于实施本发明的最佳模式。当阅读前述说明书后,对于本领域的普通技术人员,这些优选实施方案的变化可以变得显而易见。本发明人预计熟练的技术人员适当使用所有变化,并且本发明人意欲本发明以与本文具体描述不同的方式实施。因此,本发明包括在后附权利要求中引用的主题由现行法律所允许的所有改进和等价物。此外,本发明包括上述元件以其所有可能的变化的任意组合,除非本文另外指明,或者明显与上下文相抵触。
序列表
<110> 美国卫生和人力服务部
<120> 抗-表皮生长因子受体变体III嵌合抗原受体及其用于治疗癌症的用途
<130> 709980
<150> US 61/473,409
<151> 2011-04-08
<160> 14
<170> PatentIn version 3.5
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 3
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 3
Arg Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly
1 5 10 15
Ser
<210> 4
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 4
Met Val Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro
20
<210> 5
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 5
Met Val Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Arg Asn Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Thr Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
85 90 95
Val Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
His His Ser Tyr Pro Leu Thr Ser Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
165 170 175
Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Asn Tyr Ala Asp
195 200 205
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
210 215 220
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
225 230 235 240
Tyr Cys Ala Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr
245 250 255
Leu Val Thr Val Ser Ser
260
<210> 6
<211> 83
<212> PRT
<213> 人
<400> 6
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
1 5 10 15
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
20 25 30
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
35 40 45
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
50 55 60
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
65 70 75 80
His Arg Asn
<210> 7
<211> 200
<212> PRT
<213> 人
<400> 7
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 Arg Phe Ser Val Val Lys Arg
35 40 45
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
50 55 60
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
65 70 75 80
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
85 90 95
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
100 105 110
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
115 120 125
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
130 135 140
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
145 150 155 160
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
165 170 175
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
180 185 190
His Met Gln Ala Leu Pro Pro Arg
195 200
<210> 8
<211> 106
<212> PRT
<213> 人
<400> 8
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly
35 40 45
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
50 55 60
Trp Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
65 70 75 80
Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
85 90 95
Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
100 105
<210> 9
<211> 112
<212> PRT
<213> 人
<400> 9
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 10
<211> 548
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 10
Met Val Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Arg Asn Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Thr Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
85 90 95
Val Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
His His Ser Tyr Pro Leu Thr Ser Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
165 170 175
Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Asn Tyr Ala Asp
195 200 205
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
210 215 220
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
225 230 235 240
Tyr Cys Ala Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr
245 250 255
Leu Val Thr Val Ser Ser Ala Ala Ala Phe Val Pro Val Phe Leu Pro
260 265 270
Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
275 280 285
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
290 295 300
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
305 310 315 320
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
325 330 335
Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Ser Lys Arg
340 345 350
Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
355 360 365
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
370 375 380
