CN102076354A - 用于引发免疫应答的组合物和方法 - Google Patents
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Abstract
本发明涉及用于引发免疫应答的组合物、方法和试剂盒,特别是用于引发针对由癌细胞表达的至少一种抗原的免疫应答,特别是用于治疗和预防癌症。
Description
与相关申请的交叉参照
本申请根据35 USC§119要求于2008年7月3日提交的美国临时申请号61/077,922的优先权,所述美国临时申请号通过引用整体合并入本文。
发明领域
本发明涉及用于引发免疫应答,特别是针对由癌细胞表达的至少一种抗原的免疫应答的组合物、方法和试剂盒。
发明背景
用于治疗癌症的方法包括化学疗法、放射疗法和手术的使用。许多肿瘤抗原的鉴定已导致开发基于细胞的疗法的尝试。某些方法依赖于首先鉴定肿瘤抗原,即相对于非肿瘤细胞,在肿瘤细胞中优先表达的多肽。例如,几种人肿瘤抗原已从黑素瘤患者中分离,并且鉴定且表征。
尽管侵入性多科性治疗包括手术、辐射和化学疗法,但关于具有癌症的患者的预后仍相对很差。此外,用于癌症的常规疗法的非特异性质通常导致对于周围正常和全身组织的丧失能力的损害。因此,需要开发靶向肿瘤细胞的有效治疗和预防策略。
发明概述
在一个方面,本发明提供了用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法。该方法包括给受试者施用药学上可接受的组合物,其中包含多种发育细胞抗原或编码所述多种发育细胞抗原的核酸,其中所述药学上可接受的组合物当施用于受试者时,引发针对所述至少一种抗原的免疫应答。
在另一个方面,本发明提供了药学上可接受的组合物,其中包含由发育细胞表达的多种抗原,或编码所述多种抗原的核酸。该药学上可接受的组合物当施用于受试者时,引发针对由癌细胞表达的至少一种抗原的免疫应答。
在其他方面,本发明提供了预防或治疗有效量的药学上可接受的组合物,其中所述药学上可接受的组合物包含由发育细胞表达的多种抗原,或编码所述多种抗原的核酸,其中所述药学上可接受的组合物当施用于受试者时,引发针对由癌细胞表达的至少一种抗原的免疫应答。
在一个方面,本发明提供了用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法。该方法包括给受试者施用包括有效量的抗原呈递细胞、T淋巴细胞或两者的组合物,其中所述抗原呈递细胞和T淋巴细胞已在体外用致敏有效量的由发育细胞表达的多种抗原所致敏,其中所述有效量的抗原呈递细胞、T淋巴细胞或两者足以引发针对所述至少一种抗原的免疫应答。
在某些方面,本发明提供了用于制备癌抗原预致敏(primed)的抗原呈递细胞的方法,该方法包括在体外在足以使多种发育细胞抗原由抗原呈递细胞呈递的条件下,使所述抗原呈递细胞与所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸接触。
在一个方面,本发明提供了包含抗原呈递细胞的组合物,所述抗原呈递细胞已在体外在足以使多种发育细胞抗原由该抗原呈递细胞呈递的条件下与所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸接触。
在其他方面,本发明提供了用于制备癌抗原特异性淋巴细胞的方法。该方法包括:
a)在体外在足以使多种发育细胞抗原由抗原呈递细胞呈递的条件下,使所述抗原呈递细胞与所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸接触;和
b)在足以产生能够引发针对癌细胞的免疫应答的癌抗原特异性淋巴细胞的条件下,使淋巴细胞与步骤a)的抗原呈递细胞接触。
在一个方面,本发明提供了包含T淋巴细胞的组合物,所述T淋巴细胞已在足以产生能够引发针对癌细胞的免疫应答的癌抗原特异性淋巴细胞的条件下与抗原呈递细胞接触,其中所述抗原呈递细胞已在体外在足以使多种发育细胞抗原由该抗原呈递细胞呈递的条件下与所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸接触。
在另一个方面,本发明提供了用于治疗或预防受试者中的癌症的方法,该方法包括给受试者施用治疗或预防有效量的如本文描述的组合物。
在某些方面,本发明提供了用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法,该方法包括给受试者施用药学上可接受的组合物,所述组合物包含离体(exvivo)装载有多种发育细胞抗原或编码所述多种发育细胞抗原的核酸的树突状细胞,其中所述药学上可接受的组合物当施用于受试者时,引发针对该至少一种抗原的免疫应答。
在其他方面,本发明提供了在受试者中引发针对癌细胞的免疫应答的方法,该方法包括给受试者施用药学上可接受的组合物,所述组合物包含针对多种发育细胞抗原产生的抗体。
在另一个方面,依照本发明提供了试剂盒。该试剂盒包含药学上可接受的组合物,其包含由发育细胞表达的多种抗原或编码所述多种抗原的核酸,其中所述药学上可接受的组合物当施用于受试者时,引发针对由癌细胞表达的至少一种抗原的免疫应答。
附图简述
图1是显示用总肿瘤RNA的疫苗接种对具有恶性星形细胞瘤的小鼠的存活百分比的作用的曲线图。
图2是比较用总胚胎RNA或总肿瘤RNA进行疫苗接种对具有恶性神经胶质瘤小鼠的存活百分比的作用的曲线图。
图3是显示(a)扩增产物;和(b)体外转录的RNA的琼脂糖凝胶电泳。
图4是显示使用由CD133(-)RNA的扣除杂交法在CD133(+)星形细胞瘤中癌症干细胞抗原的富集的曲线图。
发明详述
申请人已发现通过使用由发育细胞表达的抗原群,或通过使用编码所述抗原的核酸,可以免疫性地靶向受试者中的癌细胞,特别是癌症干细胞。肿瘤发育类似细胞(例如在胎儿发育过程中的胚胎细胞)的增殖和侵袭状态的组织分化原始状态的逆转。因此,也可以在多种肿瘤中表达的特定发育调节的抗原可以例如在针对恶性肿瘤的免疫疗法中充当通用肿瘤排斥抗原。因此,本发明可以避免分离且鉴定肿瘤抗原的需要。
例如,本发明可应用于但不限于开发用于下述的疗法:脑癌(例如,神经胶质瘤)、肺癌、肝癌、宫颈癌、软组织肉瘤、内分泌肿瘤、造血癌症、黑素瘤、膀胱癌、乳腺癌、胰腺癌、前列腺癌、结肠癌和卵巢癌。
I.定义
术语“免疫应答”在本文中指免疫系统针对抗原或抗原决定簇的任何应答。示例性的免疫应答包括体液免疫应答(例如,抗原特异性抗体(中和性的或其他类型的)的产生)和细胞介导的免疫应答(例如,淋巴细胞增殖)。
术语“发育细胞”在本文中指胚胎细胞、胚胎干细胞(ESC)、胎儿细胞、胎儿干细胞、胎盘细胞、胎盘祖细胞、脐带干细胞、来自脐带血的胚胎样细胞和出生后的组织特异性祖细胞。“发育细胞”可以是原代细胞或由其获得的细胞系,包括采用或未采用增殖、转化、克隆和/或任何其他类型的处理获得的稳定细胞系。
术语“发育细胞抗原”在本文中指与由发育细胞表达的抗原对应的抗原。
II.方法和组合物
在一个方面,本发明提供了用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法。该方法包括给受试者施用药学上可接受的组合物,其中包含多种发育细胞抗原或编码所述多种发育细胞抗原的核酸,其中所述组合物当施用于受试者时,引发针对该至少一种抗原的免疫应答。
一般地,免疫应答可以包括体液免疫应答、细胞介导的免疫应答或两者。例如,通过涉及MHC II蛋白质的免疫学途径的抗原呈递或直接B细胞刺激可以产生体液应答;并且通过涉及MHC I蛋白质的途径呈递的抗原可以引发免疫系统的细胞应答
体液应答可以通过标准免疫测定法就来自接受药学上可接受组合物的受试者的血清样品中的抗体水平进行测定。细胞免疫应答是涉及T细胞的应答,并且可以在体外或体内进行测定。例如,一般的细胞免疫应答可以作为在施用药学上可接受组合物后在合适时间从受试者中取样的细胞(例如,外周血白细胞(PBLs))中的T细胞增殖活性来测定。在例如外周血单核细胞(PBMC)与刺激物温育合适时期后,可以测定[3H]胸苷掺入。使用流式细胞术可以测定增殖的T细胞亚群。还可以测定T细胞细胞毒性(CTh)。
在一个实施方案中,引发的免疫应答足以用于预防或治疗性处理赘生性疾病或与之相关的症状,特别是癌症(例如,肿瘤)。因此,药学上可接受的组合物的有利效应一般至少部分是免疫介导的,尽管无需正面证实免疫应答,以便使本文描述的组合物和方法属于本发明的范围内。
在本发明的范围内考虑了施用于人和非人脊椎动物。还考虑了兽医学应用。一般地,受试者是可以在其中引发免疫应答的任何活生物体。受试者的例子包括但不限于人、家畜、犬、猫、小鼠、大鼠及其转基因物种。
受试者可以具有赘生性疾病(例如,肿瘤)或处于发展赘生性疾病的危险中。受试者可以通过临床标准进行表征,例如具有晚期赘生性疾病或高肿瘤负荷、显示临床上可测量的肿瘤的那些。临床上可测量的肿瘤是可以基于肿瘤团块(例如,通过触诊、MRI、CAT扫描、X射线)进行检测的肿瘤。因此,例如,依照本发明的药学上可接受组合物可以施用于具有晚期疾病的受试者,目的是减轻其病状。优选地,由于施用本发明的药学上可接受的组合物而可能会发生肿瘤团块的减少,但任何临床改善都构成有利方面。临床改善包括例如肿瘤发展的风险或速率降低或者其病理后果的减轻。
作为另一个例子,受试者可以是具有癌症史的受试者并且已响应另一种形式的治疗。所述另一种疗法可以已包括例如手术切除、放射疗法、化学疗法和其他形式的免疫疗法,由此由于所述另一种疗法,受试者不呈现临床上可测量的肿瘤。然而,受试者可以是测定为处于癌症复发或进展(接近原始肿瘤部位或通过转移)风险中的受试者。此类受试者可以进一步分类为高危和低危受试者。可以基于在初治前或后观察到的特征进行细分。这些特征是临床领域中已知的,并且对于每种不同癌症适当地定义。高危亚群的典型特征是其中肿瘤已侵入附近组织或显示淋巴结累及的那些。因此,例如,本发明的药学上可接受的组合物可以施用于受试者,以引发主要作为针对复发的预防措施的抗癌应答。优选地,施用组合物会延迟癌症复发,或更优选地,会减少复发危险(即,提高治愈率)。此类参数可以通过与其他患者群体和其他形式的治疗比较进行测定。
所述药学上可接受的组合物可以在合适的任何时间施用。例如,施用可以在具有肿瘤负荷的受试者的常规治疗前或过程中进行,并且在肿瘤变得临床上无法检测后继续。施用也可以在显示复发体征的受试者中继续。
