CN107530410A - 包含经修饰的α病毒表面糖蛋白与肿瘤相关抗原的融合蛋白及其方法 - Google Patents
包含经修饰的α病毒表面糖蛋白与肿瘤相关抗原的融合蛋白及其方法 Download PDFInfo
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Abstract
本公开涉及包含一种或多种经修饰的α病毒表面糖蛋白和一种或多种肿瘤特异性抗原的融合蛋白。还公开了包含一种或多种经修饰的α病毒表面糖蛋白和一种或多种病毒特异性抗原的融合蛋白。还公开了包含一种或多种经修饰的α病毒表面糖蛋白的融合蛋白。本公开还涉及激活癌症患者的免疫系统以浸润并杀死肿瘤细胞或被潜伏病毒感染的细胞的方法。本公开提供了利用融合蛋白引起更快、更广泛和更强的免疫应答的平台技术。
Description
相关申请
本申请要求于2015年3月18日提交的美国申请序列号62/134,933的权益,所述申请特此通过引用将其全文结合在此。
技术领域
本公开涉及包含一种或多种经修饰的α病毒表面糖蛋白和一种或多种肿瘤特异性抗原的融合蛋白。还公开了包含一种或多种经修饰的α病毒表面糖蛋白和一种或多种病毒特异性抗原的融合蛋白。还公开了包含一种或多种经修饰的α病毒表面糖蛋白的融合蛋白。它还涉及激活癌症患者免疫系统的方法,以渗透并杀死肿瘤细胞或受潜伏病毒感染的细胞。本公开提供了一种利用融合蛋白产生更快、更广泛和更强的免疫应答的平台技术。
背景技术
在美国,卵巢癌是由妇科恶性肿瘤引起的死亡的主要原因(1)。不幸的是,大多数卵巢癌直到疾病进展到Ⅲ期或Ⅳ期时才能被诊断,此时,即使最开始已成功进行了手术和化疗(2),复发仍然十分普遍。然而,事实表明,体内的肿瘤被淋巴细胞浸润的患者的5年存活率明显高于那些肿瘤未被淋巴细胞浸润的患者(3),这表明免疫系统在对抗肿瘤生长中有重要作用,并且免疫疗法可以作为成功对抗该疾病的一种策略。此外,众所周知,很多癌症是由病毒感染引起的。
免疫系统通过一种称为“肿瘤免疫编辑”的机制在控制和预防异常肿瘤细胞生长中发挥重要的作用(4)。细胞毒性CD8 T细胞和自然杀伤(NK)细胞能够在肿瘤细胞出现时,识别并杀死它们。事实表明,缺乏这些细胞类型的免疫缺陷小鼠更容易形成肿瘤(4)。然而,肿瘤细胞能够通过产生突变来逃脱免疫系统的检测,并因此成熟的肿瘤通常具有弱免疫原性,从而阻止上述多种疗法成功转化用于患者(4)。此外,肿瘤还能形成特殊的微环境,防止自身与淋巴细胞直接接触。
然而,在应对肿瘤免疫抑制性方面取得了一些进步。最近,免疫治疗性抗体易普利单抗(Ipilimumab)和纳武单抗(nivolumab)被批准用于治疗某些癌症。这些检验点抑制剂靶向T细胞上的免疫抑制受体CTLA-4(易普利单抗)和PD-1(纳武单抗)并阻断其活性。不过,由于这些免疫抑制机制对于控制可能带来危险的自身免疫及过敏反应非常重要,故这些药物并不是没有安全隐患。嵌合抗原受体(CAR)T细胞疗法在治疗如B细胞急性淋巴母细胞白血病(ALL)等基于血液的癌症方面显示出巨大潜力。为了产生CAR T细胞,收集患者自身的T细胞并加以遗传修饰以使其表达能够识别肿瘤细胞上的特定表面抗原的受体(5)。这种方法避开了典型地存在于T细胞与抗原呈递肿瘤细胞之间的信号传导通路,使它们能对抗免疫抑制。由于该方法需要对患者自身细胞进行基因改造,并且可能会发生细胞因子释放综合症带来的潜在危险的副作用(6),故CAR T疗法需要密切个体监控,而较传统的药物疗法则不必如此。CAR T细胞对抗实体瘤(如卵巢癌)的能力仍然需要评估。
