CN111107855A - 医药试剂盒及其用途 - Google Patents
医药试剂盒及其用途 Download PDFInfo
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- CN111107855A CN111107855A CN201880051327.8A CN201880051327A CN111107855A CN 111107855 A CN111107855 A CN 111107855A CN 201880051327 A CN201880051327 A CN 201880051327A CN 111107855 A CN111107855 A CN 111107855A
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Abstract
本公开内容是关于一种用以治疗癌症的医药试剂盒。本发明医药试剂盒包含一药剂和一经改造的自然杀伤细胞。该药剂可增加癌细胞的肿瘤相关抗原的表达量,而经改造的自然杀伤细胞则具有一肿瘤相关抗原特异性嵌合抗原受体,可靶向并破坏该癌细胞。本公开内容也提供本发明医药试剂盒在治疗癌症中的用途。
Description
相关申请的交叉引用
本申请主张2017年8月6日所提交的美国临时申请号62/541,778的优先权,该美国临时申请案在此通过引用而并入其全文。
发明背景
1.技术领域
本公开内容是关于治疗癌症的领域。更具体来说,本公开内容是关于一种医药试剂盒,及其在制备用以治疗癌症的药物中的用途。
2.背景技术
癌症是一种与细胞异常增生相关的复杂性疾病。癌细胞与正常细胞有许多不同之处,包含:(1)细胞通讯:相较于正常细胞,癌细胞对于调控细胞生长或死亡的信号较不具反应性;(2)侵袭能力:癌细胞会表达较少量的细胞黏附分子;因此,该种较不受限制的细胞可通过血液或淋巴系统轻易转移或扩散至身体其他区域;(3)细胞特化:相较于正常细胞,癌细胞为未特化(unspecialized)或分化程度较低的细胞;以及(4)免疫抑制:癌细胞可通过活化免疫抑制细胞(例如,调控型T细胞(regulatory T cell,Treg)或骨髓来源的抑制性细胞(myeloid-derived suppressor cell,MDSC))和/或刺激免疫抑制因子(例如,血管内皮生长因子(vascular endothelial growth factor,VEGF)、转化生长因子-β(transforminggrowth factor-beta,TGF-β)或白介素-10(interleukin-10,IL-10))的表达来抑制免疫反应。
常见的抗癌疗法包含外科手术、放射治疗及化学治疗。不幸地,除了抑制肿瘤生长,该些治疗方式往往伴随着伤害或毒杀正常组织的风险。此外,设计用以毒杀癌细胞而不产生副作用的替代性疗法则尚在研究及临床前试验阶段。在该些治疗策略中,免疫治疗是最具潜力的治疗策略之一,其通过活化肿瘤特异性免疫细胞(例如,T细胞、B细胞、树突细胞(dendritic cell,DC)、自然杀伤细胞(natural killer cell,NK cell)及自然杀伤T细胞(natural killer T cell,NKT cell)),和/或刺激抗肿瘤因子(例如,干扰素-γ(interferon-γ,IFN-γ)及颗粒酶(granzyme))的表达/释放,来达到清除肿瘤的目的。该些经活化的免疫细胞具有目标专一性;亦即,该些免疫细胞可通过辨识及结合至过表达或仅表达于癌细胞的肿瘤相关抗原(tumor-associated antigen,TAA),而特异性地(专一地)靶向癌细胞。然而,基于癌细胞往往会降低或不表达主要组织相容性复合体(majorhistocom patibility complex,MHC)及表现于其上的TAA(一种逃避免疫反应的机制),免疫治疗在临床试验阶段的疗效并不令人满意。此外,亦有报导指出,癌细胞释出的免疫抑制因子(例如,TGF-β或IL-10)会降低NK细胞的治疗功效。
有鉴于此,相关领域亟需一种用以有效治疗癌症患者的改良方法,据以改善癌症患者的生活质量和/或寿命。
发明内容
发明内容旨在提供本公开内容的简化摘要,以使阅读者对本公开内容具备基本的理解。此发明内容并非本公开内容的完整概述,且其用意并非在指出本发明实施例的重要/关键组件或界定本发明的范围。
本公开内容的第一方面是关于一种用以治疗患有或疑似患有癌症的个体的医药试剂盒。本发明医药试剂盒包含第一容器及第二容器,其中该第一容器包含一药剂,而该第二容器则包含一经改造的(engineered,工程化的)自然杀伤细胞。依据本公开内容实施方式,该药剂可增加癌细胞上TAA的表达量,而该经改造的NK细胞则具有对该TAA具有特异性的嵌合抗原受体(chimeric antigen receptor,CAR)。
本公开内容的另一方面是关于一种利用本发明医药试剂盒来治疗患有或疑似患有癌症的个体的方法。该方法包含对该个体施予第一有效量的本发明药剂,以增加癌细胞表达TAA;以及对该个体施予第二有效量的本发明经改造的NK细胞,其具有对TAA专一(特异)的CAR。
依据本公开内容某些实施方式,该TAA是癌胚抗原(carcinoembryonic antigen,CEA)。在该些实施方式中,CAR的可变区(variable domain)、铰链区(hinge domain)及效应区(effector domain)分别包含至少85%相似于SEQ ID NO:1、2及3的氨基酸序列。依据一操作实施例,CAR包含一至少85%相似于SEQ ID NO:4的氨基酸序列。
一般来说,该药剂是选自由5-氮杂胞嘧啶核苷(5-azacytidine)、5,6-二氢-5-氮杂胞嘧啶核苷(5,6-dihydro-5-azacytidine)、5-氮-2'-脱氧胞苷(5-aza-2'-deoxycytidine)、阿拉伯呋喃糖-5-氮胞嘧啶(arabinofuranosyl-5-azacytosine)、曲古菌素A(trichostatin A,TSA)、苯丁酸盐(phenylbutyrate,PB)、丁酸钠(sodium butyrate,NaB)、丙戊酸(valproic acid,VPA)及辛二酰苯胺异羟肟酸(suberoylanilide hydroxamicacid,SAHA)所组成的群组。依据一操作实施例,该药剂为5-氮杂胞嘧啶核苷或丁酸钠。
