CN109475579A - Cmv表位 - Google Patents
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- CN109475579A CN109475579A CN201780045358.8A CN201780045358A CN109475579A CN 109475579 A CN109475579 A CN 109475579A CN 201780045358 A CN201780045358 A CN 201780045358A CN 109475579 A CN109475579 A CN 109475579A
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Abstract
本文提供与在受试者中治疗CMV感染和/或CMV癌症相关的组合物和方法。特别地,提供了CMV表位KARAKKDELR、ARAKKDELR、KARAKKDELK、ARAKKDELK、RRKMMYMYCR、KRKMIYMYCR、VLEETSVML、YILEETSVML、DELRRKMMY、ELKRKMIY、EEAIAVAYL、EDAIAAYTL、ELRRKMMYM、ELKRKMIYM、AYAQKIFKIL、TYSQKIFKIL、FMDILTTCV、NLVPMVATV、RPHERNGFTVL、TPRVTGGGAM、VTEHDTLLY、QIKVRVDMV和YSEHPTFTSQ。此外,还提供了与这样的表位结合的抗体、这样的表位的肽和核酸等同物、表达与这样的表位结合的T细胞受体(TCR)的T细胞、并入这样的表位的疫苗、具有I类MHC上呈递的这样的表位的抗原呈递细胞(APC)、以及其治疗和/或预防癌症或巨细胞病毒(CMV)感染的方法。
Description
相关申请
本申请要求于2016年5月23日提交的美国临时专利申请序列号62/340,223的优先权的权益,其特此通过引用被整体并入。
巨细胞病毒(CMV,也称为人疱疹病毒-5型)是几乎无处不在的疱疹病毒,其感染60%与90%之间的个体。在原发感染后,CMV通常建立处于受健康免疫系统控制的持续性感染。CMV采用众多免疫调节策略,以逃避宿主免疫应答。这样的策略的实例包含抑制干扰素(IFN)和IFN刺激的基因、降解HLA以防止抗原呈递至细胞毒性T细胞、以及调节激活和抑制配体以防止自然杀伤(NK)细胞功能。
虽然在健康个体中CMV感染通常未被注意,但是免疫系统受损的个体(例如,HIV感染者、器官移植受者)中的病毒潜伏期的再激活、或这样的个体中的原发感染的获得(例如,在移植期间)可以导致严重的疾病。例如,CMV是需要长期免疫抑制的移植受者的移植失败和死亡的主要原因之一,并且妊娠期间的CMV感染可以导致先天性畸形。即使在免疫活性个体中,CMV感染也已经与癌症联系起来。
目前使用纯化的血浆免疫球蛋白(CMV-IGIV)和抗病毒药(如更昔洛韦(ganciclovir)(Cytovene)和缬更昔洛韦(valganciclovir)(Valcyte))治疗免疫系统受损的个体中的CMV感染。因为CMV-IVIG源自捐献的人血浆,因此难以大量地产生,并且其使用带有传播感染性疾病的风险。耐药性CMV株已经变得越来越常见,往往使目前的疗法无效。最近对开发CMV疫苗的尝试已经被证明是不成功的。因此,存在对于用于治疗CMV和CMV相关性癌症的新的和改进的方法和组合物的极大的需要。
概述
本文提供与CMV表位(例如,表1中列出的CMV表位)相关的组合物和方法,所述CMV表位由细胞毒性T淋巴细胞(CTL)识别并且在CMV感染和/或CMV癌症(例如,表达本文提供的CMV表位的癌症)的预防和/或治疗中是有用的。
在某些方面,本文提供含有包括本文所描述的CMV表位(例如,表1中列出的CMV表位)中的一个或更多个的多肽和/或编码这样的多肽的核酸的组合物(例如,治疗组合物(如疫苗组合物)),以及通过将这样的组合物施用至受试者来治疗和/或预防CMV感染和/或癌症的方法。在一些实施方案中,多肽不是全长CMV蛋白。在一些实施方案中,多肽含有全长CMV蛋白的不超过15、20、25、30、35或40个邻接的氨基酸。在一些实施方案中,多肽基本上由本文所描述的CMV表位组成。在一些实施方案中,多肽由本文所描述的CMV表位组成。在一些实施方案中,多肽的长度不超过15、20、25、30、35或40个氨基酸。在一些实施方案中,组合物还包括佐剂。
在一些方面,本文提供例如通过将包括CTL的样品(即,PBMC样品)与呈递本文所描述的CMV表位中的一个或更多个的抗原呈递细胞(APC)(例如,呈递包括I类MHC复合体上的本文所描述的CMV表位的肽的APC)孵育,来生成CTL、激活CTL和/或诱导CTL增殖的方法,所述CTL识别本文所描述的CMV表位中的一个或更多个。在一些实施方案中,APC对于从其获得CTL的受试者是自体的。在一些实施方案中,APC对于从其获得CTL受试者不是自体的。在一些实施方案中,APC是B细胞、抗原呈递T细胞、树突状细胞、或人工抗原呈递细胞(例如,aK562细胞)。在一些方面,抗原呈递细胞(例如,aK562细胞)表达CD80、CD83、41BB-L和/或CD86。
在一些方面,本文提供包括识别本文所描述的CMV表位中的一个或更多个的CTL(即,表达与包括I类MHC复合体上呈递的本文所描述的CMV表位的肽结合的T细胞受体(TCR)的CTL)的组合物(例如,治疗组合物),以及通过将这样的组合物施用至受试者来治疗和/或预防CMV感染和/或癌症的方法。例如,在一些实施方案中,本文提供用于在受试者中治疗和/或预防癌症和/或CMV感染的方法,所述方法包括向受试者施用包括CTL的组合物,所述CTL识别本文所描述的CMV表位中的一个或更多个。在一些实施方案中,CTL对于受试者不是自体的。在一些实施方案中,T细胞对于受试者是自体的。在一些实施方案中,在CTL被施用至受试者之前,其被储存在细胞库中。在一些实施方案中,方法还包括使用本文所描述的方法生成CTL、激活CTL和/或诱导CTL的增殖。在一些方面,本文提供表达T细胞受体(TCR)的T细胞(例如,CTL),所述T细胞受体(TCR)与主要组织相容性复合体(MHC)上呈递的表1中列出的肽结合。
在一些实施方案中,本文提供呈递一种或更多种包括本文所描述的CMV表位的肽的APC(例如,呈递I类MHC上的CMV表位中的一个或更多个的APC)。在某些方面,本文提供生成呈递本文所描述的CMV表位中的一个或更多个的APC的方法,所述方法包括使APC与包括本文所描述的CMV表位的肽和/或与编码本文所描述的CMV表位的核酸接触。在一些实施方案中,APC对于从其获得CTL的受试者不是自体的。在一些实施方案中,APC是B细胞、抗原呈递T细胞、树突状细胞或人工抗原呈递细胞(例如,aK562细胞)。在一些方面,抗原呈递细胞(例如,aK562细胞)表达CD80、CD83、41BB-L、和/或CD86。在一些实施方案中,本文提供在受试者中治疗或预防癌症和/或CMV感染的方法,所述方法包括向受试者施用本文所描述的APC的步骤。
在某些方面,本文提供与本文所描述的CMV表位特异性结合的抗原结合分子(例如,抗体、抗体片段、TCR、嵌合抗原受体(CAR))。在一些实施方案中,抗原结合分子是抗体或抗体的抗原结合片段。在一些实施方案中,抗体是嵌合抗体、人源化抗体或全人源抗体。在一些实施方案中,抗体或抗体的抗原结合片段是全长免疫球蛋白分子、scFv、Fab片段、Fab’片段、F(ab’)2片段、Fv、骆驼Fv或二硫键连接的Fv。在一些实施方案中,抗体以不大于约10- 7M、10-8M或10-9M的解离常数与本文提供的表位结合。在一些实施方案中,抗原结合分子被缀合至药物(例如,作为抗体-药物缀合物的一部分)。在一些实施方案中,抗原结合分子被连接至细胞毒素剂(例如,MMAE、DM-1、美登木素、阿霉素衍生物、澳瑞他汀(auristatin)、卡开素(calcheamicin)、CC-1065、倍癌霉素(aduocarmycin)或蒽环类抗生素)。在一些实施方案中,抗原结合分子被连接至抗病毒剂(例如,更昔洛韦、缬更昔洛韦、膦甲酸、西多福韦(cidofovir)、阿昔洛韦、福米韦生(formivirsen)、马立巴韦(maribavir)、BAY 38-4766或GW275175X)。在一些实施方案中,本文提供在受试者中治疗癌症和/或CMV感染的方法,所述方法包括向受试者施用本文公开的抗原结合分子。
在一些方面,本文提供包括编码本文提供的肽中的一个或更多个的序列的核酸。在一些实施方案中,编码本文提供的肽中的一个或更多个的序列被可操作地连接至一个或更多个调控序列。在一些实施方案中,核酸是表达运载体。在一些实施方案中,核酸是腺病毒运载体。
在一些方面,本文提供药物组合物,所述药物组合物包括本文所描述的CMV肽、CTL、APC、核酸、和/或抗原结合分子以及药学上可接受的载体。在一些实施方案中,本文提供用于通过施用本文提供的药物组合物在受试者中治疗和/或预防CMV感染和/或癌症的方法。
在一些方面,本文提供鉴别适合于本文提供的治疗方法(例如,本文所描述的CTL、APC、多肽、组合物、抗体或核酸的施用)的受试者的方法,所述方法包括从受试者分离样品,并且检测样品(例如,血液样品或肿瘤样品)中本文提供的CMV表位或编码本文提供的CMV表位的核酸的存在。在一些实施方案中,通过使样品与本文提供的抗原结合分子接触检测本文提供的CMV表位。在一些实施方案中,使用治疗方法治疗被鉴别为适合于本文提供的治疗方法的受试者。
附图的简要说明
图1示出造血干细胞移植(HSCT)受者中IE-1序列变体的焦磷酸测序分析。
图2示出HSCT移植受者中病毒再激活后变体特异性T细胞激活的动力学。
图3示出IE-1变体特异性T细胞群体的功能性亲和力分析。
图4示出共感染对病毒再激活的影响和病毒再激活与整体T细胞免疫的关联。
详细说明
综述
本文提供与CMV表位(例如,表1中列出的CMV表位)相关的组合物和方法,所述CMV表位由细胞毒性T淋巴细胞(CTL)识别并且在CMV感染和/或癌症的预防和/或治疗中是有用的。在某些方面,本文提供组合物(例如,治疗组合物(如疫苗组合物))以及通过向受试者施用这样的组合物来治疗和/或预防CMV感染和/或癌症的方法,所述组合物含有包括本文所描述的CMV表位(例如,表1中列出的CMV表位)中的一个或更多个的多肽、编码这样的多肽的核酸、识别这样的肽的CTL、呈递这样的肽的APC、和/或与这样的肽特异性结合的抗原结合分子。在一些实施方案中,本文还提供鉴别适合于根据本文提供的方法的治疗的受试者的方法。
定义
为了方便起见,此处收集了说明书、实施例和所附权利要求中采用的某些术语。
本文中使用冠词“一(a)”和“一(an)”指所述冠词的一个或多于一个(即,至少一个)语法对象。举例来说,“一要素”意指一个要素或多于一个要素。
如本文所使用的,术语“施用”意指向受试者提供药剂或药物组合物,并且包含(但不限于)由医疗技术人员施用和自我施用。这样的药剂可以含有例如本文所描述的肽、本文提供的抗原呈递细胞和/或本文提供的CTL。
术语“氨基酸”旨在包括包含氨基官能性和酸官能性两者并且能够被包含在天然存在的氨基酸的聚合物中的全部分子(无论是天然的还是合成的)。示例性氨基酸包含天然存在的氨基酸;其类似物、衍生物和同源物;具有变体侧链的氨基酸类似物;以及前述中任何一种的全部立体异构体。
如本文所使用的,术语“抗体”可以指完整抗体及完整抗体的抗原结合片段两者。完整抗体是糖蛋白,所述糖蛋白包含通过二硫键互相连接的至少两条重(H)链和两条轻(L)链。每条重链包含重链可变区(本文中缩写为VH)和重链恒定区。每条轻链包含轻链可变区(本文中缩写为VL)和轻链恒定区。VH区和VL区可以进一步再分成高变区(被称为互补决定区(CDR)),所述高变区散布有更保守的区域(被称为骨架区(FR))。重链和轻链的可变区含有与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或宿主因子的结合,所述宿主组织或宿主因子包含免疫系统的各种细胞(例如,效应细胞)和经典补体系统的第一组分(Clq)。术语“抗体”包含,例如,单克隆抗体、多克隆抗体、嵌合抗体、人源化抗体、人源抗体、多特异性抗体(例如,双特异性抗体)、单链抗体和抗原结合抗体片段。
如本文所使用的,术语抗体的“抗原结合片段”和“抗原结合部分”指保留与抗原结合的能力的抗体的一个或更多个片段。包括在术语抗体的“抗原结合片段”内的结合片段的实例包含Fab、Fab’、F(ab’)2、Fv、scFv、二硫键连接的Fv、Fd、双抗体、单链抗体、骆驼抗体、分离的CDRH3、以及保留完整抗体的可变区的至少一部分的其他抗体片段。可以使用常规重组技术和/或酶促技术获得这些抗体片段,并且可以以与完整抗体相同的方式筛选抗原结合。
术语“结合”或“相互作用”指由于例如生理条件下的静电相互作用、疏水相互作用、离子相互作用和/或氢键相互作用而在两个分子之间(例如,肽和结合配偶体或药剂(例如,小分子)之间)的缔合(其可以是稳定的缔合)。