另一种被证明有潜力的治疗癌症的方法是利用溶瘤病毒(OV)或者病毒载体。这些病毒被认为是通过特异性感染并杀死癌症细胞来发挥作用。当癌症细胞被溶解时,树突状细胞能够拾取释放的肿瘤抗原,并产生较强的抗肿瘤免疫应答。然而,发现这些病毒和病毒载体能够在淋巴结或其它器官中及除预定目标肿瘤以外的地方积累。因此,仍需要提供一种能够安全有效地治疗和预防癌症且不存在上述危险和缺点的方法。
发明内容
本文描述包含一种或多种肿瘤相关抗原和一种或多种经修饰的α病毒表面糖蛋白的融合蛋白。还描述编码所述经修饰的融合蛋白的多聚体复合物及核酸,所述融合蛋白的氨基酸序列,所述融合蛋白的抗体及其应用。在某些实施例中,α病毒为辛德比斯α病毒或基孔肯雅病毒。在某些实施例中,经修饰的α病毒表面糖蛋白为E1、E2或6K。在某些实施例中,经修饰的α病毒表面糖蛋白为E1和E2。在某些实施例中,本文提供了经修饰的α病毒多聚蛋白。在某些实施例中,多聚蛋白为E3或衣壳蛋白。本文提供了包含一种或多种经修饰的α病毒表面糖蛋白和其它蛋白质的融合蛋白,如优先癌症抗原研究的美国国家癌症研究所(National Cancer Institute,NCI)的试点项目表3中所公开的内容,《临床肿瘤研究(ClinCancer Res)》(2009;15:5323-5337)。此外,本文描述了包含经修饰的α病毒表面糖蛋白和一个或多个基因或基因片段的重组融合蛋白。在某些实施例中,所述融合蛋白由构建体编码,所述构建体包含肿瘤相关抗原的基因或基因片段,它们在内部或末端插入α病毒表面糖蛋白基因片段中。在某些实施例中,所述基因或基因片段为一种或多种肿瘤相关抗原。在某些实施例中,所述融合蛋白为单体、复合物和共轭物。在某些实施例中,所述融合蛋白能形成二聚体、三聚体或多聚体。
本文还描述了包含一种或多种病毒抗原和一种或多种经修饰的α病毒表面糖蛋白的融合蛋白。
本文还描述了通过融合蛋白给药来治疗或预防疾病的方法,所述融合蛋白包含一种或多种肿瘤相关抗原和一种或多种经修饰的α病毒表面糖蛋白。在某些实施例中,本文公开的方法可治疗受试者,用于激活抑制的免疫系统。在某些实施例中,所述治疗针对癌症患者。在某些实施例中,治疗包括浸润和杀死肿瘤细胞。在某些实施例中,治疗包括杀死潜在的病毒感染细胞。
在一个实施例中,公开了用于治疗受试者内癌症一种方法,包括向需要的受试者注射融合蛋白,其中所述融合蛋白大体上由α病毒表面膜糖蛋白E1、E2以及至少一个连接肽组成,其中对受试者给药后,所述融合蛋白刺激免疫应答。
本文描述了包含用于预防和治疗疾病的融合蛋白的一种试剂盒。
公开的方法包括包含一种或多种肿瘤相关抗原和一种或多种经修饰的α病毒表面糖蛋白的融合蛋白的应用。在某些实施例中,所述经修饰的的α病毒表面糖蛋白是单体、复合体、融合体和共轭体。在某些实施例中,所述融合蛋白能形成二聚体、三聚体或多聚体。包含一种或多种肿瘤相关抗原和一种或多种经修饰的α病毒表面糖蛋白的所述融合蛋白有以下用途中的一种或多种:(i)刺激/激活人体免疫系统;(ii)刺激/激活人体T细胞生长;(iii)刺激/激活人体造血细胞,包括T细胞、NK细胞、B细胞、树突细胞、调节性T细胞、巨噬细胞、红细胞等;(iv)释放原本失活的T细胞;(v)克服T细胞的断点抑制;(vi)治疗或预防癌症;以及(vii)潜在的病毒感染细胞。