例示性的可以用本公开内容的医药试剂盒和/或方法治疗的癌症包含,但不限于,胃癌、肺癌、膀胱癌、乳腺癌、胰脏癌、肾脏癌、结肠直肠癌、子宫颈癌、卵巢癌、脑癌、前列腺癌、肝癌、黑色素瘤、食道癌、多发性骨髓瘤,以及头颈部鳞状细胞癌。依据本公开内容某些实施方式,该癌症对化学治疗、放射治疗或免疫治疗具有抗性。
在参阅下文实施方式后,本发明所属技术领域中具有普通知识者当可轻易了解本发明的基本精神及其他发明目的,以及本发明所采用的技术手段与实施方面。
附图说明
为让本发明的上述与其他目的、特征、优点与实施例能更明显易懂,附图说明如下:
图1依据本公开内容实施例2所绘示的柱状图,其是关于特定癌细胞中CEA的表达量。
图2依据本公开内容实施例2所绘示的线性图,其阐述NK92MI-CEA细胞对特定癌细胞的毒杀功效。
图3A及3B依据本公开内容实施例3所绘示的线性图,其分别阐述NK92MI-CEA细胞对经5-氮杂胞嘧啶核苷处理的癌细胞(图3A),以及经丁酸钠处理的癌细胞(图3B)的毒杀功效。
图4A-4C为依据本公开内容实施例4所绘示的线性图及柱状图,其分别阐述在给予特定治疗后,小鼠的肿瘤体积(图4A及4B)及CEA血清量(图4C)。
具体实施方式
为了使本公开内容的叙述更加详尽与完备,下文针对了本发明的实施方面与具体实施例提出了说明性的描述;但这并非实施或运用本发明具体实施例的唯一形式。实施方式中涵盖了多个具体实施例的特征以及用以建构与操作这些具体实施例的方法步骤与其顺序。然而,亦可利用其他具体实施例来达成相同或均等的功能与步骤顺序。
1.定义
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值,此处已尽可能精确地呈现具体实施例中的相关数值。然而,任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处,“约”通常系指实际数值在一特定数值或范围的正负10%、5%、1%或0.5%之内。或者是,“约”一词代表实际数值落在平均值的可接受标准误差之内,视本发明所属技术领域中具有普通知识者的考虑而定。除了实验例之外,或除非另有明确的说明,当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其他相似者)均经过“约”的修饰。因此,除非另有相反的说明,本说明书与附随权利要求书所公开的数值参数皆为约略的数值,且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与套用一般进位法所得到的数值。在此处,将数值范围表示成由一端点至另一端点或介于二端点之间;除非另有说明,此处所述的数值范围皆包含端点。
除非本说明书另有定义,此处所用的科学与技术词汇的含义与本发明所属技术领域中具有普通知识者所理解与惯用的意义相同。此外,在不和上下文冲突的情形下,本说明书所用的单数名词涵盖该名词的复数型;而所用的复数名词时亦涵盖该名词的单数型。
此处针对多肽序列所述的“氨基酸序列相似度百分比”(Percentage(%)aminoacid sequence identity)是指候选序列的氨基酸残基与参考多肽序列的氨基酸残基完全相同的百分比;在进行上述比对时,可将所述的候选多肽片段与所述的特定多肽片段并排,并于必要时引入间隙,以使二序列形成最高的序列相似度;在计算相似度时,保守性置换的氨基酸残基视为不同的残基。相关领域已有多种方法可用以进行上述并排,譬如可公开取得的软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)等。本发明所属技术领域中具有普通知识者在进行并排时,可选择适当的参数与计算方式,以得到最佳的排列方式。在本说明书中,二多肽序列间的序列比较是采用美国国家生物科技信息中心(National Center forBiotechnology Information,NCBI)所提供的蛋白质-蛋白质BLAST分析数据库Blastp来进行。候选多肽序列A相较于参考多肽序列B的氨基酸序列相似度(在本说明书中也称之为多肽序列A与多肽序列B具有特定百分比(%)的氨基酸序列相似度)的计算方式如下:
其中X是利用BLAST序列并排程序对序列A、B进行排列后所得到的相同氨基酸残基数目(identical matches),而Y是A、B二序列中较短者的氨基酸残基总数。
在本公开内容中,“周期”(cycle)、“治疗周期”(cycle of treatment或treatmentcycle)为可互换的词汇,是指对患者施予治疗的一段时间。一般来说,治疗癌症时,完成一治疗周期后会接续一段完全不给予任何治疗的休息时间。在该段休息时间后,可再次施予一或多次治疗周期,每次治疗周期后皆会接续另一段休息时间。
“治疗”(treat)一词包含部份或完全预防、改善、减轻和/或处理与癌症相关的病征(symptom)、次要病征(secondary disorder)或症状(condition)。“治疗”(treat)一词于此说明书中亦指应用或施予本公开内容之一或多种化合物/细胞至一个体,其是患有与癌症相关的病征、次要病征或症状,以达到部份或完全减轻、减缓、治愈疾病、延迟发病、抑制病程发展、降低疾病严重性,和/或降低一或多个与癌症相关的病征、症状、或次要病征的发生。与癌症相关的病征、次要病征和/或症状包含,但不限于,发烧、虚弱、疲倦、体重减轻、疼痛、咳嗽、出血、皮肤改变、腹泻或便秘、恶心、呕吐及食欲不振。在此“治疗”亦可以是施用至患有早期该些病征或症状的个体,以降低该个体发展成为与癌症相关的病征、次要病征和/或症状的风险。在此“治疗”为可以有效地减少一个或多个病征或临床标记。换句话说,在此治疗也可以是降低、减缓或终止疾病病程、病征或症状的发展。