术语“生物样品”、“组织样品”或简单地“样品”各自指从受试者的组织获得的细胞的集合。组织样品的来源可以是如来自新鲜、冷冻和/或保存的器官、组织样品、活组织检查、或抽出物的实体组织;血液或任何血液成分、血清、血液;体液,如脑脊液、羊膜水、腹膜液或间质液、尿液、唾液、粪便、眼泪;或来自受试者的妊娠或发育的任何时间的细胞。
如本文所使用的,术语“癌症”包含(但不限于)实体肿瘤和血液传播肿瘤。术语癌症包含皮肤、组织、器官、骨骼、软骨、血液和血管的疾病。术语“癌症”还包含原发性癌症和转移性癌症。
术语“表位”意为能够与抗体特异性结合的蛋白决定簇。表位通常由分子的化学活性表面基团(如氨基酸或糖侧链)组成。某些表位可以由T细胞受体或抗体能够结合的特定氨基酸序列限定。
术语“分离的核酸”指天然来源或合成来源的多核苷酸或天然来源或合成来源的多核苷酸的一些组合,其(1)与自然界中发现“分离的核酸”的细胞无关,和/或(2)被可操作地连接至在自然界中不连接的多核苷酸。
术语“分离的多肽”指在某些实施方案中由重组DNA或RNA制备的多肽、或合成来源的多肽、或其的一些组合,其(1)与通常在自然界中发现的蛋白质无关,(2)从其通常存在的细胞中分离,(3)从相同的细胞来源中分离出而不含其他蛋白质,(4)由来自不同物种的细胞表达,或(5)在自然界中不存在。
如本文所使用的,短语“药学上可接受的”指在合理的医学判断范围内适合于与人类和动物的组织接触,而没有过度毒性、刺激、过敏反应或其他问题或并发症,与合理的利益/风险比相称的那些药剂、化合物、材料、组合物和/或剂量。
如本文所使用的,短语“药学上可接受的载体”意为药学上可接受的材料、组合物或运载体(vehicle)(如液体或固体填充剂、稀释剂、赋形剂、或溶剂包封材料),其涉及将药剂从器官、或身体的一部分携带或转运至另一器官、或身体的一部分。每种载体在与制剂的其他成分相容并且对患者无害的意义上必须是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包含:(1)糖(如乳糖、葡萄糖和蔗糖);(2)淀粉(如玉米淀粉和马铃薯淀粉);(3)纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素和乙酸纤维素);(4)粉状黄芪胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂(如可可脂和栓剂蜡);(9)油类(如花生油、棉籽油、红花子油、麻油、橄榄油、玉米油和大豆油);(10)二醇类(如丙二醇);(11)多元醇(如甘油、山梨糖醇、甘露糖醇和聚乙二醇);(12)酯类(如油酸乙酯和十二烷酸乙酯);(13)琼脂;(14)缓冲剂(如氢氧化镁和氢氧化铝);(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酸酐;以及(22)药物制剂中采用的其他无毒相容物质。
术语“多核苷酸”和“核酸”被可互换地使用。它们指任何长度的核苷酸的聚合体形式,脱氧核糖核苷酸、核糖核苷酸或其类似物。多核苷酸可以具有任何三维结构,并且可以执行任何功能。以下是多核苷酸的非限制性实例:基因或基因片段的编码区或非编码区、由连锁分析确定的基因座(loci)(基因座(locus))、外显子、内含子、信使RNA(mRNA)、转移RNA、核糖体RNA、核糖酶、cDNA、重组多核苷酸、支化多核苷酸、质粒、运载体、任何序列的分离的DNA、任何序列的分离的RNA、核酸探针和引物。多核苷酸可以包括经修饰的核苷酸,如甲基化的核苷酸和核苷酸类似物。如果存在的话,对核苷酸结构的修饰可以在聚合物的组装之前或之后被赋予。多核苷酸可以被进一步修饰,如通过与标记组件偶联。在本文提供的全部核酸序列中,U核苷酸与T核苷酸是可互换的。
如本文所使用的,“预防”病况的治疗剂指化合物,当在紊乱或病况的发作之前被施用至统计样品时,相对于未经处理的对照样品,所述化合物降低经处理的样品中的紊乱或病况的发生,或相对于未经处理的对照样品,所述化合物延迟紊乱或病况的一种或更多种症状的发作或降低紊乱或病况的一种或更多种症状的严重性。
如本文所使用的,“特异性结合”指抗体与预定抗原结合的能力或肽与其预定结合配偶体结合的能力。通常,抗体或肽以对应于约10-7M或更小的KD的亲和力与其预定抗原或预定结合配偶体特异性结合,并且以比其对于与非特异性和不相关的抗原/结合配偶体(例如,BSA、酪蛋白)结合的亲和力小至少10倍、小至少100倍、或小至少1000倍的亲和力(如由KD表示的)与预定抗原/结合配偶体结合。
如本文所使用的,术语“受试者”意为被选择用于治疗或疗法的人或非人动物。
如本文所使用的,短语“治疗有效量”和“有效量”意为以适用于任何医学治疗的合理的利益/风险比在受试者中的至少一个细胞亚群中对于产生期望的治疗效果有效的药剂的量。
在受试者中“治疗”疾病或“治疗”患有疾病的受试者指使受试者经受药物治疗(例如,施用药物),使得疾病的至少一种症状被减轻或防止恶化。
术语“运载体(vector)”指工具(means),通过所述工具,核酸可以在生物体、细胞或细胞组分之间繁殖和/或转移。运载体包含质粒、病毒、噬菌体、前病毒、噬菌粒、转位子和人工染色体等,其可能能够或可能不能够自主复制或整合到宿主细胞的染色体中。
肽
本文提供包括CMV表位的肽,所述CMV表位由细胞毒性T淋巴细胞(CTL)识别,并且在CMV感染和/或癌症(例如,表达本文提供的CMV表位的癌症)的预防和/或治疗中是有用的。在某些实施方案中,CMV表位是表1中列出的表位。
表1.示例性CMV表位
在一些实施方案中,本文提供的肽是全长CMV蛋白。在一些实施方案中,本文提供的肽包括CMV病毒蛋白的小于100、90、80、70、60、50、40、30、25、20、15或10个邻接的氨基酸。在一些实施方案中,本文提供的肽包括表1中列出的CMV表位中的两个或更多个。例如,在一些实施方案中,本文提供的肽包括通过多肽连接体连接的表1中列出的CMV表位中的两个或更多个。在一些实施方案中,本文提供的肽包括表1中列出的表位中的2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个。
在一些实施方案中,本文提供的肽由表1中列出的表位组成。在一些实施方案中,本文提供的肽基本上由表1中列出的表位组成。在一些实施方案中,除表1中列出的表位之外,本文提供的肽还包括不超过20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2或1个氨基酸。
在一些实施方案中,除一个或更多个(例如,1、2、3、4、5、6、7、8、9、10或更多个)保守序列修饰之外,肽的序列包括EBV病毒蛋白序列。如本文所使用的,术语“保守序列修饰”旨在指不显著地影响或改变TCR与含有MHC上呈递的氨基酸序列的肽之间的相互作用的氨基酸修饰。这样的保守修饰包含氨基酸置换、添加(例如,向肽的N末端或C末端添加氨基酸)和缺失(例如,从肽的N末端或C末端缺失氨基酸)。保守氨基酸置换是其中氨基酸残基被具有相似侧链的氨基酸残基替代的氨基酸置换。本领域中已经定义了具有相似侧链的氨基酸残基家族。这些家族包含具有碱性侧链的氨基酸(例如,赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(例如,天门冬氨酸、谷氨酸)、具有不带电荷的极性侧链的氨基酸(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、具有非极性侧链的氨基酸(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、具有β-支化侧链的氨基酸(例如,苏氨酸、缬氨酸、异亮氨酸)和具有芳香族侧链的氨基酸(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,本文所描述的肽的一个或更多个氨基酸残基可以被来自相同侧链家族的其他氨基酸残基替代,并且可以使用本领域已知的方法测试改变的肽的TCR结合的保留。可以通过本领域已知的标准技术(如定点诱变和PCR介导的诱变)将修饰引入抗体。
为了测定两个氨基酸序列或两个核酸序列的百分比一致性,序列被比对以用于最优比较目的(例如,可以在第一氨基酸序列和第二氨基酸序列或第一核酸序列和第二核酸序列中的一个或两个中引入空位以用于最优比对,并且可以忽略非一致序列以用于比较目的)。然后比较相应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置被与第二序列中的相应位置相同的氨基酸残基或核苷酸占据时,则分子在该位置处是一致的。考虑到空位的数量和每个空位的长度(其需要被引入以用于两个序列的最优比对),两个序列之间的百分比一致性是序列共有的一致位置的数量的函数。
本文还提供嵌合蛋白或融合蛋白。如本文所使用的,“嵌合蛋白”或“融合蛋白”包括连接至不同的肽(本文提供的一个或多个肽在自然界中不连接至所述不同的肽)的本文提供的一个或多个肽(例如,包括表1中列出的表位的那些)。例如,不同的肽可以通过肽键直接地融合至肽的N-末端或C-末端或通过化学连接体间接地融合至肽的N-末端或C-末端。在一些实施方案中,本文提供的肽被连接至包括其他CMV表位的多肽。在一些实施方案中,本文提供的肽被连接至包括来自其他病毒和/或感染性疾病的表位的肽。在一些实施方案中,本文提供的肽被连接至编码癌症有关的表位的肽。
可以通过标准重组DNA技术产生本文提供的嵌合肽或融合肽。例如,根据常规技术,例如,通过采用平端末端或交错端末端以用于连接、限制酶消化以提供适当的末端、酌情补平粘性端、碱性磷酸酶处理以避免不期望的连接、以及酶促连接,将编码不同肽序列的DNA片段在框内连接在一起。在另一个实施方案中,可以通过常规技术(包含自动DNA合成仪)合成融合基因。可替代地,可以使用锚定引物进行基因片段的PCR扩增,所述锚定引物在两个连续基因片段之间产生互补突出端,其随后可以退火并且再扩增以生成嵌合基因序列(参见,例如,Current Protocols in Molecular Biology,Ausubel et al.,eds.,JohnWiley&Sons:1992)。此外,许多表达运载体是商业可获得的,所述表达运载体已经编码融合部分。
在一些方面,本文提供呈递本文所描述的肽(例如,包括表1中列出的表位的肽)的细胞。在一些实施方案中,细胞是哺乳动物细胞。在一些实施方案中,细胞是抗原呈递细胞(APC)(例如,抗原呈递T细胞、树突状细胞、B细胞、巨噬细胞或人工抗原呈递细胞(如aK562细胞))。可以通过本领域已知的标准技术产生本文中所描述的呈递肽的细胞。例如,细胞可以被施以脉冲以促进肽摄取。在一些实施方案中,用编码本文提供的肽的核酸转染细胞。在一些方面,本文提供产生抗原呈递细胞(APC)的方法,所述方法包括用本文所描述的肽对细胞施以脉冲。产生抗原呈递细胞的示例性实例可以在WO2013088114中找到,其特此被整体并入本文。
本文提供的肽可以使用标准蛋白质纯化技术通过适当的纯化方案从细胞来源或组织来源分离,可以通过重组DNA技术产生,和/或可以使用标准肽合成技术以化学方法合成。可以通过编码本发明的一种或多种肽的核苷酸的表达,在原核宿主细胞或真核宿主细胞中产生本文所描述的肽。可替代地,可以通过化学方法合成这样的肽。用于在重组宿主中表达异源肽的方法、肽的化学合成的方法和体外翻译的方法是本领域公知的,并且被进一步在Maniatis et al.,Molecular Cloning:A Laboratory Manual(1989),2nd Ed.,ColdSpring Harbor,N.Y.;Berger and Kimmel,Methods in Enzymology,Volume 152,Guideto Molecular Cloning Techniques(1987),Academic Press,Inc.,San Diego,Calif.;Merrifield,J.(1969)J.Am.Chem.Soc.91:501;Chaiken I.M.(1981)CRCCrit.Rev.Biochem.11:255;Kaiser et al.(1989)Science 243:187;Merrifield,B.(1986)Science 232:342;Kent,S.B.H.(1988)Annu.Rev.Biochem.57:957;以及Offord,R.E.(1980)Semisynthetic Proteins,Wiley Publishing中描述,其通过引用被并入本文。
核酸分子
本文提供编码本文所描述的肽的核酸分子。在一些方面,本文提供通过向受试者施用本文公开的核酸来治疗癌症或CMV的方法。核酸可以存在于例如全细胞中、细胞裂解物中、或以部分经纯化的或基本上纯的形式存在。