癌细胞可以是任何类型的癌症,包括但不限于脑癌(例如,神经胶质瘤)、肺癌、肝癌、宫颈癌、软组织肉瘤、内分泌肿瘤、造血癌症、黑素瘤、膀胱癌、乳腺癌、胰腺癌、前列腺癌、结肠癌、卵巢癌、皮肤癌及其组合。癌症还可以表征为良性或恶性的。在一个实施方案中,癌症是高级别神经胶质瘤。在另一个实施方案中,所述高级别神经胶质瘤是多形性成胶质细胞瘤、间变性神经胶质瘤或少突神经胶质瘤。
所述药学上可接受的组合物可以以治疗或预防有效量施用,其中所述药学上可接受的组合物包括单独地或与一种或多种其他抗原组合的多种发育细胞抗原或编码所述多种发育细胞抗原的核酸。可使用已知操作并且以足以达到所需效应的剂量和时间段给受试者施用本发明的药学上可接受的组合物。例如,治疗或预防有效量的药学上可接受的组合物可以根据一些因素例如受试者的年龄、性别和重量而改变。给药方案可以通过本领域普通技术人员调整,以引发所需免疫应答,包括提供治疗或预防效应的免疫应答。
药学上可接受的组合物可以在任何合适部位施用于受试者,例如对于原发性肿瘤遥远或附近的部位。施用途径可以是肠胃外、肌内、皮下、真皮内、腹膜内、鼻内、静脉内(包括经由留置导管)、经由传入淋巴管、或通过就待治疗的赘生性疾病和受试者病状而言合适的任何其他途径。优选地,剂量将以在造成所需应答有效的量和时间段施用,该所需应答可以是引发免疫应答或赘生性疾病或与之相关症状的预防或治疗性处理。
所述药学上可接受的组合物可以在其他治疗之后、之前或同时给予,所述其他治疗包括也在受试者中引发免疫应答的治疗。例如,受试者可以先前或同时通过化学疗法(例如通过烷化剂,例如替莫唑胺)、放射疗法和其他形式的免疫疗法治疗,所述其他疗法优选以不干扰本发明组合物的免疫原性的方式提供。
施用可以通过提供照顾者(例如,医生、兽医)适当地安排时间,并且可以依赖于受试者的临床病状、施用目的和/或正在考虑或施用的其他疗法。在某些实施方案中,可以施用初始剂量,并且监控受试者的免疫或临床应答,优选监控两者。免疫监控的合适方式包括使用患者的外周血淋巴细胞(PBL)作为应答者和赘生性细胞作为刺激物。免疫反应还可以通过在施用部位处的延迟炎症应答测定。在初始剂量后可以适当地给予一个或多个剂量,一般为每月一次、每半月一次或优选每周一次,直至达到所需效应。其后,需要时可以给予另外的加强或维持剂量,特别是在免疫或临床益处看起来减退时。
在胎儿发育过程中和在胚胎干细胞内表达的许多发育调节蛋白质在哺乳动物物种中(并且在某些情况下,甚至在果蝇属(Drosophila)中)是保守的,并且在蛋白质和核酸水平上显示出与人的高度同源性。因此,异种胚胎组织抗原和胚胎干细胞抗原是可以代表人胚胎抗原、依照本发明使用的合适替代物的抗原例子。在一个实施方案中,所述多种发育细胞抗原对于受试者是异种、同种异体或自体的。在另一个实施方案中,所述多种发育细胞抗原对于受试者是异种的,该多种发育细胞抗原对应于由对于受试者而言为异种的发育细胞所表达的抗原。
如下文进一步举例说明的,所述药学上可接受的组合物可以包含多种发育细胞抗原或编码该多种发育细胞抗原的核酸。
A.核酸
一般地,受试者可以通过任何肠胃外途径接种包含核酸的药学上可接受的组合物。例如,受试者可以通过静脉内、腹膜内、真皮内、皮下、吸入或肌内途径,或通过粒子轰击使用基因枪接种。优选地,肌肉组织可以是用于多核苷酸递送和表达的部位。多核苷酸剂量可以通过多次和/或重复注射而施用到肌肉内,例如以便经过长时间段延长施用。因此,肌细胞可以用编码多种发育细胞抗原的多核苷酸注射,并且所表达的抗原可以在主要组织相容性复合物抗原的背景中由肌细胞呈递,以引发针对所述发育细胞抗原的免疫应答。
表皮可以是用于多核苷酸递送和表达的另一个有用部位,例如通过直接注射或粒子轰击进行。多核苷酸的剂量可以在表皮中施用,例如通过多次注射或轰击,以经过长时间段延长施用。例如,皮肤细胞可以用编码所述多种发育细胞抗原的多核苷酸注射,并且所表达的抗原可以在主要组织相容性复合物抗原的背景中由皮肤细胞呈递,以引发针对该发育细胞抗原的免疫应答。
受试者还可以通过粘膜途径接种。多核苷酸可以通过多种方法施用于粘膜表面,包括含多核苷酸的滴鼻剂、吸入剂、栓剂、微球体封装的多核苷酸,或通过用多核苷酸包被的金颗粒轰击。例如,编码该多种发育细胞抗原的核酸可以施用于呼吸道粘膜表面。
任何合适的生理学相容的介质,例如注射盐水或用于粒子轰击的金颗粒,均适合于将多核苷酸引入受试者内。
1.RNA
在某些实施方案中,所述药学上可接受的组合物包含编码所述多种发育细胞抗原的核酸。在一个实施方案中,编码所述多种发育细胞抗原的核酸包括RNAs,例如细胞总RNA和/或多聚A+RNA。该RNAs包括可翻译的RNA模板,以指导氨基酸链的细胞内合成,所述氨基酸链提供该多种发育细胞抗原。编码所述多种发育细胞抗原的RNAs也可以在体外转录,例如逆转录,以产生cDNAs(需要时可以通过PCR扩增),并且随后在体外转录,伴随或不伴随克隆cDNA。
还包括的是作为分级分离制剂提供的RNA,该分级分离制剂是针对一种或多种非RNA组分而言,以便降低该非RNA组分例如蛋白质、脂质和/或DNA的浓度,从而就RNA而言富集制剂。因此,当RNAs由包含RNAs和非RNA组分的制剂提供时,所述制剂可以分级分离或以其他方式处理,以降低制剂中的蛋白质、脂质和/或DNA的浓度(如果存在的话),并且就RNA而言富集制剂。例如,本领域普通技术人员已知的RNA纯化方法可以用于至少部分纯化所述RNAs。任选地,用蛋白酶或无RNA酶的DNA酶处理该RNA制剂。
任选地,RNA制剂还可以就RNA而言进行分级分离(例如,通过扣除杂交法),从而提供例如癌症干细胞特异性RNAs。可以与发育细胞共享表达谱的在肿瘤细胞的干细胞级分内表达的抗原,可以通过这种方法有效靶向。癌症干细胞可以对标准疗法更有抵抗力,并且可以促成肿瘤复发。因此,技术例如扣除杂交法可以用于富集在癌症干细胞亚群中特异性表达的抗原,因此扣除杂交法可以用于提供缺乏例如编码在正常产后组织中表达的抗原的RNAs的RNA制剂。通过去除编码可能在正常组织中表达的抗原的RNAs的至少部分,此类分级分离可以提供编码在恶性细胞中表达的共享发育细胞抗原的RNAs。
因此,例如可以执行使用来自正常成人组织的RNAs的扣除杂交法。因此,在一个实施方案中,编码所述多种发育细胞抗原的核酸针对在成人细胞中不转录或如果在成人细胞中转录、那么与发育细胞比较以基本上减少的水平转录的RNA转录物进行了富集。
有许多方法可供本领域普通技术人员用于制备编码多种发育细胞抗原的RNAs。例如,通过超声处理在哺乳动物细胞培养基例如Opti-或缓冲液例如磷酸盐缓冲盐水中的发育细胞,可以制备包含释放的总RNAs的发育细胞制剂。用于破坏细胞的其他方法也是合适的,前提是该方法不完全降解RNAs。例如,还可以通过采用常规RNA纯化方法制备RNAs,例如异硫氰酸胍方法和/或寡dT色谱法用于分离多聚A+RNA。此外,例如由发育细胞制备的RNAs可以逆转录成cDNAs,其随后可以通过常规PCR技术扩增,以提供与编码抗原的RNAs对应的cDNAs基本上无限的供应。常规体外转录技术和细菌聚合酶可以用于产生体外转录的RNAs,或体外转录的RNAs可以由编码所述多种发育细胞抗原的克隆DNA序列合成。
2.DNA
在另一个实施方案中,编码所述多种发育细胞抗原的核酸包括具有编码该多种发育细胞抗原的开放读码框的DNAs。例如,包含下述表达载体的药学上可接受的组合物可以施用于受试者,所述表达载体具有编码所述多种发育细胞抗原的DNA开放读码框。
包含编码所述多种发育细胞抗原的开放读码框的基因组DNA片段和/或cDNAs可以用于本发明的方法中。使用本领域普通技术人员已知的技术,可以由编码该多种发育细胞抗原的上述RNAs制备cDNAs。
DNA可以例如通过物理断裂或优选地通过酶促切割即使用限制性核酸内切酶裂解为碎片。断裂方法是本领域技术人员众所周知的,并且可以改变(例如,通过不同限制性核酸内切酶或组合和消化时间),以获得在尺寸和组成中不同的片段。具有编码该多种发育细胞抗原的开放读码框的DNAs或其片段可以通过本领域已知的方法和试剂克隆到表达载体内。例如,包含表达载体文库或其子文库的药学上可接受的组合物可以施用于受试者。
DNA表达文库的制备可以通过众所周知的方法执行。可以采用标准克隆载体,其具有可选择标记(例如,氨苄青霉素)和优选地复制起点(例如,ori)和合适启动子。随后可以用载体转化细菌(例如,大肠杆菌)或其他合适宿主,并且通过标准操作培养转化体,通过诸如色谱或有机分离之类的方法来分离质粒DNA。例如,有质粒可供用于克隆到位点内,所述位点可以将由开放读码框表达的多种抗原导向MHC I或II。用于引发免疫应答的表达载体和使用其的方法在美国专利申请公开号20040241140中描述,将其中有关用于引发免疫应答的表达载体和其使用方法的教导合并入本文。
当由细胞(例如,肌细胞、抗原呈递细胞(APC)例如树突状细胞、巨噬细胞等)摄入时,DNA分子可以作为染色体外分子存在于细胞中和/或可以整合到染色体内。DNA可以以质粒的形式引入细胞内,所述质粒可以作为分开的遗传材料保留。可替代地,可以整合到染色体内的线性DNAs可以引入细胞内。任选地,当将DNA引入细胞内时,可以添加促进DNA整合到染色体内的试剂。
因此,优选地,DNAs包括对于开放读码框表达所需的调节元件。此类元件可以包括例如启动子、起始密码子、终止密码子和多聚腺苷酸化信号。此外,可以包括增强子。如本领域已知的,这些元件优选与编码发育细胞抗原的序列可操作地连接。优选选择在待施用的受试者物种中可操作的调节元件。优选包括与编码序列处于相同框中的起始密码子和终止密码子。
启动子的例子包括但不限于来自猿猴病毒40(SV40)的启动子、小鼠乳腺肿瘤病毒(MMTV)启动子、人免疫缺陷病毒(HIV)例如HIV长末端重复序列(LTR)启动子、莫洛尼病毒、巨细胞病毒(CMV)例如CMV立即早期启动子、EB病毒(EBV)、劳斯肉瘤病毒(RSV)以及来自人基因的启动子,例如来自人肌动蛋白、人肌球蛋白、人血红蛋白、人肌肉肌酸和人金属硫蛋白基因的启动子。合适多腺苷酸化信号的例子包括但不限于SV40多腺苷酸化信号和LTR多腺苷酸化信号。
除DNA表达所需的调节元件外,另外的元件也可以包括在DNA分子中。此类另外的元件包括增强子。增强子包括上文描述的启动子。优选的增强子/启动子包括例如人肌动蛋白、人肌球蛋白、人血红蛋白、人肌肉肌酸和病毒增强子,例如来自CMV、RSV和EBV的那些。
