CN110545847A - 用于肿瘤的靶向免疫疗法的组合物和方法 - Google Patents
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Abstract
本发明提供用于癌症的靶向治疗的通用免疫疗法组合物。本发明在其各个方面利用了包含至少两个结构域的双官能化合物或复合物。一个域在本文中称为靶向部分,其结合肿瘤细胞表面上的抗原。另一个结构域,在本文中称为原抗原,被设计为对正常(未患病)细胞和组织呈惰性,并且仅在暴露于适当的波长的光时才被激活(或“未掩蔽”或“未遮蔽”)。
Description
相关申请
基于35U.S.C.§119(e),本申请主张2017年4月25日提交的美国临时申请第62/489,913号的优先权的权益,该临时申请通过引用而整体并入本文。.
技术领域
本发明通常涉及可用于癌症和其它免疫紊乱的靶向治疗的通用免疫疗法组合物。
背景技术
临床试验已经表明,癌症免疫疗法可在晚期癌症患者体内诱发持久的反应。最成功的癌症免疫疗法之一是使用嵌合抗原受体(CAR)T细胞治疗B细胞源性白血病和淋巴瘤。用来对抗这些癌症的嵌合体是,将CD19特异性的单链抗体融合至CD28(T细胞共刺激蛋白),且再融合至CD3ζ(T细胞受体(TCR)信号传导蛋白)。表达这一构造的T细胞接收一级和二级信号,并生成对抗所有表达CD19的细胞的强健免疫反应,该细胞包括正常的B细胞。迄今为止,CAR T细胞疗法仅在对抗部分实体肿瘤中表现出一定程度的成功,因为它非常难以鉴别唯独在肿瘤上表达而不在未转化的细胞上表达的抗原。本发明解决这一问题。
发明内容
癌症免疫疗法的最大障碍之一是鉴别唯独在肿瘤细胞上表达而不在正常、健康细胞上表达的抗原。本发明利用多向技术创新来创建有效且通用的基于CAR-T的细胞疗法体系,该体系具有显著降低的脱靶组织效应,从而绕开了这一挑战。
本发明在其多个方面使用含有至少两个结构域的双官能化合物或络合物。一个结构域在本文中称为靶向部分,其结合位于肿瘤细胞表面上的抗原。另一结构域在本文中称为前抗原,其被设计为对于正常(未病变)细胞和组织为惰性,且仅在暴露于适宜波长的光时变成活化的(或“未掩蔽的”或“未遮蔽的”)。本发明还使用嵌合抗原受体(CAR)T细胞。这些T细胞配备有杀灭其所结合细胞的机制。本发明的CAR-T细胞被设计为特异性地结合所述前抗原,但仅在其以未掩蔽形式或活化形式时结合。将光引入肿瘤内和肿瘤周围,造成所述前抗原的活化。结果,CAR-T细胞选择性地以病变细胞为靶向并消除该细胞。
据此,本发明的第一方面针对双官能化合物,该化合物包括共价链接至靶向部分的前抗原。构建了本发明化合物的一个官能性模块的前抗原,是具有一个或多个光可裂解的保护基的小分子。构建了本发明化合物的第二股官能性模块的靶向部分,特异性地结合肿瘤相关抗原。
在一些具体实施例中,小分子是荧光分子,诸如荧光素、蒽、alexa fluor、若丹明、对甲氨基酚、吖啶或氧杂蒽。
在一些具体实施例中,光可裂解的保护基是邻硝基苄基、苯乙酮酯基、8-喹啉基苯磺酸酯基、双香豆素基、6-溴-7-烷氧基香豆素-4-基甲氧基羰基、双滿(bimane)基或双芳基腙基。在某些具体实施例中,光可裂解的保护基是邻硝基苄基。在某些具体实施例中,邻硝基苄基保护基是其中X是NH或O,R是C1-4烷基或H,以及,n是0至3。在某些具体实施例中,邻硝基苄基保护基是
在一些具体实施例中,双官能化合物具有式(A)或(A’):
其中X是C或O,Y是C或N,光可裂解的保护基存在于位置1至9中的一处或多处,以及,Q表示一个或多个任选经取代的环或光可裂解的保护基。任选经取代的环是4至7元碳环或杂环或稠环系,其可以是饱和的或不饱和的,其中杂原子可选自N、O和S。
在一些具体实施例中,双官能化合物具有式(I):
其中R1是O、OH或光可裂解的保护基;
R2是O、OH或所述光可裂解的保护基;以及
R3是
或其异体异构体。
在一些具体实施例中,双官能化合物具有式(Ia):或其立体异构体。
在一些具体实施例中,双官能化合物具有式(Ib):
或其立体异构体。
在一些具体实施例中,双官能化合物具有式(II):其中R4和R4’各自独立为O或光可裂解的保护基;以及
R5是
或其立体异构体。
在一些具体实施例中,双官能化合物具有式(IIa):
或其立体异构体。
在一些具体实施例中,靶向部分是抗体、抗体片段、配体、适配体或纳米抗体。
在一些具体实施例中,靶向部分特异性地结合位于癌细胞上的肿瘤相关抗原。肿瘤相关抗原的代表性实例包括:血小板源生长因子受体α(PDGFRa)、1型激活素a受体(ACVR1)、人类表皮生长因子受体2(HER2)、前列腺干细胞抗原(PSCA)、甲胎蛋白(AFP)、癌胚抗原(CEA)、癌抗原-125(CA-125)、CA19-9、钙视网膜蛋白、MUC-1、表皮膜蛋白(EMA)、表皮肿瘤抗原(ETA)、酪氨酸酶、黑色素瘤相关抗原(MAGE)、CD34、CD45、CD99、CD117、嗜铬粒蛋白、细胞角蛋白、肌间线蛋白、胶质原纤维酸性蛋白(GFAP)、巨囊性病液状蛋白(GCDFP-15)、HMB-45抗原、蛋白黑色素A(由T淋巴细胞识别的黑色素瘤抗原;MART-1)、myo-D1、肌肉特异性肌动蛋白(MSA)、神经丝、神经元特异性烯醇化酶(NSE)、胎盘碱性磷酸酶、突触素、甲状腺球蛋白、甲状腺转录因子-1、丙酮酸激酶M2型同工酶的二聚体形式(肿瘤M2-PK)、异常的ras蛋白、异常的p53蛋白、间皮素、EGFRvIII、EGFR1、二神经节苷脂GD2、白介素13受体α(IL13Rα)、成纤维细胞活化蛋白(FAP)、和L1细胞粘附分子(L1CAM)。
在一些具体实施例中,靶向部分特异性地结合在光可抵达的肿瘤上表达或过度表达的肿瘤相关抗原。光可抵达的肿瘤的代表性实例包括位于乳腺、卵巢、皮肤、宫颈、膀胱、前列腺、胆管、胰腺、胃、脑、口、喉、阴道、阴门或鼻腔通道的组织中的那些。
在一些具体实施例中,靶向部分是曲妥珠单抗(trastuzumab)、西妥昔单抗(cetuximab)、帕尼单抗(panitumamab)、扎鲁木单抗(zalutumumab)、尼妥珠单抗(nimotuzumab)、马妥珠单抗(matuzumab)、吉非替尼(gefitinib)、埃罗替尼(erlotinib)、拉帕替尼(lapatinib)、帕妥珠单抗(pertuzumab)、托西莫单抗(tositumomab)、利妥昔单抗(rituximab)、替伊莫单抗(ibritumomab tiuxetan)、达克珠单抗(daclizumab)、CEA-scan、colo101、OC125单克隆抗体、Ab75705、抗AFP抗体或其片段、人源化B3、B72.3、贝伐单抗、抗CD99抗体或其片段、抗HER2抗体或其片段和抗EGFR抗体或其片段。
另一方面,也提供治疗有效量的化合物与药学可接受的载体的药物组合物。
另一方面,也提供制作本申请的化合物的方法。
另一方面,也提供该化合物与CAR-T细胞的系统。
另一方面,也提供含有一种或多种该化合物的试剂盒。一些具体实施例中,试剂盒含有一种或多种化合物、以及用于产生特异性地识别未掩蔽的本发明化合物的自体CAR-T细胞的试剂。一些具体实施例中,试剂盒含有一种或多种化合物、以及特异性地识别未掩蔽的本发明化合物的同种异体CAR-T细胞。
在其它方面,提供治疗癌症的方法,该方法包括向有此需要的受试者给药治疗有效量的本发明化合物、波长适于裂解所述保护基的光、以及治疗有效量嵌合抗原受体T(CAR-T)细胞,其中所述CAR-T细胞包括特异性地结合未掩蔽的前抗原的细胞外配体。
在一些具体实施例中,化合物和光在给药CAR-T细胞之前给药至受试者。在其它具体实施例中,化合物和光在给药CAR-T细胞之后给药至受试者。在其它具体实施例中,化合物和光与CAR-T细胞同时给药至受试者。
在一些具体实施例中,化合物以0.01mg/kg至500mg/kg体重的剂量给药。在一些具体实施例中,CAR-T细胞以每千克体重104至109个细胞的剂量给药。在一些具体实施例中,光以10至600nm的波长给药。在一些具体实施例中,CAR-T细胞经肠道外给药。在一些具体实施例中,光经由无创过程或微创过程给药。在一些具体实施例中,光在外科手术过程中或之后给药。在一些具体实施例中,化合物和光给药超过一次,而CAR-T给药一次。
附图说明
图1A显示接合至牛血清白蛋白(BSA)的由光可裂解基团掩蔽的荧光素衍生物的结构,以及在暴露于365nm波长的光后生成的未掩蔽的产物的化学结构。
图1B是显示抗荧光素抗体(抗体4M5.3)结合至未掩蔽的荧光素(FL)的化学模型的示意图。以黄色点线指示抗荧光素抗体氨基酸极性触点。以紫色指示的具有氨基酸侧链的触点假定为在荧光素被掩蔽时被直接替换。
图1C是显示鼠抗荧光素CAR-T细胞被未掩蔽的荧光素衍生物特异性活化的图。或在光活化不存在(掩蔽的)下或在暴露于365nm光的光活化存在(未掩蔽的)下,将接合有BSA的掩蔽的荧光素涂覆在固体支撑物上。将鼠抗荧光素CAR-T细胞与掩蔽的、未掩蔽的或仅BSA共同温育大约5小时。仅在未掩蔽的荧光素存在(将接合有BSA的掩蔽的荧光素暴露于365nm的光)下,鼠抗荧光素CAR-T细胞上调了早期活化标记物CD69。
图2是显示抗FL CAR-T细胞将不识别附接至识别肿瘤相关抗原的抗体的遮蔽的FL分子的图。
图3是说明当暴露于适宜波长的光以裂解保护基时,将接合至患者肿瘤靶向抗体的FL去掩蔽的图。
图4是说明当通过暴露于适宜波长的光以裂解保护基而去掩蔽后,FL被抗FL CAR-T细胞识别的图。
图5A是说明保护基的光裂解的图,由光可裂解的链接基和聚合物(浅色折线)组成的保护基裂解以生成附接至肿瘤靶向部分(深色折线)的小分子抗原(星形)。
图5B是说明保护基的光裂解的图,由聚合物(浅色折线)组成的保护基裂解以生成附接至肿瘤靶向部分(深色折线)的小分子抗原(星形加上光可裂解的基团)。
图6是显示人抗荧光素CAR-T细胞对于未掩蔽的荧光素衍生物的特异性体外细胞毒性的图。将人α-荧光素CAR T细胞与涂覆有抗CD99的人尤文肉瘤(Ewing Sarcoma)细胞系(A673)或阴性对照抗体以20:1的效应子与靶点比率共同培养大约4小时。当作为通过365nm的光处理去掩蔽的(未遮蔽的)抗CD99遮蔽的荧光素的靶点时,A673肿瘤细胞被特异性地杀灭;而抗CD99遮蔽的荧光素(遮蔽的)无此结果。在以遮蔽的抗CD99荧光素为靶向的A673细胞与阴性对照抗体(IgG同型对照FITC)之间没有观察到统计学显著差异。使用Kruskal-Wallis单向方差分析加上预先选择的成对比较来计算统计学显著性(*p<0.05)。使用在CART细胞不存在使用其各自抗体处理的细胞计算特异性杀灭。实验平行进行4组。
图7是含有伯胺基的肿瘤靶向部分与NHS-酯荧光素衍生物的化学接合的化学流程示意图。
具体实施方式
除非另做定义,否则本文中使用的所有科技术语均具有与本文主题所属领域技术人员所一般理解的相同的意义。为了促进对本发明的理解,如说明书和所附权利要求书中所用,除非指明为相反,否则下述术语具有所指示的意义。