在一些实施方案中,本文提供含有本文所描述的核酸分子的运载体(例如,病毒运载体,如基于腺病毒的表达运载体)。如本文所使用的,术语“运载体”指能够转运已经与其连接的另一核酸的核酸分子。一种类型的运载体是“质粒”,其指环状双链DNA环,附加的DNA区段可以连接至所述环状双链DNA环中。另一种类型的运载体是病毒运载体,其中附加的DNA区段可以连接至病毒基因组中。某些运载体能够在其被引入的宿主细胞中自主复制(例如,具有细菌复制起点的细菌运载体、游离型哺乳动物运载体)。其他运载体(例如,非游离型哺乳动物运载体)在被引入到宿主细胞时可以被整合到宿主细胞基因组中,并且从而与宿主基因组一起被复制。此外,某些运载体能够指导基因的表达。这样的运载体在本文中被称为“重组表达运载体”(或简单地“表达运载体”)。在一些实施方案中,本文提供被可操作地连接至表达运载体中的一个或更多个调控序列(例如,启动子)的核酸。在一些实施方案中,细胞转录本文提供的核酸,并且从而表达本文所描述的抗体、抗体的抗原结合片段或肽。核酸分子可以被整合到细胞的基因组中,或其可以在染色体外。
在一些实施方案中,本文提供的核酸是疫苗的一部分。在一些实施方案中,疫苗在运载体中递送至受试者,所述运载体包含(但不限于)细菌运载体和/或病毒运载体。细菌运载体的实例包含(但不限于)牛分支杆菌(BCG)、鼠伤寒沙门菌亚种、伤寒沙门菌亚种、梭菌属孢子、大肠杆菌Nissle 1917、大肠杆菌K-12/LLO、产单核细胞李斯特菌、以及弗氏志贺菌。病毒运载体的实例包含(但不限于)牛痘、腺病毒、RNA病毒(复制子)、以及复制缺陷型如禽痘、鸟痘、金丝雀痘、MVA和腺病毒。
在一些实施方案中,本文提供含有本文所描述的核酸(例如,编码本文所描述的抗体、其抗原结合片段、或肽的核酸)的细胞。细胞可以是,例如,原核的、真核的、哺乳动物的、禽的、鼠科的和/或人的。在一些实施方案中,细胞是哺乳动物细胞。在一些实施方案中,细胞是APC(例如,抗原呈递T细胞、树突状细胞、B细胞或aK562细胞)。在本发明的方法中,本文所描述的核酸可以例如以核酸无需递送运载体(vehicle)被施用至细胞、与递送试剂组合被施用至细胞。在一些实施方案中,本领域已知的任何核酸递送方法可以被用于本文所描述的方法中。合适的递送试剂包含(但不限于)例如,Mirus Transit TKO亲脂性试剂;转化脂(lipofectin);阳离子脂质体(lipofectamine);细胞转染剂(cellfectin);聚阳离子(例如,聚赖氨酸)、缺端胶原、纳米颗粒系统(nanoplexe)和脂质体。在本文所描述的方法的一些实施方案中,脂质体被用于将核酸递送至细胞或受试者。适合于在本文所描述的方法中使用的脂质体可以由标准囊泡形成脂类形成,所述标准囊泡形成脂类通常包含中性的或带负电的磷脂和甾醇(如胆甾醇)。通常由考虑因素(如期望的脂质体尺寸和脂质体在血流中的半衰期)来指导脂类的选择。已知用于制备脂质体的各种各样的方法,例如,如Szoka etal.(1980),Ann.Rev.Biophys.Bioeng.9:467;和美国专利号4,235,871、4,501,728、4,837,028和5,019,369中所描述的,其全部公开内容通过引用被并入本文。
抗体
在一些方面,本文提供的组合物和方法涉及与CMV感染的细胞或癌症细胞的质膜上表达的蛋白质(例如,包括表1中列出的表位的蛋白质)特异性结合的抗体和所述抗体的抗原结合片段。在一些实施方案中,抗体与本文提供的肽中的一个的特定表位结合。在一些实施方案中,抗体与包括表1中具有氨基酸序列的表位的CMV蛋白结合,其中CMV蛋白不是全长CMV蛋白。在一些实施方案中,表位是细胞外表位。在一些实施方案中,表位是表1中列出的表位。在一些实施方案中,抗体可以是多克隆的或单克隆的,并且可以是,例如,鼠科的、嵌合的、人源化的或完全人源的。在一些实施方案中,抗体是全长免疫球蛋白分子、scFv、Fab片段、Fab’片段、F(ab’)2片段、Fv、骆驼抗体或二硫键连接的Fv。
可以通过用肽免疫原(例如,表1中列出的氨基酸序列)免疫适合的受试者(例如,小鼠)来制备多克隆抗体。在一些实施方案中,肽免疫原包括本文提供的靶蛋白的细胞外表位。可以通过标准技术(如使用固定化肽用酶联免疫吸附测定(ELISA))随时间监控经免疫的受试者中的肽抗体滴度。如果期望,可以从哺乳动物中(例如,从血液中)分离针对抗原的抗体,并且通过公知的技术(如蛋白A层析)进一步纯化以获得IgG级分。
在免疫之后的适当时间(例如,当抗体滴度最高时),可以从受试者获得抗体产生细胞,并且用于使用标准技术(如最初由Kohler and Milstein(1975)Nature 256:495-497描述的杂交瘤技术(另参见Brown et al.(1981)J.Immunol.127:539-46;Brown et al.(1980)J.Biol.Chem.255:4980-83;Yeh et al.(1976)Proc.Natl.Acad.Sci.76:2927-31;以及Yeh et al.(1982)Int.J.Cancer 29:269-75)、人B细胞杂交瘤技术(Kozbor et al.(1983)Immunol.Today 4:72)、EBV杂交瘤技术(Cole et al.(1985)MonoclonalAntibodies and Cancer Therapy,Alan R.Liss,Inc.,pp.77-96)或三体杂交瘤(trioma)技术)制备单克隆抗体。用于产生单克隆抗体杂交瘤的技术是公知的(通常参见Kenneth,R.H.in Monoclonal Antibodies:A New Dimension In Biological Analyses,PlenumPublishing Corp.,New York,New York(1980);Lerner,E.A.(1981)Yale J.Biol.Med.54:387-402;Gefter,M.L.et al.(1977)Somatic Cell Genet.3:231-36)。简而言之,将永生细胞系(典型地是骨髓瘤)与来自如上所述用免疫原免疫的哺乳动物的淋巴细胞(典型地是脾细胞)融合,并且筛选所得到的杂交瘤细胞的培养物上清液,以鉴别产生与肽抗原结合(优选特异性地)的单克隆抗体的杂交瘤。
作为制备分泌单克隆抗体的杂交瘤的供替代的选择,可以通过用适当的肽(例如包括表1的表位的肽)筛选重组组合免疫球蛋白信息库来获得与本文所描述的靶蛋白结合的单克隆抗体,以从而分离结合肽的免疫球蛋白信息库成员。
此外,可以使用标准重组DNA技术制造对于本文提供的靶蛋白和/或本文提供的靶蛋白的细胞外表位特异性的重组抗体(如嵌合单克隆抗体或人源化单克隆抗体)。这样的嵌合单克隆抗体和人源化单克隆抗体可以通过本领域已知的重组DNA技术产生,例如使用描述于下列中的方法:美国专利号4,816,567;美国专利号5,565,332;Better et al.(1988)Science 240:1041-1043;Liu et al.(1987)Proc.Natl.Acad.Sci.USA 84:3439-3443;Liuet al.(1987)J.Immunol.139:3521-3526;Sun et al.(1987)Proc.Natl.Acad.Sci.84:214-218;Nishimura et al.(1987)Cancer Res.47:999-1005;Wood et al.(1985)Nature314:446-449;以及Shaw et al.(1988)J.Natl.Cancer Inst.80:1553-1559);Morrison,S.L.(1985)Science229:1202-1207;Oi et al.(1986)Biotechniques 4:214;Winter美国专利5,225,539;Jones et al.(1986)Nature 321:552-525;Verhoeyan et al.(1988)Science 239:1534;以及Beidler et al.(1988)J.Immunol.141:4053-4060。
可以使用携带人免疫系统的部分而不是小鼠系统的部分的转基因小鼠或转染色体小鼠生成对于本文提供的靶蛋白和/或本文提供的细胞外表位特异性的人单克隆抗体。例如,“HuMAb小鼠”含有编码未经重排的人重(μ和γ)链免疫球蛋白序列和κ轻链免疫球蛋白序列的人免疫球蛋白基因微型基因座(miniloci),和使内源μ链基因座和κ链基因座失活的靶向突变(Lonberg,N.et al.(1994)Nature 368(6474):856 859)。因此,小鼠表现出小鼠IgM或κ的降低的表达,并且响应于免疫,引入的人重链转基因和轻链转基因经历类别转换和体细胞突变以生成高亲和力人IgGκ单克隆抗体(Lonberg,N.et al.(1994),如上;Lonberg,N.(1994)Handbook of Experimental Pharmacology 113:49 101中综述的;Lonberg,N.and Huszar,D.(1995)Intern.Rev.Immunol.Vol.13:65 93,以及Harding,F.and Lonberg,N.(1995)Ann.N.Y Acad.Sci 764:536 546)。HuMAb小鼠的制备描述于下列中:Taylor,L.et al.(1992)Nucleic Acids Research 20:6287 6295;Chen,J.et al.(1993)International Immunology 5:647 656;Tuaillon et al.(1993)Proc.Natl.Acad.Sci USA 90:3720 3724;Choi et al.(1993)Nature Genetics 4:117123;Chen,J.et al.(1993)EMBO J.12:821 830;Tuaillon et al.(1994)J.Immunol.152:2912 2920;Lonberg et al.,(1994)Nature 368(6474):856 859;Lonberg,N.(1994)Handbook of Experimental Pharmacology 113:49 101;Taylor,L.et al.(1994)International Immunology 6:579 591;Lonberg,N.and Huszar,D.(1995)Intern.Rev.Immunol.Vol.13:6593;Harding,F.and Lonberg,N.(1995)Ann.N.Y.Acad.Sci764:536 546;Fishwild,D.et al.(1996)Nature Biotechnology 14:845 851。另外参见美国专利号:5,545,806;5,569,825;5,625,126;5,633,425;5,789,650;5,877,397;5,661,016;5,814,318;5,874,299;5,770,429;和5,545,807。
在一些实施方案中,本文提供的抗体能够以不大于10-6M、10-7M、10-8M或10-9M的解离常数与表1中列出的表位结合。评价抗体的结合能力的标准测定是本领域已知的,其包含例如,ELISA、免疫印迹和RIA。也可以通过本领域已知的标准测定(如通过Biacore分析)评估抗体的结合动力学(例如,结合亲和力)。
在一些实施方案中,抗体是抗体-药物缀合物的一部分。抗体-药物缀合物是治疗分子,所述治疗分子包括连接至生物活性剂(如细胞毒素剂或抗病毒剂)的抗体(例如,与表1中列出的蛋白质结合的抗体)。在一些实施方案中,生物活性剂经由化学连接体被连接至抗体。这样的连接体可以基于任何稳定的化学基序,所述化学基序包含二硫化物、腙、肽或硫醚。在一些实施方案中,连接体是可裂解的连接体,并且在抗体与质膜靶蛋白结合时,生物活性剂从抗体释放。在一些实施方案中,连接体是不可裂解的连接体。
在一些实施方案中,抗体-药物缀合物包括连接至细胞毒素剂连接的抗体。在一些实施方案中,可以使用能够杀死CMV感染的细胞的任何细胞毒素剂。在一些实施方案中,细胞毒素剂是MMAE、DM-1、美登木素、阿霉素衍生物、澳瑞他汀、卡开素、CC-1065、倍癌霉素或蒽环类抗生素。
在一些实施方案中,抗体-药物缀合物包括连接至抗病毒剂的抗体。在一些实施方案中,使用能够抑制CMV复制的任何抗病毒剂。在一些实施方案中,抗病毒剂是更昔洛韦、缬更昔洛韦、膦甲酸、西多福韦、阿昔洛韦、福米韦生、马立巴韦、BAY 38-4766或GW275175。在一些实施方案中,本文提供由本文所描述的抗体或抗体-药物缀合物构成的疫苗。
细胞