“有效量”(effective amount)在此处是指一药物的用量足以产生欲求的疗效反应。有效量也指一种化合物或组合物,其治疗有益效果超越其毒性或有害影响。具体的有效量取决于多种因素,如欲治疗的特定状况、患者的生理条件(如,患者体重、年龄或性别)、接受治疗的哺乳动物或动物的类型、治疗持续时间、目前疗法(如果有的话)的本质以及所用的具体配方和化合物或其衍生物的结构。举例来说,可将有效量表示成药物的总重量(譬如以克、毫克或微克为单位)或表示成药物重量与体重之比例(其单位为毫克/公斤(mg/kg))。或者是,可将有效量表示成活性成分(例如,本发明经改造的NK细胞)的密度,例如每体积培养液中的细胞数量;或将有效量表示成活性成分(例如,本发明药剂)的浓度,例如摩尔浓度、重量浓度、体积浓度、重量摩尔浓度、摩尔分率、重量分率及混合比值。具体来说,“治疗有效量”(therapeutically effective amount)一词若与本公开内容之药剂或经改造的NK细胞共同使用时,是指药剂或经改造的NK细胞的施予量,其足以减缓或减轻个体与癌症相关的病征。本领域技术人员可依据动物模式的剂量来计算药物(如本公开内容之药剂或细胞)的人体等效剂量(human equivalent dose,HED)。举例来说,本领域技术人员可依据美国食品药物管理局(US Food and Drug Administration,FDA)所公告的“估算成人健康志愿者在初始临床治疗测试的最大安全起始剂量”(Estimating the Maximum SafeStarting Dose in Initial Clinical Trials for Therapeutics in Adult HealthyVolunteers)来估算人体使用的最高安全剂量。
在本公开内容中,“肿瘤相关抗原”(tumor-associated antigen或TAA)一词包含偏好表达于肿瘤/癌细胞表面的蛋白或多肽。“偏好表达”(preferentially expressed)一词在此是指一抗原于肿瘤/癌细胞的表达量至少10%(例如,10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、110%、150%、200%、400%或更多)高于该抗原在非肿瘤/癌细胞中的表达量。在某些实施方式中,该抗原为偏好表达于一肿瘤细胞的表面的抗原,其中该肿瘤是选自由胃癌、肺癌、膀胱癌、乳腺癌、胰脏、肾脏癌、结肠直肠癌、子宫颈癌、卵巢癌、脑癌、前列腺癌、肝癌、黑色素瘤、食道癌、多发性骨髓瘤,以及头颈部鳞状细胞癌所组成的群组。
在本公开内容中,“嵌合抗原受体”(chimeric antigen receptor或CAR)一词是指一经改造的受体,赋予一抗体对一细胞(例如一T细胞或一NK细胞)的特异性(专一性)。更具体来说,经改造的受体包含一可结合至一抗原的胞外域、一源自一多肽的穿膜域(该穿膜域与该胞外域源自不同的多肽),以及至少一胞内域。有时亦将一“嵌合抗原受体”称为一“嵌合受体”(chimeric receptor)、一“T-体”(T-body)或一“嵌合免疫受体”(chimeric immunereceptor或CIR)。“可结合至一抗原的胞外域”是指任何可结合至抗原的寡肽或多肽。“胞内域”则是指任何可传递一信号以活化或抑制一细胞的生物反应的寡肽或多肽。“穿膜域”是指任何穿经细胞膜,且连接该胞外域与信号传递域的寡肽或多肽。嵌合抗原受体可以可选地包含一“铰链区”(hinge domain),其作为一连接符,以连接该胞外域及该穿膜域。
“经改造的”(engineered)一词在本公开内容是指经基因操作或修饰的生物分子,例如DNA、RNA和/或蛋白,或是生物技术领域所熟知的相似技术。
“个体”(subject)一词是指可接受本发明方法治疗的包含人类的哺乳动物。除非特定指出,否则“个体”(subject)一词同时意指男性及女性。
2.本公开内容实施方式
TAA的表达/过量表达往往与肿瘤形成相关。举例来说,已知某些TAA(例如,生长因子或其受体、信号传递因子及转录因子)会诱发细胞增生或侵袭,而其他TAA(例如,细胞激素或其受体,以及免疫检查点)则与逃避免疫反应相关。此外,有报导指出,TAA亦与癌细胞对化学治疗产生抗性相关。基于TAA的促肿瘤特性,目前多数治疗皆着重于中和或降低TAA的表达,以达到抗肿瘤的目的。本发明至少部分是基于发明人首次发现增加TAA表达的药剂不但不会促使癌化反应,反而会相加地或加乘地增加免疫治疗的抗癌功效。
据此,本公开内容的第一方面是关于一种用以治疗有需要的个体(举例来说,一患有或疑似患有癌症之个体)的医药试剂盒。依据本公开内容实施方式,本发明医药试剂盒包含一第一容器及一第二容器,其中该第一容器包含一第一药剂,其可增加癌细胞之TAA的表达量,而该第二容器则包含一经改造的NK细胞,其具有一可特异性地辨识及结合至该TAA的CAR。一旦将本公开内容的医药试剂盒施予至个体,该具有TAA特异的CAR的改造NK细胞可特异地靶向并破坏具有TAA表达的癌细胞。
一般来说,该可增加癌细胞之TAA表达量的药剂可以是组蛋白去乙酰酶(histonedeacetylase,HDAC)抑制剂,举例来说,曲古菌素A、苯丁酸盐、丁酸钠、丙戊酸,以及辛二酰苯胺异羟肟酸。或者是,该药剂可以是DNA去甲基化药剂,例如5-氮杂胞嘧啶核苷、5,6-二氢-5-氮杂胞嘧啶核苷、5-氮-2'-脱氧胞苷,以及阿拉伯呋喃糖-5-氮胞嘧啶。依据本公开内容一操作实施例,该药剂为5-氮杂胞嘧啶核苷。依据本公开内容另一操作实施例,该药剂为丁酸钠。
可选择地,该药剂可以是多肽,其可刺激或增加癌细胞表达TAA(例如,表达CEA);举例来说,一重组干扰素(例如,重组IFN-α、IFN-β及IFN-γ)。可利用本领域技术人员所熟知的方法来制备该多肽;举例来说,将一用以编码该多肽的多核苷酸导入一适当的细胞(例如,293T),藉以表达及制备该多肽。或者是,可利用诸如t-BOC或FMOC保护α-氨基等方法来合成该多肽。二种方法皆采逐步合成,由肽的C端为起始点,每步骤加入单一个氨基酸。也可由熟知的固相多肽合成法来合成本发明多肽。