连词“包含”与“包括”、“含有”或“特征在于”同义,是包含或开放性的,且并不排除额外的未引用的元件或方法步骤。相比之下,连词“由...组成”排除未在该主张中具体指出的任何元件、步骤或成分。连词“主要由...组成”将所主张的范畴限制为具体的材料或步骤,以及“那些不在材料上影响本发明主张的基本特征和新颖特征的材料或步骤”。
从下述对本发明优选具体实施例的说明和权利要求书可明了本发明的其它特征和优点。除非另做定义,否则本文中使用的所有科技术语均具有与本发明所属领域技术人员所一般理解的相同的意义。尽管於本文中揭示者类似或等效的方法和材料可用于实践或测试本发明,但适当的方法和材料揭示如下。在矛盾的情况下,包括定义在内,以本说明书为准。此外,材料、方法和实施例仅做例示性说明之用,而非试图限制。
本发明涉及治疗癌症的通用免疫疗法系统/试剂盒、组合物和方法。
癌症免疫疗法的最大障碍之一是鉴别唯独在肿瘤组织上表达而不在正常、健康组织上表达的抗原。通过利用多种技术创新来创建有效的CAR T细胞疗法系统,本发明克服了这些挑战。具体地,本发明提供能够检测肿瘤上的任何抗原并生成对抗该肿瘤的免疫反应性而没有脱靶组织效应的试剂。
简单地说,在多个方面,本发明由三部分构成:(1)肿瘤靶向结合分子(即,靶向部分),(2)掩蔽的小分子(即,前抗原),和(3)对于该小分子为特异性的CAR-T细胞。该掩蔽对于光子敏感,导致该小分子的“去掩蔽”。优选该掩蔽是光敏性的。例如,该掩蔽对于紫外线敏感。
本发明是对于PCT/US2017/018216所公开的发明的改善,该PCT申请的内容通过引用而整体并入本文。具体地,不同于其中肿瘤本身程序性抵达(即,未掩蔽)小分子的先前公开,本发明令医师通过直接将适宜波长的光引入肿瘤而程序性抵达该小分子。
整体策略在图2至图4中示意性地呈现,一系列双重事件决定了CAR T细胞是否将会被合成小分子活化。这些使用嵌合抗原受体(BAT-CAR)的双重活化的T细胞在被掩蔽的小分子存在下应为完全惰性,且仅在该小分子未掩蔽处的位点被活化。可调整本发明的系统和组合物,以引导T细胞反应而以患者特异性的模式对抗任何实体肿瘤。
本发明的另一方面为,可将任何嵌合细胞受体工程化以令其通过给药小分子而被刺激。换句话说,单链抗体与任何细胞受体的融合可产生新颖的嵌合受体。因此,给药被该单链抗体识别的小分子可刺激靶点细胞的下游效应,其特征为使用其天然配体刺激该受体。在本发明中,通过给药小分子而令T细胞受体信号传导成为可能。换句话说,给药被融合至T细胞信号传导细胞(例如但不唯一性地见于,CD28和CD3 zeta)的该单链抗体识别的小分子,导致T细胞中以T细胞受体信号传导为代表的标志变化。通过制作小分子结合单链抗体与任何细胞受体的嵌合体,可通过给药被该单链抗体识别的小分子诱发具体的生物学结果。
根据本发明的试剂在不具有前述肿瘤新抗原信息的肿瘤内特异性地产生T细胞导向的免疫反应。使用肿瘤中富含但不必特有的抗原(例如,肿瘤相关抗原;TAA)的靶向部分完成以肿瘤为靶向。这一靶向部分将被连接至小分子。该小分子作为靶点用于使用对该小分子为特异性的细胞外结合结构域工程化的通用CAR T细胞。本文中称为“使用嵌合抗原受体(BAT-CAR)双重活化的T细胞”的这一通用CAR T细胞,在该小分子的缺席下是完全惰性的。使用掩蔽的接合靶向部分的小分子对患者进行全身性治疗,将会把该小分子递送至肿瘤,创造BAT-CAR的独特靶点。为了防止BAT-CAR T细胞的脱靶活化,使用光敏基团掩蔽或遮蔽该小分子。尽管完整,但该遮蔽防止小分子结合并活化BAT-CAR T细胞。医师通过将对于未掩蔽的分子适宜的波长的光投放到含有癌组织的位点而控制活化。
靶向部分
根据本发明的靶向部分具有对于肿瘤相关抗原(TAA)的结合特异性。靶向部分在本文中也称为“结合分子”或“肿瘤靶向单元”。术语“肿瘤相关抗原”在本文中也称为“肿瘤抗原”或“癌症相关抗原”,是指在癌细胞表面上表达的分子(典型为蛋白质、碳水化合物或脂质),或是完整的或作为片段(例如,MHC/肽),且可用于令药剂优先以癌细胞为靶向。
如本文中所用,术语“结合”(bind或binding)是指展现相互亲和性或结合能力的相对应成对分子或其部分之间的典型由于特异性或非特异性结合或相互作用导致的相互作用,包括但不限于,生化相互作用、生理相互作用、和/或化学相互作用。“生物结合”界定了一种类型的相互作用,其出现在成对分子之间,该分子包括蛋白质、核酸、糖蛋白、碳水化合物、激素等。术语“结合伙伴”是指可与特定分子结合的分子。“特异性结合”是指能以实质上高于其它、类似的生物学整体的程度结合至或识别结合伙伴(或有限数目的结合伙伴)的分子。
靶向部分的代表性实例包括抗体分子及其功能性(即,抗原结合)片段、受体配体、肽、半抗原、适配体、亲和体、T细胞受体四聚体和该领域技术人员已知的其它靶向分子。举例而言,靶向部分可包括核酸、多肽、糖蛋白、碳水化合物或脂质。
在某些具体实施例中,靶向部分是抗体或抗体片段。举例而言,抗体包括单克隆抗体;多克隆抗体;Fv、Fab、Fab'和F(ab')2免疫球蛋白片段;合成的稳定化Fv片段,例如,单链Fv片段(scFv)、二硫醚稳定化的Fv片段(dsFv);单可变区结构域(dAb)微小抗体、联合抗体和多价抗体,诸如双体和多scFv;来自骆驼或工程化人等效物的单一结构域。抗体或通过传统免疫化(例如,多克隆血清和杂交瘤)或作为重组片段而制备,通常在从噬菌体展示库和核糖体展示库中选择后表达在大肠杆菌(E.coli)中。或者,包含非共价关联的VH结构域和VL结构域的“联合抗体”可以从产生双体的细菌克隆体的组合创建的矩阵格式产生。术语“抗体”也包括任何具有与免疫球蛋白结合结构域同源或很大程度上同源的结合结构域的蛋白质。此类蛋白质可源自天然来源,或部分或全部经合成产生。
在某些具体实施例中,该靶向部分是亲和体。亲和体是被工程化以展示肽环的高度稳定的小蛋白,该肽环提供对于特异性靶点蛋白的高亲和性结合表面。它是源自半胱氨酸蛋白酶抑制剂家族——血清胱抑素(cystatin)——的低分子量(12至14kDa)蛋白质。亲和体蛋白由支架构成,该支架是基于血清胱抑素蛋白质折叠的稳定蛋白。它们展示两个肽环和可经随机化而以类似于抗体的高亲和性和特异性结合不同靶点蛋白质的N端序列。当蛋白质支架约束肽可能采取的可能构象时,该肽得以稳定化,因此,结合亲和性和特异性比游离肽库有所增加。
在某些具体实施例中,该靶向部分是结合至细胞类型特异性标记物的核酸结合分子(如,适配体)。通常,适配体是结合至特定靶点诸如多肽的寡核苷酸(例如,DNA、RNA、或其类似物或衍生物)。适配体是特异性地结合至多种分子靶点诸如小分子、蛋白质、核酸、甚至细胞和组织的合成性短单链寡核苷酸。这些小核酸分子可形成能特异性地结合蛋白质或其它细胞靶点的二级和三级结构,且基本上是抗体的化学等效物。适配体是高度特异性的,尺寸相对较小,且是非免疫原性的。适配体通常使用称为SELEX(指数富集配体进化技术)的生物淘洗方法选择(Ellington et al.Nature.1990;346(6287):818-822;Tuerk et al.,Science.1990;249(4968):505-510;Ni et al.,Curr Med Chem.2011;18(27):4206-14;文献均通过引用而整体并入本文)。生成用于任何给定靶点的适配体的方法是该领域中已知的。
在一些具体实施例中,靶向部分可以是用于细胞表面受体的天然配体或合成配体。
一些具体实施例中,该靶向部分是碳水化合物。碳水化合物可以是天然的或合成的。碳水化合物可以是衍生化的天然碳水化合物。在一些具体实施例中,碳水化合物包含单糖或二糖,包括但不限于,葡萄糖、果糖、半乳糖、核糖、乳糖、蔗糖、麦芽糖、海藻糖、纤维二糖、甘露糖、木糖、阿拉伯糖、葡萄糖醛酸、半乳糖醛酸、甘露糖醛酸、葡萄糖胺、半乳糖胺、或神经氨酸。在一些具体实施例中,碳水化合物是多糖,诸如但不限于,普鲁兰多糖(pullulan)、纤维素、微晶纤维素、羟丙基甲基纤维素(HPMC)、羟基纤维素(HC)、甲基纤维素(MC)、葡聚糖、环糊精、糖原、淀粉、羟乙基淀粉、角叉菜胶、聚糖、直链淀粉、壳聚糖、N,O-羧甲基壳聚糖、藻胶和海藻酸、淀粉、甲壳质、肝素、蒟蒻、葡甘露聚糖、石耳素、肝素、透明质酸、凝胶多糖(curdlan)和黄原胶。在一些具体实施例中,碳水化合物是糖醇,诸如但不限于,甘露醇、山梨醇、木糖醇、赤藓糖醇、麦芽糖醇或乳糖醇。
靶向部分的代表性实例在表1中详述:
表1
根据本发明的靶向部分具有对于肿瘤相关抗原的结合特异性。肿瘤相关抗原意为肿瘤细胞上的任何细胞表面分子或分子的组合。优选的,肿瘤抗原将肿瘤细胞与正常细胞区分开来。通过唯独在肿瘤细胞上表达或比正常细胞更大量地呈递在肿瘤细胞内,肿瘤抗原可将肿瘤细胞与正常细胞区分开来。肿瘤抗原是多肽、肽(例如,MHC肽)、脂质或碳水化合物。
在一些具体实施例中,肿瘤抗原是由正常细胞和癌细胞两者表达的标记物,例如,谱系标记物如B细胞上的CD19。在一些具体实施例中,肿瘤抗原是细胞表面分子,其在癌细胞中比在正常细胞中过度表达,例如,比正常细胞1倍过度表达、2倍过度表达、3倍过度表达或更多。在一些具体实施例中,肿瘤抗原是细胞表面分子,其在癌细胞中被不适宜地合成,例如,与在正常细胞上表达的分子相比,含有删除、加入或突变。在一些具体实施例中,肿瘤相关抗原是呈递MHC的肽。正常情况下,源自内源性蛋白质的肽填充I类主要组织相容性复合体(MHC)分子的袋,且被CD8+ T淋巴细胞上的T细胞受体(TCR)识别。I类MHC复合体被全部有核细胞构造性地表达。在癌症中,病毒特异性的和/或肿瘤特异性的肽/MHC复合体表示用于免疫疗法的特有的一类细胞表面靶点。
结合TAA的靶向部分是该领域中已知的。在某些具体实施例中,靶向部分指向被所投放的光可抵达的肿瘤(“光可抵达肿瘤”)表达的TAA。光可抵达的肿瘤的代表性实例包括位在乳腺、卵巢、皮肤、子宫、膀胱、前列腺、胆管、胰腺、胃、脑、口、喉、阴道、阴门和鼻腔通道的组织中发现的那些。在一些具体实施例中,可经由间质疗法将光递送至一些肿瘤,其牵涉使用成像测试(诸如CT扫描)而用针或其它微创手段将光纤直接引导至肿瘤内。经由间质疗法递送的光可用来治疗在乳腺、卵巢、头颈、前列腺、肝和肺中发现的肿瘤。在其它具体实施例中,可在外科手术过程中或手术后将光递送至任何可能在肿瘤切除后剩余的癌组织。
可作为靶向部位指向目标的肿瘤相关抗原(TAA)的代表性实例包括:血小板源生长因子受体α(PDGFRa)、1型激活素a受体(ACVR1)、人类表皮生长因子受体2(HER2)、前列腺干细胞抗原(PSCA)、甲胎蛋白(AFP)、癌胚抗原(CEA)、癌抗原-125(CA-125)、CA19-9、钙视网膜蛋白、MUC-1、表皮膜蛋白(EMA)、表皮肿瘤抗原(ETA)、酪氨酸酶、黑色素瘤相关抗原(MAGE)、CD34、CD45、CD99、CD117、嗜铬粒蛋白、细胞角蛋白、肌间线蛋白、胶质原纤维酸性蛋白(GFAP)、巨囊性病液状蛋白(GCDFP-15)、HMB-45抗原、蛋白黑色素A(由T淋巴细胞识别的黑色素瘤抗原;MART-1)、myo-D1、肌肉特异性肌动蛋白(MSA)、神经丝、神经元特异性烯醇化酶(NSE)、胎盘碱性磷酸酶、突触素、甲状腺球蛋白、甲状腺转录因子-1、丙酮酸激酶M2型同工酶的二聚体形式(肿瘤M2-PK)、异常的ras蛋白、异常的p53蛋白、间皮素、EGFRvIII、EGFR1、二神经节苷脂GD2、白介素13受体α(IL13Rα)、成纤维细胞活化蛋白(FAP)、和L1细胞粘附分子(L1CAM)。