在一些方面,本文提供抗原呈递细胞(APC)(例如,呈递表1中列出的CMV表位中的一个或更多个的APC),所述抗原呈递细胞(APC)在其表面上表达呈递一种或更多种包括本文所描述的CMV表位的肽的MHC。在一些实施方案中,MHC是I类MHC。在一些实施方案中,MHC是II类MHC。在一些实施方案中,I类MHC具有α链多肽,所述α链多肽是HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-g、HLA-K或HLA-L。在一些实施方案中,II类MHC具有α链多肽,所述α链多肽是HLA-DMA、HLA-DOA、HLA-DPA、HLA-DQA或HLA-DRA。在一些实施方案中,II类MHC具有β链多肽,所述β链多肽是HLA-DMB、HLA-DOB、HLA-DPB、HLA-DQB或HLA-DRB。
在一些实施方案中,APC是B细胞、抗原呈递T细胞、树突状细胞、或人工抗原呈递细胞(例如,aK562细胞)。可以通过从患者样品中取出PBMC并且将其粘附至塑料来制备用于过程的树突状细胞。通常,单核细胞群体粘着,并且全部其他细胞可以被清洗掉。然后用IL-4和GM-CSF分化粘附的群体,以产生单核细胞来源的树突状细胞。这些细胞可以通过添加IL-1β、IL-6、PGE-1和TNF-α(其上调树突状细胞的表面上的重要的共刺激分子)来成熟化,并且然后用本文提供的肽中的一种或更多种转导。
在一些实施方案中,APC是人工抗原呈递细胞(如aK562细胞)。在一些实施方案中,将人工抗原呈递细胞被工程化以表达CD80、CD83、41BB-L和/或CD86。示例性人工抗原呈递细胞(包含aK562细胞)描述于美国专利公布号2003/0147869中,其特此通过引用被并入。
在某些方面,本文提供生成呈递本文所描述的CMV表位中的一个或更多个的APC的方法,所述方法包括使APC与包括本文所描述的CMV表位的肽和/或与编码本文所描述的CMV表位的核酸接触。在一些实施方案中,APC被照射。
在某些方面,本文提供T细胞(例如,CD4T细胞和/或CD8T细胞),所述T细胞(例如,CD4T细胞和/或CD8T细胞)表达识别MHC上呈递的本文所描述的肽(包括表1中列出的CMV表位的肽)的TCR(例如,αβTCR或γδTCR)。在一些实施方案中,T细胞是CD8T细胞(CTL),所述CD8T细胞(CTL)表达识别I类MHC上呈递的本文所描述的肽的TCR。在一些实施方案中,T细胞是CD4T细胞(辅助性T细胞),所述CD4T细胞(辅助性T细胞)识别II类MHC上呈递的本文所描述的肽。
在一些方面,本文提供生成T细胞(例如,CTL)、激活T细胞(例如,CTL)和/或诱导T细胞(例如,CTL)的增殖的方法,所述T细胞(例如,CTL)识别本文所描述的CMV表位中的一个或更多个。在一些实施方案中,将包括CTL的样品(即,PBMC样品)在培养基中与本文提供的APC(例如,呈递包括I类MHC复合物上的本文所描述的CMV表位的肽的APC)孵育。在一些实施方案中,APC对于从其获得T细胞的受试者是自体的。在一些实施方案中,将含有T细胞的样品与本文提供的APC孵育2次或更多次。在一些实施方案中,在存在至少一种细胞因子的情况下将T细胞与APC孵育。在一些实施方案中,细胞因子是IL-4、IL-7和/或IL-15。例如,美国专利公布号2015/0017723(其特此通过引用被并入)中提供用于使用APC诱导T细胞增殖的示例性方法。
在一些方面,本文提供包括本文提供的T细胞和/或APC的组合物(例如,治疗组合物)。在一些实施方案中,通过向受试者施用有效量的组合物,将这样的组合物用于在受试者中治疗和/或预防癌症和/或CMV感染。在一些实施方案中,T细胞和/或APC对于受试不是自体的。在一些实施方案中,T细胞和/或APC对于受试是自体的。在一些实施方案中,在T细胞和/或APC被施用至受试者之前,其被储存在细胞库中。
药物组合物
在一些方面,本文提供组合物(例如,药物组合物(如疫苗组合物)),以及使用这样的药物组合物治疗癌症或CMV感染的方法,所述组合物含有与药学上可接受的载体一起配制的本文所描述的肽(例如,包括来自表1的表位)、核酸、抗体、CTL或APC。在一些实施方案中,组合物包含本文提供的多种(例如,两种或更多种)药剂的组合。
在一些实施方案中,药物组合物还包括佐剂。如本文所使用的,术语“佐剂”大体上指影响患者或受试者中的免疫应答或生理应答的剂。例如,佐剂可以随时间增加抗原的存在或对于感兴趣的区域(像肿瘤),帮助吸收抗原呈递细胞抗原,激活巨噬细胞和淋巴细胞,并且支持细胞因子的产生。通过改变免疫应答,佐剂可以容许较小剂量的免疫相互作用剂以增加特定剂量的免疫相互作用剂的有效性或安全性。例如,佐剂可以防止T细胞耗尽,并且因此增加特定免疫相互作用剂的有效性或安全性。佐剂的实例包含(但不限于)免疫调节蛋白、佐剂65、α-GalCer、磷酸铝、氢氧化铝、磷酸钙、β-葡聚糖肽、CpG DNA、GPI-0100、脂质A、脂多糖、利波夫(Lipovant)、Montanide、N-乙酰基-胞壁酰-L-丙氨酰基-D-异谷氨酰胺、Pam3CSK4、quil A和海藻糖二霉菌酸酯。
制备这些制剂或组合物的方法包含使本文所描述的剂与载体和可选地一种或更多种助剂缔合的步骤。通常,通过将本文所描述的剂与液体载体或精细粉碎的固体载体或两者均匀地且密切地缔合,并且然后使产品成型(如果必要的话)而制备制剂。
适合于非肠道施用的本发明的药物组合物包括一种或更多种本文所描述的药剂与一种或更多种药学上可接受的无菌等渗水性溶液或非水性溶液、分散液、混悬液或乳剂、或无菌粉剂(所述无菌粉剂可以在使用之前重构成无菌可注射溶液或分散液)的组合,其可以含有糖类、醇类、抗氧化剂、缓冲剂、抑菌剂、使得制剂与预期受者的血液等渗的溶质、或助悬剂或增稠剂。
可以在本发明的药物组合物中采用的适合的水性载体和非水性载体的实例包含水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)及其适合的混合物、植物油(如橄榄油)和可注射的有机酯(如油酸乙酯)。例如,通过使用包衣材料(如卵磷脂)、通过保持就分散体而言所需要的颗粒尺寸,以及通过使用表面活性剂,可以保持适当的流动性。
不考虑选择的施用途径,通过本领域技术人员已知的常规方法将本发明的药剂(其可以以适合的水合形式使用)和/或本发明的药物组合物配制成药学上可接受的剂型。
治疗方法
在某些实施方案中,本文提供在受试者中治疗CMV感染和/或癌症的方法,所述方法包括向受试者施用本文提供的药物组合物。
在一些实施方案中,本文提供在受试者中治疗CMV感染的方法。在一些实施方案中,被治疗的受试者是免疫系统受损的。例如,在一些实施方案中,受试者患有T细胞缺陷。在一些实施方案中,受试者患有白血病、淋巴瘤或多发性骨髓瘤。在一些实施方案中,受试者感染有HIV和/或患有AIDS。在一些实施方案中,受试者已经经历组织、器官和/或骨髓移植。在一些实施方案中,受试者正在被施用免疫抑制药物。在一些实施方案中,受试者已经经历和/或正在经历化学疗法。在一些实施方案中,受试者已经经历和/或正在经历放射疗法。
在一些实施方案中,受试者还被施用抑制CMV复制的抗病毒药。例如,在一些实施方案中,受试者被施用更昔洛韦、缬更昔洛韦、膦甲酸、西多福韦、阿昔洛韦、福米韦生、马立巴韦、BAY 38-4766或GW275175。
在一些实施方案中,受试者患有癌症。在一些实施方案中,本文描述的方法可以被用于治疗任何癌性肿瘤或癌前期肿瘤。在一些实施方案中,癌症表达本文提供的CMV表位(例如,表1中列出的CMV表位)中的一个或更多个。在一些实施方案中,癌症包含实体肿瘤。可以通过本文提供的方法和组合物治疗的癌症包含,但不限于,来自膀胱、血液、骨骼、骨髓、脑、乳腺、结肠、食管、胃肠、牙龈、头部、肾脏、肝脏、肺、鼻咽、颈部、卵巢、前列腺、皮肤、胃、睾丸、舌或子宫的癌细胞。此外,癌症可以具体地是以下组织学类型,但不限于这些:恶性新生物;癌;未分化的癌;巨型梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移形细胞癌;乳头状移形细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;肝细胞癌合并胆管癌;小梁状腺癌;腺样囊性癌;腺瘤性息肉内腺癌;腺癌,家族性结肠息肉病;实体癌;恶性类癌瘤;细支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱细胞癌;透明细胞腺癌;颗粒细胞型癌;滤泡性腺癌;乳头状和滤泡性腺癌;非包裹性硬化型癌(nonencapsulating sclerosing carcinoma);肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;大汗腺腺癌;皮脂腺癌;盯聍腺腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;乳腺派杰氏病;腺泡细胞癌;腺鳞状癌;腺癌伴鳞状上皮化生;恶性胸腺瘤;恶性卵巢间质肿瘤;恶性泡膜细胞瘤;恶性粒层细胞肿瘤;以及恶性成神经细胞瘤(malignant roblastoma);塞托利细胞癌;恶性莱迪希细胞肿瘤;恶性脂质细胞肿瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;血管球肉瘤;恶性黑素瘤;无黑素性黑素瘤;浅表扩张性黑素瘤;巨大色素痣内恶性黑素瘤;上皮样细胞黑素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性皮肤纤维瘤;粘液肉瘤;脂肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;腺泡性横纹肌肉瘤;间质肉瘤;恶性混合瘤;苗勒混合肿瘤(mullerian mixedtumor);肾母细胞瘤;肝胚细胞瘤;癌肉瘤;恶性间充质瘤;恶性卵巢纤维上皮瘤;恶性叶状肿瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎性癌;恶性畸胎瘤;恶性甲状腺肿样卵巢瘤;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮细胞瘤;卡波西肉瘤;恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性成软骨细胞瘤;间充质型软骨肉瘤;骨巨细胞瘤;尤因肉瘤;恶性牙源性肿瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;恶性松果体瘤;脊索瘤;恶性神经胶质瘤;室管膜瘤;星形细胞瘤;原浆性星形细胞瘤;纤维性星形细胞瘤;成星形细胞瘤;成胶质细胞瘤;少突神经胶质瘤;成少突神经胶质细胞瘤;原始神经外胚层;小脑肉瘤;成神经节细胞瘤;成神经细胞瘤;成视网膜细胞瘤;嗅神经源性肿瘤;恶性脑脊膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性颗粒细胞肿瘤;恶性淋巴瘤;霍奇金病;霍奇金淋巴瘤;类肉芽肿;小淋巴细胞恶性淋巴瘤;弥散性大细胞恶性淋巴瘤;滤泡性恶性淋巴瘤;蕈样肉芽肿病;其他规定的非霍奇金淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴细胞白血病;血浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓细胞白血病;嗜碱细胞白血病;嗜酸细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;髓系肉瘤;和毛细胞白血病。
在一些实施方案中,受试者还被施用抗癌化合物。示例性抗癌化合物包含(但不限于)阿仑单抗(Alemtuzumab)阿利维A酸阿那曲唑贝伐单抗贝沙罗汀硼替佐米(Bortezomib)博苏替尼(Bosutinib)本妥昔单抗(Brentuximab vedotin)卡博替尼(Cabozantinib)(CometriqTM)、卡非佐米(Carfilzomib)(KyprolisTM)、西妥昔单抗克唑替尼(Crizotinib)达沙替尼地尼白介素(Denileukin diftitox)盐酸厄洛替尼(Erlotinib hydrochloride)依维莫司依西美坦氟维司群(Fulvestrant)吉非替尼替伊莫单抗(Ibritumomab tiuxetan)甲磺酸伊马替尼(Imatinib mesylate)伊匹单抗(Ipilimumab)(YervoyTM)、二甲苯磺酸拉帕替尼(Lapatinib ditosylate)来曲唑尼洛替尼奥法木单抗帕尼单抗盐酸帕唑帕尼(Pazopanib hydrochloride)培妥珠单抗(Pertuzumab)(PerjetaTM)、普拉曲沙瑞戈非尼(Regorafenib)利妥昔单抗罗米地辛(Romidepsin)对甲苯磺酸索拉非尼(Sorafenib tosylate)苹果酸舒尼替尼(Sunitinibmalate)他莫昔芬、坦罗莫司(Temsirolimus)托瑞米芬托西莫单抗(Tositumomab)和131I-托西莫单抗曲妥单抗(Trastuzumab)维A酸凡德他尼维莫非尼(Vemurafenib)伏林司他以及阿柏西普(Ziv-aflibercept)