例示性的TAA包含CEA、CD19、CD20、CD23、CD30、CD56、CD73、CD123、甲胎蛋白(alpha-fetoprotein,AFP)、癌抗原125(cancer antigen 125,CA-125;亦称为粘蛋白16(mucin 16)或MUC 16)、粘蛋白1(MUC-1)、CO17-1A(亦称为GA733、KS1-4、KSA或EpCAM)、前列腺特异性抗原(prostatic specific antigen,PSA)、前列腺干细胞抗原(prostate stemcell antigen,PSCA)、黑色素瘤相关抗原(melanoma-associated antigen,MAA)、酪氨酸酶(tyrosinase)、弹性蛋白酶(elastase)、细胞自溶酶G(cathepsin G,CatG)、Wilms氏肿瘤(Wilms tumor,WT1)、纤维母细胞生长因子5(fibroblast growth factor 5,FGF-5)、类胰岛素生长因子受体-1(insulin-like growth factor receptor-1,IGF-1R)、Lewis(y)抗原、突变的p53、突变的ras、人类上皮生长因子2(human epidermal growth factorreceptor 2,HER2;亦称为Neu、ErbB-2或CD340)、上皮生长因子受体(epidermal growthfactor receptor,EGFR)、血管内皮生长因子2(vascular endothelial growth factorreceptor 2,VEGFR2)、血小板衍生生长因子(platelet derived growth factorreceptor,PDGFR)、叶酸盐结合蛋白(folate binding protein,FBP)、HIV-1外膜糖蛋白gp120、HIV-1外膜糖蛋白gp41、GD2、GD3、c-Met(亦称为肝细胞生长因子受体或HGF受体)、间皮素(mesothelin,MSLN)、人类内生性反转录病毒-K(human endogenous retrovirus-K,HERV-K)、IL-11R-α、存活素(surviving),以及硫酸软骨素蛋白多糖4(chondroitinsulfate proteoglycan 4,CSPG4)。依据本公开内容某些实施方式,该TAA为CEA。
本发明医药试剂盒的NK细胞优选为经改造的会表达嵌合受体的细胞,其中该嵌合受体可特异性地辨识并与癌细胞的相对应TAA结合。用以改造NK细胞的方法包含,但不限于,转染法(即,利用物理和/或化学处理,将一多核苷酸导入NK细胞中)、病毒转导法(即,利用病毒或病毒载体将一多核苷酸导入NK细胞中),以及核染法(nucleofection;即,对NK细胞施加特定电压或试剂,以便将一多核苷酸导入NK细胞中)。依据本公开内容一实施方式,是以慢病毒转导来制备本发明经改造的NK细胞。
优选地,改造本公开内容的NK细胞使其表达对CEA特异(专一)的CAR,其中该CAR从N端到C端包含一可变区、一铰链区及一效应区。依据本公开内容某些实施方式,该用以辨识CEA的可变区包含一至少85%相似于SEQ ID NO:1的氨基酸序列;即,该CEA特异性可变区的氨基酸序列与SEQ ID NO:1具有85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的相似度。优选地,该CEA特异性可变区的氨基酸序列至少90%相似于SEQ ID NO:1。更优选地,该CEA特异性可变区的氨基酸序列至少95%相似于SEQ ID NO:1。依据本公开内容一操作实施例,该CEA特异性可变区包含100%相似于SEQID NO:1的氨基酸序列。
该铰链区作为连接该可变区及该效应区的连接符(linker,连接部)。一般来说,该铰链区会影响CAR的稳定性、表达及功能。依据本公开内容某些实施方式,本发明CAR的铰链区包含一至少85%相似于SEQ ID NO:2的氨基酸序列,举例来说,85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相似于SEQ ID NO:2的氨基酸序列。优选地,该铰链区的氨基酸序列至少90%相似于SEQ ID NO:2。更优选地,该铰链区的氨基酸序列至少95%相似于SEQ ID NO:2。依据本公开内容一特定实施例,该铰链区包含100%相似于SEQ ID NO:2的氨基酸序列。
本发明CAR的效应区可将活化信号传递至NK细胞,据以诱导NK细胞破坏会表达CEA的癌细胞。依据本公开内容某些实施方式,本发明CAR的效应区包含一至少85%相似于SEQID NO:3的氨基酸序列,举例来说,85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相似于SEQ ID NO:3的氨基酸序列。优选地,该效应区的氨基酸序列至少90%相似于SEQ ID NO:3。更佳地,该效应区的氨基酸序列至少95%相似于SEQ ID NO:3。依据本公开内容的一操作实施例,该效应区包含100%相似于SEQ IDNO:3的氨基酸序列。
依据本公开内容某些实施方式,本发明CAR包含一至少85%相似于SEQ ID NO:4的氨基酸序列,举例来说,85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相似于SEQ ID NO:4的氨基酸序列。优选地,本发明CAR的氨基酸序列至少90%相似于SEQ ID NO:4。更优选地,本发明CAR的氨基酸序列至少95%相似于SEQ ID NO:4。依据本公开内容一操作实施例,本发明CAR包含100%相似于SEQ ID NO:4的氨基酸序列。
可以诸如玻璃或塑料等不同材料来制备适合用以承载本公开内容的药剂和/或经改造的NK细胞的容器。第一容器可承载一有效量的本公开内容的药剂或其药学剂型,其中该有效量可增加癌症表达TAA。第二容器可承载一有效量的本公开内容的经改造的NK细胞或其药学剂型,其中该有效量可消灭该癌症。该试剂盒可还包含一随附于容器的标签或包装内含物。该标签或包装内含物指示分别置于第一及第二容器的药剂及经改造的NK细胞是用以治疗特定癌症。或是或此外,试剂盒可还包含一第三容器,其包含一药学上可接受的缓冲液,例如磷酸盐缓冲生理食盐水、林格氏液或葡萄糖溶液。其可还包含其他商业或使用者所需要的材料,包含其他缓冲液、稀释液、过滤器、针头及注射器。试剂盒可包含用以说明施予药剂及经改造的NK细胞的指示说明。