前抗原
本发明的前抗原是含有光可裂解的保护基的小分子。在本文中也称为“掩蔽的标签”、“遮蔽的标签”、“掩蔽的识别结构域”或“遮蔽的识别结构域”的前抗原,在其不结合并活化CAR-T细胞的情况下,除非它在暴露在适宜波长的光中而变为未掩蔽的或未遮蔽的,否则是惰性的。
标签/识别结构域
“标签”或“识别结构域”用作通用CAR T细胞的靶点。本文中,识别结构域也称为“抗原小分子”或“小分子”。识别结构域被链接之靶向部分,链接方式为不干扰该靶向部分结合其配体如TAA的能力。识别结构域是一个或多个(即,复数个)小分子。小分子是合成的或非天然出现的。小分子具有或不具有生物学活性。如本文中所用,短语“生物学活性”是指任何物质在生物系统和/或有机体中具有活性的特征。例如,当将一物质给药至有机体时,该物质对该有机体具有生物学效果,则将该物质视为具有生物学活性。
通常,“小分子”在该领域中理解为大小低于约5千道尔顿(kD)的有机分子。在一些具体实施例中,小分子低于约4kD、约3kD、约2kD、或约4kD。在一些具体实施例中,该小分子低于约800道尔顿(D)、约600D、约500D、约400D、约300D、约200D、或约100D。在一些具体实施例中,小分子低于约2000g/mol、低于约1500g/mol、低于约1000g/mol、低于约800g/mol、或低于约500g/mol。
可被链接至靶向部分的小分子的代表性实例包括荧光素、蒽、对甲氨基酚、alexafluor、吖啶、氧杂蒽、哌嗪、苯丙胺、苯二氮平、苯甲酰爱康宁(benzoylecgonine)、丁丙诺啡(buprenorphine)、阿片样物质、大麻素、苯环己哌啶、三环抗抑郁药、右美沙芬(dextromethorphan)、芬太尼、甲丙氨酯(meprobamate)、美沙酮(methadone)、甲基苯丙胺、羟考酮(oxycodone)、THC、曲马多(tramadol)、唑吡坦(zolpidem)、氯胺酮(ketamine)、LSD、MDMA、甲喹酮(methaqualone)、丙氧芬(propoxyphene)或去甲氯胺酮(norketimine)。其它用于本发明中的例示性小分子包括http://www.randoxtoxicology.com/products/biochip-array和http://www.randoxtoxicology.com/products/biochip-array/doa-I所列的那些。
可被链接至靶向部分的荧光素衍生物的代表性实例包括5-羧基荧光素、6-羧基荧光素、5-(碘乙酰胺基)荧光素、盐酸5-([4,6-二氯三嗪-2-基]胺基)荧光素、5-(溴甲基)荧光素、荧光素-5(6)-异硫氰酸酯和荧光素-5-氨基甲酰基甲基硫代丙酸。
可被链接至靶向部分的蒽衍生物的代表性实例包括蒽醌、蒽醌-2-甲酸酯、2-氨基蒽醌、2-碘蒽醌、2-氯蒽醌、2-溴蒽醌、2-乙炔基蒽醌、2-氰基蒽醌、蒽醌-2-磺酸酯、蒽醌-2-甲酰氯和2-羟基蒽醌。
本发明的化合物可使用诸如化学连接和化学交联的技术将靶向部分接合至前抗原而制备。在一些具体实施例中,前抗原可经由链接基接合至靶向部分。脂肪族链接基的代表性实例包括甘氨酸、氨基庚酸、氨基己酸、氨基戊酸和氨基丁酸。极性链接基的代表性实例包括具有2、4或6个重复单元的聚乙二醇。
保护结构域
标签或识别结构域被链接至保护结构域。本文中,保护结构域也称为“掩蔽”或“遮蔽”。保护结构域用来掩蔽识别结构域,以防止该识别结构域结合并活化CAR-T细胞。保护结构域在整体上或部分上是光敏的,即,光可裂解的。如本文中所用,术语“光敏的”和“光可裂解的”是可互换的。在一些具体实施例中,该保护结构域由一个或多个光可裂解的基团构成。当将光可裂解的基团暴露在光中时,前抗原被去掩蔽,从而生成标签或识别结构域。
在一些方面,保护结构域由光可裂解的基团和掩蔽聚合物构成。
大量生物可降解的和不可降解的生物相容聚合物是生物聚合材料、药物控释和组织工程化领域中已知的(见,举例而言,Vacanti的美国专利6,123,727、5,804,178、5,770,417、5,736,372、5,716,404;Shastri的美国专利6,095,148、5,837,752;Anseth的美国专利5,902,599;Mikos的美国专利5,696,175、5,514,378、5,512,600;Barrera的美国专利5,399,665;Domb的美国专利5,019,379;Ron的美国专利5,010,167;d'Amore的美国专利4,946,929;以及Kohn的美国专利4,806,621、4,638,045;也见Langer,Acc.Chem.Res.33:94,2000;Langer,J.Control Release 62:7,1999;和Uhrich et al.,Chem.Rev.99:3181,1999;上述文献全部通过引用并入本文)。
聚合物的代表性实例包括聚酰胺、聚碳酸酯、聚烯烃、聚亚烷基二醇、聚环氧烷、聚对苯二甲酸亚烷基二酯、聚乙烯醇、聚乙烯基醚、聚乙烯基酯、聚卤乙烯、聚乙交酯、聚硅氧烷、聚氨酯及其共聚物、烷基纤维素、羟基烷基纤维素、纤维素醚、纤维素酯、小基纤维素、丙烯酸酯和甲基丙烯酸酯的聚合物、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、醋酸纤维素、丙酸纤维素、醋丁酸纤维素、醋酸邻苯二甲酸纤维素、羧乙基纤维素、三醋酸纤维素、硫酸纤维素钠盐、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚甲基丙烯酸丁酯、聚甲基丙烯酸异丁酯、聚甲基丙烯酸己酯、聚甲基丙烯酸异癸酯、聚甲基丙烯酸月桂酯、聚甲基丙烯酸苯酯、聚丙烯酸甲酯、聚丙烯酸异丙酯、聚丙烯酸异丁酯、聚丙烯酸十八酯、聚乙烯、聚丙烯、聚乙二醇、聚环氧乙烷)、聚对苯二甲酸乙二酯、聚乙烯醇、聚醋酸乙烯酯、聚氯乙烯和聚苯乙烯。
生物不可降解的聚合物的代表性实例包括乙烯-醋酸乙烯酯、聚(甲基)丙烯酸、聚酰胺、它们的共聚物和混合物。
生物可降解的聚合物的代表性实例包括合成聚合物,诸如乳酸和乙醇酸的聚合物、聚酸酐类、聚(原酸)酯类、聚氨酯类、聚丁酸、聚戊酸、聚己内酯、聚(羟基丁酸酯)、聚乙丙交酯和聚(丙交酯-共-己内酯);以及天然聚合物,诸如,藻酸盐和其它多糖,包括葡聚糖和纤维素、胶原、其化学衍生物(化学基团例如烷基、亚烷基的取代、加成、羟基化、氧化和该领域技术人员常规做出的其它改性)、白蛋白和其它亲水性蛋白、玉米蛋白和其它醇溶谷蛋白、疏水性蛋白、它们的共聚物和混合物。通常,这些材料或通过酶促水解或在体内暴露于水中而通过表面或本体溶蚀而降解。前述材料可单独使用,或作为物理混合物(掺混物)或作为共聚物使用。在一些具体实施例中,该聚合物是聚酯类、聚酸苷类、聚苯乙烯、聚乳酸、聚乙醇酸、乳酸和乙醇酸的共聚物、以及它们的掺混物。
PVP是平均分子量为大约10,000至700,000范围内的非离子化的、亲水性聚合物,其化学式为(C6H9NO)n。PVP也称为聚[1-(2-氧代-1-吡咯烷基)乙烯]、PovidoneTM、PolyvidoneTM、RP 143TM、KollidonTM、Peregal STTM、PeristonTM、PlasdoneTM、PlasmosanTM、ProtagentTM、SubtosanTM和VinisilTM。PVP是无毒的、高吸湿的,且易溶于水或有机溶剂。
聚乙二醇(PEG),也称聚(氧乙烯)二醇,是环氧乙烷与水的缩聚物,其化学通式为HO(CH2CH2O)nH。
聚乙烯醇(PVA)是通过将醋酸根置换为羟基而从聚醋酸乙烯酯制备的聚合物,其通式为(CH2CHOH)n。大多数聚乙烯醇可溶于水。PEG、PVA和PVP可从化学品供应商诸如西格玛化学公式(Sigma Chemical Company(St.Louis,Mo.))商购。
在某些具体实施例中,该聚合物可包含聚乙丙交酯(PLGA)。
光可裂解的基团的代表性实例包括基于邻硝基苄基的基团、基于苯甲酰甲基酯的基团、8-羟基喹啉苯磺酸酯基、二香豆素剂、6-溴-7-烷氧基香豆素-4-基甲氧基羰基、基于双滿的基团、和基于双芳基腙的基团。通常的结构和裂解条件如下:
在某些具体实施例中,该光可裂解的保护基是
其中X是NH或O,R是C1-4烷基或H,以及,n是0至3。在一些具体实施例中,该基于邻硝基苄基的基团是在300至365nm裂解。
虚线指示裂解位点。
双官能化合物
在一些具体实施例中,双官能化合物具有式(A)或(A’):
其中X是C或O,Y是C或N,光可裂解的保护基存在于位置1至9中的一处或多处,以及,Q表示一个或多个任选经取代的环或光可裂解的保护基。任选经取代的环是4至7元碳环或杂环或稠环系,其可以是饱和的或不饱和的,其中杂原子可选自N、O和S。
在一些具体实施例中,双官能化合物具有式(I):
其中R1是O、OH或光可裂解的保护基;
R2是O、OH或所述光可裂解的保护基;以及
R3是
或其异体异构体。
在一些具体实施例中,双官能化合物具有式(Ia):
或其立体异构体。
在一些具体实施例中,双官能化合物具有式(Ib):
或其立体异构体。
在一些具体实施例中,双官能化合物具有式(II):其中R4和R4’各自独立为O或光可裂解的保护基;以及
R5是
或其立体异构体。
在一些具体实施例中,双官能化合物具有式(IIa):
或其立体异构体。
本申请的化合物可以是立体异构体的形式,如本文中所用,其涵盖每个化合物的仅在其原子的空间取向上有所不同的所有异构体。术语“立体异构体”包括化合物的镜像异构体(对映异构体)、化合物的镜像异构体的混合物(镜像异构体的物理混合物、以及外消旋体或外消旋混合物)、化合物的几何(顺/反或E/Z、R/S)异构体、以及具有超过一个手性中心的化合物的并非彼此镜像的异构体(非对映异构体)。
因此,本申请的化合物可以独立异构体且基本上不含其它异构体的形式存在,或以各种异构体的混合物形式即立体异构体的外消旋混合物形式存在。
如本文中所用,“环状”是指环烷基、杂环烷基、芳基或杂芳基。
如本文中所用,单独使用或与其它术语合用的术语“环烷基”意为C3-C10饱和的环状烃环。环烷基可以是典型含有3至7个环碳原子的单环。单环的环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基等。环烷基还可以是多环的或含有不止一个环。多环的环烷基的实例包括桥环、稠环、和螺环碳环基。