在某些实施例中,所述方法包括向需要的受试者进行融合蛋白给药,所述融合蛋白包含肿瘤相关抗原及经修饰的α病毒表面糖蛋白,用于:(i)刺激/激活人体免疫系统;(ii)刺激/激活人体T细胞生长;(iii)刺激/激活人体造血细胞,包括T细胞、NK细胞、B细胞、树突细胞、调节性T细胞、巨噬细胞、红细胞等;(iv)释放原本无活性的T细胞;(v)克服T细胞的断点抑制;以及(vi)治疗或预防癌症。在某些实施例中,本文公开的方法用于治疗受试者以激活癌症患者抑制的免疫系统来渗透和杀死肿瘤细胞。在其它实施例中,所述融合蛋白包含一种或多种病毒抗原和一种或多种经修饰的α病毒表面糖蛋白,可用于杀死潜在的病毒感染细胞。
附图说明
图1A-Bα病毒的结构蛋白。(A)辛德毕斯病毒的冷冻电镜(cryo-EM)密度表现出T=4对称。一个不对成单位中有4个E2分子。这些组成了每二十面的三重轴上的一个三聚体刺突和一个一般位置的刺突。(B)辛德毕斯病毒的结构多蛋白穿过内质网膜,显示衣壳、E3、E2、6K和E1蛋白的位置(李,L等人,《甲病毒融合时包膜蛋白的结构变化(Structuralchanges of envelope proteins during alphavirus fusion)》,《自然(Nature)》,468,705-708(2010))。
图2A-B糖蛋白刺突的区域结构。(A)p62-El异源二聚体的带状图。E1区域I、II和III分别用红色、黄色和蓝色标出,融合环(FL)用橘色标出。E3为白/灰色,并且E2区域A为青色,区域B为深绿色,区域C为粉红色,β带为暗紫色。N连接的糖链为球形和棒状,根据原子类型上色并标记。二硫化物为绿色棒状。黑色箭头(在粉色和蓝色星星旁边,分别表示P62和E1的C端)指向病毒膜。将异源二聚体“板”画成“不扭曲”的插图、示意图表明这些区域相对于彼此之间的位置及联系。(B)p62的组成,大致面向a的90°显示E3(沃斯·JE等人,《X射线结晶学揭示的基孔肯雅病毒颗粒的糖蛋白组织(Glycoprotein organization ofchikungunya virus particles revealed by x-ray crystallography)》《自然(Nature)》,468,709-712(2010))。
图3改造的重组辛德毕斯VGP结构图。左边为由辛德毕斯病毒(SINV)编码的完整结构蛋白组成。右边为改造的缺失跨膜区和6K区并与肿瘤相关抗原(TAA)连接的VGP。
图4A-C改造的病毒糖蛋白构建体E2 E1二聚体和TAA形成三聚体刺突跨膜区和6K区被去除,并且E2和E1由柔性连接肽相连。E3序列作为ER靶向序列,有助于E2/E1的二聚化。通过另一个柔性连接肽和蛋白酶切割位点将TAA加入E1的C端。VGPs三聚化以在高尔基体中分泌形成携带TAAs的可溶性刺突。
图5融合蛋白E3-E2-连接肽-EL-TEV-连接肽-NY-ESO-1-6X His一个示例的氨基酸序列。1-65位为E3-氨基酸残基的位置;66-429位为E2-氨基酸残基的位置;430-448位为连接肽-氨基酸残基的位置;449-854位为E1-氨基酸残基的位置;855-876位为TEV-连接肽-氨基酸残基的位置;877-978位为NY-ESO-1肽片段氨基酸残基的位置;979-984位为6X His-氨基酸残基的位置。粗体的N为糖基化位点:在氨基酸残基的261位、383位、587位和693位。
图6融合蛋白E3-E2-连接肽-E1-TEV-连接肽-NY-ESO-1-6X His一个示例的核苷酸序列