本公开内容的第二方面是关于一种利用本发明医药试剂盒来治疗有需要的个体(例如,患有癌症的个体,或疑似患有癌症的个体)的方法。该方法包含:
(a)对该个体施予第一有效量的本发明药剂;以及
(b)对该个体施予第二有效量的本发明经改造的NK细胞。
在步骤(a)中,是对该个体施予本发明药剂,以增加癌细胞的TAA表达量。依据某些实施方式,该个体为一小鼠,其中是对该个体施予每日每公斤个体体重0.1毫克到1公斤(即,0.1毫克-1公斤/公斤/日)的药剂。优选地,是对该个体施予1毫克-100公克/公斤/日的药剂。更优选地,是对该个体施予10毫克-10公克/公斤/日的药剂。依据本公开内容一操作实施例,100-500毫克/公斤/日的本公开内容药剂足以增加癌细胞的TAA表达量,以便增加本发明经改造的NK细胞的抗癌功效。
本发明所属技术领域具有普通知识者可依据由动物模式所决定的剂量来计算本发明药剂的人体等效剂量(human equivalent dose,HED)。据此,施予至人体的药剂的剂量约为每日每公斤个体体重1微克-100克(1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600、610、620、630、640、650、660、670、680、690、700、710、720、730、740、750、760、770、780、790、800、810、820、830、840、850、860、870、880、890、900、910、920、930、940、950、960、970、980或990微克,或1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600、610、620、630、640、650、660、670、680、690、700、710、720、730、740、750、760、770、780、790、800、810、820、830、840、850、860、870、880、890、900、910、920、930、940、950、960、970、980或990毫克,或1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90或100克)。优选地,施予至人体的药剂的剂量为10微克-10克/公斤/日。更优选地,施予至人体的药剂的剂量为100微克-1000毫克/公斤/日。
或者是,可依据个体的体表面积来施予该药剂。举例来说,当个体为一小鼠时,则药剂的施予剂量为每日每平方米个体体表面积0.1毫克-1公斤(0.1毫克-1公斤/平方米/日)。在该种情况下,HED约为1微克-100克/平方米/日。
依据治疗目的的不同,可以任何适当途径来施予药剂,举例来说,肠内、口服、鼻腔、非口服(例如肿瘤内、肌肉内、静脉内、动脉内、皮下、腹腔内、颅内、脑室内或鞘内注射)、局部或经黏膜施予。
为有效增加TAA的表达量,可对该个体施予一或多次的药剂。举例来说,可在完整疗程中施予一次药剂。或者是,可每日施予药剂,至少施予7日;举例来说,施予7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28或更多日。依据本公开内容某些实施方式,是每日对个体施予丁酸钠,共施予9剂,以增加癌细胞的TAA的表达量。
在步骤(b)中,是对个体施予每日每平方米个体体表面积1x104-5x1011(例如,1x104、1.5x104、2x104、2.5x104、3x104、3.5x104、4x104、4.5x104、5x104、5.5x104、6x104、6.5x104、7x104、7.5x104、8x104、8.5x104、9x104、9.5x104、1x105、1.5x105、2x105、2.5x105、3x105、3.5x105、4x105、4.5x105、5x105、5.5x105、6x105、6.5x105、7x105、7.5x105、8x105、8.5x105、9x105、9.5x105、1x106、1.5x106、2x106、2.5x106、3x106、3.5x106、4x106、4.5x106、5x106、5.5x106、6x106、6.5x106、7x106、7.5x106、8x106、8.5x106、9x106、9.5x106、1x107、1.5x107、2x107、2.5x107、3x107、3.5x107、4x107、4.5x107、5x107、5.5x107、6x107、6.5x107、7x107、7.5x107、8x107、8.5x107、9x107、9.5x107、1x108、1.5x108、2x108、2.5x108、3x108、3.5x108、4x108、4.5x108、5x108、5.5x108、6x108、6.5x108、7x108、7.5x108、8x108、8.5x108、9x108、9.5x108、1x109、1.5x109、2x109、2.5x109、3x109、3.5x109、4x109、4.5x109、5x109、5.5x109、6x109、6.5x109、7x109、7.5x109、8x109、8.5x109、9x109、9.5x109、1x1010、1.5x1010、2x1010、2.5x1010、3x1010、3.5x1010、4x1010、4.5x1010、5x1010、5.5x1010、6x1010、6.5x1010、7x1010、7.5x1010、8x1010、8.5x1010、9x1010、9.5x1010、1x1011、1.5x1011、2x1011、2.5x1011、3x1011、3.5x1011、4x1011、4.5x1011或5x1011)的经改造的NK细胞。