术语“杂环烷基”是指非芳族的、饱和或部分饱和的、单环或多环的3至15元环系统,该环系统具有至少一个选自O、N、S、S(O)、S(O)2、NH或C(O)的杂原子或杂基,且剩余的环原子独立选自碳、氧、氮和硫组成的组。“杂环烷基”的实例包括氮杂环丁烷基、氧杂环丁烷基、咪唑烷基、吡咯烷基、噁唑烷基、噻唑烷基、吡唑烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉基、硫代吗啉基、1,4-二氧六环基、二氧化硫代吗啉基、氧杂哌嗪基、氧杂哌啶基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢吡喃基、吲哚啉基、吲哚啉基甲基、氮杂环庚烷基、2-氮杂双环[2.2.2]辛烷基、吖辛因基(azocinyl)、色烷基、氧杂蒽基、以及它们的N-氧化物。杂环烷基取代基的附接可经由碳原子或杂原子出现。杂环烷基可任选地经取代,其中一个或多个合适的基团被一个或多个前述基团取代。
如本文中所用,单独使用或与其它术语合用的术语“芳基”意为含有一个或两个环的碳环状芳族系统,其中该环可以是稠合的。术语“稠合”意为第二个环通过具有与第一个环共有的两个相邻原子而附接或形成。术语“稠合”等同于术语“缩合”。芳基的实例包括苯基、萘基、茚满基等。除非明确排除,否则本文中描述的所有芳基均可为经取代的或未取代的。
术语“杂芳基”是指含有5至20个环原子且合适地为5至10个环原子的芳族杂环状环系统,其可以是单个环(单环)或稠合在一起或共价链接的多个环(双环、三环或多环)。优选的,“杂芳基”是5元环或6元环。该环可含有选自N、O和S的1至4个杂原子,其中N或S原子任选经氧化,或N原子任选经季胺化。杂芳基部分的任何合适的环位置可共价链接至所界定的化学结构。
杂芳基的实例包括呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、噌啉基、异噁唑基、噻唑基、异噻唑基、1H-四唑基、噁二唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并呋喃基、苯并噻吩基、苯并三嗪基、酞嗪基、噻蒽基、二苯并呋喃基、二苯并噻吩基、苯并咪唑基、吲哚基、异吲哚基、吲唑基、喹啉基、异喹啉基、喹唑啉基、喹噁啉基、嘌呤基、蝶啶基、9H-咔唑基、α-咔啉基、吲哚嗪基、苯并异噻唑基、苯并噁唑基、吡咯并吡啶基、呋喃并吡啶基、嘌呤基、苯并噻二唑基、苯并噁二唑基、苯并三唑基、苯并二唑基、咔唑基、二苯并噻吩基、吖啶基等。优选的,“杂芳基”是指选自由呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、噌啉基、异噁唑基、噻唑基、异噻唑基、1H-四唑基、噁二唑基、三唑基、吡啶基、嘧啶基、哌嗪基和哒嗪基所组成组的5元环或6元环。更优选为吡唑基、嘧啶基、噁唑基和呋喃基。所有杂芳基任选地被一个或多个前述基团取代。
应理解,本发明化合物上的取代基或取代方式可由该领域技术人员选择以获得化学稳定的化合物,该化合物可通过该领域中已知的技术或下文中详述的那些方法从可轻易获取的起始材料轻易地合成。如果取代基本身被不止一个基团取代,则应理解,这些多个基团可以位于相同碳原子上或位于不同碳原子上,只要得到稳定的结构即可。
如本文中所用,术语“任选经取代的”是指将给定结构的一至六个氢置换为特定的取代基,该取代基包括卤素、氰基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、芳基、杂芳基、氨基、氰基、硝基、烷基胺基、芳基胺基、烷基胺基烷基、芳基胺基烷基、羟基、羟基烷基、环烷基、芳基、杂环基和脂肪族基团。应理解,取代基可进一步经取代。
本发明的双官能化合物可根据该领域中已知的方法合成。参见,例如,WO2010/008519。通常,本发明的小分子具备或可经衍生以具备与多肽的伯胺(例如,多肽的N端胺或赖氨酸)或与巯基(例如,多肽的半胱氨酸)反应的化学基团,形成该双官能化合物的靶向部分。举例而言,见图6。本发明的双官能化合物也可使用点击化学(click chemistry)合成。
CAR
本发明的方法中使用的效应子细胞可以是自体的、同源的或同种异体的,且依据待治疗的疾病和待使用的手段而选择。可用于该方法中的适合的效应子细胞群落包括任何具有细胞溶解活性的免疫细胞,诸如T细胞。T细胞的例示性亚群包括表达CD3+的那些,诸如CD3+CD8+ T细胞、CD3+CD4+ T细胞、和NKT细胞。尽管在一些具体实施例中该T细胞是HLA-A2+外周血单核细胞(PBMC),但它们可以是来自PBMC的任何HLA背景且可用于自体的、同源的或同种异体的体系。T细胞也可从任何来源分离,包括从待治疗的受试者的肿瘤外植体或待治疗受试者的肿瘤内T细胞分离。为了方便起见,后文中称效应子细胞为T细胞,但应理解,除非明确排除,否则任何对T细胞的引述均指代本文中界定的所有效应子细胞类型。
在本发明中使用的基因工程化的T细胞体现出极大的灵活性。它们具有对于特定未掩蔽的前抗原(本文中也称为标签)的结合特异性,其中该前抗原接合至结合至肿瘤相关抗原(TAA)的靶向部分(诸如抗体或其功能性片段)。CAR的其它特征可包括当T细胞结合并活化时诱导有效靶点溶胞的活化结构域,以及将CAR的scFv部分取代或置换为具有对于任何一种本发明的未掩蔽的前抗原或标签的特异性者的能力。由于未掩蔽的前抗原用作被工程化为具有特异性结合该未掩蔽的前抗原的细胞外结合结构域的CAR T细胞的靶点并因此间接地结合至TAA,本发明中使用的CAR-T细胞可称为通用CAR-T细胞或双重活化的T细胞(BAT-CAR)。
BAT-CAR多肽典型包括三个结构域。第一结构域是细胞外配体或标签结合结构域。这一结构域典型存在于BAT-CAR多肽的氨基端,并因此处于T细胞外部,其允许无拘束的标签结合结构域接近被结合至靶点细胞的带标签蛋白。标签结合结构域典型是抗体或其抗原结合片段。在一些具体实施例中,该抗体是人抗体或人源化抗体。
标签结合结构域被设计为特异性地结合未掩蔽的前抗原,该前抗原共价链接至结合靶点细胞(例如,癌细胞)的靶向部分。举例而言,当标签或未掩蔽的前抗原是荧光素或荧光素衍生物时,标签结合结构域特异性地结合荧光素或荧光素衍生物,其实例是该领域中已知的,例如,4M5.3 ScFv,公开在Midelfort,et al.J.Mol.Biol.343:685-701(2004)中。
该类型的抗体并非关键性的;且也可以是多克隆的、单克隆的、嵌合的或人源化的。该抗体可从多个动物物种获得,例如,人、猿、小鼠、大鼠、兔、豚鼠、马、牛、绵羊、山羊、猪、狗或猫。也不存在对于可使用的抗体的特定类别的限制,包括IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE抗体。也可使用的抗体片段包括单链可变片段(scFv)、单链抗体、F(ab')2片段、Fab片段、以及通过Fab表达库产生的片段,限制条件为抗体片段保留结合所选择的标签的能力。
本发明的BAT-CAR可使用可商购的细胞外配体生产,至少达到未掩蔽的前抗原为已知的程度。或者,特异性地结合未掩蔽的前抗原的抗体及其片段可使用标准技术制备,例如,使用培养中的连续细胞系进行单克隆抗体生产。代表性的技术包括最先由Koehler和Milstein描述的杂交瘤技术(Nature 256:495-497(1975))、人B细胞杂交瘤技术(Kosboret al.,Immunol Today 4:72(1983);Cote et al.,Proc Natl.Acad.Sci80:2026-2030(1983))、以及EBV杂交瘤技术(Cole et al.,Monoclonal Antibodies and CancerTherapy,Alan R.Liss Inc,New York N.Y.,pp 77-96(1985))。也可使用研发用于生产“嵌合抗体”的技术,即,将小鼠抗体基因剪接至人抗体基因以获得具有适宜的抗原特异性和生物活性的分子的技术(Morrison et al.,Proc Natl.Acad.Sci 81:6851-6855(1984);Neuberger et al.,Nature 312:604-608(1984);Takeda et al.,Nature314:452-454(1985))。如该领域中已知的,人源化抗体或抗体片段具有一个或多个氨基酸残基,该氨基酸典型来自非人来源的抗体的可变结构域。人源化抗体或抗体片段可含有来自非人免疫球蛋白分子的一个或多个CDR,以及完全源自或大部分源自人类生殖系的框架区。进行抗体或抗体片段人源化的技术是周知的,且包括CDR接枝、镶贴或表面置换、以及链替换。也见,Jones et al.,Nature 321:522-525(1986);Riechmann et al.,Nature,332:323-327(1988);Verhoeyen et al.,Science,239:1534-1536(1988))。
在一些具体实施例中,BAT-CAR-T的标签结合结构域是单链可变片段(scFv)。scFv包括抗体的重链可变区(VH)和轻链可变区(VL)。可使用链接基将VH的N端与VL的C端相连,反之亦然。scFv可根据该领域中已知的方法制备(见,例如,Bird et al.,(1988)Science242:423-426(1988)和Huston et al.,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883(1988))。scFv可通过将VH区和VL区链接在一起而产生,典型使用具有1至50个,例如10至25个或5至10个氨基酸残基的柔性多肽链接基链接。在一些具体实施例中,链接基序列包括氨基酸甘氨酸和丝氨酸,而在一些情况下,包括多组甘氨酸和丝氨酸重复序列,诸如(Gly4Ser)n,其中n是大于或等于1的整数。链接基的长度和氨基酸组成可变,例如,以实现最优折叠和VH与VL见的最优相互作用,从而创建功能性表位。见,例如,Hollinger etal.1993Proc Natl Acad.Sci.U.S.A.90:6444-6448(1993)。
可用于本发明的具有对于未掩蔽的前抗原的特异性的其它类型的抗体片段包括Fv片段、Fab片段和(Fab')2片段。见,例如,美国专利4,946,788。
第二个结构域是跨膜(TM)结构域,其允许将BAT-CAR锚定在T细胞的细胞膜内。可将BAT-CAR设计为包括附接至CAR的细胞外结构域的跨膜结构域。跨膜结构域可衍生自相同的蛋白,或衍生自作为CAR的其它结构域(例如,信号传导结构域、共刺激结构域和铰链结构域)来源的不同蛋白。跨膜结构域可源自天然来源或源自重组来源。若来源是天然的,则该结构域可源自任何膜结合蛋白或跨膜蛋白。可用于本发明中的跨膜结构域的代表性实例包括T细胞受体、CD28、CD27、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154的α、β或ζ链的跨膜区。
在一些具体实施例中,跨膜结构域被经由铰链诸如来自人蛋白的交联附接至CAR的胞外区,例如,CAR的抗原结合结构域。铰链结构域的来源包括人Ig(免疫球蛋白)铰链(例如,IgG4铰链、IgD铰链)和CD8(例如,CD8α铰链)。