图7Western Blot纯化融合蛋白在100ml培养液中收集上清液,并且用Ni亲和层析色谱法进行蛋白纯化。预测分子量:106.8kDa
M2道:Western标记物
1道:细胞裂解培养液
2道:流过
3道:用20mM咪唑洗脱
4道:用500mM咪唑洗脱
5道:洗脱后的树脂
抗体:抗His抗体(GenScript,Cat.No.A00186)
图8A-F可用于制造本文公开的融合蛋白的抗原的氨基酸序列(SEQ IDNO:3-11)。
图9辛德毕斯结构蛋白全长序列(衣壳、E3、E2、E2的胞外结构域、E2的跨膜结构域、6K、E1的胞外结构域、E1的跨膜结构域)的SEQ IDNO:12。
4.1定义
如本文所用,术语“α病毒”在本领域有其传统的定义,包括各种物种如VEE、SFV、辛德毕斯、罗斯河病毒、西方马脑炎病毒、东部马脑炎病毒、基孔肯雅病毒、S.A.AR86、埃弗格赖德病毒、穆坎博、巴马森林病毒、米德尔堡病毒、皮春纳病毒、奥尼翁-尼翁(O'n.yong-nyong)病毒、盖塔病毒、鹭山病毒、贝巴鲁病毒、马亚罗病毒、乌纳病毒、奥拉病毒、瓦塔罗阿病毒、Banbanki病毒、孜拉加奇(Kyzylagach)病毒、高地J(Highlands J)病毒、摩根堡(Fort.Morgan)病毒、恩杜茂病毒和博吉河(Buggy Creek)病毒。在某些实施例中,本发明公开的构建体和方法中应用的α病毒为VEE、S.AAR86、辛德毕斯(如TR339,参见美国专利号No.6,008,035)和SFV。
术语“佐剂”是指与免疫原性抗原决定簇/抗原/核酸构建体混合给药的任何物质,增加或改变所述决定簇的免疫应答。
术语“氨基酸”是指合成的或自然存在的氨基羧酸,包括肽和多肽中的任何氨基酸,包括体内合成的蛋白和酶,因此包括对氨基酸的修饰。本文所述氨基酸是术语“氨基酸残基”的同义词,其意指包含所述氨基酸,这些氨基酸已与至少一个其它物种发生反应,如2个物种,如3个物种,如3个以上其它物种。通用术语“氨基酸”包括天然氨基酸和非天然氨基酸两者,它们中的任何一种可以是“D”或“L”异构体。
术语“抗体”是指免疫球蛋白分子和免疫球蛋白分子的活性部分。例如,抗体可为完整的免疫球蛋白分子或其保持免疫活性的片段。
术语“抗原”是指任何可以结合克隆分布的免疫受体的物质(T细胞受体或B细胞受体)。通常可为肽、多肽或聚合体多肽。优选地,抗原能够激发免疫应答。
本文所用的术语“提升”即利用加强注射或剂量以进行提高,是给予额外剂量的免疫制剂,如疫苗,为维持相同试剂以之前剂量引起的免疫应答,在初次给药后的某个时间再次给药。
术语“载体”是指与抗原偶联以帮助诱导免疫应答的实体或化合物。
术语“融合蛋白”是指基因工程改造的蛋白质,其由两个或更多个结合在一起的完整或部分基因或一系列核酸形成的核苷酸序列所编码。可替代地,可通过结合两个或更多个异源肽来制造融合蛋白。
术语“细胞因子”是指生长调节剂或分化调节剂,本文非决定性使用。除了细胞因子以外,粘附分子或辅助分子或其任何组合均可单独使用或与细胞因子联合使用。
术语“细胞毒性T淋巴细胞”是指和T细胞受体一起表达CD8的T细胞亚群,因此能够应答I类分子所呈递的抗原。
术语“运载工具”是指核苷酸序列或多肽或两者都可以利用其从至少一种媒介传送到另一种媒介的实体。
术语“片段”是指核酸或多肽的非全长部分。
术语“受试者”是指鸟类、哺乳动物、人类、非人类、鱼类、两栖动物或爬行动物中的任何种类或亚种。