Ala Ala Tyr Arg Ser Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys
385 390 395 400
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
405 410 415
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
420 425 430
Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
435 440 445
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
450 455 460
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
465 470 475 480
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
485 490 495
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
500 505 510
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
515 520 525
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
530 535 540
Leu Pro Pro Arg
545
<210> 11
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 11
Met Val Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Arg Asn Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Thr Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
85 90 95
Val Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
His His Ser Tyr Pro Leu Thr Ser Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
165 170 175
Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Asn Tyr Ala Asp
195 200 205
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
210 215 220
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
225 230 235 240
Tyr Cys Ala Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr
245 250 255
Leu Val Thr Val Ser Ser Ala Ala Ala Ile Glu Val Met Tyr Pro Pro
260 265 270
Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys
275 280 285
Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro
290 295 300
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
305 310 315 320
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
325 330 335
Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly
340 345 350
Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala
355 360 365
Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
370 375 380
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
385 390 395 400
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
405 410 415
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
420 425 430
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
435 440 445
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
450 455 460
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
465 470 475 480
Leu Pro Pro Arg
<210> 12
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 12
atggttctgc tggtcaccag cctgctgctg tgcgaactgc cccaccccgc ctttctgctg 60
atccccgaca tccagatgac ccagagccct agcagcctga gcgccagcgt gggcgacaga 120
gtgaccatca cctgtcgggc cagccagggc atcagaaaca acctggcctg gtatcagcag 180
aagcccggca aggcccccaa gagactgatc tacgctgcca gcaatctgca gagcggcgtg 240
cccagcagat tcaccggaag cggctccggc accgagttca ccctgatcgt gtccagcctg 300
cagcccgagg acttcgccac ctactactgc ctgcagcacc acagctaccc tctgaccagc 360
ggcggaggca ccaaggtgga gatcaagcgg accggcagca ccagcggcag cggcaagcct 420
ggcagcggcg agggaagcga ggtccaggtg ctggaatctg gcggcggact ggtgcagcct 480
ggcggcagcc tgagactgag ctgtgccgcc agcggcttca ccttcagcag ctacgccatg 540
tcttgggtcc ggcaggctcc tggaaagggc ctggaatggg tgtccgccat cagcggctct 600
ggcggctcca ccaactacgc cgacagcgtg aagggccggt tcaccatcag ccgggacaac 660
agcaagaaca ccctgtatct gcagatgaac agcctgagag ccgaggacac cgccgtgtac 720
tactgtgccg gcagcagcgg gtggagcgag tactggggcc agggcacact ggtcacagtg 780
tctagc 786
<210> 13
<211> 1647
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 13
atggttctgc tggtcaccag cctgctgctg tgcgaactgc cccaccccgc ctttctgctg 60
atccccgaca tccagatgac ccagagccct agcagcctga gcgccagcgt gggcgacaga 120
gtgaccatca cctgtcgggc cagccagggc atcagaaaca acctggcctg gtatcagcag 180
aagcccggca aggcccccaa gagactgatc tacgctgcca gcaatctgca gagcggcgtg 240
cccagcagat tcaccggaag cggctccggc accgagttca ccctgatcgt gtccagcctg 300
cagcccgagg acttcgccac ctactactgc ctgcagcacc acagctaccc tctgaccagc 360
ggcggaggca ccaaggtgga gatcaagcgg accggcagca ccagcggcag cggcaagcct 420
ggcagcggcg agggaagcga ggtccaggtg ctggaatctg gcggcggact ggtgcagcct 480
ggcggcagcc tgagactgag ctgtgccgcc agcggcttca ccttcagcag ctacgccatg 540
tcttgggtcc ggcaggctcc tggaaagggc ctggaatggg tgtccgccat cagcggctct 600
ggcggctcca ccaactacgc cgacagcgtg aagggccggt tcaccatcag ccgggacaac 660
agcaagaaca ccctgtatct gcagatgaac agcctgagag ccgaggacac cgccgtgtac 720