BAT-CAR的第三个结构域是T细胞活化结构域,也称为细胞内信号传导结构域,其在CAR结合至键结到靶点细胞的标签化蛋白时辅助T细胞活化。细胞内信号传导结构域与通常响应已经将CAR引入其中的效应子细胞的至少一种正常效应子功能的活化。术语“效应子功能”是指细胞的特异化功能,在T细胞的情况下,效应子功能包括诱导细胞因子和趋化因子的产生以及对细胞的溶胞活性的活化。用于本发明的CAR中的细胞内信号传导结构域的实例包括T细胞受体(TCR)和共同受体的胞质序列,其协同作用以在抗原受体参与后启动信号转导。通过TCR单独生成的信号不足以完全活化T细胞;因此,也需要二级信号或共刺激信号。因此,T细胞活化由两类截然不同的胞质信号传导序列介导,即那些通过TCR启动抗原依赖性一级活化的序列(即,一级细胞内信号传导结构域)和那些以抗原依赖模式作动以提供二级信号或共刺激信号的序列(即,二级胞质结构域或共刺激结构域)。一级信号传导结构域以刺激途径或抑制途径调节TCR复合体的活化。以刺激模式作动的一级细胞内信号传导结构域可含有被称为基于免疫受体酪氨酸的活化基序(ITAM)的信号传导基序。适用于本发明的含有ITAM的一级细胞内信号传导结构域的代表性实例包括CD3ζ、共有FcRγ(FCER1G)、Fc-γRIIa、FcR-β(Fc-εR1b)、CD3γ、CD3δ和CD3ε的那些。在一些具体实施例中,BAT-CAR包括含有CD3ζ的一级信号传导结构域的细胞内信号传导结构域。
BAT-CAR的细胞内信号传导结构域也可包括至少一个其它细胞内信号传导结构域或共刺激结构域。共刺激分子是除了淋巴细胞对抗原产生有效响应所需的抗原受体或其配体以外的细胞表面分子。可用于本发明的BAT-CAR中的共刺激结构域的代表性实例包括CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、HVEM(LIGHTR)、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C和B7-H3。举例而言,已经证明,CD27提升了人CART细胞在体外的扩张、效应子功能和存活率,并增大了T细胞在体内的持久性和抗肿瘤活性(Song et al.Blood 119(3):696-706(2012))。
可将细胞内信号传导结构域设计为包括一个或多个,例如1、2、3、4、5或更多个共刺激信号传导结构域,它们可以具体的或随机的次序任选地经由链接分子链接至彼此。长度为约1至10个氨基酸的多肽链接基可链结连续的细胞内信号传导序列。此类链接基的实例包括双氨基酸诸如Gly-Ser,以及单个氨基酸例如Ala和Gly。可构建T细胞活化结构域的组合可以是基于CD28、CD137(4-1BB)、OX40和HVEM的胞质区,其用来提升T细胞存活率和增殖;以及CD3、CD3ζ和FcRε,其诱导T细胞活化。举例而言,含有3个ITAM的CD3ζ是最常用的CAR细胞内结构域成分,它在结合抗原之后将活化信号传输至T细胞。但是,为了提供额外的汞刺激信号传导,可将CD28和CD137(4-1BB)结构域与CD3ζ合用,令BAT-CAR T细胞能传输增殖/存活信号。
编码抗-FL CAR-CD28-4-1BB-CD3ζ的多核苷酸的代表性实例具有表示为SEQ IDNO:1的序列:
ATGGCTCTGCCTGTGACAGCTCTGCTGCTGCCTCTGGCTCTGCTTCTGCATGCCGCCAGACCTGACGTGGTCATGACACAGACACCTCTGAGCCTGCCTGTGTCTCTGGGAGATCAGGCCAGCATCAGCTGCAGATCTAGCCAGAGCCTGGTGCACAGCAACGGCAACACCTACCTGCGGTGGTATCTGCAGAAGCCCGGCCAGTCTCCTAAGGTGCTGATCTACAAGGTGTCCAACAGAGTGTCCGGCGTGCCCGATAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGAAGATCAATAGAGTGGAAGCCGAGGACCTGGGCGTGTACTTCTGTAGCCAGTCTACCCACGTGCCATGGACCTTTGGCGGCGGAACAAAGCTGGAAATCAAGAGCAGCGCCGACGACGCCAAGAAGGACGCCGCTAAGAAGGATGACGCCAAAAAAGACGATGCCAAAAAGGATGGCGGCGTGAAGCTGGACGAAACAGGCGGAGGACTTGTTCAGCCTGGCGGAGCCATGAAGCTGAGCTGTGTGACCAGCGGCTTCACCTTCGGCCACTACTGGATGAACTGGGTCCGACAGAGCCCTGAGAAAGGCCTGGAATGGGTCGCCCAGTTCAGAAACAAGCCCTACAACTACGAAACCTACTACAGCGACAGCGTGAAGGGCAGATTCACCATCAGCCGGGACGACAGCAAGTCCAGCGTGTACCTGCAGATGAACAACCTGCGCGTGGAAGATACCGGCATCTACTACTGTACCGGCGCCAGCTACGGCATGGAATATCTCGGCCAGGGCACCAGCGTGACCGTGTCTACAACAACCCCTGCTCCTCGGCCTCCTACACCAGCTCCTACAATTGCCAGCCAGCCACTGTCTCTGAGGCCCGAAGCTTGTAGACCTGCTGCAGGCGGAGCCGTGCATACAAGAGGACTGGATTTCGCCTGCGACTTCTGGGTGCTCGTGGTTGTTGGCGGAGTGCTGGCTTGTTACTCCCTGCTGGTTACCGTGGCCTTCATCATCTTTTGGGTCCGAAGCAAGCGGAGCCGGCTGCTGCACAGCGACTACATGAACATGACCCCTAGACGGCCCGGACCTACCAGAAAGCACTACCAGCCTTACGCTCCTCCTAGAGACTTCGCCGCCTACAGATCCAAGCGGGGCAGAAAGAAGCTGCTGTACATCTTCAAGCAGCCCTTCATGCGGCCCGTGCAGACCACACAAGAGGAAGATGGCTGCTCCTGCAGATTCCCCGAGGAAGAAGAAGGCGGCTGCGAGCTGAGAGTGAAGTTCAGCAGATCCGCCGACGCTCCTGCCTATCAGCAGGGACAGAACCAGCTGTACAACGAGCTGAACCTGGGGAGAAGAGAAGAGTACGACGTGCTGGACAAGCGGAGAGGCAGAGATCCTGAGATGGGCGGAAAGCCCCAGCGGAGAAAGAATCCTCAAGAGGGCCTGTATAATGAGCTGCAGAAAGACAAGATGGCCGAGGCCTACAGCGAGATCGGAATGAAGGGCGAGCGCAGAAGAGGCAAGGGACACGATGGACTGTACCAGGGCCTGAGCACCGCCACCAAGGATACCTATGATGCCCTGCACATGCAGGCCCTGCCACCTAGATGATGA(SEQ ID NO:1)
可根据已知技术将T细胞工程化以表达BAT-CAR。通常,构建编码BAT-CAR的多核苷酸载体,并将该载体转染至T细胞群落内。随后令细胞在促进该编码BAT-CAR的多核苷酸被T细胞表达的条件下生长。可经由标准技术实施T细胞对BAT-CAR的成功转染(或转导,转导是指病毒介导的基因整合)和展示。
在一些具体实施例中,可通过首先构建编码所选择的BAT-CAR的逆转录病毒载体而将T细胞工程化以产生BAT-CAR。可使用已知技术实施逆转录病毒转导(例如,Johnson,etal.Blood 114:535-546(2009))。可通过例如流式细胞计测定BAT-CAR在被转导的T细胞上的表面表达。
可使用已知技术配制BAT-CAR T细胞群落用于给药至受试者。包括表达BAT-CAR的T细胞群落的制剂可包括一种或多种药学可接受的赋形剂。制剂中包括的赋形剂可具有不同的目的,取决于例如标签结合结构域的特性、所使用的T细胞亚群、和给药模式。赋形剂的代表性实例包括盐水、缓冲盐水、葡萄糖、输液用水、甘油、乙醇、及其组合;稳定剂、增溶剂和表面活性剂;缓冲剂和防腐剂;张度剂、膨松剂和润滑剂。包括BAT-CAR T细胞群落的制剂典型在任何非人成分诸如动物血清(例如,牛血清白蛋白)的不存在下制备和培养。
制剂可包括一种BAT-CAR T细胞的群落,或超过一种诸如两种、三种、四种、五种、六种或更多种表达BAT-CAR的T细胞的群落。BAT-CAR T细胞的不同群落可以在活化结构域、T细胞亚群的同一性等方面有所差别。
本发明的系统和试剂盒
本文所述的任何组合物可包含在试剂盒或系统内。在非限制性实例中,一种或多种用于细胞疗法的细胞和/或用来生成一种或多种用于细胞疗法的细胞的携带重组表达载体的试剂可包含在试剂盒或系统中。在一些具体实施例中,试剂盒包括本文公开的一种或多种双官能化合物。在其它具体实施例中,试剂盒包括一种或多种本文公开的双官能化合物和一种或多种用于生产自体CAR-T细胞的试剂(例如,基因构造体、递送载体)。在其它具体实施例中,试剂盒包括本文公开的一种或多种双官能化合物和同种异体的CAR-T细胞。试剂盒组分提供在适合的容器机构中。
试剂盒的一些组分可封装在水性介质中或作为冻干形式封装。试剂盒的容器机构通常将包括至少一个小瓶、试管、烧瓶、瓶、注射器或其它容器机构,其内放置有组分且优选适当等量化的组分。若试剂盒中存在不止一种组分,则试剂盒通常也将含有第二、第三或其它额外的容器,其内可单独放置有额外的组分。但是,组分的各种组合也可包含在一个小瓶内。本发明的试剂盒典型也将包括将组分包含在紧密限制物内用于商售的机构。此类容器可包括注塑或吹塑的塑料容器,其内部保留所希望的小瓶。
当试剂盒的组分提供为一种和/或多种溶液时,溶液是水容器,且尤其可用的是无菌水溶液。在一些情况下,容器机构可本身为注射器、吸移管和/或其它此类设备,制剂可从该容器机构施加到身体的感染区域、注射到动物体内、和/或甚至施加到试剂盒的其它组分和/或与试剂盒的其它组分混合。
但是,试剂盒的组分可提供为干粉。当试剂和/或组分被提供为干粉时,该粉末可通过加入适合的溶剂而得以重建。设想该溶剂亦可提供在另一容器机构中。试剂盒也可包含第二容器机构,用于包含无菌的、药学可接受的缓冲剂和/或其它稀释剂。
在本发明的具体具体实施例中,待用于细胞疗法的细胞被提供在试剂盒内,且在一些情况下,该细胞基本上是试剂盒的唯一组分。试剂盒可包含用来制作所希望的细胞的试剂和材料。在特定的具体实施例中,该试剂和材料包括用于扩增所希望序列的引物、核苷酸、适合的缓冲剂或缓冲试剂、盐等,且在一些情况下,该试剂可包括载体和/或编码如本文所述的CAR的DNA和/或用于它们的调节元件。