术语“分离的”与核酸、多肽和抗体有关,是指其已被鉴别并从其自然的、典型的细胞和环境成分中分离和/或恢复。
术语“核酸、多肽和抗体”优选分离的,并且本发明的疫苗和其它组合物优选包括分离的核酸、多肽或分离的抗体。
术语“MHC或主要组织相容性复合体”是指MHC I类和II类的两个主要亚类。
术语“核酸”是指传递遗传信息的核苷酸链或核苷酸序列。核酸构建体是指基因工程改造的核酸。通常包含多个因子,如基因或基因片段、启动子、增强子、终结子、多(聚)腺苷酸(poly A)尾,连接肽、多聚连接肽、可操作性(operative)连接肽、多克隆位点(MCS)、标记物、终止密码子、其它调控因子、内部核糖体进入位点(IRES)等。
术语“病原体”是指导致疾病的特定物质,特别是生物制剂,如病毒、细菌、朊病毒或可引起宿主的疾病寄生虫,也被称为感染因子。
术语“癌症”或“肿瘤”是指由于细胞生长异常失控而导致的赘生物或肿瘤。术语“癌症”包括一种包括癌前细胞和肿瘤细胞的疾病。在一些实施例中,癌症是指细胞的局部过度生长,没有扩散到受试者的其它部位,即良性肿瘤。在其它实施例中,癌症是指恶性肿瘤,侵入并破坏邻近的身体结构并扩散到远处的部位。在另外的其它实施例中,癌症与特定的癌症抗原相关。
本文所用术语“有效量”是指能充分抑制肿瘤发展、复发或肿瘤和其一个或多个症状产生的治疗量,可提高或改善另一种治疗的预防效果,减轻严重症状、减少癌症的持续时间,改善一个或多个癌症症状,防止癌症的发展,引发癌症的衰退,和/或提高或改善另一种疗法的治疗效果。在一个实施例中,在一个、两个、三个或更多个治疗药物给药后,治疗量能够有效实现一个、二个、三个或更多个以下结果:(1)稳定、减少或消除癌症干细胞的数量;(2)稳定、减少或消除癌细胞的数量;(3)稳定或减少肿瘤或赘生物的生长;(4)破坏肿瘤的形成;(5)根除、移除或控制原发性、区域性和/或转移性癌症;(6)降低死亡率;(7)无病、无复发、无进展情况和/或总生存时间或生存率的增加;(8)应答速率、反应的持续性、应答患者或在缓解期患者的数量的增加;(9)住院率降低;(10)住院的时长降低;(11)维持肿瘤的大小不增加或大小增加不到10%,优选地小于5%,优选地小于4%,优选地小于2%;(12)在缓解期患者的数量增加;(13)在缓解期的时长增加;(14)癌症的复发率降低;(15)癌症复发的间隔时间增加;和(16)与癌症相关的症状和/或生活质量的改善。
术语“肽”是指多个共价连接的氨基酸残基,其定义序列并通过酰胺键连接。所述术语类似寡肽和多肽。天然和/或非天然氨基酸可通过肽键或非肽键连接。术语“肽”还包含了本领域的技术人员熟知的通过化学或酶催化反应引入的翻译后修饰。所述术语可以指多肽的变体或片段。
术语“药物载体、赋形剂或稳定剂”在其使用的剂量和浓度上对细胞或个体是无毒的。通常生理上可接受的载体是pH缓冲溶液。生理上可接受的载体的实例包括缓冲液,如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸;低分子量(小于约10个残基)多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬氨酸、精氨酸或赖氨酸;单糖、双糖和其它碳水化合物,包括葡萄糖、甘露糖或环糊精;螯合剂,如EDTA;糖醇,如甘露醇或山梨醇;成盐反离子,如钠;和/或非离子表面活性剂,如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。