任选地,可以将DNAs可操作地掺入载体或递送载体内。有用的递送载体包括但不限于生物可降解的微胶囊、免疫刺激复合物(ISCOMs)或脂质体、和遗传改造的减毒活载体例如病毒或细菌。
任选地,DNAs还可以与改善遗传材料经由细胞的摄取的试剂一起提供。例如,所述DNA可以与摄取促进试剂结合配制或施用,所述摄取促进试剂选自苯甲酸酯类、酰苯胺类、脒和氨基甲酸酯类(urethans)。
B.抗原
在其他实施方案中,药学上可接受的组合物包括多种发育细胞抗原。所述多种发育细胞抗原可以以任何形式,包括例如全细胞裂解物、蛋白质或肽提取物、细胞材料(例如,活的或灭活的细胞)、颗粒物例如但不限于细胞碎片、凋亡细胞、脂质聚集物例如脂质体、膜质囊泡、微球体等。
在一个实施方案中,所述多种发育细胞抗原包括发育细胞。发育细胞可以与其他组分直接组合,所述其他组分可以存在于该药学上可接受的组合物中。需要时,所述发育细胞可以被灭活,以使施用于受试者后的增殖降到最低或得到阻止。可以使用任何物理、化学或生物学灭活方法,包括但不限于照射和用丝裂霉素C处理。发育细胞还可以用化学制品例如戊二醛、多聚甲醛或福尔马林固定。它们还可以处于离子或非离子型去污剂例如脱氧胆酸盐或辛基葡糖苷中,或例如使用病毒进行处理。
需要时,发育细胞的溶解化细胞悬浮液可以澄清或实施许多标准生物化学分离操作中的任何操作,以富集所述多种抗原,例如使用免疫沉淀法或亲和纯化方案。该多种抗原的富集程度可以超过全细胞裂解物的至少2、3、4、6、8、10倍或更多,优选100倍。在一个实施方案中,富集与发育细胞的外膜结合的抗原。
在与所述药学上可接受的组合物的其他组分组合前,所述发育细胞可以被消除了用于处理其的化学制品,例如通过离心且洗涤固定细胞,或溶解悬浮液的透析。优选地,从细胞制剂中至少部分去除可以用于培养细胞的生长培养基和/或因子。例如,可以去除培养基中的血清(例如,胎牛血清、牛血清)组分或其他生物学补充物,以便避免针对此类组分的免疫学副反应。
例如,药学上可接受的组合物的细胞组分可以例如通过反复离心而洗涤到合适的药理学相容的赋形剂内。相容的赋形剂包括等渗盐水,连同或不连同生理学相容的缓冲剂如磷酸盐或HEPES和营养物例如右旋糖、生理学相容的离子或氨基酸、和适合于与发育细胞群体一起使用的各种培养基,特别是消除了其他免疫原性组分的那些。还可以使用运输试剂例如白蛋白和血浆级分以及非活性增稠剂。至其存在于药学上可接受的组合物中的程度,非活性生物学组分优选衍生自相同物种,并且更加优选事先得自待施用的受试者。
C.树突状细胞疗法
本领域技术人员应认识到,在体外产生树突状细胞(DCs)的能力也可以依照本发明用于离体使DCs装载所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸,并且施用‘DC疫苗’作为用于引发针对由癌细胞表达的该至少一种抗原的免疫应答的策略。临床前研究已显示DCs是B和T淋巴细胞中的从新和回忆应答的有效激活物。
在某些实施方案中,本发明提供了用于在受试者中引发针对由癌细胞表达的所述至少一种抗原的免疫应答的方法,该方法包括给受试者施用药学上可接受的组合物,其包含离体装载有多种发育细胞抗原或编码该多种发育细胞抗原的核酸的树突状细胞,其中所述药学上可接受的组合物当施用于受试者时,引发针对该至少一种抗原的免疫应答。
因此,本发明的发育细胞抗原预致敏的抗原呈递细胞和用这些抗原呈递细胞产生的发育抗原特异性T淋巴细胞,可以用作免疫调节组合物中的活性化合物用于预防或治疗应用。如下所述,在某些实施方案中,本发明的抗原预致敏的抗原呈递细胞可以用于产生细胞毒性T淋巴细胞(CTL)(例如,CD8+或CD4+CTL),用于过继转移给受试者。
D.组合物
在其他方面,本发明提供了药学上可接受的组合物,其包含由发育细胞表达的多种抗原或编码所述多种抗原的核酸。该药学上可接受的组合物当施用于受试者时,可以引发针对癌细胞的至少一种抗原的免疫应答。本发明的药学上可接受的组合物可以用作疫苗组合物,用于赘生性疾病或其症状的预防或治疗性处理,特别是用于预防或治疗受试者中的癌症(例如,肿瘤)。
由发育细胞表达的所述多种抗原或编码该多种抗原的核酸如上所述。在某些实施方案中,该药学上可接受的组合物进一步包含生理学上可接受的载体、稀释剂或赋形剂。用于配制和施用的技术也可见于Remington′s Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA,最新版本中。
本领域已知的药学上可接受的载体包括但不限于无菌水、盐水、葡萄糖、右旋糖或缓冲溶液。试剂例如稀释剂、稳定剂(例如,糖和氨基酸)、防腐剂、湿润剂、乳化剂、pH缓冲剂、增强粘度的添加剂等。优选地,介质或载体将产生最低限度的不良反应或无不良反应。
在其他实施方案中,该药学上可接受的组合物进一步包含生理学上可接受的佐剂。优选地,所采用的佐剂提供了增加的免疫原性。佐剂可以是提供抗原的缓慢释放的佐剂(例如,佐剂可以是脂质体),或它可以是本身是免疫原性、从而与抗原协同作用的佐剂。例如,佐剂可以是已知佐剂或者促进核酸摄取、将免疫系统细胞召募至施用部位、或促进应答淋巴样细胞的免疫活化的其他物质。佐剂包括但不限于免疫调节分子(例如,细胞因子)、油和水乳状液、氢氧化铝、葡聚糖、硫酸葡聚糖、氧化铁、海藻酸钠、Bacto-Adjuvant、合成聚合物例如多聚氨基酸和氨基酸共聚物、皂苷、石蜡油和胞壁酰二肽。
在某些实施方案中,佐剂包括不完全弗氏佐剂(Montanide ISA 51)或粒状棒状杆菌(Corynebacterium granulosum)P40。
在一个实施方案中,佐剂包括免疫调节分子。例如,所述免疫调节分子可以是重组蛋白质细胞因子、趋化因子、或免疫刺激剂或者编码设计用于增强免疫应答的细胞因子、趋化因子或免疫刺激剂的核酸。佐剂可以与所述多种抗原或编码该多种抗原的核酸组合或缀合。无法由载体表达的佐剂可以同时或顺次,以任何次序施用。
免疫调节细胞因子的例子包括干扰素(例如,IFNα、IFNβ和IFNγ)、白介素(例如,IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12和IL-20)、肿瘤坏死因子(例如,TNFα和TNFβ)、促红细胞生成素(EPO)、FLT-3配体、gIp10、TCA-3、MCP-1、MIF、MIP-1α、MIP-1β、Rantes、巨噬细胞集落刺激因子(M-CSF)、粒细胞集落刺激因子(G-CSF)、和粒细胞-巨噬细胞集落刺激因子(GM-CSF)、以及前述任何细胞因子的功能性片段。与趋化因子受体即CXC、CC、C或CX3C趋化因子受体结合的任何免疫调节性趋化因子,也可以在本发明的背景中使用。趋化因子的例子包括但不限于Mip1α、Mip-1β、Mip-3α(Larc)、Mip-3β、Rantes、Hcc-1、Mpif-1、Mpif-2、Mcp-1、Mcp-2、Mcp-3、Mcp-4、Mcp-5、Eotaxin、Tarc、Elc、I309、IL-8、Gcp-2 Gro-α、Gro-β、Gro-γ、Nap-2、Ena-78、Gcp-2、Ip-10、Mig、I-Tac、Sdf-1和Bca-1(Blc)、以及前述任何趋化因子的功能性片段。
在另一个实施方案中,佐剂包括选自下述的细胞因子:GM-CSF、G-CSF、IL-2、IL-4、IL-7、IL-12、IL-15、IL-21、TNF-α和M-CSF。在某些实施方案中,佐剂包括弗氏佐剂(Montanide ISA 51)或粒状棒状杆菌P40。例如,在一个实施方案中,编码GM-CSF或IL-7的序列可以包括在具有编码发育细胞抗原的开放读码框的载体上,或包括在分开的载体上,所述分开的载体与抗原施用同时或接近同时施用。在另一个实施方案中,药学上可接受的组合物包括由发育细胞或细胞系形式的发育细胞表达的多种抗原,其中所述发育细胞或细胞系被遗传改变,以便产生细胞因子以提供免疫刺激,产生针对该多种抗原的特异性免疫应答。在某些实施方案中,该药学上可接受的组合物包括由发育细胞或细胞系形式的发育细胞表达的多种抗原;和表达一种或多种细胞因子的细胞系。可以针对每种类型的癌症或针对每个受试者,通过包括合适数目的细胞因子产生细胞,或用以合适比的产生多种细胞因子的此类细胞混合物,对这类组合物进行定制。
本领域普通技术人员已知本发明的方法和组合物可以用作联合治疗的部分,例如作为包括一种或多种其他试剂的方法和/或组合物,所述其他试剂包括但不限于化学治疗剂、免疫治疗剂、免疫调节剂、抗血管生成剂和激素试剂。在各种实施方案中,所述一种或多种其他试剂可以是天然存在或合成的化学治疗剂,例如如″CancerChemotherapeutic Agents″,American Chemical Society,1995,W.O.Foye Ed中描述的。
在一个实施方案中,所述化学治疗剂选自小分子受体拮抗剂,例如瓦他拉尼、SU 11248或AZD-6474,EGFR或HER2拮抗剂例如吉非替尼、厄洛替尼、CI-1033或赫赛汀,抗体例如贝伐珠单抗、西妥昔单抗、利妥昔单抗,DNA烷化药物例如顺铂、奥沙利铂或卡铂,蒽环类例如多柔比星或表柔比星,抗代谢药例如5-FU、培美曲塞、吉西他滨或卡培他滨,喜树碱例如伊立替康或托泊替康,抗癌药物例如紫杉醇或多西他赛,表鬼臼毒素例如依托泊苷或替尼泊苷,蛋白酶体抑制剂例如硼替佐米或抗炎药例如塞来考昔或罗非考昔,其任选地为药学上可接受的盐的形式、为水合物和/或溶剂化物的形式,且任选地为单个光学异构体、各单个对映异构体的混合物或其外消旋物的形式。