在一些实施方案中,受试者还被施用化学治疗剂。这样的化学治疗剂的实例包含(但不限于)烷化剂,如塞替派和环磷酰胺;烷基磺酸盐,如白消安、英丙舒凡(improsulfan)和哌泊舒凡;氮丙啶类,如苯并多巴(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimines)和甲基氨基吖啶类(methylamelamines),包含六甲蜜胺(altretamine)、曲他胺、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲密胺(trimethylolomelamine);多聚乙酰类(acetogenins)(尤其是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包含合成类似物托泊替康(topotecan));苔藓抑素;多烯酮类化合物(callystatin);CC-1065(包含其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素(cryptophycin)(特别是隐藻素1和隐藻素8);多拉司他汀;倍癌霉素(duocarmycin)(包含合成类似物、KW-2189和CB1-TM1);艾榴素(eleutherobin);水鬼蕉亭(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥类(nitrogen mustards),如苯丁酸氮芥、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、氮芥(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀、曲磷胺(trofosfamide)、乌拉莫司汀(uracil mustard);亚硝基脲类,如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素,如烯二炔类抗生素(enediyne antibiotics)(例如,加里刹霉素(calicheamicin)、尤其是加里刹霉素γ1I和加里刹霉素ωl1);达内霉素(dynemicin),包含达内霉素A;二磷酸盐,如氯膦酸盐;埃斯培拉霉素(esperamicin);以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团、阿克拉霉素(aclacinomysins)、放线菌素、蒽霉素(authrarnycin)、偶氮丝氨酸(azaserine)、博来霉素、放线菌素C、卡拉比星(carabicin)、卡诺霉素(caminomycin)、嗜癌菌素、色霉素(chromomycinis)、放线菌素D、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、阿霉素(包含吗啉代-阿霉素、氰基吗啉代-阿霉素、2-吡咯啉-阿霉素和脱氧阿霉素(deoxydoxorubicin))、表柔比星、依索比星(esorubicin)、伊达比星、麻西罗霉素、丝裂霉素类,如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素类(olivomycins)、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链佐星、杀结核菌素、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星;抗代谢物,如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷;雄激素类(androgens),如卡鲁睾酮、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇、美雄烷(mepitiostane)、睾内酯;抗肾上腺素物质(anti-adrenals),如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂(folic acidreplenisher),如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸;恩尿嘧啶;安吖啶;百垂布西(bestrabucil);比生群;依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛;地吖醌;依氟鸟氨酸(elformithine);依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登素类化合物(maytansinoids),如美登素和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌;莫哌达醇(mopidanmol);尼曲吖啶(nitraerine);喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙肼;丙卡巴肼;PSK多糖复合物);雷佐生;利索新;西佐喃(sizofuran);锗螺胺(spirogermanium);细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢霉烯类(trichothecenes)(尤其是T-2毒素、粘液霉素A(verracurin A)、杆孢菌素A和蛇形菌素(anguidine));氨基甲酸乙酯;长春地辛(vindesine);达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加西托新(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;塞替派;紫杉烷类,例如,紫杉醇和多西他赛(doxetaxel);苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂配位络合物,如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊甙(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;盐酸米托蒽醌;替尼泊甙;依达曲沙;柔红霉素;氨喋呤;希罗达(xeloda);伊班膦酸盐(ibandronate);伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine)(DMFO);类视黄醇(retinoids),如视黄酸;卡培他滨;以及上述中任一种的药学上可接受的盐、酸或衍生物。
在一些实施方案中,受试者还被施用免疫治疗剂。免疫疗法指使用受试者的免疫系统治疗癌症的治疗,例如,癌症疫苗、细胞因子、癌症特异性抗体的使用、T细胞疗法和树突状细胞疗法。
在一些实施方案中,受试者还被施用免疫调节蛋白。免疫调节蛋白的实例包含(但不限于)B淋巴细胞化学引诱物(“BLC”)、C-C基序趋化因子11(“嗜酸性粒细胞趋化因子-1(Eotaxin-1)”)、嗜酸粒细胞趋化蛋白2(“嗜酸性粒细胞趋化因子-2(Eotaxin-2)”)、粒细胞集落刺激因子(G-CSF)、粒-巨噬细胞集落刺激因子(“GM-CSF”)、1-309、胞间粘连分子1(“ICAM-1”)、干扰素γ(“IFN-γ”)、白细胞介素-1α(“IL-1α”)、白细胞介素-1β(“IL-1β”)、白细胞介素1受体拮抗剂(“IL-1ra”)、白细胞介素-2(“IL-2”)、白细胞介素-4(“IL-4”)、白细胞介素-5(“IL-5”)、白细胞介素-6(“IL-6”)、白细胞介素-6可溶性受体(“IL-6sR”)、白细胞介素-7(“IL-7”)、白细胞介素-8(“IL-8”)、白细胞介素-10(“IL-10”)、白细胞介素-11(“IL-11”)、白细胞介素-12β亚基(“IL-12p40”或“IL-12p70”)、白细胞介素-13(“IL-13”)、白细胞介素-15(“IL-15”)、白细胞介素-16(“IL-16”)、白细胞介素-17(“IL-17”)、趋化因子(C-C基序)配体2(“MCP-1”)、巨噬细胞集落剌激因子(“M-CSF”)、干扰素γ诱导的单核因子(“MIG”)、趋化因子(C-C基序)配体2(“MIP-1α”)、趋化因子(C-C基序)配体4(“MIP-1β”)、巨噬细胞炎性蛋白-1-δ(“MIP-1δ”)、血小板源性生长因子亚基B(“PDGF-BB”)、趋化因子(C-C基序)配体5、调控活化的正常T细胞表达和分泌的因子(“RANTES”)、TIMP金属肽酶抑制剂1(“TIMP-1”)、TIMP金属肽酶抑制剂2(“TIMP-2”)、肿瘤坏死因子淋巴毒素-α(“TNFα”)、肿瘤坏死因子淋巴毒素-β(“TNFβ”)、可溶性1型TNF受体(“sTNFRI”)、sTNFRIIAR、脑源性神经营养因子(“BDNF”)、碱性成纤维细胞生长因子(“bFGF”)、骨形态生成蛋白4(“BMP-4”)、骨形态生成蛋白5(“BMP-5”)、骨形态生成蛋白7(“BMP-7”)、神经生长因子(“b-NGF”)、表皮生长因子(“EGF”)、表皮生长因子受体(“EGFR”)、内分泌腺性血管内皮生长因子(“EG-VEGF”)、成纤维细胞生长因子4(“FGF-4”)、角质形成细胞生长因子(“FGF-7”)、生长分化因子15(“GDF-15”)、胶质细胞源性神经营养因子(“GDNF”)、生长激素、肝素结合EGF样生长因子(“HB-EGF”)、肝细胞生长因子(“HGF”)、胰岛素样生长因子结合蛋白1(“IGFBP-1”)、胰岛素样生长因子结合蛋白2(“IGFBP-2”)、胰岛素样生长因子结合蛋白3(“IGFBP-3”)、胰岛素样生长因子结合蛋白4(“IGFBP-4”)、胰岛素样生长因子结合蛋白6(“IGFBP-6”)、胰岛素样生长因子1(“IGF-1”)、胰岛素、巨噬细胞集落刺激因子(“M-CSF R”)、神经生长因子受体(“NGF R”)、神经营养因子-3(“NT-3”)、神经营养因子-4(“NT-4”)、破骨细胞生成抑制因子(“骨保护素(Osteoprotegerin)”)、血小板源性生长因子受体(“PDGF-AA”)、磷脂酰肌醇-聚糖生物合成(“PIGF”)、Skp、滞蛋白(Cullin)、含F框的复合物(“SCF”)、干细胞因子受体(“SCF R”)、转化生长因子α(“TGFα”)、转化生长因子β-1(“TGFβ1”)、转化生长因子β-3(“TGFβ3”)、血管内皮生长因子(“VEGF”)、血管内皮生长因子受体2(“VEGFR2”)、血管内皮生长因子受体3(“VEGFR3”)、VEGF-D 6Ckine、酪氨酸蛋白激酶受体UFO(“Axl”)、细胞素(“BTC”)、粘膜相关上皮趋化因子(“CCL28”)、趋化因子(C-C基序)配体27(“CTACK”)、趋化因子(C-X-C基序)配体16(“CXCL16”)、C-X-C基序趋化因子5(“ENA-78”)、趋化因子(C-C基序)配体26(“嗜酸性粒细胞趋化因子-3”)、粒细胞趋化蛋白2(“GCP-2”)、GRO、趋化因子(C-C基序)配体14(“HCC-l”)、趋化因子(C-C基序)配体16(“HCC-4”)、白细胞介素-9(“IL-9”)、白细胞介素-17F(“IL-17F”)、白细胞介素-18-结合蛋白(“IL-18BPa”)、白细胞介素-28A(“IL-28A”)、白细胞介素29(“IL-29”)、白细胞介素31(“IL-31”)、C-X-C基序趋化因子10(“IP-10”)、趋化因子受体CXCR3(“I-TAC”)、白血病抑制因子(“LIF”)、轻型趋化因子(C基序)配体(“淋巴细胞趋化因子”)、单核细胞化学诱导物蛋白2(“MCP-2”)、单核细胞化学诱导物蛋白3(“MCP-3”)、单核细胞化学诱导物蛋白4(“MCP-4”)、巨噬细胞源性趋化因子(“MDC”)、巨噬细胞游走抑制因子(“MIF”)、趋化因子(C-C基序)配体20(“MIP-3α”)、C-C基序趋化因子19(“MIP-3β”)、趋化因子(C-C基序)配体23(“MPIF-1”)、巨噬细胞刺激蛋白α链(“MSPα”)、核小体组装蛋白1样4(“NAP-2”)、分泌性磷蛋白1(“骨桥蛋白”)、肺部活化调控细胞因子(“PARC”)、血小板因子4(“PF4”)、基质细胞源性因子-1α(“SDF-1α”)、趋化因子(C-C基序)配体17(“TARC”)、胸腺表达趋化因子(“TECK”)、胸腺基质淋巴细胞生成素(“TSLP4-IBB”)、CD 