依据本公开内容某些实施方式,个体为一小鼠。在某些实施方式中,是对该个体施予每日每平方米个体体表面积1x106到5x1011的经改造的NK细胞;优选地,施予每日每平方米个体体表面积1x107到5x1010细胞;更优选地,施予每日每平方米个体体表面积1x108到5x109细胞。可每周对个体施予2-4次(例如,2、3或4次;优选地,2次)经改造的NK细胞,共施予4周;或于第一周对个体施予4-6次(例如,4、5或6次;优选地,5次)经改造的NK细胞,在第二周施予1-3次(例如,1、2或3次;优选地,2次)经改造的NK细胞,而在第三周施予1-3次(例如,1、2或3次;优选地,1次)经改造的NK细胞。或者是,每日对个体施予1x104到1x1011的经改造的NK细胞;优选地,每日1x105到1x1010细胞;更优选地,每日1x106到1x109细胞,其中可每5-8日对个体施予一次(例如每5、6、7或8日一次)经改造的NK细胞,至少施予1个月。在一操作实施例中,每4日对个体施予一次经改造的NK细胞。
当个体为一人类时,可施予每日每平方米个体体表面积1-5x109的经改造的NK细胞。依据某些实施方式,连续二日对个体施予经改造的NK细胞。依据某些实施方式,在一或多治疗周期中,对个体施予经改造的NK细胞,其中各次治疗的间隔时间约为12小时到数个月。依据治疗目的之不同,治疗间隔时间可为12、13、14、15、16、17、18、19、20、21、22或23小时;为1、2、3、4、5、6、7、8、9、10、15、20或25日;或为1、2、3、4或数月。优选地,在每治疗周期的第1、3及5日对个体施予经改造的NK细胞。举例来说,可在治疗第1日对个体施予每平方米体表面积1x109之经改造的NK细胞,在治疗第3日施予每平方米体表面积3x109的经改造的NK细胞,以及在治疗第5日施予每平方米体表面积5x109的经改造的NK细胞。
或者是,临床医护人员可依据个体的身体及生理因素来决定本发明药剂及经改造的NK细胞的实际施予剂量,该些因素包含,但不限于,年龄、性别、体重、体表面积、欲治疗的疾病、疾病的严重程度、先前病史、其他药物服用与否及施予途径等。
例示性的施予途径包含,但不限于,肠内、口服、鼻腔、非口服、局部或经黏膜施予,其中非口服可以是肿瘤内、肌肉内、静脉内、动脉内、皮下、腹腔内、颅内、脑室内或鞘内注射。
依据本公开内容实施方式,该表达TAA特异性CAR的经改造的NK细胞,对经本发明药剂处理或前处理的癌细胞具有结合亲和性及特异性(专一性)。在该些实施方式中,本发明药剂可相加地或加乘地增加本发明经改造的NK细胞的抗癌功效。
当可想见,本发明药剂可在施予本公开内容的经改造NK细胞之前或同时,施予至个体体内。优选地,本发明药剂是在施予经改造的NK细胞之前,施予至个体体内。可选地,先施予至少2剂本发明药剂后,再施予经改造的NK细胞。举例来说,先对个体施予3、4、5、6、7、8、9、10或更多次的本发明药剂,其中各剂之间的间隔时间约为1天;之后再施予1、2、3或更多次的经改造的NK细胞。
适用以本发明医药试剂盒和/或方法治疗的癌症可为一对化学治疗(例如,5-氟尿嘧啶(5-fluorouracil,5-FU))、一放射治疗(例如,紫外线(ultraviolet,UV)照射)或一免疫治疗(例如,免疫输入疗法(adoptive immune cell therapy或AIT))具有抗性的癌症。据此,本公开内容的医药试剂盒和/或方法可用以治疗对癌症疗法产生抗性的癌症患者。
或者是,本发明经改造的NK细胞可在不经本发明药剂处理(例如,共同处理或前处理)的情况下,单独施予至癌症患者体内。更具体来说,当癌症患者的TAA表达量高于正常个体的表达量时,可在不施予本公开内容的药剂的情况下,直接以本发明经改造的NK细胞治疗该癌症患者。举例来说,当癌症患者的CEA表达量高于健康个体的表达量时,则可对该患者施予包含CEA特异性CAR(例如,包含一可变区的CAR,其中该可变区包含SEQ ID NO:1的氨基酸序列)的经改造的NK细胞,以便清除会表达CEA的癌细胞。
例示性的可以本公开内容的经改造的NK细胞、医药试剂盒和/或方法治疗的癌症包含,但不限于,胃癌、肺癌、膀胱癌、乳腺癌、胰脏、肾脏癌、结肠直肠癌、子宫颈癌、卵巢癌、脑癌、前列腺癌、肝癌、黑色素瘤、食道癌、多发性骨髓瘤,以及头颈部鳞状细胞癌。依据本公开内容一特定实施例,该癌症为结肠癌或直肠癌。
基本上,该个体为一哺乳动物,举例来说,人类、小鼠、大鼠、仓鼠、天竺鼠、兔子、狗、猫、牛、山羊、绵羊、猴子及马。优选地,该个体为人类。
下文提出多个实验例来说明本发明的某些方面,以利本发明所属技术领域中具有普通知识者实作本发明,且不应将这些实验例视为对本发明范围的限制。据信本领域技术人员在阅读了此处提出的说明后,可在不需过度解读的情形下,完整利用并实践本发明。此处所引用的所有公开文献,其全文皆视为本说明书的一部分。
实施例
材料及方法
制备NK92MI-CEA细胞
以下述方法制备NK92MI-CEA细胞。利用重叠PCR反应来扩增及组合分别用以编码mAb T84.66的重链(heavy chain,VH)及轻链(light chain,VL)可变区的序列。将用以编码抗-CEA scFv片段及CD8α铰链区域(氨基酸105-165)的序列克隆至质粒pcDNA3.1/V5-TA中。由制得的pcDNA3.1-scFv(抗-CEA)-CD8a-CD3z构建体制备完整的CAR序列,并通过SfiI及ClaI克隆位点将该CAR序列克隆至一包含前导序列及HA标签的经改造的反转录病毒pLNCX载体中,以便制备重组反转录病毒载体pLNCX-scFv(抗-CEA抗体)-CD8α-CD3ζ。接着将该载体pLNCX-scFv(抗-CEA抗体)-CD8α-CD3ζ与质粒pVSV-G(外膜质粒)共转染至细胞株GP2-293。转染48小时后,由细胞培养液收集包含反转录病毒颗粒的上清液,并以一0.45微米的低蛋白结合过滤器进行过滤。接着,在包含聚凝胺(polybrene,每毫升5微克)的环境中,将经过滤的上清液加至NK92MI细胞株。于37℃培养24小时后,以硫酸新霉素(neomycin sulfate-G418,每毫升500毫克)筛选经转化的NK92MI细胞,以制备NK92MI-CEA细胞,其具有一肿瘤抗原CEA特异(专一)的CAR(SEQ ID NO:4)。
细胞培养