在另一个实施方案中,化学治疗剂选自小分子VEGF受体拮抗剂例如瓦他拉尼(PTK-787/ZK222584)、SU-5416、SU-6668、SU-11248、SU-14813、AZD-6474、AZD-2171、CP-547632、CEP-7055、AG-013736、IM-842或GW-786034,双重EGFR/HER2拮抗剂例如吉非替尼、埃罗替尼、CI-1033或GW-2016,EGFR拮抗剂例如易瑞沙(ZD-1839)、它赛瓦(OSI-774)、PKI-166、EKB-569、HKI-272或赫赛汀,丝裂原活化蛋白质激酶的拮抗剂例如BAY-43-9006或BAY-57-9006,喹唑啉衍生物例如4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧)喹唑啉或4-[(3-氯-4-氟苯基)氨基]-6-{[4-(高吗啉-4-基)-1-氧-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧]-喹唑啉,或其药学上可接受的盐,未分类在合成小分子下的蛋白质激酶受体拮抗剂例如阿曲生坦、利妥昔单抗、西妥昔单抗、Avastin.TM.(阿瓦斯丁,贝伐珠单抗)、IMC-1C11、爱必妥(C-225)、DC-101、EMD-72000、αVβ3人源化抗单抗(vitaxin)、伊马替尼,作为融合蛋白的蛋白质酪氨酸激酶抑制剂例如VEGFtrap,烷化剂或铂化合物例如美法仑、环磷酰胺、氧氮磷环、顺铂、卡铂、奥沙利铂、沙铂、四铂、异丙铂、丝裂霉素、链佐星、卡莫司汀(BCNU)、罗莫司汀(CCNU)、白消安、异环磷酰胺、链佐星、噻替派、苯丁酸氮芥、氮芥例如二氯甲基二乙胺(氮芥)、乙撑亚胺化合物、烷基磺酸酯、柔红霉素、多柔比星(阿霉素)、多柔比星脂质体(doxil)、表柔比星、伊达比星、米托蒽醌、安吖啶、放线菌素D、偏端霉素或其衍生物、纺锤菌素、pibenzimol、丝裂霉素、CC-1065、多卡米星、光辉霉素、色霉素、橄榄霉素、phtalanilide例如普罗帕脒或二脒替、安曲霉素、吖丙啶、亚硝基脲或其衍生物,嘧啶或嘌呤类似物或二磷酸核苷还原酶的拮抗剂或抑制剂例如阿糖胞苷、5-氟尿嘧啶(5-FU)、培美曲塞、替加氟/尿嘧啶、尿嘧啶氮芥、氟达拉滨、吉西他滨、卡培他滨、巯嘌呤、克拉屈滨、硫鸟嘌呤、甲氨蝶呤、喷司他丁、羟基脲或叶酸,腐草霉素、博来霉素或其衍生物或盐,CHPP,BZPP,MTPP,BAPP,似博霉素(liblomycin),吖啶或其衍生物,利福霉素,放线菌素,甲烯土霉素(adramycin),喜树碱例如伊立替康(camptosar)或托泊替康,安吖啶或其类似物,三环甲酰胺,组蛋白脱乙酰基酶抑制剂例如SAHA、MD-275、曲古抑菌素A、CBHA、LAQ824或丙戊酸,来自植物的抗癌药物例如紫杉醇(泰素)、多西他赛或泰索帝,长春花生物碱例如诺维本、长春碱、长春新碱、长春地辛或长春瑞滨,托酚酮生物碱例如秋水仙碱或其衍生物,大环内酯例如美坦辛、安丝菌素或利索新(根霉素),抗有丝分裂肽例如拟茎点霉毒素或多拉司他汀,表鬼臼毒素或鬼臼毒素衍生物例如依托泊苷或替尼泊苷,五加前胡素,抗有丝分裂氨基甲酸酯衍生物例如考布他汀或amphetinile,丙卡巴肼,蛋白酶体抑制剂例如硼替佐米,酶例如天冬酰胺酶、聚乙二醇化天冬酰胺酶(培门冬酶)或胸苷磷酸化酶抑制剂,促孕激素或雌激素例如雌莫司汀(T-66)或甲地孕酮,抗雄激素例如氟他胺、康士得、尼鲁米特(anandron)或乙酸环丙孕酮,芳香酶抑制剂例如氨鲁米特、阿那曲唑、福美坦(formestan)或来曲唑,GNrH类似物例如亮丙瑞林、布舍瑞林、戈舍瑞林或曲普瑞林,抗雌激素例如它莫西芬或其柠檬酸盐、屈洛昔芬、曲沃昔芬、雷洛昔芬或秦哚昔芬,17β-雌二醇衍生物例如ICI 164,384或ICI 182,780,氨鲁米特,福美坦,法倔唑,非那雄胺,酮康唑,LH-RH拮抗剂例如亮丙瑞林,类固醇例如泼尼松、泼尼松龙、甲泼尼龙、地塞米松、布地奈德、氟可龙或曲安西龙,干扰素例如干扰素β,白介素例如IL-10或IL-12,抗TNFα抗体例如依那西普,免疫调节药物例如沙立度胺、其R和S-对映异构体及其衍生物,或revimid(CC-5013),白三烯拮抗剂,丝裂霉素C,氮丙啶醌(aziridoquinone)例如BMY-42355、AZQ或EO-9,2-硝基咪唑例如米索硝唑、NLP-1或NLA-1,硝基吖啶,硝基喹啉,硝基吡唑并吖啶,“双重功能”硝基芳香族例如RSU-1069或RB-6145,CB-1954,氮芥的N氧化物例如氧氮芥,氮芥的金属络合物,抗CD3或抗CD25抗体,耐受诱导剂,双膦酸酯或其衍生物例如米诺膦酸或其衍生物(YM-529、Ono-5920、YH-529)、唑来膦酸一水合物、伊班膦酸钠水合物或氯膦酸二钠,硝基咪唑例如甲硝唑、米索硝唑、苄硝唑或尼莫唑,硝基芳基化合物例如RSU-1069,硝酰基或N氧化物例如SR-4233,卤代嘧啶类似物例如溴脱氧尿苷、碘脱氧尿苷,硫代硫酸酯例如WR-2721,光化学活化药物例如卟吩姆、光敏素、苯并卟啉衍生物、脱镁叶绿酸盐衍生物,部花青(merocyanin)540(MC-540)或初卟啉(tinetioporpurin)锡,抗模板或反义RNA或DNA例如奥利美生(oblimersen),非甾体抗炎药例如乙酰水杨酸、美沙拉嗪(mesalazin)、布洛芬、萘普生、氟比洛芬、非诺洛芬、芬布芬、酮洛芬、吲哚洛芬、吡洛芬、卡洛芬、奥沙普秦、普拉洛芬、咪洛芬、硫噁洛芬、舒洛芬、阿明洛芬、噻洛芬酸、氟洛芬、吲哚美辛、舒林酸、托美丁、佐美酸、萘丁美酮、双氯芬酸、芬氯酸、阿氯芬酸、溴芬酸、异丁芬酸、乙氯芬酸、阿西美辛、芬替酸、环氯茚酸、依托度酸、oxpinac、甲芬那酸、甲氧芬那酸、氟芬那酸、尼氟灭酸(nifluminic acid)、托芬那酸、二氟尼柳、氟苯柳、吡罗昔康、替诺昔康、氯诺昔康、尼美舒利、美洛昔康、塞来考昔、罗非考昔或非甾体抗炎药的药学上可接受的盐,细胞毒性抗生素,靶向癌细胞表面分子的抗体例如阿泊珠单抗或1D09C3,金属蛋白酶的抑制剂例如TIMP-1或TIMP-2,锌,癌基因的抑制剂例如P53和Rb,稀土元素络合物例如镧系元素的杂环络合物,光化学治疗剂例如PUVA,转录因子复合物ESX/DRIP130/Sur-2的抑制剂,HER-2表达的抑制剂例如热休克蛋白HSP90调节物格尔德霉素及其衍生物17-烯丙基氨基格尔德霉素或17-AAG,选自IM-842、四硫钼酸盐、角鲨胺、combrestatin A4、TNP-470、马立马司他、新伐司他、比卡鲁胺、阿巴瑞克、奥戈伏单抗、米妥莫单抗、TLK-286、阿仑珠单抗、替伊莫单抗、替莫唑胺、地尼白介素、阿地白介素、达卡巴嗪、氟尿苷、普卡霉素、米托坦、哌泊溴烷、普卡霉素、它莫西芬和睾内酯的治疗剂。优选化合物包括小分子VEGF受体拮抗剂例如瓦他拉尼(PTK-787/ZK222584)、SU-5416、SU-6668、SU-11248、SU-14813、AZD-6474,EGFR/HER2拮抗剂例如CI-1033或GW-2016,EGFR拮抗剂例如易瑞沙(吉非替尼、ZD-1839)、它赛瓦(厄洛替尼、OSI-774)、PKI-166、EKB-569、HKI-272或赫赛汀,丝裂原活化蛋白质激酶的拮抗剂例如BAY-43-9006或BAY-57-9006,阿曲生坦、利妥昔单抗、西妥昔单抗、Avastin.TM.(贝伐珠单抗)、IMC-1C11、爱必妥(C-225)、DC-101、EMD-72000、αVβ3人源化抗单抗、伊马替尼,烷化剂或铂化合物例如美法仑、环磷酰胺、氧氮磷环、顺铂、卡铂、奥沙利铂、沙铂、柔红霉素、多柔比星(阿霉素)、多柔比星脂质体(doxil)、表柔比星、伊达比星,嘧啶或嘌呤类似物或二磷酸核苷还原酶的拮抗剂或抑制剂例如阿糖胞苷、5-氟尿嘧啶(5-FU)、培美曲塞、替加氟/尿嘧啶、吉西他滨、卡培他滨、巯嘌呤、甲氨蝶呤,抗癌药物例如紫杉醇(泰素)或多西他赛,长春花生物碱例如诺维本、长春碱、长春新碱、长春地辛或长春瑞滨,抗有丝分裂肽例如多拉司他汀,表鬼臼毒素或鬼臼毒素衍生物例如依托泊苷或替尼泊苷,非甾体抗炎药例如美洛昔康、塞来考昔、罗非考昔,靶向癌细胞表面分子的抗体例如阿泊珠单抗或ID09C3或热休克蛋白HSP90调节物格尔德霉素及其衍生物17-烯丙基氨基格尔德霉素或17-AAG。
在另一个实施方案中,所述化学治疗剂选自与微管蛋白相互作用或结合微管蛋白的化合物,合成小分子VEGF受体拮抗剂,小分子生长因子受体拮抗剂,EGF受体和/或VEGF受体和/或整联蛋白受体或未分类在合成小分子下的任何其他蛋白质酪氨酸激酶受体的抑制剂,针对EGF受体和/或VEGF受体和/或整联蛋白受体或其为融合蛋白的任何其他蛋白质酪氨酸激酶受体的抑制剂,与核酸相互作用且分类为烷化剂或铂化合物的化合物,与核酸相互作用且分类为蒽环类、DNA嵌入剂或DNA交联剂的化合物,包括DNA小沟结合化合物,抗代谢药,天然存在、半合成或合成博来霉素型抗生素,DNA转录酶的抑制剂,特别地拓扑异构酶I或拓扑异构酶II抑制剂,染色质改性剂,有丝分裂抑制剂,抗有丝分裂剂,细胞周期抑制剂,蛋白酶体抑制剂,酶,激素,激素拮抗剂,激素抑制剂,类固醇生物合成的抑制剂,类固醇,细胞因子,缺氧选择性细胞毒素,细胞因子的抑制剂,淋巴因子,针对细胞因子的抗体,经口和肠胃外耐受诱导剂,支持性试剂,化学辐射致敏剂和保护剂,光化学活化药物,任选修饰或缀合的合成多核苷酸或寡核苷酸,非甾体抗炎药,细胞毒性抗生素,靶向癌细胞表面分子的抗体,靶向生长因子或其受体的抗体,金属蛋白酶的抑制剂,金属,癌基因的抑制剂,基因转录或RNA翻译或蛋白质表达的抑制剂,稀土元素的络合物,和光化学治疗剂。
在其他实施方案中,所述化学治疗剂选自紫杉醇(泰素)、多西他赛,长春花生物碱例如诺维本、长春碱、长春新碱、长春地辛或长春瑞滨,烷化剂或铂化合物例如美法仑、环磷酰胺、氧氮磷环、顺铂、卡铂、奥沙利铂、沙铂、四铂、异丙铂、丝裂霉素、链佐星、卡莫司汀(BCNU)、罗莫司汀(CCNU)、白消安、异环磷酰胺、链佐星、噻替派、苯丁酸氮芥、氮芥例如二氯甲基二乙胺,免疫调节药物例如沙立度胺、其R和S-对映异构体及其衍生物(氮芥),或revimid(CC-5013),乙撑亚胺化合物、烷基磺酸酯、柔红霉素、多柔比星(阿霉素)、多柔比星脂质体(doxil)、表柔比星、伊达比星、米托蒽醌、安吖啶、放线菌素D、偏端霉素或其衍生物、纺锤菌素、pibenzimol、丝裂霉素、CC-1065、多卡米星、光辉霉素、色霉素、橄榄霉素、phtalanilide例如普罗帕脒或二脒替、安曲霉素、吖丙啶、亚硝基脲或其衍生物,嘧啶或嘌呤类似物或二磷酸核苷还原酶的拮抗剂或抑制剂例如阿糖胞苷、5-氟尿嘧啶(5-FU)、尿嘧啶氮芥、氟达拉滨、吉西他滨、卡培他滨、巯嘌呤、克拉屈滨、硫鸟嘌呤、甲氨蝶呤、喷司他丁、羟基脲或叶酸,吖啶或其衍生物,利福霉素,放线菌素,甲烯土霉素,喜树碱例如伊立替康(camptosar)或托泊替康,安吖啶或其类似物,三环甲酰胺,组蛋白脱乙酰基酶抑制剂例如SAHA、MD-275、曲古抑菌素A、CBHA、LAQ824或丙戊酸,蛋白酶体抑制剂例如硼替佐米,小分子VEGF受体拮抗剂例如瓦他拉尼(PTK-787/ZK222584)、SU-5416、SU-6668、SU-11248、SU-14813、AZD-6474、AZD-2171、CP-547632、CEP-7055、AG-013736、IM-842或GW-786034,丝裂原活化蛋白质激酶的拮抗剂例如BAY-43-9006或BAY-57-9006,双重EGFR/HER2拮抗剂例如吉非替尼、厄洛替尼、CI-1033或GW-2016,EGFR拮抗剂例如易瑞沙(ZD-1839)、它赛瓦(OSI-774)、PKI-166、EKB-569、HKI-272或赫赛汀,喹唑啉衍生物例如4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧)喹唑啉或4-[(3-氯-4-氟苯基)氨基]-6-{[4-(高吗啉-4-基)-1-氧-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧]-喹唑啉,或其药学上可接受的盐,转录因子复合物ESX/DRIP130/Sur-2的抑制剂,HER-2表达的抑制剂例如热休克蛋白HSP90调节物格尔德霉素及其衍生物17-烯丙基氨基格尔德霉素或17-AAG,未分类在合成小分子下的蛋白质激酶受体拮抗剂例如阿曲生坦、利妥昔单抗、西妥昔单抗、Avastin.TM.(贝伐珠单抗)、IMC-1C11、爱必妥(C-225)、DC-101、EMD-72000、αVβ3人源化抗单抗、伊马替尼,和靶向癌细胞表面分子的抗体例如阿泊珠单抗或1D09C3。