166抗原(“ALCAM”)、分化群80(“B7-1”)、肿瘤坏死因子受体超家族成员17(“BCMA”)、分化群14(“CD14”)、分化群30(“CD30”)、分化群40(“CD40配体”)、癌胚抗原相关细胞粘连分子1(胆汁糖蛋白)(“CEACAM-1”)、死亡受体6(“DR6”)、脱氧胸苷激酶(“Dtk”)、1型膜糖蛋白(“内皮素”)、受体酪氨酸蛋白激酶erbB-3(“ErbB3”)、内皮细胞白细胞粘连分子1(“E-选择素”)、凋亡抗原1(“Fas”)、Fms样酪氨酸激酶3(“Flt-3L”)、肿瘤坏死因子受体超家族成员1(“GITR”)、肿瘤坏死因子受体超家族成员14(“HVEM”)、胞间粘连分子3(“ICAM-3”)、IL-1R4、IL-1RI、IL-10Rβ、IL-17R、IL-2Rγ、IL-21R、溶酶体膜蛋白2(“LIMPII”)、中性粒细胞明胶酶相关脂质运载蛋白(“脂质运载蛋白-2”)、CD62L(“L-选择素”)、淋巴管内皮细胞(“LYVE-1”)、I类MHC多肽相关序列A(“MICA”)、I类MHC多肽相关序列B(“MICB”)、NRGl-βl、β型血小板源性生长因子受体(“PDGFRβ”)、血小板内皮细胞粘连分子(“PECAM-1”)、RAGE、甲型肝炎病毒细胞受体1(“TIM-1”)、肿瘤坏死因子受体超家族成员IOC(“TRAIL R3”)、Trappin蛋白转谷氨酰胺酶结合域(“Trappin-2”)、尿激酶受体(“uPAR”)、血管细胞粘连蛋白1(“VCAM-1”)、XEDAR、激活素A、刺鼠相关蛋白(“AgRP”)、核糖核酸酶5(“血管生长素”)、血管生成素1、血管抑素、组织蛋白酶S、CD40、隐藏家族蛋白IB(“Cripto-1”)、DAN、Dickkopf相关蛋白1(“DKK-1”)、E-钙粘连素、上皮细胞粘连分子(“EpCAM”)、Fas配体(FasL或CD95L)、Fcg RIIB/C、FoUistatin、半乳凝素-7、胞间粘连分子2(“ICAM-2”)、IL-13Rl、IL-13R2、IL-17B、IL-2Ra、IL-2Rb、IL-23、LAP、神经元细胞粘连分子(“NrCAM”)、纤溶酶原激活物抑制剂-1(“PAI-1”)、血小板源性生长因子受体(“PDGF-AB”)、抵抗素、基质细胞衍生因子1(“SDF-1β”)、sgpl30、分泌型卷曲相关蛋白2(“ShhN”)、唾液酸结合性免疫球蛋白样凝集素(“Siglec-5”)、ST2、转化生长因子-β2(“TGFβ2”)、Tie-2、血小板生成素(“TPO”)、肿瘤坏死因子受体超家族成员10D(“TRAILR4”)、骨髓细胞上表达的触发受体1(“TREM-1”)、血管内皮生长因子C(“VEGF-C”)、VEGFRl、脂联素、降脂蛋白(“AND”)、甲胎蛋白(“AFP”)、血管生成素样4(“ANGPTL4”)、β-2-微球蛋白(“B2M”)、基底细胞粘连分子(“BCAM”)、糖抗原125(“CA125”)、癌抗原15-3(“CA15-3”)、癌胚抗原(“CEA”)、cAMP受体蛋白(“CRP”)、人表皮生长因子受体2(“ErbB2”)、卵泡抑素、促卵泡激素(“FSH”)、趋化因子(C-X-C基序)配体1(“GROα”)、人绒毛膜促性腺激素(“βHCG”)、胰岛素样生长因子1受体(“IGF-1sR”)、IL-1sRII、IL-3、IL-18Rb、IL-21、瘦素、基质金属蛋白酶-1(“MMP-1”)、基质金属蛋白酶-2(“MMP-2”)、基质金属蛋白酶-3(“MMP-3”)、基质金属蛋白酶-8(“MMP-8”)、基质金属蛋白酶-9(“MMP-9”)、基质金属蛋白酶-10(“MMP-10”)、基质金属蛋白酶-13(“MMP-13”)、神经细胞粘连分子(“NCAM-1”)、巢蛋白(Entactin)(“巢蛋白-1(Nidogen-1)”)、神经元特异性烯醇酶(“NSE”)、制瘤素M(“OSM”)、降钙素原、催乳素、前列腺特异性抗原(“PSA”)、唾液酸结合性免疫球蛋白样凝集素9(“Siglec-9”)、ADAM 17肽链内切酶(“TACE”)、甲状腺球蛋白、金属蛋白酶抑制剂4(“TIMP-4”)、TSH2B4、含解聚素和金属蛋白酶的蛋白质9(“ADAM-9”)、血管生成素2、肿瘤坏死因子配体超家族成员13/酸性富亮氨酸核磷蛋白32家族成员B(“APRIL”)、骨形态生成蛋白2(“BMP-2”)、骨形态生成蛋白9(“BMP-9”)、补体成分5a(“C5a”)、组织蛋白酶L、CD200、CD97、趋化素、肿瘤坏死因子受体超家族成员6B(“DcR3”)、脂肪酸结合蛋白2(“FABP2”)、成纤维细胞活化蛋白α(“FAP”)、成纤维细胞生长因子19(“FGF-19”)、半乳凝素-3、肝细胞生长因子受体(“HGF R”)、IFN-α/βR2、胰岛素样生长因子2(“IGF-2”)、胰岛素样生长因子2受体(“IGF-2R”)、白细胞介素-1受体6(“IL-1R6”)、白细胞介素24(“IL-24”)、白细胞介素33(“IL-33”)、激肽释放酶14、天冬酰胺酰肽链内切酶(“天冬酰胺内肽酶(Legumain)”)、氧化型低密度脂蛋白受体1(“LOX-1”)、甘露糖结合凝集素(“MBL”)、脑啡肽酶(“NEP”)、易位相关Notch同源物1(果蝇(Drosophila))(“Notch-1”)、肾母细胞瘤过度表达(“NOV”)、骨激活素(Osteoactivin)、程序性细胞死亡蛋白1(“PD-1”)、N-乙酰胞壁酰-L-丙氨酸酰胺酶(“PGRP-5”)、丝氨酸蛋白酶抑制剂A4、分泌型卷曲相关蛋白3(“sFRP-3”)、血栓调节蛋白、Toll样受体2(“TLR2”)、肿瘤坏死因子受体超家族成员10A(“TRAIL Rl”)、转铁蛋白(“TRF”)、WIF-lACE-2、白蛋白、AMICA、血管生成素4、B-细胞活化因子(“BAFF”)、糖抗原19-9(“CA19-9”)、CD 163、丛生蛋白、CRT AM、趋化因子(C-X-C基序)配体14(“CXCL14”)、胱抑素C、饰胶蛋白(“DCN”)、Dickkopf相关蛋白3(“Dkk-3”)、δ样蛋白1(“DLL1”)、胎球蛋白A、肝素结合生长因子1(“aFGF”)、叶酸受体α(“FOLR1”)、弗林蛋白酶、GPCR相关分拣蛋白1(“GASP-1”)、GPCR相关分拣蛋白2(“GASP-2”)、粒细胞集落刺激因子受体(“GCSF R”)、丝氨酸蛋白酶hepsin(“HAI-2”)、白细胞介素-17B受体(“IL-17B R”)、白细胞介素27(“IL-27”)、淋巴细胞活化基因3(“LAG-3”)、载脂蛋白A-V(“LDL R”)、胃蛋白酶原I、视黄醇结合蛋白4(“RBP4”)、SOST、硫酸类肝素蛋白多糖(“多配体蛋白聚糖1”)、肿瘤坏死因子受体超家族成员13B(“TACI”)、组织因子通道抑制剂(“TFPI”)、TSP-1、肿瘤坏死因子受体超家族成员10b(“TRAIL R2”)、TRANCE、肌钙蛋白I、尿激酶纤维蛋白溶酶原激活剂(“uPA”)、钙粘连素5、2型或VE-钙粘连素(血管内皮细胞)也称为CD144(“VE-钙粘连素”)、WNTl诱导的信号通路蛋白1(“WISP-1”)、以及核因子κB受体活化因子(“RANK”)。
在一些实施方案中,受试者还被施用免疫检查点抑制剂。免疫检查点抑制概括地指抑制癌症细胞可以产生的检查点以预防或下调免疫应答。免疫检查点蛋白的实例包含(但不限于)CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG3、TIM-3或VISTA。免疫检查点抑制剂可以是与免疫检查点蛋白结合并且抑制免疫检查点蛋白的抗体或所述抗体的抗原结合片段。免疫检查点抑制剂的实例包含(但不限于)纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、皮地利珠单抗(pidilizumab)、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、MEDI-4736、MSB-0020718C、AUR-012和STI-A1010。
在一些实施方案中,预防性地施用本文提供的组合物(例如,本文提供的疫苗组合物)以预防癌症和/或CMV感染。在一些实施方案中,施用疫苗以抑制肿瘤细胞扩增。可以在患者中检测癌细胞或CMV感染的细胞之前或之后施用疫苗。肿瘤细胞扩增的抑制被理解为指防止、终止、减缓肿瘤细胞的生长或杀死肿瘤细胞。在一些实施方案中,在施用包括本文所描述的肽、核酸、抗体或APC的疫苗之后,诱导促炎应答。促炎免疫应答包括产生促炎细胞因子和/或趋化因子(例如,干扰素γ(IFN-γ)和/或白细胞介素2(IL-2))。促炎细胞因子和趋化因子是本领域公知的。
联合疗法包含顺序、同时和单独、和/或共同施用活性化合物,以这样的方式,当施用随后的治疗时,施用的第一药剂的治疗效果尚未完全消失。在一些实施方案中,第二药剂可以与第一药剂共同配制或配制在单独的药物组合物中。
本文提供的药物组合物中的活性成分的实际剂量水平可以变化,以便获得活性成分的量,所述活性成分的量对实现特定患者、组合物和施用模式的期望的治疗响应是有效的,而对患者没有毒性。
所选择的剂量水平将取决于各种各样的因素,所述因素包含所采用的特定药剂的活性、施用途径、施用时间、正在被采用的特定化合物的排泄或代谢的速率、治疗的持续时间、与所采用的特定化合物组合使用的其他药物、化合物和/或材料、正在被治疗的患者的年龄、性别、体重、病况、总体健康状况和先前的病史,以及医学领域中众所周知的类似因素。
在一些方面,本文提供鉴别适合于本文提供的疗法(在受试者中治疗CMV感染和/或癌症的方法,所述方法包括向受试者施用本文提供的药物组合物)的受试者的方法。在一些实施方案中,方法包括从受试者中分离样品(例如,血液样品、组织样品、肿瘤样品)并且检测样品中表1中列出的CMV表位的存在。在一些实施方案中,使用ELISA测定、免疫印迹测定、FACS测定、荧光显微术测定、埃德曼降解法测定和/或质谱测定(例如,蛋白质测序)检测表位。在一些实施方案中,通过检测编码CMV表位的核酸来检测CMV表位的存在。在一些实施方案中,使用核酸探针、核酸扩增测定和/或测序测定检测编码CMV表位的核酸。
可以在本文提供的方法中使用的核酸扩增测定的实例包含(但不限于)聚合酶链反应(PCR)、LATE-PCR、连接酶链反应(LCR)、链置换扩增(SDA)、转录介导的扩增(TMA)、自主序列复制(3SR)、基于Qβ复制酶的扩增、基于核酸序列的扩增(NASBA)、修复链反应(RCR)、反向DNA扩增(BDA)和/或滚环扩增(RCA)。
在一些实施方案中,扩增反应的产物被检测作为样品中细菌的存在和/或同一性的指示。在一些实施方案中,在完成扩增反应之后,检测扩增产物(即,终点检测)。终点检测方法的实例包含基于凝胶电泳的方法、基于探针结合的方法(例如,分子信标、HPA探针、开光/关光探针(lights-on/lights-off probe))和基于双链DNA结合荧光染料的方法(例如,溴化乙锭、SYBR-green)。在一些实施方案中,当扩增产物在扩增反应中产生时,其被检测到(即,实时检测)。实时检测方法的实例包含基于探针结合的方法(例如,分子信标、TaqMan探针、蝎型探针(scorpion probe)、开光/关光探针)和基于双链DNA结合荧光染料的方法(例如,溴化乙锭、SYBR-green)。在一些实施方案中,通过测序(例如,通过使用本文所描述的测序测定)检测和/或鉴别扩增反应的产物。
在一些实施方案中,核酸序列的检测包括使核酸序列与核酸探针接触,所述核酸探针与核酸序列特异性杂交。在一些实施方案中,探针被可检测地标记。在一些实施方案中,用荧光部分(直接地或间接地)标记探针。在本文提供的方法中有用的荧光部分的实例包含(但不限于)别藻蓝蛋白、荧光素、藻红蛋白、多甲藻素-叶绿素蛋白复合物、AlexaFluor350、Alexa Fluor 405、Alexa Fluor 430、Alexa Fluor 488、Alexa Fluor 514、Alexa Fluor 532、Alexa Fluor 546、Alexa Fluor 555、Alexa Fluor 568、Alexa Fluor594、Alexa Fluor 633、Alexa Fluor 635、Alexa Fluor 647、Alexa Fluor 660、AlexaFluor 680、Alexa Fluor 700、Alexa Fluor750、Alexa Fluor 790、GFP、RFP、YFP、EGFP、mPlum、mCherry、mOrange、mKO、EYFP、mCitrine、Venus、YPet、Emerald、Cerulean和CyPet。在一些实施方案中,探针是分子信标探针、分子火炬探针(molecular torch probe)、TaqMan探针、SDA探针、蝎型探针、HPA探针或开光/关光探针。