在具体的具体实施例中,试剂盒内存在一个或多个适用于从个体提取一个或多个样品的设备。该设备可以是注射器、解剖刀等。
在本发明的一些情况下,除了细胞疗法的具体实施例之外,试剂盒也包括,举例而言,第二癌症疗法诸如化疗、激素疗法和/或免疫疗法。可调整试剂盒以令其适用于个体的特定癌症,且该试剂盒包含用于该个体的对应第二癌症疗法。
方法
本发明的方法包括治疗罹患癌症或经诊断为患有癌症的受试者。如本文中所用,术语“治疗”(treat、treating和treatment)具有其常规和自定义的意义,且包括阻断和缓解受试者癌症的症状或降低其严重性和/或发作频率。在一些具体实施例中,接受治疗的受试者是人。在其它具体实施例中,受试者是非人动物,例如非人灵长动物、鸟类、马、牛、山羊、绵羊、陪伴动物诸如狗、猫或啮齿动物、或其它哺乳动物。
可能对使用本发明的治疗方式进行治疗适应良好的癌症以实体瘤的存在为特征。宽泛地说,它们包括成年体和幼年体的腺瘤、癌、肉瘤、淋巴瘤。癌症可以是血管化的肿瘤、或尚未实质上血管化的肿瘤、或非血管化的肿瘤。
可根据本发明治疗的以实体瘤为特征的癌症的代表性实例包括乳腺肿瘤(包括HER2+和转移的)、结直肠肿瘤、结肠肿瘤、食道肿瘤、胆管肿瘤、肺肿瘤(包括小细胞和非小细胞肺肿瘤、肺腺癌和肺鳞状细胞癌)、肝肿瘤、表皮样瘤、鳞状细胞肿瘤诸如头颈肿瘤、上皮鳞状细胞癌、甲状腺肿瘤、宫颈肿瘤、卵巢肿瘤、消化系统的神经内分泌肿瘤、神经内分泌肿瘤、嗜铬细胞瘤、腹膜癌、肝母细胞瘤、HPCR、脑癌(例如,弥漫性真性脑桥神经胶质瘤、毛细血管成血管细胞瘤、脑膜瘤和脑转移瘤、神经胶质瘤、成胶质细胞瘤(多形性成胶质细胞瘤)和成神经细胞瘤、以及成神经管细胞瘤、室管膜细胞瘤)、膀胱癌、肝癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或直肠癌、骨癌、软组织肉瘤(包括胚胎性和肺泡性横纹肌肉瘤、GIST、直肠肉瘤、胰腺肉瘤、前列腺肉瘤、胃肠(胃和胃部)肉瘤、腺泡状软组织肉瘤和透明细胞肉瘤)、胆管性肝癌、胆道癌、胆囊癌、骨髓瘤、外阴癌、阴茎癌、视网膜肿瘤、雄激素依赖性肿瘤、非雄激素依赖性肿瘤、卡波西肉瘤、滑膜肉瘤、血管活性肠肽分泌肿瘤、CNS赘生物、黑色素瘤、横纹肌肉瘤,包括,EMB、RMS、ALV、肾母细胞癌(Wilm's cancer)、伊文思癌(Ewing'scancer)、骨肉瘤、PNT、杆状横纹肌肉瘤、视网膜神经胶质瘤、肾上腺皮质癌、肾上腺癌、以及平滑肌肉瘤。
光可抵达的肿瘤的代表性实例包括位在乳腺、卵巢、皮肤、子宫、膀胱、前列腺、胆管、胰腺、胃、脑、口、喉、阴道、阴门和鼻腔通道的组织中发现的那些。可经由间质疗法将光递送至一些肿瘤,其牵涉使用成像测试(诸如CT扫描)而用针或其它微创手段将光纤直接引导至肿瘤内。经由间质疗法递送的光可用来治疗在乳腺、卵巢、头颈、前列腺、肝和肺中发现的肿瘤。对于处于患者身体内更大深度的肿瘤,可在外科手术过程中或手术后将光递送至任何可能在肿瘤切除后剩余的癌组织。
待治疗的癌症包括原发性肿瘤和继发性肿瘤或转移性肿瘤,例如,从肺、乳腺或前列腺转移的肿瘤,以及复发性肿瘤或难治性肿瘤。复发性肿瘤涵盖表现为被使用此类剂的治疗所抑制,但在治疗中断五年后、或甚至十年后或更久后复发的肿瘤。难治性肿瘤是对于使用一种或多种用于特定肿瘤类型的传统的、改进的或实验性疗法没有反应或具有抗性的肿瘤。
本发明的治疗方法可以是“一线的”,即,对尚未进行任何抗癌治疗的患者进行的最初治疗,该最初治疗或单独进行或与其它治疗合用。本发明的治疗方法也可以是“二线的”,在此意义上,它们被应用至已经进行至少一种在先抗癌治疗策略例如化疗、放射免疫疗法、毒素疗法、前药活化酶疗法、抗体疗法、外科手术疗法、免疫疗法、放射疗法、靶向疗法或它们的任意组合的患者,本发明的治疗方法或单独进行或与其它治疗合用。在一些情况下,在先疗法可能已经是不成功的,或是部分成功的但患者变得对特定治疗不耐受。本发明的方法也可用作辅助治疗,例如,以抑制不具备当前可检测疾病的患者体内癌症的复发或在外科手术移除肿瘤后癌症的复发。
制剂含有BAT-CAR T细胞,该细胞的数目对于治疗具体癌症是有效的。因此,治疗有效的BAT-CAR T细胞群落被给药至受试者。给药至受试者的BAT-CAR T细胞数目将在宽范围内可变,取决于癌症的位置、来源、特点、程度和严重性以及待治疗个体的年龄和身体情况等。医师将最终决定待使用的适宜剂量。通常,给药含有约1x 104至约1x1010个BAT-CAR T细胞的制剂。在一些具体实施例中,制剂含有约1x105至约1x 109个BAT-CAR T细胞、约5x105至约5x 108个BAT-CAR T细胞、或约1x 106至约1x 107个BAT-CAR T细胞。
可根据可接受的医疗实践将BAT-CAR T细胞的制剂给药至有此需要的受试者。例示性给药模式是静脉注射。其它模式包括肿瘤内注射、皮内注射、皮下(s.c.、s.q.、sub-Q、Hypo)注射、肌肉(i.m.)注射、腹膜(i.p.)注射、动脉注射、髓内注射、心内注射、关节内(接合处)注射、滑膜内(关节液区域)注射、颅内注射、脊柱内注射和囊内(脊髓液)注射。可使用任何可用于该制剂的肠道外注射或输液的已知装置来实现此类给药模式。
将“化合物”和BAT-CAR T细胞共同给药至受试者,用于本发明的目的,包括在同一治疗方案过程中给药。可在给药BAT-CAR T细胞之前、过程中或之后给药该化合物,使得该化合物将结合靶点细胞且一旦去掩蔽,BAT-CAR细胞将结合未掩蔽的前抗原或标签。
可以有效治疗特定癌症的量将含有该化合物的制剂给药至受试者。可使用该领域技术人员已知的技术将该化合物配制为用于给药至受试者。该化合物的制剂可包括药学可接受的赋形剂,该赋形剂可基于诸如靶向部分的特性、前抗原和给药模式等因素而选择。通常使用的赋形剂的代表性实例包括盐水、缓冲盐水、葡萄糖、输液用水、甘油、乙醇、及其组合;稳定剂、增溶剂和表面活性剂;缓冲剂和防腐剂;张度剂、膨松剂和润滑剂。
通常,给药至受试者的制剂中该化合物的量将在宽范围内可变,取决于癌症的位置、来源、特点、程度和严重性以及待治疗个体的年龄和身体情况等。医师将最终决定待使用的适宜剂量。典型地,考虑给药途径、症状等,制剂可含有约0.1mg/kg至约100mg/kg体重的该化合物,且在一些具体实施例中含有约1mg/kg至约10mg/kg体重的该化合物。通常,给药至受试者以治疗疾病或病变诸如癌症的本申请化合物的剂量为0.01至500mg/kg受试者体重的范围内,例如,0.1至100mg/kg受试者体重的范围内。举例而言,基于患者的体重,给药至受试者的化合物剂量可以是0.1mg/kg至50mg/kg或1mg/kg至50mg/kg,更优选在0.1mg/kg至25mg/kg、或1mg/kg至25mg/kg的范围内。又如,基于受试者的体重,给药至受试者以预防、治疗和/或管理患者癌症的本发明化合物的剂量为500mg/kg或更低,优选250mg/kg或更低、100mg/kg或更低、95mg/kg或更低、90mg/kg或更低、85mg/kg或更低、80mg/kg或更低、75mg/kg或更低、70mg/kg或更低、65mg/kg或更低、60mg/kg或更低、55mg/kg或更低、50mg/kg或更低、45mg/kg或更低、40mg/kg或更低、35mg/kg或更低、30mg/kg或更低、25mg/kg或更低、20mg/kg或更低、15mg/kg或更低、10mg/kg或更低、5mg/kg或更低、2.5mg/kg或更低、2mg/kg或更低、1.5mg/kg或更低、或1mg/kg或更低。
可根据可接受的医疗实践将该化合物给药至有此需要的受试者。例示性给药模式是静脉注射。其它模式包括肿瘤内注射、皮内注射、皮下(s.c.、s.q.、sub-Q、Hypo)注射、肌肉(i.m.)注射、腹膜(i.p.)注射、动脉注射、髓内注射、心内注射、关节内(接合处)注射、滑膜内(关节液区域)注射、颅内注射、脊柱内注射和囊内(脊髓液)注射。可使用任何可用于该制剂的肠道外注射或输液的已知装置来实现该化合物的给药。
通过局部施加适宜波长的光以完成保护基从标签或识别结构域的裂解或移除,从而实现对前抗原的活化。保护基的特性将决定待施加的光的适宜波长。当暴露于UV辐射或MALDI(基质辅助激光解吸电离(Matrix-Assisted Laser Desorption/Ionization))条件下时,本发明的光敏保护基被裂解。通常,被施加到受试者以通过将保护基从前抗原裂解而产生标签或识别结构域,从而激活CAR-T细胞的光的波长为10至600nm的范围内,例如,在250至550nm的范围内。举例而言,施加到受试者的光的波长可为250至300nm、300至350nm、350至400nm、400至450nm、450至500nm或500至550nm的范围内。又如,施加到受试者以裂解光敏保护基的光的波长为550nm或更短,优选525nm或更短、500nm或更短、475nm或更短、450nm或更短、425nm或更短、400nm或更短、375nm或更短、350nm或更短、325nm或更短、300nm或更短、275nm或更短、250nm或更短、225nm或更短、或200nm或更短。
含有BAT-CAR-T细胞群落的制剂和该化合物制剂的给药频率、以及暴露于适宜薄产的光的频率和持续时间将依据多种因素而变,该因素可包括待治疗的疾病、BAT-CAR-T细胞和该化合物的结构、以及给药模式。各自可每天、每两天、每三天、每四天、每五天、每六天、每周、每八天、每九天、每十天、每两周、每个月、每两个月给药4次、3次、2次或一次。治疗的持续时间也可变,基于例如被治疗的疾病而定,且由主治医师最佳地决定。但是,预期治疗持续进行多天、多周或甚至多月。
本发明的方法可能需要将化合物、BAT-CAR-T细胞和适宜波长的光独立地或共同地以单剂、一次性剂量、或多剂(例如,2、3、4、5、6、7、8、10、15、20或更多剂)给药至受试者。因此,BAT-CAR-T细胞可以单剂给药,而化合物与适宜波长的光的给药频率可从每天一次至单剂的范围。另一实例中,化合物、BAT-CAR-T细胞和适宜波长的光可从单剂至约每周一次到约每六周一次的频率共同给药。在一些具体实施例中,给药可以是单次给药和共同给药的组合(例如,化合物、BAT-CAR-T细胞和适宜波长的光可在第一次给药时共同给药,随后每三周一次到约每四至六周一次给药该化合物和适宜波长的光)。
组合疗法
在本发明的某些具体实施例中,本发明的用于临床方面的方法与其它在过度增殖疾病的治疗中有效的剂如抗癌剂合用。“抗癌”剂能通过例如杀死癌细胞、诱导癌细胞的凋亡、降低癌细胞的生长速率、降低转移的发生率或数目、减小肿瘤尺寸、抑制肿瘤生长、减少对肿瘤或癌细胞的血液供给、促进对癌细胞或肿瘤的免疫反应、防止或抑制癌症的进展、或延长患癌受试者的寿命而对受试者体内的癌症造成负面影响。更通常地说,这些其它组合物将会以对杀死细胞或抑制细胞增殖有效的组合量而提供。这一过程可牵涉令癌细胞同时与表达构造和一种或多种剂或多种因素接触。这可以通过将该细胞与包括两种剂的单一组合物或药物制剂接触实现,或通过将该细胞同时与两种截然不同的组合物或制剂接触而实现,其中一种组合物包括该表达构造,而另一种组合物包括第二剂。