在某些其他实施方案中,化学治疗剂是减少由一种或多种ABC转运蛋白介导的透明质酸转运的化合物,或药物转运抑制剂例如P糖蛋白(P-gp)抑制剂分子或抑制剂肽,MRP1抑制剂,针对且能够阻断ABC转运蛋白的抗体,针对一种或多种ABC转运蛋白的反义寡聚物iRNA、siRNA或适体。依照本发明的P糖蛋白(P-gp)抑制剂分子的例子是zosuquidar(LY 335973)、其盐(特别是三氯化物盐)及其多型物,环孢菌素A(也称为环孢霉素),维拉帕米或其R同分异构体,它莫西芬,奎尼丁,d-α生育酚聚乙二醇1000琥珀酸酯,VX-710,PSC833,吩噻嗪,GF120918(II),SDZ PSC 833,TMBY,MS-073,S-9788,SDZ 280-446,XR(9051)以及它们的功能性衍生物、类似物和同分异构体。
在一个实施方案中,本发明涉及如本文定义的药物组合物用于制备用于治疗癌症的药剂的用途。
E.过继免疫疗法
在各种其他方面,所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸也可以提供组合物和方法用于提供癌细胞预致敏的抗原呈递细胞,和用这些抗原呈递细胞产生的癌抗原特异性T淋巴细胞,例如在用于癌症的预防或治疗应用的免疫调节组合物和方法中用作活性化合物。
因此,在一个方面,本发明提供了用于制备癌细胞预致敏的抗原呈递细胞的方法,其中包括:
在体外在足以使多种发育细胞抗原由抗原呈递细胞呈递的条件下,使所述抗原呈递细胞与该多种发育细胞抗原或编码该多种发育细胞抗原的核酸接触。
所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸如上所述。
该多种发育细胞抗原或编码该多种发育细胞抗原的核酸可以与包含抗原呈递细胞的同质、基本上同质或异质组合物接触。例如,所述组合物可以包括但不限于全血、新鲜血或其级分,例如但不限于外周血单个核细胞、全血的血沉棕黄层级分、红细胞压积(packed redcells)、经照射的血液、树突状细胞、单核细胞、巨噬细胞、嗜中性粒细胞、淋巴细胞、天然杀伤细胞和天然杀伤T细胞。如果任选地使用抗原呈递细胞的前体,那么前体可以在足以使该前体分化成抗原呈递细胞的合适培养条件下培养。优选地,抗原呈递细胞(或任选地前体)选自单核细胞、巨噬细胞、髓样谱系的细胞、B细胞、树突状细胞或朗格汉斯细胞。
待置于与抗原呈递细胞接触的多种发育细胞抗原或编码该多种发育细胞抗原的核酸的量可以通过本领域普通技术人员通过例行实验进行测定。一般地,将抗原呈递细胞与所述多种发育细胞抗原或编码该多种发育细胞抗原的核酸接触,其接触时间足以使细胞呈递加工形式的抗原用于T细胞调节。在一个实施方案中,抗原呈递细胞在多种发育细胞抗原或编码该多种发育细胞抗原的核酸的存在下温育小于约1周,例如约1分钟-约48小时、约2分钟-约36小时、约3分钟-约24小时、约4分钟-约12小时、约6分钟-约8小时、约8分钟-约6小时、约10分钟-约5小时、约15分钟-约4小时、约20分钟-约3小时、约30分钟-约2小时、和约40分钟-约1小时。例如使用脉冲示踪法可以测定抗原呈递细胞加工且呈递抗原所需的抗原或编码该抗原的核酸的时间和量,其中接触之后进行清除期和暴露于读出系统,例如抗原反应性T细胞。
一般地,抗原呈递细胞在其表面上呈递抗原所需的时间长度可以依赖于许多因素而改变,所述因素包括抗原或所采用的抗原形式(例如,肽与编码多核苷酸比较)、其剂量和所采用的抗原呈递细胞、以及进行抗原装载的条件。这些参数可以通过技术人员使用常规操作进行测定。通过在体外测定T细胞细胞毒性活性或使用抗原呈递细胞作为CTLs的靶,可以测定抗原呈递细胞的预致敏效率。本发明还考虑了可以检测抗原呈递细胞表面上抗原的存在情况的其他方法。
用于将抗原递送给抗原呈递细胞的内源加工途径的许多方法是已知的。此类方法包括但不限于这样的方法,其涉及pH敏感性脂质体,抗原与有效佐剂的偶联,凋亡细胞递送,使细胞脉冲剂树突状细胞上,将包括抗原的重组嵌合病毒样颗粒(VLPs)递送给树突状细胞系的MHCI类加工途径。
在一个实施方案中,将溶解的发育细胞抗原与抗原呈递细胞一起温育。在其他实施方案中,可以将发育细胞抗原与细胞溶素偶联,以增强抗原转移到抗原呈递细胞的细胞溶胶内,用于递送给MHC I类途径。示例性的细胞溶素包括皂苷化合物,例如含皂苷的免疫刺激复合物(ISCOMs)、成孔毒素(例如,α毒素)、和革兰氏阳性菌的天然细胞溶素例如李斯特菌溶血素O(LLO)、链球菌溶血素O(SLO)和产气荚膜梭菌溶素O(PFO)。
作为另一个例子,在其他实施方案中,可以根据本领域已知的方法分离抗原呈递细胞,优选树突状细胞和巨噬细胞,并且通过本领域已知的方法用多核苷酸转染,用于将编码该多种抗原的核酸引入APCs内。转染试剂和方法(例如,)也是商购可得的。例如,编码所述多种抗原的RNAs可以在合适介质(例如,Opti-)中提供,并且在与APCs接触前与脂质(例如,阳离子脂质)组合。脂质的非限制性例子包括LIPOFECTINTM、LIPOFECTAMINETM、DODAC/DOPE和CHOL/DOPE。所得到的多核苷酸-脂质复合物随后可以与APCs接触。备选地,可以使用一些技术,例如电穿孔或磷酸钙转染,将多核苷酸引入APCs内。装载多核苷酸的APCs随后可以用于在体内或离体刺激细胞毒性T淋巴细胞(CTL)增殖。在一个实施方案中,在过继免疫疗法的方法中,将离体扩增的CTL施用于受试者。装载多核苷酸的抗原呈递细胞刺激CTL应答的能力可以通过已知方法进行测定,例如通过测定效应细胞裂解靶细胞的能力。使用装载有例如RNA的抗原呈递细胞的方法和组合物在授予Nair等人的美国专利号6,306,388中有描述,所述专利就其产生和使用装载有RNA的APCs的方法的教导通过引用合并入本文。
在另一个方面,本发明提供了包括抗原呈递细胞的组合物,所述抗原呈递细胞已在体外在足以使多种发育细胞抗原由抗原呈递细胞呈递的条件下与该多种发育细胞抗原或编码该多种发育细胞抗原的核酸相接触。
在另一个方面,本发明提供了用于制备对于癌细胞的所述至少一种抗原特异性的淋巴细胞的方法。该方法包括在足以产生能够引发针对癌细胞的免疫应答的至少一种癌抗原特异性淋巴细胞的条件下,使淋巴细胞与上述抗原呈递细胞接触。因此,所述抗原呈递细胞还可以用于提供淋巴细胞,包括T淋巴细胞和B淋巴细胞,用于引发针对癌细胞的所述至少一种抗原的免疫应答。
在一个实施方案中,使T淋巴细胞的制剂与上述抗原呈递细胞接触一段时间,优选至少约24小时,以便使T淋巴细胞对由抗原呈递细胞呈递的发育细胞抗原预致敏。
例如,在另一个实施方案中,可以将抗原呈递细胞的群体与外周血T淋巴细胞的异质群体连同多种发育细胞抗原或编码该多种抗原的核酸一起共培养。细胞可以在足以使所述多种抗原或其加工形式由抗原呈递细胞呈递,并且抗原呈递细胞预致敏T淋巴细胞群体以响应癌细胞的至少一种抗原的时间段和条件下共培养。因此,可以制备已被预致敏处理以响应癌细胞的至少一种抗原的T淋巴细胞和B淋巴细胞。
如本文描述的,诱导淋巴细胞显示出免疫应答的能力可以通过任何方法进行测定,包括但不限于,使用例如发育细胞抗原特异性的抗原呈递细胞作为发育细胞抗原特异性细胞溶解性T淋巴细胞(CTL)的靶,在体外测定T淋巴细胞细胞裂解活性;测定发育细胞抗原特异性T淋巴细胞的增殖;和使用例如ELISA方法测定针对发育细胞抗原的B细胞应答。
T淋巴细胞可以得自任何合适来源,例如外周血、脾脏和淋巴结。T淋巴细胞可以粗制剂或者部分纯化或基本上纯化的制剂形式使用,其可以通过标准技术获得,包括但不限于涉及免疫磁性的方法或使用抗体的流式细胞法技术。
在本发明的范围内还考虑的是已遗传修饰的细胞(例如,遗传改造以在其表面上表达细胞特异性抗体的T细胞)用于细胞的特异性识别。在某些实施方案中,抗原特异性T细胞通过本领域已知的基因转移技术进行修饰,以表达一种或多种异源基因,例如标记基因或其基因产物可以对抗原特异性T细胞增强或赋予特定表型或功能的基因。因此,例如,标记基因可以在响应抗原脉冲的树突状细胞的活化T细胞内表达,并且允许抗原特异性T细胞的选择性富集和修饰。作为另一个例子,可以修饰抗原特异性T细胞,以表达受体(例如,趋化因子受体)以在体外和体内朝向受体配体迁移。已修饰用于选择性富集或用于靶向的抗原特异性T细胞由Mitchell等人,Human GeneTherapy,19:511(2008)描述,其就有关于修饰T细胞的教导通过引用合并入本文。在其他方面,本发明提供了包含上述抗原呈递细胞或淋巴细胞、和药学上可接受的载体和/或稀释剂的组合物。在某些实施方案中,组合物进一步包含如上所述的佐剂。