术语“启动子”是指DNA链中的一个结合位点,通过附近的一个或多个结构基因,RNA聚合酶与所述结合位点结合并启动信使RNA的转录。
术语“信号肽”是指氨基酸的短序列,其决定细胞内蛋白质的最终位置,也称为排序肽。
术语“表面活性剂”是指能够降低溶解其的液体的表面张力的表面活性物质。表面活性剂是包含亲水性极性基团和疏水性非极性基团并且通常包含脂肪链的化合物。
术语“疫苗”是指能够诱导动物产生免疫应答的物质或组合物,也被称为免疫原性组合物。免疫应答是诱导有机体记忆的免疫应答(体液或抗体和/或细胞),可导致感染因子与二次而非初级反应相遇,从而减少其对宿主有机体的影响。疫苗可作为预防性和/或治疗性药物。所述组合物可包括一种或多种以下物质:与一种或多种肿瘤相关抗原结合的VGP,包含操作性连接到一种或多种抗原、载体、佐剂和药用载体的核酸构建体。
术语“变异体”是指与特定参考核酸或多肽有某种程度的序列同源性或一致性的核酸或多肽,但又与所述参考核酸或多肽不同。
具体实施方式
5.1包含经修饰的α病毒糖蛋白和抗原的融合蛋白
与其它所有α病毒一样,辛德毕斯基因组编码4个能进行RNA复制的非结构蛋白(nsP1-4)和5个结构蛋白(衣壳、E3、E2、6K和E1)。结构蛋白以单一多蛋白形式表达,通过细胞蛋白酶切除以形成成熟蛋白(见图1)。衣壳蛋白形成包围着病毒基因组的内核,并与E2包膜糖蛋白的胞质尾区相互作用(7)。E3蛋白中有一段氨基酸序列,可作为包含E3和E2的前体蛋白pE2的信号序列,E3蛋白能调控适当的E2折叠,并且对于E2和E1的异二聚体化十分必要(7)。在高尔基体中进行蛋白加工时,E3被弗林蛋白酶内切,并在病毒从细胞出芽时脱落(7)。辛德毕斯病毒(“SINV”)E2是一个跨膜糖蛋白,在196和318位上有2个N连接的糖基化位点。6K蛋白中有一段氨基酸序列,可作为E1的信号序列,6K蛋白被信号肽酶从E1和E2上切除,以最少量存在于成熟的毒粒中。辛德毕斯病毒E1是一个跨膜糖蛋白,在139和245位上有2个N连接的糖基化位点(8)。当病毒从细胞中出芽释放后,来源于宿主细胞膜上的病毒包膜覆盖着衣壳。E2/E1异二聚体在病毒包表面膜外形成三聚体刺突。E2区负责与靶细胞上的受体相互作用,而E1则触发晚期胞内体和溶酶体在低pH条件下的膜融合(8)。
本文描述了由经修饰的病毒糖蛋白(VGPs)组成的融合蛋白,即E1与E2蛋白共同表达为单一的重组蛋白(见图3),将其与肿瘤特异性抗原结合形成用于治疗的融合蛋白VGP-TAA。在具体实施例中,融合蛋白不包含跨膜蛋白、6K区和非结构蛋白。在具体实施例中,用于表达融合蛋白的表达载体不是病毒载体。在一个实施例中,融合蛋白具有SEQ ID NO:1中的氨基酸序列。在某些实施例中,融合蛋白具有SEQ ID NO:1中的氨基酸序列,但作了如下修饰:(1)删除1-65、979-978位的氨基酸残基。融合蛋白是由核苷酸编码形成的重组蛋白,所述核苷酸具有一段与一种或多种肿瘤相关抗原与操作性相连的病毒表面膜糖蛋白的核苷酸序列。在某些实施例中,在优先癌症抗原研究的美国国家癌症研究所试点项目表3中公开了一种或多种肿瘤相关抗原,《临床肿瘤研究(Clin Cancer Res)》(2009;15:5323-5337)。
在某些实施例中,融合蛋白的肿瘤相关抗原部分可具有与SEQ ID NO:3-11至少a%一致性的氨基酸序列。在某些实施例中,融合蛋白的肿瘤相关抗原部分可具有与SEQ IDNO:1中877-978位氨基酸残基有至少a%一致性的氨基酸序列。