肿瘤细胞对化疗和放疗的抗性代表了临床肿瘤学的主要问题。目前,癌症研究的一个目标是寻找通过将化疗和放疗与其它疗法组合而改善化疗和放疗功效的途径。在本发明的情况下,预计将会类似地将细胞疗法与化疗、放疗或免疫疗法干预以及前凋亡或细胞周期调节剂联合使用。
或者,本发明的疗法可在其它剂治疗之前或之后并与其它剂治疗间隔数分钟至数周进行。在其它剂和本发明单独施加至个体的具体实施例中,通常将会确保在每次递送之间不存在显著的时间段,使得该剂和本发明疗法仍能发挥对该细胞的有利组合效果。在此类例子中,预计可令该细胞与两种方式接触,两种方式彼此相距12至24小时内,更优选彼此相距6至12小时内。在一些情形中,可能有利的是显著延长治疗的时间点,但在两次给药之间相距数天(2、3、4、5、6或7天)或数周(1、2、3、4、5、6、7或8周)。
预期将会按需要重复治疗循环。还预计将各种标准疗法以及外科手术干预与本发明的细胞疗法合用。
化疗
癌症疗法也包括各种具有基于化学的治疗与基于放射的治疗两者的组合疗法。组合化疗包,举例而言,白蛋白结合型紫杉醇(abraxane)、六甲蜜胺、多西他赛(docetaxel)、赫赛汀(herceptin)、甲氨蝶呤(methotrexate)、米托蒽醌(novantrone)、诺雷德(zoladex),顺铂(CDDP)、卡铂、甲基苄肼(procarbazine)、氮芥(mechlorethamine)、环磷酰胺、喜树碱、异环磷酰胺(ifosfamide)、米尔法兰(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、亚硝基脲、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、阿霉素(doxorubicin)、博来霉素、光神霉素(plicomycin)、丝裂霉素、依托泊苷(etoposide)(VP16)、它莫西芬(tamoxifen)、雷洛昔芬(raloxifene)、雌激素受体结合剂、紫杉醇(taxol)、吉西他滨(gemcitabien)、长春瑞滨(navelbine)、法尼基蛋白转移酶抑制剂、反铂(transplatinum)、5-氟尿嘧啶、长春新碱、长春碱和甲氨蝶呤、或前述者的任何类似物或衍生物变种以及它们的组合。
在具体具体实施例中,例如在给药本发明之前、过程中和/或之后,将用于个体的化疗与本发明联合使用。
放疗
其它造成DNA损伤并已经广泛使用的因素包括通常称为γ射线、X射线、和/或直接将放射性同位素引导至肿瘤细胞的因素。也预期其它形式的DNA损伤因素诸如微波和紫外辐射。这些因素很有可能全部对DNA、DNA前体、DNA的复制和修复、以及染色体的组装和维护造成广泛损伤。X射线的剂量范围是从50至200伦琴的日剂量进行长时间照射(3至4周),到2000至6000伦琴的一次性剂量。放射性同位素的剂量范围变动大,且取决于同位素的半衰期、所发射的辐射强度和类型、以及赘生性细胞的吸收。
本文中,当术语“接触”或“暴露”用于细胞时,该术语描述治疗性构造和化疗剂或放疗剂借以递送至靶点细胞或借以直接与靶点细胞毗邻的方法。为了实现细胞杀灭或生长抑制,将两种剂以有效杀灭细胞或阻止其分裂的组合量递送至该细胞。
免疫疗法
免疫疗法通常依赖于使用免疫效应子细胞和分子而以癌细胞为达到并摧毁癌细胞。免疫效应子可以是,举例而言,对于肿瘤细胞表面上的一些标记物为特异性的抗体。该抗体可独自用作疗法的效应子,或它可召集其它细胞以事实上完成细胞杀灭。该抗体也可接合之药物或毒素(化疗、放射性核素、蓖麻毒素A链、霍乱毒素、百日咳毒素等),且仅充当靶向剂。或者,效应子可以是携带或直接或键结与肿瘤细胞靶点相互作用的表面分子的淋巴细胞。各种效应子细胞包括细胞毒T细胞和NK细胞。
除了本文所述创新疗法之外的免疫疗法将会因此被作为组合疗法的一部分而与本发明的细胞疗法联合使用。用于组合疗法的通常路径探讨如下。通常,肿瘤细胞必须带有一些标记物,该标记物承担靶向作用,即,在大多数其它细胞上不存在。存在众多肿瘤标记物,且这些中的任一种均可能适用于在本发明的情况下作为靶点。常见的中秋标记物包括PD-1、PD-L1、CTLA4、癌胚抗原、前列腺特异性抗原、泌尿系统肿瘤相关抗原、胚胎抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸化路易斯抗原(Sialyl Lewis Antigen)、MucA、MucB、PLAP、雌激素受体、层粘连蛋白受体、erb B和p155。
基因
在又一具体实施例中,二级治疗是基因疗法,在该疗法中,将治疗性多核苷酸在本发明临床具体实施例之前、之后或同时给药。多种表达产物涵盖在本发明内,包括细胞增殖诱导剂、细胞增殖抑制剂、或程序性细胞死亡调节剂。
外科手术
大约60%的癌症患者将会进行某些类型的外科手术,包括预防性的、诊断性的或分阶段的、治愈性的和姑息性的外科手术。治愈性外科手术是可与其它疗法诸如本发明的治疗、化疗、放疗、激素疗法、基因疗法、免疫疗法和/或替代疗法联合使用的癌症治疗。
治愈性外科手术包括切除术,在该手术中,全部或部分的癌组织被物理性移除、切离和/或摧毁。肿瘤切除术是指肿瘤的至少一部分的物理性移除。除了肿瘤切除术之外,通过外科手术治疗还包括激光手术、冷冻手术、电外科手术、和显微镜控制下的外科手术(莫氏手术)。进一步预期,本发明可与浅表性癌、癌前期或附带量的正常组织的移除联合使用。
当切离部分或全部癌细胞、组织或肿瘤时,可能在体内形成空洞。可通过向该区域输注、直接注射或局部应用额外的抗癌疗法而实施治疗。此类治疗可例如每1、2、3、4、5、6或7天或每1、2、3、4和5周或每1、2、3、4、5、6、7、8、9、10、11或12个月重复一次。这些治疗也可改变剂量。
其它剂
预期其它剂可与本发明合用以改善治疗的疗效。这些额外的剂包括免疫调节剂、影响细胞表面受体和CAP连接上调的剂、细胞生长抑制剂和分化剂、细胞粘附抑制剂、或增加过度增殖细胞对于凋亡诱导剂的敏感性的剂。免疫调节剂包括肿瘤坏死因子;干扰素α、干扰素β和干扰素γ;IL-2及其它细胞因子;F42K和其它细胞因子类似物;或MIP-1、MIP-1β、MCP-1、RANTES和其它趋化因子。进一步预期细胞表面受体或其配体诸如Fas/Fas配体、DR4或DR5/TRAIL的上调将会通过建立对于过度增殖细胞的自分泌或旁分泌效应而加强本发明的细胞凋亡诱导能力。通过提升CAP连接的数目而增加细胞间信号传导,将会增加对于相邻过度增殖细胞群落的抗过度增殖效应。在其它具体实施例中,可将细胞生长抑制剂或分化剂可与本发明合用以改善治疗的抗过度增殖功效。细胞粘附的抑制剂被预期改善本发明的功效。细胞粘附抑制剂的实例是黏着斑激酶(FAK)抑制剂和洛伐他汀(Lovastatin)。进一步预期,增加过度增殖细胞对于细胞凋亡的敏感性的其它剂诸如抗体c225将会与本发明合用以改善治疗功效。
当将下述工作实施例一并考虑时,将明了本发明的这些和其它方面,该实施例旨在例示性说明本发明的某些特定具体实施例而非试图限制由权利要求书界定的本发明范畴。
[实施例]
实施例1:抗荧光素CAR T及其组分的构建
构造#1,编码包含“抗荧光素CAR T”的多肽
抗-荧光素-4M5.3抗体(抗原结合结构域)
DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRVSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIKSSADDAKKDAAKKDDAKKDDAKKDGGVKLDETGGGLVQPGGAMKLSCVTSGFTFGHYWMNWVRQSPEKGLEWVAQFRNKPYNYETYYSDSVKGRFTISRDDSKSSVYLQMNNLRVEDTGIYYCTGASYGMEYLGQGTSVTVS(SEQ ID NO:2)
信号肽-CD8a-sp|P01732|1-21
MALPVTALLLPLALLLHAARP(SEQ ID NO:3)
铰链区-CD8a-sp|P01732|138-182
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:4)
跨膜区(TM)-CD28-sp|P10747|153-179
FWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO:5)
细胞内结构域(ICD)-CD28-sp|P10747|180-220
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:6)
细胞内结构域(ICD)-41BB-sp|Q07011|214-255
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:7)
细胞内结构域(ICD)-CD3z-sp|P20963|52-164
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:8)
抗-荧光素CAR T-全肽
MALPVTALLLPLALLLHAARPDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRVSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIKSSADDAKKDAAKKDDAKKDDAKKDGGVKLDETGGGLVQPGGAMKLSCVTSGFTFGHYWMNWVRQSPEKGLEWVAQFRNKPYNYETYYSDSVKGRFTISRDDSKSSVYLQMNNLRVEDTGIYYCTGASYGMEYLGQGTSVTVSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR**(SEQ ID NO:9)
实施例2:抗-蒽醌-2-甲酸酯CAR T及其组分的构建
构造#2,编码包含“抗-蒽醌-2-甲酸酯CAR T”的多肽
抗-蒽醌-2-甲酸酯–MC48.B11抗体(抗原结合结构域)
QVRLQGSGPSLVKPSQTLSLTCTVSGFSLTSNAVDWVRQAPGKVPEWLGFIRGGGSTFYNSALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARASCSGDIYTDTCGIDYWGPGLLVTVSSEGKSSGSGSESKVDQSALTQPSSVSRSLGQSVSITCSGSSSNVGAGNYVNWFRLIPGSAPKSLIYAATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCSSYDITAVNLFGSGTRLTVLG(SEQ ID NO:10)
信号肽-CD8a-sp|P01732|1-21
MALPVTALLLPLALLLHAARP(SEQ ID NO:3)