在另一个方面,本发明提供了用于引发针对癌细胞的所述至少一种抗原的免疫应答的方法,该方法包括给受试者以足以引发免疫应答的有效量施用上述抗原呈递细胞或淋巴细胞。在某些实施方案中,本发明提供了用于治疗或预防赘生性疾病或与之相关症状的方法,该方法包括给受试者施用有效量的上述抗原呈递细胞或淋巴细胞。在一个实施方案中,抗原呈递细胞或淋巴细胞被全身性施用,优选,通过注射进行。备选地,可以局部地而不是全身性(例如经由注射)直接施用到组织内,优选以贮库或持续释放制剂形式。此外,可以在靶向药物递送系统中施用,例如在用组织特异性抗体包被的脂质体中。脂质体可以被靶向组织且由组织特异性摄入。在另一个实施方案中,本发明提供了抗原呈递细胞或淋巴细胞在制备药剂中的用途,所述药剂用于引发针对癌细胞的所述至少一种抗原的免疫应答,优选用于治疗或预防癌症。
因此,本发明的抗原预致敏的抗原呈递细胞和用这些抗原呈递细胞产生的抗原特异性T淋巴细胞可以在用于癌症的预防或治疗应用的免疫调节组合物中用作活性化合物。在某些实施方案中,本发明的发育细胞抗原预致敏的抗原呈递细胞可以用于产生CD8+、CD4+CTL或B细胞淋巴细胞用于过继转移给受试者。因此,例如,发育细胞抗原特异性CTLs可以在患有恶性肿瘤例如神经胶质瘤的受试者中过继转移用于治疗目的。
上述发育细胞抗原呈递细胞和淋巴细胞可以单独或组合地施用于受试者,用于引发免疫应答,特别是用于引发针对癌细胞的至少一种抗原的免疫应答。因此,此类基于细胞的组合物可用于治疗或预防癌症。细胞可以通过引发针对癌细胞的所述至少一种抗原的免疫应答的任何方式引入受试者内。此外,细胞可以衍生自受试者(即,自体细胞),或衍生自与受试者MHC匹配或不匹配的不同受试者(例如,同种异体的)。注射部位可以选自皮下、腹膜内、肌内、真皮内、静脉内或淋巴内。
细胞的单次或多次施用可以采用由提供照顾者(例如,医生)选择的细胞数目和处理方式执行。优选地,细胞在药学上可接受的载体中施用。合适载体可以是细胞在其中生长的生长培养基,或任何合适的缓冲介质例如磷酸盐缓冲盐水。细胞可以单独地或作为与其他治疗剂相结合的辅助疗法施用。
因此,本发明涵盖用于治疗和/或预防癌症的方法,该方法包括给需要此类治疗或预防的受试者施用治疗/预防有效量的如本文描述的组合物。
用于配制和施用的技术可以在Remington′s PharmaceuticalSciences,Mack Publishing Co.,Easton,PA,最新版本中找到。合适途径可以例如包括经口、直肠、经粘膜或肠施用;肠胃外递送,包括肌内、皮下、髓内注射以及鞘内、直接心室内、静脉内、腹膜内、鼻内或眼内注射。对于注射,本发明的治疗/预防组合物可以在水溶液中配制,优选在生理学相容的缓冲液例如汉克斯液、林格氏溶液或生理盐水缓冲液中配制。
F.抗体
本发明的组合物还可以用于产生针对由癌细胞表达的所述至少一种抗原的抗体。因此,在其他方面,本发明的组合物和方法提供针对癌细胞的所述至少一种抗原的一种或多种抗体,所述抗体其自身具有许多用途,例如被动免疫接种或用于效应物的靶特异性递送、以及用于基于免疫结合的诊断测试和试剂盒的用途。因此,在某些实施方案中,本发明提供了可以在治疗和/或诊断应用中使用的癌细胞特异性抗体。
本发明的癌细胞特异性抗体可以在筛选或诊断应用中使用。根据本发明的癌细胞特异性抗体对于体外和体内诊断目的是有价值的。例如,癌细胞特异性抗体可以用于蛋白质印迹法、免疫沉淀法、酶联免疫吸附测定法(ELISA)、荧光激活细胞分选(FACS)、间接免疫荧光显微镜检查、免疫组织化学(IHC)等。在一个实施方案中,本发明提供了用于测定癌细胞的免疫学方法,该方法包括使细胞与如本文公开的至少一种癌细胞特异性抗体接触。
例如,所述癌细胞特异性抗体可以用作诊断剂用于针对检测癌症表达细胞进行测定。考虑到其与癌症的结合亲和力,本发明的癌症结合抗体应特别适合作为诊断剂。基本上,怀疑包含癌症表达细胞(例如,癌细胞)的样品将与抗体一起温育足够时间,以允许免疫学相互作用发生。技术人员应认识到在这些基本操作中可以存在许多变异。这些变异包括例如RIA、ELISA、沉淀、凝集、补体结合和免疫荧光。优选地,受试抗体将进行标记,以允许检测抗体-癌症免疫复合物。此外,本发明的癌细胞特异性抗体也可用于在体外检测和定量癌症,以杀死且消除来自混合细胞群体的癌症表达细胞作为纯化其他细胞中的一个步骤。
用于制备标记形式抗体的标记包括可以直接检测的部分,例如放射性标记和荧光染料,以及必须进行反应或衍生以便检测的部分例如酶。放射性标记包括但不限于99Tc、203Pb、67Ga、68Ga、72As、111In、113mIn、97Ru、62Cu、641Cu、52Fe、52mMn、51Cr、186Re、188Re、77As、90Y、67Cu、169Er、121Sn、127Te、142Pr、143Pr、198Au、199Au、161Tb、109Pd、165Dy、149Pm、151Pm、153Sm、157Gd、159Gd、166Ho、172Tm、169yb、175Yb、177Lu、105Rh和111Ag。放射性标记可以通过目前可用的计数操作中的任何一种进行检测。
酶标记可以通过目前利用的量热、分光光度计测量、荧光分光光度计测量或气体定量技术中的任何一种进行检测。用桥接分子使酶与抗体组合,所述桥接分子例如碳二亚胺、高碘酸盐、二异氰酸盐、戊二醛等。可以在这些操作中使用的许多酶是已知的并且可以利用。例子是过氧化物酶、碱性磷酸酶、β-葡糖苷酸酶、β-D-葡糖苷酶、尿素酶、葡萄糖氧化酶加上过氧化物酶、半乳糖氧化酶加上过氧化物酶和酸性磷酸酶。可以使用的荧光材料包括例如荧光素及其衍生物、罗丹明及其衍生物、金胺、丹酰、伞形酮、luciferia、2,3-二氢酞嗪二酮、辣根过氧化物酶、碱性磷酸酶、溶菌酶和6-磷酸葡萄糖脱氢酶。抗体可以通过已知方法用此类标记进行标记。例如,偶联剂例如醛、碳化二亚胺、二马来酰亚胺、亚氨酸酯、琥珀酰亚胺、双重氮化联苯胺等,可以用于用上述荧光、化学发光和酶标记标记抗体。各种标记技术在Morrison,Methods in Enzymology,(1974),32B,103;Syvanen等人,J.Biol.Chem.,(1973),284,3762;以及Bolton和Hunter,Biochem J.,(1973),133,529中描述。
抗体和标记抗体可以用于多种免疫成像或免疫测定法操作中,以检测患者中癌症的存在或监控已诊断具有癌症的患者中此类癌症的状态。当用于监控癌症的状态时,必须使用定量免疫测定法操作。如果定期进行此类监控测定法并且比较结果,那么可以确定患者的肿瘤负荷是否已增加或降低。可以使用的常见测定法技术包括直接和间接测定法。
例如,在治疗应用的情况下,抗体可以用于抑制涉及疾病进展的靶,或用于造成靶细胞的细胞毒性死亡。此外,此类治疗性抗体可以抑制信号转导途径或诱导抗体依赖性的细胞介导的细胞毒性、补体依赖性的细胞毒性等。
本发明的癌细胞特异性抗体因此可提供有效的靶向部分,其可以但无需与效应物瞬时或永久偶联(从而形成杂交分子或嵌合部分),并且用于将那种效应物导向特定靶细胞(例如,癌细胞)。
效应分子指待被特异性转运至靶细胞的分子或分子群。效应分子一般具有待递送给靶细胞的特征性活性。效应分子包括但不限于细胞毒素、标记、放射性核素(例如,211At)、配体、抗体、药物、脂质体、表位、标记等。优选的效应物包括细胞毒素(例如,假单胞菌(Pseudomonas)外毒素、白树毒素、蓖麻蛋白、相思豆毒蛋白、白喉毒素等)、免疫调节剂(例如,IL2、TNF-α、GM-CSF、B 7.1、H60)、或细胞毒性药物或药物前体,在这些情况下杂交分子可以充当有效的细胞杀死试剂,将细胞毒素特异性靶向具有癌症靶的细胞。
效应物的进一步例子包括但不限于颗粒酶、萤光素酶、血管内皮生长因子、b-内酰胺酶、Tr-apo-1、Ang II、TAT、烷化剂、道诺霉素、阿霉素、苯丁酸氮芥、抗代谢药(例如,氨甲蝶呤)、蒴莲根毒蛋白(modaccin)A链、α-帚曲菌素、油桐(Aleurites fordii)蛋白质、石竹素蛋白质、美洲商陆(Phytolacca americana)蛋白质(PAPI、PAPII和PAP-S)、苦瓜(Momordica charantia)抑制剂、麻疯树毒蛋白、巴豆毒蛋白、石碱草(Sapaonaria officinalis)抑制剂、mitogellin、局限曲菌素(restrictocoin)、酚霉素和依诺毒素。
在另外的其他实施方案中,效应物可以包括封装药物的脂质体(例如抗癌药物,例如多柔比星、长春碱、泰素或本文描述的其他化学治疗剂)、刺激通过免疫系统的组分识别结合细胞的抗原、和特异性结合免疫系统组分且将其导向具有癌症的细胞的抗体等。
其他合适的效应分子包括药理学试剂或包含各种药理学试剂的封装系统。因此,杂交分子的靶向分子可以与待直接递送给肿瘤的药物直接附着。此类药物是本领域技术人员众所周知的,并且包括但不限于多柔比星、长春碱、染料木黄酮、反义分子、本文描述的各种其他化学治疗剂等。
备选地,效应分子可以是封装系统,例如病毒衣壳、脂质体或包含治疗组合物的胶束,所述治疗组合物例如药物、核酸(例如反义核酸)、或优选屏蔽直接暴露于循环系统的另一种治疗部分。制备与抗体附着的脂质体的方法是本领域技术人员众所周知的。参见例如,美国专利号4,957,735;Connor,J.等人(1985)Pharmacol.Ther.,28:341-365。
III.试剂盒
本发明的组合物可以以单位剂量或试剂盒形式供应。试剂盒可以包含在分开的容器中提供的药学上可接受的组合物或其疫苗的各种组分,以及各种其他活性成分或试剂,包括化学治疗剂。例如,容器中可以分开包含由发育细胞表达的所述多种抗原或编码该多种抗原的核酸,从而使得当与试剂盒的其他组分组合时,一起构成以单位剂量或多种剂型的药学上可接受的组合物。优选的试剂盒至少在分开的容器中部分包含抗原来源(例如,由发育细胞表达的多种抗原或编码所述多种抗原的核酸);和一种或多种佐剂(例如,细胞因子)。试剂盒可以进一步包含在分开容器中的生理学上可接受的载体、稀释剂或赋形剂。任选地,试剂盒中可以进一步包含递送试剂例如纳米颗粒或转染试剂。本发明的包装组合物和试剂盒也可以包括用于贮存、制备和施用的说明书。
本发明将通过实施例更详细地举例说明,但应当指出本发明并不限于实施例。
实施例
实施例1
用RNA进行疫苗接种在保护不受恶性星形细胞瘤生长中是有效的
肿瘤细胞系和动物模型
SMA 560细胞系衍生自来自VM/Dk小鼠(H-2b)的自发性星形细胞瘤的脑内移植,并且在包含5%(体积/体积)胎牛血清(FCS)的锌任选培养基(GIBCO BRL,Gaithersburg,MD)中生长。所有细胞系显示不含支原体(Mycoplasma)污染。依照Laboratory Animal ResourcesCommission标准,所有实验使用在无病毒环境中繁殖且维持的6-12周龄雌性VM/Dk小鼠。