将人类结肠癌细胞株LS174T(CL-188TM)及WiDr细胞(CCL-218TM)培养于包含1.5g/L碳酸氢钠及10%胎牛血清(fetal bovine serum,FBS)的α-MEM培养液中。将HCT116细胞(CCL-247TM)培养于包含1.5g/L碳酸氢钠、4.5g/L葡萄糖、10mM HEPES、1.0mM丙酮酸钠及10%FBS的McCoy's 5A培养液中。将NK92MI及NK92MI-CEA细胞培养于包含1.5g/L碳酸氢钠、0.2mM肌醇、0.02mM叶酸、0.01mM2-巯乙醇、10%FBS及12.5%马血清的α-MEM培养液中。所有的细胞皆是培养于包含5%CO2的37℃潮湿培养箱中。
确定CEA表达
以流式细胞仪确定癌细胞上CEA的表达量。以人类CEA特异性抗体染色癌细胞后,利用流式细胞仪进行分析。记录至少105细胞的荧光强度,并以软件分析。选择几何平均值作为平均荧光强度(mean fluorescence intensity,MFI)。
细胞毒杀试验
本实验是以癌细胞(即,HCT116或WiDr细胞)及the NK细胞(即,NK92MI或NK92MI-CEA细胞)分别作为目标及效应细胞。简单来说,将10:1、5:1、1:1及0.5:1等不同比例的目标细胞(靶细胞)与效应细胞共同培养于圆底96孔洞培养盘中。于37℃培养24小时后,收集50微升的上清液,并于平底96孔洞酶分析盘中与50微升的CYTOTOX试剂混合。将混合物置于室温反应30分钟后,加入50微升的中止溶液(H2SO4)以中止反应。测量490奈米时的吸光值。以下列公式计算各效应:目标细胞比例的细胞毒杀百比分:(实验值-培养液背景值)-(效应细胞自发释放值-培养液背景值)-(目标自发释放值-培养液背景值)/(目标最大释放值-体积校正对照值-目标自发释放值-培养液背景值)×100。
动物试验
将2×106WiDr细胞皮下种植于9周大的SCID小鼠的背部。当肿瘤体积约为100-200立方毫米时,连续5日以腹腔注射方式对小鼠施予每公斤200毫克的丁酸钠。之后,将小鼠分为5组:(1)对照组,每日口服施予PBS,且每4日腹腔施予PBS;(2)NaB组,每日口服施予5g/L的丁酸钠,且每4日腹腔施予PBS;(3)NK92MI组,每日口服施予PBS,且每4日腹腔施予NK92MI细胞;(4)NK92MI-CEA组,每日口服施予PBS,且每4日腹腔施予NK92MI-CEA细胞;以及(5)NK92MI-CEA+NaB组,每日口服施予5g/L的丁酸钠,且每4日腹腔施予NK92MI-CEA。每2-3日测量一次肿瘤大小,并以下列公式计算肿瘤体积:长度x(宽度)2÷2(*p<0.05)。
统计分析
在分析活体实验时,是以单向Anova试验与Bonferroni事后检测法进行多方比对,以比对肿瘤的体积。
实施例1 CEA表达与药物抗性的相关性
有报导指出,CEA的表达会与化学治疗的抗性相关。本实施例将探讨CEA过量表达对5-氟尿嘧啶抗性的影响。
以丁酸钠(0.1mM)或5-氮杂胞嘧啶核苷(1μM)及不同浓度的5-氟尿嘧啶(1.2、2.4、4.8、9.6或19.2μM)共同处理HCT116及WiDr细胞72小时。相较于仅施予5-氟尿嘧啶的组别,同时施予丁酸钠或5-氮杂胞嘧啶核苷会增加细胞的5-FU的IC50值(表1及2)。该些数据证实施予5-氮杂胞嘧啶核苷或丁酸钠会增加癌细胞对药物的抗性。
表1丁酸钠或5-氮杂胞嘧啶核苷诱发HCT116细胞产生药物抗性
以三次独立实验的平均值±SD来表示结果。
P值(与施予5-氟尿嘧啶的组别进行比对)。
表2丁酸钠或5-氮杂胞嘧啶核苷诱发WiDr细胞产生药物抗性
以三次独立实验的平均值±SD来表示结果,每次三重复。
P值(与施予5-氟尿嘧啶的组别进行比对)。
实施例2 NK92MI-CEA细胞对会表达CEA的癌细胞的功效
为评估CEA的表达是否会影响经改造的NK细胞的细胞毒杀功效,先以流式细胞仪来分析HCT细胞、WiDr细胞及LS174T细胞上CEA的表达状况。如图1所示,相较于HCT116及WiDr细胞,LS174T具有最高的CEA表达量。NK92MI-CEA细胞对三种癌细胞的细胞毒杀功效与其于图1所示的CEA表达量相关;结果显示在三种细胞中,LS174T具有显著较高的细胞溶解百分比(图2)。
该些结果证实NK92MI-CEA细胞对会表达CEA的癌细胞具有结合亲和性及细胞毒杀功效,其中该细胞毒杀功效是与CEA的表达量呈正相关。
实施例3 NK92MI-CEA细胞对经抗癌药物前处理的癌细胞的功效
在本实施例中,先以不同抗癌药物处理癌细胞,之后再施予NK92MI-CEA细胞。结果指出,某些抗癌药物(例如,5-氮杂胞嘧啶核苷及丁酸钠)会使癌细胞对化学治疗及放射治疗产生抗性(结果未显示)。此外,癌细胞治疗抗性与CEA的表达量相关(结果未显示)。依据该结果,施予5-氮杂胞嘧啶核苷或丁酸钠会显著增加癌细胞上CEA的表达量(结果未显示)。
基于该些结果,将经5-氮杂胞嘧啶核苷或丁酸钠处理的HCT116细胞与NK92MI-CEA细胞共同培养,其中效应细胞/目标细胞比例(E/T比)为10:1、5:1、1:1或0.5:1。相较于对照组(即,共同培养HCT116及未经改造的NK细胞)及未处理组(即,共同培养HCT116及经改造的NK细胞),施予5-氮杂胞嘧啶核苷(图3A)或丁酸钠(图3B)会显著增加NK92MI-CEA细胞的细胞毒杀功效。
实施例4 NK92MI-CEA细胞在动物模式中的功效
本实施例将评估NK92MI-CEA细胞于活体内的抗肿瘤功效。依据材料及方法所述流程处理小鼠,图4A-4C阐述该些结果。
图4A的结果指出,相较于对照组、NaB组及NK92MI组,施予NK92MI-CEA细胞可显著抑制肿瘤生长。此外,结果亦显示共同施予丁酸钠会明显增加NK92MI-CEA细胞的抗肿瘤功效。
如图4B的结果所示,相较于对照组,施予丁酸钠或NK-92MI细胞不会明显抑制肿瘤生长。然而,施予NK92MI-CEA细胞可显著减少肿瘤体积,而合并施予NK92MI-CEA细胞及丁酸钠则可达到更显著的抑制功效。