铰链区-CD8a-sp|P01732|138-182
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:4)
跨膜区(TM)-CD28-sp|P10747|153-179
FWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO:5)
细胞内结构域(ICD)-CD28-sp|P10747|180-220
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:6)
细胞内结构域(ICD)-41BB-sp|Q07011|214-255
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:7)
细胞内结构域(ICD)-CD3z-sp|P20963|52-164
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:8)
抗-蒽醌-2-甲酸酯CAR T-全肽
MALPVTALLLPLALLLHAARPQVRLQGSGPSLVKPSQTLSLTCTVSGFSLTSNAVDWVRQAPGKVPEWLGFIRGGGSTFYNSALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARASCSGDIYTDTCGIDYWGPGLLVTVSSEGKSSGSGSESKVDQSALTQPSSVSRSLGQSVSITCSGSSSNVGAGNYVNWFRLIPGSAPKSLIYAATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCSSYDITAVNLFGSGTRLTVLGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR**(SEQ ID NO:11)
所有专利和非专利出版物均以本发明所属领域技术人员的水平表示。所有这些出版物通过引用并入本文,其并入程度与各出版物具体且独立地通过引用并入相同。
尽管本文中已经参考特定具体实施例描述了本发明,但应理解,这些具体实施例仅用于对本发明的原理和申请的例示性说明。因此应理解,可对示例性具体实施例做出各种修饰且可衍生出其它安排,而不悖离本发明的由所附权利要求书界定的精神和范畴。
尽管已经连通其详细说明书而揭示本发明,但前述说明书试图例示性说明本发明而非限制本发明的范畴,本发明的范畴应为所附权利要求书的范畴所界定。其它方面、优点和修饰处于后附权利要求书的范畴内。
Claims (42)
1.一种化合物,包含共价链接至靶向部分的前抗原,其中所述前抗原包含具有光可裂解的保护基的小分子和靶向部分,所述靶向部分特异性地结合至肿瘤相关抗原。
2.根据权利要求1所述的化合物,其中所述小分子是荧光分子。
3.根据权利要求2所述的化合物,其中所述荧光分子是荧光素、蒽、alexa fluor、若丹明、对甲氨基酚、吖啶或氧杂蒽。
4.根据权利要求1至3中任一项所述的化合物,其中所述光可裂解的保护基是邻硝基苄基、苯乙酮酯基、8-喹啉基苯磺酸酯基、双香豆素基、6-溴-7-烷氧基香豆素-4-基甲氧基羰基、双滿基或双芳基腙基。
5.根据权利要求4所述的化合物,其中所述光可裂解的保护基是邻硝基苄基。
6.根据权利要求中1至5任一项所述的化合物,由式(A)或(A’)表示:
其中X是C或O,Y是C或N,所述光可裂解的保护基存在于位置1至9中的一处或多处,以及,Q表示一个或多个任选经取代的环或光可裂解的保护基。
7.根据权利要求6所述的化合物,其中所述任选经取代的环是饱和或不饱和的4至7元碳环或杂环或稠环系,其中杂原子是N、O或S。
8.根据权利要求6或7所述的化合物,由式(I)表示:
其中R1是O、OH或所述光可裂解的保护基;
R2是O、OH或所述光可裂解的保护基;以及
R3是 或其异体异构体。
9.根据权利要求6至8中任一项所述的化合物,其中所述光可裂解的保护基是邻硝基苄基、苯乙酮酯基、8-喹啉基苯磺酸酯基、双香豆素基、6-溴-7-烷氧基香豆素-4-基甲氧基羰基、双滿基或双芳基腙基。
10.根据权利要求9所述的化合物,其中所述光可裂解的保护基是邻硝基苄基。
11.根据权利要求10所述的化合物,其中所述邻硝基苄基是
其中X是NH或O,R是C1-4烷基或H,以及,n是0至3。
12.根据权利要求10所述的化合物,其中所述邻硝基苄基是
13.根据权利要求12所述的化合物,由式(Ia)表示:
或其立体异构体。
14.根据权利要求13所述的化合物,由式(Ib)表示:
或其立体异构体。
15.根据权利要求6或7所述的化合物,由式(II)表示:
其中R4和R4’各自独立为O或光可裂解的保护基;以及
R5是 或其立体异构体。
16.根据权利要求15所述的化合物,其中所述光可裂解的保护基是邻硝基苄基、苯乙酮酯基、8-喹啉基苯磺酸酯基、双香豆素基、6-溴-7-烷氧基香豆素-4-基甲氧基羰基、双滿基或双芳基腙基。
17.根据权利要求16所述的化合物,其中所述光可裂解的保护基是邻硝基苄基。
18.根据权利要求17所述的化合物,其中所述邻硝基苄基是
其中X是NH或O,R是C1-4烷基或H,以及,n是0至3。
19.根据权利要求17所述的化合物,其中所述邻硝基苄基是
20.根据权利要求19所述的化合物,是由式(IIa)表示:
或其立体异构体。
21.根据权利要求1至20中任一项所述的化合物,其中所述靶向部分包含抗体、抗体片段、配体、适配体或纳米抗体。
22.根据权利要求1至21中任一项所述的化合物,其中所述靶向部分特异性地结合选自下列各者所组成群组的肿瘤相关抗原:血小板源生长因子受体α(PDGFRa)、1型激活素a受体(ACVR1)、人类表皮生长因子受体2(Her2)、前列腺干细胞抗原(PSCA)、甲胎蛋白(AFP)、癌胚抗原(CEA)、癌抗原-125(CA-125)、CA19-9、钙视网膜蛋白、MUC-1、表皮膜蛋白(EMA)、表皮肿瘤抗原(ETA)、酪氨酸酶、黑色素瘤相关抗原(MAGE)、CD34、CD45、CD99、CD117、嗜铬粒蛋白、细胞角蛋白、肌间线蛋白、胶质原纤维酸性蛋白(GFAP)、巨囊性病液状蛋白(GCDFP-15)、HMB-45抗原、蛋白黑色素A(由T淋巴细胞识别的黑色素瘤抗原;MART-1)、myo-D1、肌肉特异性肌动蛋白(MSA)、神经丝、神经元特异性烯醇化酶(NSE)、胎盘碱性磷酸酶、突触素、甲状腺球蛋白、甲状腺转录因子-1、丙酮酸激酶M2型同工酶的二聚体形式(肿瘤M2-PK)、异常的ras蛋白、异常的p53蛋白、间皮素、EGFRvIII、EGFR1、二神经节苷脂GD2、白介素13受体α(IL13Rα)、成纤维细胞活化蛋白(FAP)、和L1细胞粘附分子(L1CAM)。
23.根据权利要求1至21中任一项所述的化合物,其中所述靶向部分特异性地结合在光可抵达的肿瘤上表达或过度表达的肿瘤相关抗原。
24.根据权利要求23所述的化合物,其中所述光可抵达的肿瘤位于乳腺、卵巢、皮肤、宫颈、膀胱、前列腺、胆管、胰腺、胃、脑、口、喉、阴道、阴门或鼻腔通道的组织中。
25.根据权利要求1至24中任一项所述的化合物,其中所述靶向部分选自下列所组成的群组:曲妥珠单抗、西妥昔单抗、帕尼单抗、扎鲁木单抗、尼妥珠单抗、马妥珠单抗、吉非替尼、埃罗替尼、拉帕替尼、帕妥珠单抗、托西莫单抗、利妥昔单抗、替伊莫单抗、达克珠单抗、CEA-scan、colo101、OC125单克隆抗体、Ab75705、抗AFP抗体或其片段、人源化B3、B72.3、贝伐单抗、抗CD99抗体或其片段、抗HER2抗体或其片段和抗EGFR抗体或其片段。
26.一种药物组合物,其包含治疗有效量的根据权利要求1至25中任一项所述的化合物、以及药学可接受的载体。
27.一种系统,其包含:
a)根据权利要求1至25中任一项所示的化合物;以及
b)特异性地识别未掩蔽的根据权利要求1至22中任一项所述的化合物的CAR-T细胞。
28.一种试剂盒,其包含:
a)根据权利要求1至25中任一项所示的化合物。
29.根据权利要求28所述的试剂盒,进一步包含:
b)用于产生特异性地识别未掩蔽的根据权利要求1至25中任一项所述的化合物的自体CAR-T细胞的试剂。
30.根据权利要求28所述的试剂盒,进一步包含:
c)特异性地识别未掩蔽的根据权利要求1至25中任一项所述的化合物的同种异体CAR-T细胞。
31.一种治疗癌症的方法,包含向有此需要的受试者给药治疗有效量的根据权利要求1至25中任一项所述的化合物、波长适于裂解所述保护基的光、以及一个或多个嵌合抗原受体T(CAR-T)细胞,其中所述CAR-T细胞包含特异性地结合未掩蔽的前抗原的细胞外配体。
32.根据权利要求31所述的方法,其中所述化合物和光在给药所述CAR-T细胞之前给药至所述受试者。
33.根据权利要求31所述的方法,其中所述化合物和光在给药所述CAR-T细胞之后给药至所述受试者。
34.根据权利要求31所述的方法,其中所述化合物和光与所述CAR-T细胞同时给药至受试者。
35.根据权利要求31至34中任一项所述的方法,其中所述化合物以0.01mg/kg至500mg/kg体重的剂量给药。
36.根据权利要求31至35中任一项所述的方法,其中所述CAR-T细胞以每千克体重104至109个细胞的剂量给药。
37.根据权利要求31至36中任一项所述的方法,其中所述光以10g至600nm的波长给药。
38.根据权利要求31至37中任一项所述的方法,其中所述化合物和所述CAR-T细胞经肠道外给药。
39.根据权利要求31至38中任一项所述的方法,其中所述光经由无创过程或微创过程给药。
40.根据权利要求31至38中任一项所述的方法,其中所述光在外科手术过程中或之后给药。
41.根据权利要求31至40中任一项所述的方法,其中所述化合物和所述光给药超过一次,而所述CAR-T给药一次。
42.根据权利要求31至38中任一项所述的方法,其中所述光给药至乳腺、卵巢、皮肤、宫颈、膀胱、前列腺、胆管、胰腺、胃、脑、口、喉、阴道、阴门或鼻腔通道。
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EP3813863A4 (en) * | 2018-06-28 | 2022-07-06 | Dana Farber Cancer Institute, Inc. | TARGETING MULTIPLE ANTIGENS BY MULTIPLEX CAR-T CELLS IN SOLID AND LIQUID MALIGNITIES |
EP3980033A4 (en) * | 2019-06-05 | 2023-08-23 | Emory University | PHOTOLYSIS TO UNLOCK CAGED PROTEIN-LIKE THERAPEUTIC AGENTS |
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