RNA-NP复合物
使用标准方法(例如,Ashley等人,J.Experimental Medicine,186:1177(1997)从SMA560肿瘤细胞中分离总肿瘤RNA。购买来自胚胎发育第10天(E10)(Zyagen,San Diego,CA)或第18天(E18)鼠类胚胎(Ambion,Austin,TX)的胚胎RNA、胚胎脑总RNA(Zyagen,San Diego,CA)。根据制造商的说明书,在室温下执行RNA与树枝状聚合物(dendrimer)纳米颗粒(Qiagen,Valencia,CA)的复合。
体内RNA疫苗接种
VM/Dk小鼠未经处理或用在100μL体积(在每只耳基底50μL)中的NP-RNA(75μg NP:25μg RNA)复合物在两耳基底以每周一次的间隔皮内免疫接种1次或3次。在第三次免疫接种后1周,用5000个同基因的自发衍生的星形细胞瘤细胞(SMA50)颅内攻击小鼠。在某些实验中,通过紧在皮内注射前将在10μL PBS中的1μg GM-CSF加入NP-RNA复合物中,将1μg鼠类GM-CSF(PeproTech,Inc.,RockyHill,NJ)与NP-RNA复合物进行共注射。
颅内肿瘤攻击
收获肿瘤细胞,与等体积的在PBS中的10%甲基纤维素混合,并且装载到250-μL Hamilton注射器(Hamilton,Reno,NV)内。小鼠(VM/Dk或无胸腺BALB/c)用赛拉嗪/氯胺酮的混合物进行麻醉,并且置于立体定向框(Kopf Instruments,Tujunga,CA)内。注射针置于前卤右侧2mm和头盖骨表面下4mm。将在5μL体积中的细胞(1.0×104)递送到右大脑半球内。在注射后,用骨蜡封闭头盖骨洞,并且用手术U形钉(Stoelting Co.,Wood Dale,IL)闭合伤口。每天监控小鼠,当根据Laboratory Animal Resources Commission标准处于垂死状态时处死小鼠。使用Kaplan-Meier方法分析存活。
颅内肿瘤处理
如上所述收获且植入肿瘤细胞。如上所述用NP-RNA复合物的处理在肿瘤植入后第4天起始,并且每天监控小鼠的存活。当根据Laboratory Animal Resources Commission标准处于垂死状态时处死小鼠。使用Kaplan-Meier方法分析存活。
实施例2
在治疗已建立的恶性神经胶质瘤方面用总胚胎RNA的疫苗接种比总肿瘤RNA更有效
使25μg总肿瘤RNA(TTRNA)和25μg或75μg GM-CSF RNA与75μg树枝状聚合物纳米颗粒(NP)复合。在用同基因的星形细胞瘤系SMA-560进行致命颅内攻击前1周,通过在耳基底进行皮内注射将RNA:纳米颗粒复合物(TTRNA-NP)递送给VM/Dk小鼠。如图1中所示,用总肿瘤RNA和GM-CSF的疫苗接种在保护不受恶性星形细胞瘤的生长中有效。
使25μg的第18天胚胎(E18)总胚胎RNA(E18RNA)或来自SMA-560星形细胞瘤的总肿瘤RNA(TTRNA)与75μg树枝状聚合物纳米颗粒(NP)复合。RNA:纳米颗粒复合物作为单次皮内注射递送给荷有第4天颅内星形细胞瘤的小鼠。进行用总肿瘤RNA纳米颗粒(NP-TTRNA)的2次疫苗接种。如图2中所示,所有未经处理的小鼠在肿瘤植入30天内死亡。用总胚胎RNA(NP-E18 RNA)疫苗接种一次的小鼠有50%由单次疫苗接种治愈了已建立的肿瘤,而总肿瘤RNA纳米颗粒(NP-TTRNA)的2次疫苗接种治愈了33%的小鼠。结果还指出,胚胎抗原可以用作针对恶性神经胶质瘤的发育抗原的有效来源。由于现成可用性和扩增胚胎组织RNA的能力,这些结果还支持关于胚胎RNA疫苗可以作为用于疫苗接种的通用平台的原理,所述疫苗接种可以对抗脑瘤和与发育细胞共享基因表达模式的其他众多其他癌症。
实施例3
自体DC的离体产生
将Leukapheresis Product(LP)袋的内容物置于1L无菌康宁(corning)瓶中,并且加入等体积的磷酸缓冲盐水(PBS)以稀释LP。使用离心管,用30mL稀释LP轻轻在20mL HistopaqueTM(Sigma#1077-1)上成层,随后在1300xg下旋转25分钟。去除界面(1个界面/管);加入PBS至50mL;并且使细胞在500xg室温(RT)下形成团块5分钟。倾析上清液,并且使团块重悬浮于50mL PBS中,随后如上形成团块。倾析上清液,并且使2个团块在50mL PBS中组合,随后如上形成团块。再次,倾析上清液,并且使2个团块在50mL PBS中组合,随后如上形成团块。将团块组合,并用PBS洗涤,直至所有细胞组合到1个管内。
执行台盼蓝排除法,以借助血细胞计数器测定活和死细胞数目。使细胞以2×108/mL重悬浮于具有2%人AB血清(HABS)(ValleyBiomedical #HP1022)的AIM V培养基(Life Technologies #870112dk)中。将包含2%HABS的29mL AIM V培养基和1mL PBMC细胞悬浮液加入T-150细胞培养瓶中。将所有细胞培养瓶置于单个专用增湿温箱内在37℃、5%CO2下2小时,以允许单个核细胞前体贴壁。在贴壁期后,去除非贴壁细胞,并且剩余单层用PBS洗涤1次。在贴壁细胞中装满30ml AIM-V/烧瓶,所述AIM-V中补充有800U/mL重组人GM-CSF(Berlex Laboratories,Inc.)和500U/mL重组人IL-4(R&D Systems # 204-IL/CF),并且在增湿温箱中在37℃、5%CO2下温育7天。
在7天培养期后,用冷PBS洗涤贴壁DCs。加入10ml无酶的解离缓冲液(Dissociation Buffer Enzyme-Free)(Life Technologies#13150-016),并且使DCs在4℃下温育10分钟。从烧瓶中冲洗出其余贴壁DC,并且与先前收获的DC合并,随后在500xg下在4℃下形成团块10分钟。在用冷PBS洗涤1次后,检查细胞数目和活力。
实施例4
树突状细胞的RNA或肽装载和成熟
如上所述产生的树突状细胞2.5×107个细胞/mL ViaSpan(Belzer UW-CSS,DuPont Pharmaceuticals,Wilmington,DE)重悬浮。随后将200μL悬浮液置于比色杯(Gene Pulser Cuvette,Bio-Rad #165-2086)中,连同约25μg胚龄第18天(E18)的总胚胎RNA、发育细胞RNA、或稳定浓度的来自发育细胞的肽提取物,并且使细胞在300伏特下电穿孔(BTX Electro Square Porator#ECM830)500微秒。将约1×108个电穿孔细胞转移至包含50mL AIM V中的T225烧瓶内,所述AIM V中补充有800U/mL重组人GM-CSF(BerlexLaboratories,Inc.)和500U/ml重组人IL-4(R&D Systems #204-IL/CF),随后在37℃、5%CO2下温育1小时。在温育期结束时,在成熟混合物中加入合适量的具有成熟细胞因子的培养基至细胞因子的以下终浓度:10ng/ml TNF-α(R&D Systems,#210-TA/CF);10ng/mlIL-1β(R&D Systems,# 201-LB/CF);和1000单位/ml IL-6(R&DSystems,# 208-IL/CF)。将细胞在37℃和5%CO2下温育过夜。
在成熟期结束时,取出上清液并且置于在冰上冷冻的50ml锥形管中。其余单层用冰冷的PBS洗涤;与上清液组合;随后在500xg下在4℃下形成团块5分钟。使团块重悬浮于10ml冰冷的PBS中,并且维持在冰上。加入10-20ml无酶的解离缓冲液(LifeTechnologies # 13150-016),并且使细胞维持在4℃下,并且每5分钟监控实现的细胞进展。烧瓶用10ml冰冷的PBS洗涤2次,与来自解离缓冲液的细胞合并,并且使用500xg形成团块。将细胞与其他细胞合并,使体积达到50ml,计数。
实施例5
用于疫苗接种的树突状细胞的制剂
在50mL锥形离心管和25ml PBS中缓慢加入装载有成熟抗原的树突状细胞,随后使细胞在200xg下在22℃下形成团块5分钟。使用2ml移液管使细胞重悬浮于10ml PBS中,取出100μl悬浮液样品,并且如上所述使用血细胞计数器和台盼蓝计数细胞。在进展前细胞测定为≥70%存活。使细胞在500xg下在22℃下形成团块5分钟,并且以5×104细胞/mL重悬浮于0.9%氯化钠中。将细胞装载到具有25 G 5/8号针的1cc注射器内。在施用前对样品进行革兰氏染色和内毒素测试。
实施例6
T细胞的活化
由正常志愿者和具有癌症的受试者产生DCs,并且在AIM-V培养基-2%人AB血清中在37℃下用发育细胞肽提取物脉冲3小时。备选地,对于用编码多种发育细胞抗原的mRNA装载,洗涤DCs且重悬浮于Opti-MEM中用于电穿孔。用BTX ECM 830根据DCs的量电穿孔编码多种发育细胞抗原的mRNA的合适浓度。DCs用45ml AIM-V培养基洗涤1次,并且以1∶10比(DC∶T细胞)加入自体应答者淋巴细胞。作为T淋巴细胞来源,从具有例如恶性神经胶质瘤的受试者和正常个体中由外周血单核细胞(PBMCs)产生非贴壁(NA)细胞。通过Ficoll-Hypaque梯度分离(LSM;MP Biomedicals,Solon,OH)分离来自外周血的单个核细胞。
使体积调整至约2×106个细胞/ml,并且使细胞在37℃下在包含5%CO2的增湿气氛中温育。3天后,加入具有2%合并人AB血清加上IL-2(10U/ml)的等量AIM-V培养基,并且以1ml/孔的体积将细胞转移至24孔板。其后,每2-3天,就生长情况评估细胞并且调整至约1×106个细胞/ml。在与脉冲DCs共培养8-11天后,收获T细胞。
实施例7
疫苗的纳米颗粒/脂质递送
来自胚胎或胎儿组织、多能干细胞或组织衍生的祖细胞的发育细胞RNAs、蛋白质或肽裂解物各自与临床级别的纳米颗粒或脂质制剂复合,用于体内递送到人受试者内。合适复合剂的例子包括但不限于GMP级别的DOTAP & DOTAP:Cholesterol(Boehringer Mannheim,Germany)、cGMP级另的体内jetPEITM(Polyplus transfection,Inc.NY,NY)、和树枝状聚合物纳米颗粒。使RNA沉淀在金或银纳米颗粒上,用于通过基因枪技术的皮内递送。合适比的RNAs、蛋白质或肽裂解物与复合转染试剂在体外混合,以形成肽或RNA:纳米颗粒/脂质体复合物,并且随后通过静脉内、真皮内、皮下或肌内递送而递送给人受试者,以便诱导针对发育细胞抗原和共享癌抗原的免疫应答。在用发育细胞抗原进行疫苗接种之前、之时和之后,执行佐剂的递送(例如,在疫苗接种之前24小时、之时和之后24小时,在疫苗部位处递送150微克GM-CSF)。