ELISA数据证实,施予丁酸钠(不论是单独施予丁酸钠,或合并施予丁酸钠及NK92MI-CEA细胞)后,小鼠血清中循环CEA(cCEA)的表达量会高于对照组(即施予PBS、NK92MI细胞或NK92MI-CEA细胞的小鼠)血清中cCEA的表达量(图4C)。小鼠血清中cCEA的表达量分别为每毫升520微微克(对照组)、每毫升990微微克(NaB组)、每毫升200微微克(NK92MI组)、每毫升540微微克(NK92MI-CEA组),以及每毫升870微微克(NK92MI-CEA+NaB组)。
总结上述,本公开内容提供一种包含一第一组件及一第二组件的医药试剂盒,其中该第一组件包含一可增加欲治疗的癌细胞上TAA(例如,CEA)表达量的药剂(例如,5-氮杂胞嘧啶核苷或丁酸钠);而该第二组件则包含经改造的NK细胞,该经改造的NK细胞会表达对TAA特异的受体(例如,NK92MI-CEA细胞)。本发明医药试剂盒可用以治疗癌症,特别是该些对传统癌症疗法无反应的癌症;据此,本公开内容可用以改善癌症患者的生活质量或寿命。
虽然上文实施方式中揭露了本发明的具体实施例,然其并非用以限定本发明,本发明所属技术领域中具有普通知识者,在不悖离本发明的原理与精神的情形下,当可对其进行各种更改与修饰,因此本发明的保护范围当以附随权利要求书所界定者为准。
序列表
<110> 强普生技股份有限公司
<120> 医药试剂盒及其用途
<130> P2999-CN
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Claims (21)
1.一种用以治疗个体的癌症的医药试剂盒,包含
第一容器,包含可增加所述癌症的肿瘤相关抗原(tumor-associated antigen,TAA)的表达的药剂;以及
第二容器,包含经改造的自然杀伤细胞,其具有对所述TAA具有特异性的嵌合抗原受体(chimericantigen receptor,CAR)。
2.如权利要求1所述的医药试剂盒,其中
所述TAA是癌胚抗原(carcinoembryonicantigen,CEA);以及
所述CAR包含一可变区,其包含至少85%相似于SEQ ID NO:1的氨基酸序列。
3.如权利要求2所述的医药试剂盒,其中所述CAR还包含分别位于所述可变区C端的一铰链区及一效应区,其中所述铰链区及所述效应区分别包含至少85%相似于SEQ ID NO:2及3的氨基酸序列。
4.如权利要求1所述的医药试剂盒,其中
所述TAA是CEA,以及
所述CAR包含至少85%相似于SEQ ID NO:4的氨基酸序列。
5.如权利要求1所述的医药试剂盒,其中所述药剂是选自由5-氮杂胞嘧啶核苷、5,6-二氢-5-氮杂胞嘧啶核苷、5-氮-2'-脱氧胞苷、阿拉伯呋喃糖-5-氮胞嘧啶、曲古菌素A、苯丁酸盐、丁酸钠、丙戊酸及辛二酰苯胺异羟肟酸所组成的群组。
6.如权利要求1所述的医药试剂盒,其中所述癌症是选自由胃癌、肺癌、膀胱癌、乳腺癌、胰脏、肾脏癌、结肠直肠癌、子宫颈癌、卵巢癌、脑癌、前列腺癌、肝癌、黑色素瘤、食道癌、多发性骨髓瘤,以及头颈部鳞状细胞癌所组成的群组。
7.如权利要求6所述的医药试剂盒,其中所述癌症对化学治疗、放射治疗或免疫治疗具有抗性。
8.一种药剂及经改造的自然杀伤细胞用于制备用以治疗个体癌症的药物的组合用途,其中所述药剂可增加所述癌症的一肿瘤相关抗原(tumor-associatedantigen,TAA)的表达,且所述经改造的自然杀伤细胞具有对所述TAA具有特异性的嵌合抗原受体(chimericantigen receptor,CAR)。
9.如权利要求8所述的用途,其中
所述TAA是癌胚抗原(carcinoembryonicantigen,CEA);以及
所述CAR包含一可变区,其包含至少85%相似于SEQ ID NO:1的氨基酸序列。
10.如权利要求9所述的用途,其中所述CAR更包含分别位于所述可变区C端的一铰链区及一效应区,其中所述铰链区及所述效应区分别包含至少85%相似于SEQ ID NO:2及3的氨基酸序列。
11.如权利要求8所述的用途,其中
所述TAA是CEA,以及
所述CAR包含至少85%相似于SEQ ID NO:4的氨基酸序列。
12.如权利要求8所述的用途,其中所述药剂是选自由5-氮杂胞嘧啶核苷、5,6-二氢-5-氮杂胞嘧啶核苷、5-氮-2'-脱氧胞苷、阿拉伯呋喃糖-5-氮胞嘧啶、曲古菌素A、苯丁酸盐、丁酸钠、丙戊酸及辛二酰苯胺异羟肟酸所组成的群组。
13.如权利要求8所述的用途,其中所述癌症是选自由胃癌、肺癌、膀胱癌、乳腺癌、胰脏、肾脏癌、结肠直肠癌、子宫颈癌、卵巢癌、脑癌、前列腺癌、肝癌、黑色素瘤、食道癌、多发性骨髓瘤,以及头颈部鳞状细胞癌所组成的群组。
14.如权利要求13所述的用途,其中所述癌症对化学治疗、放射治疗或免疫治疗具有抗性。
15.一种用以治疗个体的癌症的方法,包含对所述个体施予一第一有效量的药剂及一第二有效量的经改造的自然杀伤细胞,其中所述药剂可增加所述癌症的一肿瘤相关抗原(TAA)的表达,且所述经改造的自然杀伤细胞具有对所述TAA具有特异性的嵌合抗原受体(CAR)。
16.如权利要求15所述的方法,其中
所述TAA是癌胚抗原(CEA);以及
所述CAR包含一可变区,其包含至少85%相似于SEQ ID NO:1的氨基酸序列。
17.如权利要求16所述的方法,其中所述CAR还包含分别位于所述可变区C端的一铰链区及一效应区,其中所述铰链区及所述效应区分别包含至少85%相似于SEQ ID NO:2及3的氨基酸序列。
18.如权利要求15所述的方法,其中
所述TAA是CEA,以及
所述CAR包含至少85%相似于SEQ ID NO:4的氨基酸序列。
19.如权利要求15所述的方法,其中所述药剂是选自由5-氮杂胞嘧啶核苷、5,6-二氢-5-氮杂胞嘧啶核苷、5-氮-2'-脱氧胞苷、阿拉伯呋喃糖-5-氮胞嘧啶、曲古菌素A、苯丁酸盐、丁酸钠、丙戊酸及辛二酰苯胺异羟肟酸所组成的群组。
20.如权利要求15所述的方法,其中所述癌症是选自由胃癌、肺癌、膀胱癌、乳腺癌、胰脏、肾脏癌、结肠直肠癌、子宫颈癌、卵巢癌、脑癌、前列腺癌、肝癌、黑色素瘤、食道癌、多发性骨髓瘤,以及头颈部鳞状细胞癌所组成的群组。
21.如权利要求20所述的方法,其中所述癌症对化学治疗、放射治疗或免疫治疗具有抗性。
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