在一些实施方案中,通过测序(例如,全基因组测序、转录组序列和/或靶向基因测序)来检测核酸序列。可以在本文提供的方法中使用的测序方法的实例包含(但不限于)链终止测序、大规模平行信号测序、离子半导体测序、聚合酶克隆测序、illumina测序、连接测序、合成测序、焦磷酸测序、单分子实时测序、SOLiD测序、DNA纳米球测序、Heliscope单分子测序、单分子实时测序、454测序、纳米孔测序、隧道电流DNA测序或杂交测序。
在一些实施方案中,本文提供的方法还包括使用本文提供的治疗方法治疗鉴别的受试者(例如,通过向受试者施用本文提供的药物组合物)。
实施例
实施例1:HSCT受者中病毒再激活后CMV遗传变体的出现的动力学
招募26个经历同种异体造血干细胞移植(HSCT)的患者以用于本研究。这些患者的临床特征在表4中列出。全部患者接受T细胞充足的骨髓或G-CSF动员的外周血干细胞移植物,并且没有患者患有体内T细胞耗尽。CMV血清反应阳性患者或接受来自血清反应阳性供者的移植物的患者从第5天至第28天或直至获准离开时用高剂量阿昔洛韦预防性地治疗,然后用伐昔洛韦(valacicolvir)预防性地治疗直至第100天。具有>600拷贝/mL的血浆中CMV DNA血症的患者用更昔洛韦每天处理两次共14天,随后保持每天一次,直至血浆DNA血症<600拷贝/mL;或用900mg的缬更昔洛韦每天处理两次,随后保持900mg每天一次。膦甲酸被用于治疗非响应的或表现出来自更昔洛韦的显著毒性的患者。被招募用于本研究的26个HSCT受者中,17个表现出病毒再激活的迹象,如由CMV DNA血症>600拷贝/ml所限定的。早期CMV再激活在这些患者中的16个中出现,而晚期CMV在4个中被检测到。这些患者中的两个患有CMV有关的疾病:一个结肠炎以及一个肠炎。十七个中的十四个表现出不稳定的CMV特异性免疫应答(如通过CMV-QuantiFERON测定评估的)。当前研究中包含的9个患者表现出CMV免疫重建,而没有病毒再激活的迹象。
为了描绘在HSCT受者的此群组中遗传变体的出现对T细胞免疫重建的影响,从CMV的即刻早期(Immediate Early)(IE-1)蛋白中选择八种不同的HLA I类限制性CD8+T细胞表位。使用Genbank数据库,鉴别了这些表位中的每个的一系列变体序列。设计焦磷酸测序分析以鉴别CMV编码的CD8+T细胞表位内的单核苷酸多形性(SNP)。最初,在显示出CMV再激活的全部HSCT受者中的病毒载量的峰值处进行这些SNP分析。基于核苷酸序列推测每个变体位置处的氨基酸残基。图1A中的数据表示在每个位置处显示出一个或两个氨基酸的受者的比例。如材料和方法中所概述的,针对每个位置的错误率校正数据。在某些位置的氨基酸使用(特别是在第201、205、248、250和323个位置处分别优先使用R、M、A、A和M残基)中观察到偏差,在其他残基处注意到显著更多的变化。此分析还揭示了,高比例的HSCT受者在再激活后具有多种IE-1变体,其中每个位置处的6-35%的样品与两种氨基酸的检测有关,并且17个HSCT受者中的9个显示出混合感染的明确迹象,所述混合感染的特征在于在至少一个位置上同时检测到两个变体残基。在来自17个HSCT受者中的15个的病毒再激活期间,使用纵向血浆样品随着时间评估病毒变体的稳定性。从4个受者评估的全部SNP的代表性纵向分析在图1B中示出。虽然一些HSCT受者在主要单一变体的检测(受者4)或可能的共感染(受者17)后表现出SNP表达模式的极小的变化,但其他HSCT受者在病毒再激活时期期间表现出SNP频率的变化(受者19和受者28);表明免疫选择压力对这些HSCT受者的外周血中显性病毒分离物的潜在影响。
实施例2:共感染对T细胞动力学的影响
为了评估表位变化和共感染对IE-1特异性T细胞免疫的影响,用全部潜在的HLA匹配的变体肽表位刺激来自显示出病毒再激活迹象的HSCT受者的PBMC样品,然后在存在IL-2的情况下离体培养两周。另外用HLA匹配的变体肽表位(表2)刺激来自显示出免疫重建而没有CMV再激活迹象的9个HSCT受者的PBMC。作为对照,用至少两个保守HLA匹配的表位刺激PBMC。叠加有病毒再激活动力学的来自这些患者中的三个的代表性纵向分析在图2A-C中示出。针对每个表位测试的HSCT受者数量和应答的HSCT受者数量的总体概括在表3中示出。有趣地,这些观察结果表明,虽然一些患者能够有效识别通过焦磷酸测序分析检测到的多种病毒变体(由患者28代表,图2(B和E)),但其他显示出优先识别,在某些情况下靶向针对亚优势表位变体。如图2D中所示,焦磷酸测序分析揭示了,在第201个和第205个氨基酸残基处受者17中的IE-1序列由氨基酸残基R和M占主导地位,其将对应于HLA-B8个体中的ELRRKMMYM表位。尽管如此,受者17仅生成针对亚优势ELKRKMIYM变体的T细胞应答(图2A)。
表2:示例性IE-1表位变体的列表
有趣地,受者17还显示出在病毒再激活期间不存在针对免疫显性保守T细胞表位VTEHDTTLY的可检测的应答,并且即使在病毒感染消退之后也未能生成针对显性ELRRKMMYM变体的T细胞应答。对于受者44,类似的观察结果是明显的(图2F)。检测编码两种HLA-B44变体的序列是可能的,但是没有检测到在病毒再激活期间针对DELKRKMIY变体的应答。有趣地,这些观察结果在两种HLA-B44限制性表位的其他HLA-B44阳性HSCT受者中也是明显的(表3)。这对于可以在7个HLA B44阳性HSCT受者中的6个中检测到、但是未能在任何受者中诱导显著的T细胞应答的EDAIAAYTL变体特别明显。
表3:HSCT受者的CMV特异性肽表位识别的概括
N.D.未完成
#在两周的培养之后在回收后具有>5%的产生IFN-γ的CD8+T细胞的患者被认为是应答者。
为了进一步评估我们的受者群组中表位变体的识别,用同源肽和变体肽两者的连续稀释液刺激来自全部HSCT受者的经培养的T细胞,并且评估IFN-α的产生。然后,基于诱导50%的最大IFN-γ产生所要求的肽的浓度来计算有效浓度(EC)50。图3A中显示出在回收具有VLEETSVML表位变体和YILEETSVML表位变体的10倍连续稀释液的YILEETSVML刺激的T细胞培养物后的代表性分析。虽然对HLA-A2限制性表位(VLEETSVML和YILEETSVML)特异性的T细胞始终以相似的效率识别两种变体(图3B和图3C),但是针对HLA-B8表位(ELRRKMMYM和ELKRKMIYM)的交叉反应性是患者依赖性的,所述HLA-B8表位(ELRRKMMYM和ELKRKMIYM)的特征在于对于一些个体(受者17)中的单一变体的偏好和在其他个体(受者34和受者37)中的交叉反应(图3D和图3E)。没有对于两种B44限制性表位(DELRRKMMY和EEAIVAYTL)特异性的T细胞中的交叉反应性的迹象,所述T细胞表现出对单一变体的优先偏倚,而不论暴露于多种变体的迹象(图3F和图3G)。这些观察结果进一步证明了,暴露于多种病毒分离物不会自动导致交叉反应性T细胞免疫的有效诱导,并且在遗传上无关的个体中可能存在谱系“空洞”。
实施例3:暴露于多种病毒分离物对病毒控制的影响
为了确定针对变体IE-1和/或保守表位的CMV特异性T细胞应答的重建是否与病毒再激活有关,比较了具有再激活的迹象和不具有再激活的迹象的HSCT受者中在移植后早期(90-106天)和晚期(>180天)对于IE-1变体表位和保守表位两者特异性的CD8+T细胞的频率。移植后早期和晚期全部可检测的CMV特异性T细胞应答的频率的成对分析证明了,相比于不具有再激活的HSCT受者(图4B),具有病毒再激活迹象的HSCT受者(图4A)显示出其T细胞应答的较低的稳定性。此外,相比于不具有再激活的HSCT受者(其表现出其病毒特异性T细胞应答的频率的微乎其微的变化),具有再激活的HSCT受者在早期应答与晚期应答之间的CMV特异性T细胞的频率方面显示出显著更大的倍数差异(图4C)。为了进一步评估用多种病毒分离物再激活对病毒控制的影响,比较了具有单一变体或多种变体的迹象的HSCT受者中在其外周血中(i)病毒再激活的数量;(ii)峰值病毒载量以及(iii)第一病毒再激活的持续时间。这些分析揭示了,来自具有和不具有多种病毒分离物的迹象的患者的病毒再激活的数量(图4D)、峰值病毒载量(图4E)或再激活的持续时间(图4F)没有显著差异。这些观察结果表明,虽然变体特异性免疫的诱导可以在用多种CMV的分离物再激活后控制病毒再激活中起作用,但是诱导稳定的CMV特异性免疫重建至保守表位或经由交叉反应性应答诱导稳定的CMV特异性免疫重建的能力与HSCT后CMV再激活的有效控制更相关。
表4:本研究中包含的HSCT受者的临床特征
N.A.不适用
*CMV再激活被定义为CMV DNA血症>600拷贝/ml
本文提到的全部出版物、专利、专利申请和序列登录号通过引用被整体并入,犹如每个单独的出版物、专利或专利申请被具体地和单独地表明通过引用被并入。在冲突的情况下,本申请(包含本文中的任何定义)将受约束。
本领域技术人员将认识到或能够使用仅仅常规实验来确定本文中描述的本发明的具体的实施方案的许多等同物。这样的等同物旨在由以下权利要求涵盖。
Claims (57)
1.一种在受试者中治疗癌症的方法,所述方法包括向所述受试者施用包括细胞毒性T细胞(CTL)的药物组合物,所述细胞毒性T细胞(CTL)包括与I类MHC上呈递的包括表1中列出的表位的肽特异性结合的T细胞受体(TCR)。
2.一种在受试者中治疗巨细胞病毒(CMV)感染的方法,所述方法包括向所述受试者施用包括细胞毒性T细胞(CTL)的药物组合物,所述细胞毒性T细胞(CTL)包括与I类MHC上呈递的包括表1中列出的表位的CMV肽特异性结合的T细胞受体(TCR)。
3.如权利要求1或2所述的方法,其中所述CTL对于所述受试者是自体的。
4.如权利要求1或2所述的方法,其中所述CTL对于所述受试者不是自体的。
5.如权利要求4所述的方法,其中所述CTL从CTL信息库或CTL库获得。
6.一种诱导CMV特异性细胞毒性T细胞(CTL)的增殖的方法,所述方法包括将包括CTL的样品与呈递包括表1中列出的表位的CMV肽的抗原呈递细胞(APC)孵育,从而诱导所述样品中肽特异性CTL的增殖。
7.如权利要求6所述的方法,其中所述样品还包括一个或更多个细胞因子。
8.如权利要求6或7所述的方法,其中所述APC是B细胞。
9.如权利要求6或7所述的方法,其中所述APC是抗原呈递T细胞。
10.如权利要求6或7所述的方法,其中所述APC是树突状细胞。
11.如权利要求6或7所述的方法,其中所述APC是aK562细胞。
12.如权利要求6至10中任一项所述的方法,其中所述样品包括外周血单核细胞(PBMC)。
13.如权利要求1至10中任一项所述的方法,其中所述T细胞是细胞毒性T细胞。
14.如权利要求1至13中任一项所述的方法,其中所述CMV肽的长度为不超过20个氨基酸。
15.如权利要求14所述的方法,其中所述CMV肽的长度为不超过15个氨基酸。
16.如权利要求14所述的方法,其中所述CMV肽的长度为不超过10个氨基酸。
17.如权利要求1至16中任一项所述的方法,其中所述CMV肽包括序列KARAKKDELR。
18.如权利要求1至16中任一项所述的方法,其中所述CMV肽包括序列ARAKKDELR。
19.如权利要求1至16中任一项所述的方法,其中所述CMV肽包括序列RRKMMYMYCR。
20.一种包括表1中列出的氨基酸序列的肽,其中所述肽不包括CMV蛋白的超过30个连续氨基酸。
21.如权利要求20所述的肽,其中所述表1中列出的氨基酸序列是KARAKKDELR、ARAKKDELR或RRKMMYMYCR。
22.如权利要求20或21所述的肽,其中所述肽包括两个或更多个表1中列出的序列。
23.一种疫苗组合物,所述疫苗组合物包括权利要求20至22中任一项所述的肽。
24.如权利要求23所述的疫苗组合物,所述疫苗组合物还包括佐剂。
25.一种在受试者中治疗和/或预防癌症的方法,所述方法包括向所述受试者施用如权利要求23或24所述的疫苗组合物。
26.一种在受试者中治疗和/或预防CMV感染的方法,所述方法包括向所述受试者施用如权利要求23或24所述的疫苗组合物。
27.一种抗原呈递细胞(APC),所述抗原呈递细胞(APC)包括I类MHC上呈递的如权利要求20至22中任一项所述的肽。
28.如权利要求27所述的APC,其中所述APC是抗原呈递T细胞。
29.如权利要求27所述的APC,其中所述APC是树突状细胞。
30.如权利要求27所述的APC,其中所述APC是B细胞。
31.如权利要求27所述的APC,其中所述APC是人工APC。
32.如权利要求31所述的APC,其中所述人工APC是aK562细胞。
33.一种产生呈递CMV肽的抗原呈递细胞(APC)的方法,所述方法包括将所述抗原呈递细胞与如权利要求20至22中任一项所述的肽或编码如权利要求20至22中任一项所述的肽的核酸孵育。
34.如权利要求33所述的方法,其中所述APC是抗原呈递T细胞。