实施例8
产生扩增的cDNA模板用于连续RNA生产
为了证实来自有限量分选细胞的RNA可以扩增至临床规模用于连续RNA生产,以便用于各种应用(例如,用于装载DCs)中,在FDA批准的临床级别细胞加工设备中,由少至500个CD133+癌症干细胞和CD133-分选肿瘤细胞成功产生了扩增的mRNA。使用掺入跨越在基因5′末端上的外显子连接区的基因特异性探针和引物的实时比较PCR,在扩增过程中每5个循环测定4种看家基因(即,18S、β-肌动蛋白、GADPH、HPRT)和CD133基因,用于检测全长或接近全长的扩增cDNA产物。在从CD133-细胞中分离的RNA中未检测出CD133基因表达。
CD133 RNA与个别看家基因的比较PCR定量显示于表1中。使用500个细胞-1000个输入细胞检测的针对4种看家基因各自标准化的CD133 RNA比是约2
表1:CD133 RNA的PCR定量
使用琼脂糖凝胶电泳显现扩增产物(图3a)。基因的相对比例在起始cDNA文库合成后高达30个扩增循环保持恒定,这之后观察到与看家基因比较而言CD133的逐步减少。使用cDNA文库的25个扩增循环作为用于RNA合成的终止点,在测试的2个患者样品中由500个CD133+细胞产生超过10μg模板cDNA。
来自8μg模板的RNA合成得到超过980μg体外转录的mRNA(IVT-RNA)(图3b)。通过凝胶电泳分析IVT-RNA,并且证实长度从100bp到超过4.0kb的一系列核酸种类。以较少量的较大RNA种类是可见的,但丰富得多的较小RNAs的过度暴露导致无法照相评估。这些结果证实了从有限数目的分选细胞(例如,CD133+肿瘤细胞)扩增RNA到临床规模的能力,例如用于DCs装载。
实施例9
通过扣除杂交法富集抗原
任选地去除由正常成人组织共享的抗原可以减少自身免疫风险且增强针对所需靶抗原的免疫。通过许多技术可以执行发育细胞抗原的富集,例如通过扣除杂交法富集编码发育细胞抗原的核酸。例如,Oligo(dT)25(Invitrogen Corporation,Carlsbad,CA)可以用于产生减除cDNA探针,用于筛选和分离罕见和/或差异表达的mRNAs。珠结合的寡核苷酸-dT序列可以用于引发cDNA合成,以产生对于特定细胞类型或组织特异的cDNA文库。
使用在恶性脑肿瘤样品中正常脑RNA和非癌症干细胞RNA的扣除杂交法,可以富集例如癌症干细胞抗原。通过使用例如商购可得的扣除杂交法试剂盒(Invitrogen Corporation,Carlsbad,CA),可以执行扣除杂交方案和cDNA文库合成,产生模板用于编码在发育细胞中特异性表达的抗原的RNA生产。扣除杂交法也描述于例如Hansen-Hagge等人,Nucl.Acids Res.29(4):e20(2001);Pradel等人,Appl.Env.Microbiol.68:2316-2325(2002);和Laveder等人,Nucleic Acids Res.30(9):e38(2002)中,这几篇文献均就其关于扣除杂交法的教导而合并入本文。
例如,靶mRNA包含总发育细胞或胚胎干细胞RNA;并且减除物mRNA包含来自靶组织(即,脑)的正常RNA或来自人器官的正常RNA库,以减少全身性交叉反应性。在最后的杂交步骤后,在10μL总反应体积中用PowerScriptTM Reverse Transcriptase(ClontechLaboratories,Inc,Mountain View,CA),采用经修饰的寡聚-dT引物(5’-AAG CAG TGG TAT CAA CGC AGA GTA C(T)64VN-3’)和T7链转换引物(5’-AAG CAG TGG TAT CAA CGC AGA GTG GCC ATA TTGGCC rGrGrG/3AmMC6-3’)引发,使来自发育细胞的被扣除mRNA逆转录为全长eDNA文库;并且使用实时PCR扩增。
由来自成胶质细胞瘤(定义为CD133+肿瘤细胞)的少至500个癌症干细胞的RNA扩增结果显示于图4中。RNA可以由来自发育细胞的现有cDNA文库(即,胚胎干细胞cDNA文库)制备或由原代发育细胞或已建立的细胞系制备。
Claims (32)
1.用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法,所述方法包括:
给所述受试者施用药学上可接受的组合物,其中包含多种发育细胞抗原或编码所述多种发育细胞抗原的核酸,其中所述药学上可接受的组合物当施用于所述受试者时,引发针对所述至少一种抗原的免疫应答。
2.权利要求1的方法,其中所述药学上可接受的组合物以足以预防或治疗受试者中的癌症的预防或治疗有效量提供。
3.权利要求1的方法,其中所述多种发育细胞抗原或编码所述多种发育细胞抗原的核酸对应于来自胚胎干细胞的抗原或编码该抗原的核酸。
4.权利要求1的方法,其中所述编码多种抗原的核酸是来自发育细胞的总RNA或多聚A+RNA。
5.权利要求1的方法,其中所述编码多种抗原的核酸是由来自发育细胞cDNA文库的cDNAs转录的RNAs。
6.权利要求1的方法,其中所述多种抗原是发育细胞的全细胞裂解物。
7.权利要求4的方法,其中所述编码多种抗原的核酸包括就以下转录物富集的RNAs,所述转录物(i)在正常产后组织中不转录;或(ii)相对于所述发育细胞,在正常产后组织中以基本上减少的水平转录。
8.权利要求1的方法,其中所述药学上可接受的组合物进一步包含至少一种佐剂、或编码所述佐剂的核酸。
9.权利要求8的方法,其中所述佐剂是选自下述的细胞因子:GM-CSF、G-CSF、IL-2、IL-4、IL-7、IL-12、IL-15、IL-21、TNF-α和M-CSF。
10.权利要求8的方法,其中所述佐剂包含不完全弗氏佐剂(Montanide ISA 51)或粒状棒状杆菌(Corynebacterium granulosum)P40。
11.权利要求1的方法,其中所述发育细胞对于所述受试者而言是异种的。
12.药学上可接受的组合物,其包含由发育细胞表达的多种抗原或编码所述多种抗原的核酸,其中所述药学上可接受的组合物当施用于受试者时,引发针对由癌细胞表达的至少一种抗原的免疫应答。
13.权利要求12的药学上可接受的组合物,其进一步包含生理学上可接受的载体、稀释剂或赋形剂。
14.权利要求12的药学上可接受的组合物,其进一步包含佐剂。
15.权利要求14的药学上可接受的组合物,其中所述佐剂是细胞因子。
16.权利要求14的药学上可接受的组合物,其中所述佐剂是选自下述的细胞因子:GM-CSF、G-CSF、IL-2、IL-4、IL-7、IL-12、IL-15、IL-21、TNF-α和M-CSF。
17.根据权利要求12-16中任一项的预防或治疗有效量的药学上可接受的组合物。
18.用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法,所述方法包括:
给所述受试者施用包含有效量的抗原呈递细胞、T淋巴细胞或两者的组合物,其中所述抗原呈递细胞和T淋巴细胞已在体外被致敏有效量的由发育细胞表达的多种抗原所致敏,其中所述有效量的抗原呈递细胞、T淋巴细胞或两者足以引发针对所述至少一种抗原的免疫应答。
19.权利要求19的方法,其中所述抗原呈递细胞或T淋巴细胞是自体的。
20.用于制备癌抗原预致敏的抗原呈递细胞的方法,所述方法包括:
在体外在足以使所述多种发育细胞抗原由所述抗原呈递细胞呈递的条件下,使抗原呈递细胞与多种发育细胞抗原或编码所述多种发育细胞抗原的核酸接触。
21.包括抗原呈递细胞的组合物,所述抗原呈递细胞已在体外在足以使所述多种发育细胞抗原由所述抗原呈递细胞呈递的条件下与多种发育细胞抗原或编码所述多种发育细胞抗原的核酸接触。
22.用于制备癌抗原特异性淋巴细胞的方法,所述方法包括:
a)在体外在足以使所述多种发育细胞抗原由所述抗原呈递细胞呈递的条件下,使抗原呈递细胞与多种发育细胞抗原或编码所述多种发育细胞抗原的核酸接触;和
b)在足以产生能够引发针对癌细胞的免疫应答的癌抗原特异性淋巴细胞的条件下,使淋巴细胞与步骤a)的抗原呈递细胞接触。
23.权利要求22的方法,其中所述淋巴细胞是T淋巴细胞。
24.包括T淋巴细胞的组合物,所述T淋巴细胞已在足以产生能够引发针对癌细胞的免疫应答的癌抗原特异性淋巴细胞的条件下与抗原呈递细胞接触,其中所述抗原呈递细胞已在体外在足以使所述多种发育细胞抗原由所述抗原呈递细胞呈递的条件下与多种发育细胞抗原或编码所述多种发育细胞抗原的核酸接触。
25.用于治疗或预防受试者中的癌症的方法,所述方法包括:
给所述受试者施用治疗或预防有效量的如权利要求12-17、21或24中任一项的组合物。
26.用于在受试者中引发针对由癌细胞表达的至少一种抗原的免疫应答的方法,所述方法包括:
给所述受试者施用药学上可接受的组合物,其包含离体装载有多种发育细胞抗原或编码所述多种发育细胞抗原的核酸的树突状细胞,其中所述药学上可接受的组合物当施用于所述受试者时,引发针对所述至少一种抗原的免疫应答。
27.在受试者中引发针对癌细胞的免疫应答的方法,所述方法包括:
给所述受试者施用药学上可接受的组合物,其包含针对多种发育细胞抗原产生的抗体。
28.权利要求27的方法,其中所述抗体与毒性部分缀合,由此所述抗体将细胞毒性剂量的所述毒性部分有效递送给所述癌细胞。
29.权利要求28的方法,其中所述毒性部分是放射性同位素,由此所述抗体将所述细胞毒性剂量作为微粒辐射递送给所述癌细胞。
30.试剂盒,其包含药学上可接受的组合物,所述组合物包含由发育细胞表达的多种抗原或编码所述多种抗原的核酸,其中所述药学上可接受的组合物当施用于受试者时,引发针对由癌细胞表达的至少一种抗原的免疫应答。
31.权利要求30的试剂盒,其进一步包含佐剂。
32.权利要求30的试剂盒,其进一步包含化学治疗剂。
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