tactgtgccg gcagcagcgg gtggagcgag tactggggcc agggcacact ggtcacagtg 780
tctagcgcgg ccgcattcgt gccggtcttc ctgccagcga agcccaccac gacgccagcg 840
ccgcgaccac caacaccggc gcccaccatc gcgtcgcagc ccctgtccct gcgcccagag 900
gcgtgccggc cagcggcggg gggcgcagtg cacacgaggg ggctggactt cgcctgtgat 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaccacag gaacaggagt aagaggagca ggctcctgca cagtgactac 1080
atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1140
ccacgcgact tcgcagccta tcgctcccgt ttctctgttg ttaaacgggg cagaaagaag 1200
ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 1260
ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc 1320
agcaggagcg cagacgcccc cgcgtaccag cagggccaga accagctcta taacgagctc 1380
aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 1440
atggggggaa agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 1500
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 1560
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1620
cacatgcagg ccctgccccc tcgctaa 1647
<210> 14
<211> 1455
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 14
atggttctgc tggtcaccag cctgctgctg tgcgaactgc cccaccccgc ctttctgctg 60
atccccgaca tccagatgac ccagagccct agcagcctga gcgccagcgt gggcgacaga 120
gtgaccatca cctgtcgggc cagccagggc atcagaaaca acctggcctg gtatcagcag 180
aagcccggca aggcccccaa gagactgatc tacgctgcca gcaatctgca gagcggcgtg 240
cccagcagat tcaccggaag cggctccggc accgagttca ccctgatcgt gtccagcctg 300
cagcccgagg acttcgccac ctactactgc ctgcagcacc acagctaccc tctgaccagc 360
ggcggaggca ccaaggtgga gatcaagcgg accggcagca ccagcggcag cggcaagcct 420
ggcagcggcg agggaagcga ggtccaggtg ctggaatctg gcggcggact ggtgcagcct 480
ggcggcagcc tgagactgag ctgtgccgcc agcggcttca ccttcagcag ctacgccatg 540
tcttgggtcc ggcaggctcc tggaaagggc ctggaatggg tgtccgccat cagcggctct 600
ggcggctcca ccaactacgc cgacagcgtg aagggccggt tcaccatcag ccgggacaac 660
agcaagaaca ccctgtatct gcagatgaac agcctgagag ccgaggacac cgccgtgtac 720
tactgtgccg gcagcagcgg gtggagcgag tactggggcc agggcacact ggtcacagtg 780
tctagcgcgg ccgcaattga agttatgtat cctcctcctt acctagacaa tgagaagagc 840
aatggaacca ttatccatgt gaaagggaaa cacctttgtc caagtcccct atttcccgga 900
ccttctaagc ccttttgggt gctggtggtg gttggtggag tcctggcttg ctatagcttg 960
ctagtaacag tggcctttat tattttctgg gtgaggagta agaggagcag gctcctgcac 1020
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 1080
tatgccccac cacgcgactt cgcagcctat cgctccagag tgaagttcag caggagcgca 1140
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 1200
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 1260
ccgagaagga agaaccctca ggaaggcctg tacaatgaac tgcagaaaga taagatggcg 1320
gaggcctaca gtgagattgg gatgaaaggc gagcgccgga ggggcaaggg gcacgatggc 1380
ctttaccagg gtctcagtac agccaccaag gacacctacg acgcccttca catgcaggcc 1440
ctgccccctc gctaa 1455
Claims (20)
1.一种嵌合抗原受体(CAR),其包含人抗体139的抗原结合结构域、细胞外铰链结构域、跨膜结构域和细胞内T细胞信号传导结构域。
2.根据权利要求1所述的CAR,其中所述抗原结合结构域包含含有SEQ ID NO:1的轻链可变区。
3.根据权利要求1或2所述的CAR,其中所述抗原结合结构域包含含有SEQ ID NO:2的重链可变区。
4.根据权利要求1或2所述的CAR,其中所述抗原结合结构域包含含有SEQ ID NO:3的接头肽。
5.根据权利要求1或2所述的CAR,其中所述抗原结合结构域包含含有SEQ ID NO:4的前导序列。
6.根据权利要求1或2所述的CAR,其中所述抗原结合结构域包含SEQ ID NO:5。
7.根据权利要求1或2所述的CAR,所述CAR进一步包含细胞内铰链结构域。
8.根据权利要求1或2所述的CAR,其中所述细胞外铰链结构域和跨膜结构域包含CD8(SEQ ID NO:6)。
9.根据权利要求1或2所述的CAR,其中所述细胞内T细胞信号传导结构域包含CD28、4-1BB和/或CD3ζ(SEQ ID NO:7)。
10.根据权利要求1或2所述的CAR,其中所述细胞外铰链结构域、跨膜结构域和细胞内T细胞信号传导结构域包含CD28(SEQ ID NO:8)和/或CD3ζ(SEQ ID NO:9)。
11.根据权利要求1或2所述的CAR,所述CAR包含选自由SEQ ID NO:10-11组成的组的氨基酸序列。
12.一种核酸,其包含编码根据权利要求1-11中任一项所述的CAR的核苷酸序列。
13.根据权利要求12所述的核酸,所述核酸包含选自由SEQ ID NO:12-14组成的组的核苷酸序列。
14.一种重组表达载体,其包含权利要求12或13所述的核酸。
15.一种分离的宿主细胞,其包含权利要求14所述的重组表达载体。
16.包含至少一个权利要求15所述的宿主细胞的细胞群。
17.特异性地结合根据权利要求1-11中任一项所述的CAR的抗体或其抗原结合部分。
18.一种药物组合物,其包含:权利要求1-11所述的CAR、权利要求12-13所述的核酸、权利要求14所述的重组表达载体、权利要求15所述的宿主细胞、权利要求16所述的细胞群或者权利要求17所述的抗体或其抗原结合部分,以及药用载体。
19.一种检测癌症存在的体外方法,所述方法包括:
(a)使包含来自宿主的一个或多个细胞的样品与权利要求1-11所述的CAR、权利要求12-13所述的核酸、权利要求14所述的重组表达载体、权利要求15所述的宿主细胞、权利要求16所述的细胞群或者权利要求17所述的抗体或其抗原结合部分接触,由此形成复合物,和
(b)检测所述复合物,其中检测到所述复合物指示癌症的存在。
20.权利要求1-11所述的CAR、权利要求12-13所述的核酸、权利要求14所述的重组表达载体、权利要求15所述的宿主细胞、权利要求16所述的细胞群、权利要求17所述的抗体或其抗原结合部分、或者权利要求18所述的药物组合物用于制备治疗、预防或检测宿主中癌症的药物中的应用。
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CN201710395649.1A Active CN107188969B (zh) | 2011-04-08 | 2012-03-21 | 抗-表皮生长因子受体变体iii嵌合抗原受体及其用于治疗癌症的用途 |
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