35.如权利要求33所述的方法,其中所述APC是树突状细胞。
36.如权利要求33所述的方法,其中所述APC是B细胞。
37.如权利要求33所述的方法,其中所述APC是人工APC。
38.如权利要求33所述的方法,其中所述人工APC是aK562细胞。
39.一种在受试者中治疗或预防癌症的方法,所述方法包括向所述受试者施用如权利要求27至32中任一项所述的APC。
40.如权利要求39所述的方法,其中所述APC对于所述受试者是自体的。
41.如权利要求39所述的方法,其中所述APC对于所述受试者不是自体的。
42.一种在受试者中治疗或预防CMV感染的方法,所述方法包括向所述受试者施用如权利要求37至41中任一项所述的APC。
43.如权利要求42所述的方法,其中所述APC对于所述受试者是自体的。
44.如权利要求42所述的方法,其中所述APC对于所述受试者不是自体的。
45.一种编码如权利要求20至22中任一项所述的肽的核酸。
46.如权利要求45所述的核酸,其中所述核酸是表达运载体。
47.如权利要求46所述的核酸,其中所述表达运载体是病毒运载体。
48.如权利要求47所述的核酸,其中所述病毒运载体是基于腺病毒的表达运载体。
49.一种包括如权利要求45至48中任一项所述的核酸的疫苗组合物。
50.一种在受试者中治疗和/或预防癌症的方法,所述方法包括向所述受试者施用如权利要求49所述的疫苗组合物。
51.一种在受试者中治疗或预防CMV感染的方法,所述方法包括向所述受试者施用如权利要求49所述的疫苗组合物。
52.一种与表1中列出的CMV表位结合的抗体或所述抗体的抗原结合片段。
53.如权利要求52所述的抗体或所述抗体的抗原结合片段,其中所述抗体或所述抗体的抗原结合片段是:
全长免疫球蛋白分子;
scFv;
Fab片段;
Fab’片段;
F(ab’)2;
Fv;
骆驼抗体;或
二硫键连接的Fv。
54.一种在受试者中治疗癌症的方法,所述方法包括向所述受试者施用如权利要求52或权利要求53所述的抗体或所述抗体的抗原结合片段。
55.一种在受试者中治疗CMV感染的方法,所述方法包括向所述受试者施用如权利要求52或权利要求53所述的抗体或所述抗体的抗原结合片段。
56.一种表达T细胞受体(TCR)的T细胞,所述T细胞受体(TCR)与主要组织相容性复合体(MHC)上呈递的包括表1中列出的表位的肽结合。
57.如权利要求56所述的T细胞,其中所述T细胞是细胞毒性T细胞(CTL)。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN111875698A (zh) * | 2020-07-29 | 2020-11-03 | 广州呈源生物免疫技术有限公司 | 靶向hcmv的tcr及其获得方法和应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
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EP3692058A1 (en) | 2017-10-06 | 2020-08-12 | Oslo Universitetssykehus HF | Chimeric antigen receptors |
WO2019220209A1 (en) * | 2018-05-18 | 2019-11-21 | The Council Of The Queensland Institute Of Medical Research | Adoptive t-cell therapy for cmv infection and cmv-associated diseases |
EP4143208A4 (en) * | 2020-04-28 | 2024-06-05 | Council Queensland Inst Medical Res | VACCINE COMPOSITION OF HUMAN CYTOMEGALOVIRUS POLYEPITOPES |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1512891A (zh) * | 2001-04-06 | 2004-07-14 | 表位序列 | |
WO2010037397A1 (en) * | 2008-10-01 | 2010-04-08 | Dako Denmark A/S | Mhc multimers in cmv immune monitoring |
CN102119170A (zh) * | 2008-06-10 | 2011-07-06 | 肿瘤疗法科学股份有限公司 | Mybl2表位肽及包含它的疫苗 |
US20130045221A1 (en) * | 2009-09-29 | 2013-02-21 | Ucl Business Plc | T-cell receptor capable of recognising an antigen from cytomegalovirus |
CN104661675A (zh) * | 2012-05-16 | 2015-05-27 | 阿德莱德研究创新私人有限公司 | 细胞疫苗和诱导受试者免疫反应的方法 |
WO2015142671A2 (en) * | 2014-03-17 | 2015-09-24 | Flugen, Inc. | Influenza virus vectors and uses therefor |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU5963500A (en) * | 1999-06-04 | 2000-12-28 | Florian Kern | Peptides for vaccinating against human cmv |
DE10009341A1 (de) * | 2000-02-22 | 2001-09-06 | Florian Kern | Verfahren zur antigen-spezifischen Stimulation von T-Lymphozyten |
AUPR593101A0 (en) * | 2001-06-26 | 2001-07-19 | Council Of The Queensland Institute Of Medical Research, The | Cytomegalovirus t cell epitopes |
AU2004257214B2 (en) * | 2003-07-11 | 2010-04-22 | Alphavax, Inc. | Alphavirus-based cytomegalovirus vaccines |
AU2012227280B2 (en) * | 2004-11-29 | 2016-09-22 | The Council Of The Queensland Institute Of Medical Research | Human cytomegalovirus immunotherapy |
WO2010014567A2 (en) * | 2008-08-01 | 2010-02-04 | Merck & Co., Inc. | Variant hcmv pp65, ie1, and ie2 polynucleotides and uses thereof |
HRP20221303T1 (hr) * | 2012-02-09 | 2022-12-23 | Baylor College Of Medicine | SMJESE PEPTIDA ZA NASTAJANJE MULTIVIRUSNIH CITOTOKSIČNIH T-LIMFOCITA(CTLs) ŠIROKE SPECIFIČNOSTI |
GB201312133D0 (en) * | 2013-07-05 | 2013-08-21 | Univ Birmingham | Immunotherapy |
-
2017
- 2017-05-23 CA CA3025234A patent/CA3025234A1/en active Pending
- 2017-05-23 AU AU2017271136A patent/AU2017271136A1/en not_active Abandoned
- 2017-05-23 US US16/303,677 patent/US20200316119A1/en active Pending
- 2017-05-23 CN CN201780045358.8A patent/CN109475579A/zh active Pending
- 2017-05-23 JP JP2018561467A patent/JP2019520332A/ja active Pending
- 2017-05-23 WO PCT/IB2017/000849 patent/WO2017203370A2/en unknown
- 2017-05-23 EP EP17802274.5A patent/EP3463400A4/en active Pending
-
2023
- 2023-02-13 JP JP2023020200A patent/JP2023071724A/ja active Pending
- 2023-03-01 AU AU2023201279A patent/AU2023201279A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1512891A (zh) * | 2001-04-06 | 2004-07-14 | 表位序列 | |
CN102119170A (zh) * | 2008-06-10 | 2011-07-06 | 肿瘤疗法科学股份有限公司 | Mybl2表位肽及包含它的疫苗 |
WO2010037397A1 (en) * | 2008-10-01 | 2010-04-08 | Dako Denmark A/S | Mhc multimers in cmv immune monitoring |
US20130045221A1 (en) * | 2009-09-29 | 2013-02-21 | Ucl Business Plc | T-cell receptor capable of recognising an antigen from cytomegalovirus |
CN104661675A (zh) * | 2012-05-16 | 2015-05-27 | 阿德莱德研究创新私人有限公司 | 细胞疫苗和诱导受试者免疫反应的方法 |
WO2015142671A2 (en) * | 2014-03-17 | 2015-09-24 | Flugen, Inc. | Influenza virus vectors and uses therefor |
Non-Patent Citations (2)
Title |
---|
GIBSON,L.等: "CYTOMEGALOVIRUS IE1-AND PP65-SPECIFIC CD8+ T CELL RESPONSES BROADEN OVER TIME AFTER PRIMARY CMV INFECTION IN INFANTS", 《JOURNAL OF INFECTIOUS DISEASES》 * |
KREN,F,等: "TARGET STRUCTURES OF THE CD8+-T-CELL RESPONSE TO HUMAN CYTOMEGALOVIRUS:THE 72-KILODALTON MAJOR IMMEDIATE-EARLY PROTEIN REVISITED", 《JOURNAL OF VIROLOGY》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111875698A (zh) * | 2020-07-29 | 2020-11-03 | 广州呈源生物免疫技术有限公司 | 靶向hcmv的tcr及其获得方法和应用 |
CN111875698B (zh) * | 2020-07-29 | 2021-11-05 | 广州呈源生物免疫技术有限公司 | 靶向hcmv的tcr及其获得方法和应用 |
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US20200316119A1 (en) | 2020-10-08 |
AU2023201279A1 (en) | 2023-04-20 |
WO2017203370A2 (en) | 2017-11-30 |
JP2023071724A (ja) | 2023-05-23 |
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