在某些实施例中,肿瘤相关抗原包含如SEQ ID NO:3-11中任一个所示的至少7、至少8、至少9、至少10、至少12、至少14、至少16、至少18、至少20、至少25、至少30、至少35、至少40、至少50、至少60、至少70、至少80、至少90、至少100、至少150、至少200、至少250个或更多连续的氨基酸,其中所述连续氨基酸具有免疫原性。
在某些实施例中,肿瘤相关抗原由SEQ ID NO:3-11中的10-20、20-30、30-50、50-150、150-200、200-400、400-500个氨基酸组成。在某些实施例中,肿瘤相关抗原不包含SEQID NO:3-11的全长蛋白。
在某些实施例中,肿瘤相关抗原的氨基酸比SEQ ID NO:3-11中的蛋白氨基酸少1200个氨基酸,少1100个氨基酸,少1000个氨基酸,少950个氨基酸,少900个氨基酸,少850个氨基酸,少800个氨基酸,少750个氨基酸,少700个氨基酸,少650个氨基酸,少600个氨基酸,少590个氨基酸或少580个氨基酸。
包括但不限于上述讨论的SEQ ID NO:3-11中的肿瘤相关抗原片段是免疫原性片段,可以与佐剂(包括但不限制于任何在下面“免疫原性成分和药物”部分所列出或讨论的佐剂)或与经多肽偶联的合适载体以合适的组合物注入受试者中,诱导抗体或T细胞调控的免疫应答,分别识别已分离的衍生出免疫原性片段的SEQ ID NO:3-11的全长多肽。
肿瘤相关抗原与SEQ ID NO:3-11中的任一个相比,可包含一个或多个(如1、2、3、4、5、6、7、8、9等)氨基酸取代,例如保守替换(即将一个氨基酸用另一个具有相关侧链的氨基酸进行替换)。基因编码的氨基酸一般分为四个家族:(1)酸性氨基酸即天冬氨酸、谷氨酸;(2)碱性氨基酸即赖氨酸、精氨酸、组氨酸;(3)非极性氨基酸即丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸;(4)不带电荷极性氨基酸即甘氨酸、天冬酰胺、谷氨酰胺、半胱氨酸、丝氨酸、苏氨酸、酪氨酸。苯丙氨酸、色氨酸、酪氨酸有时还会一起列入芳香族氨基酸。一般来说,这些家族的单个氨基酸取代不会对生物活性造成太大影响。
相对于SEQ ID NO:3-11中的任一个,多肽可包含一个或多个(如1个、2个、3个、4个、5个、6个、7个、8个、9个等)单氨基酸删除。同样,相对于SEQ ID NO:3-11中的任一个,多肽可包含一个或多个(如1个、2个、3个、4个、5个、6个、7个、8个、9个等)插入(如每1个、2个、3个、4个或5个氨基酸)。
删除或取代可发生在N端和/或C端,或可在这两端之间。因此,截断是删除的一个实例。截断可涉及删除N端和/或C端多达40个(或更多个)氨基酸。
一般来说,当本发明的多肽包含一段与SEQ ID NO:3-11的全部序列不相同的序列(如当多肽包含一段与以上序列有小于100%一致性的序列,或当多肽包含其中的片段),优选地,所述多肽可诱导产生能够识别包含全部SEQ ID序列的多肽的抗体,即所述抗体与所述的SEQ ID NO:3-11中的一个或多个结合。这种抗体不与非同系物的其它蛋白结合,而可分别与SEQ ID NO:3-11特异性结合,且亲和力大大超过了所述抗体与作为非特异性结合对照标准的人血清白蛋白的非特异性亲和力。
本发明的多肽可包含金属离子,如由多肽链中的一个或多个氨基酸调控的金属离子。例如,所述多肽可包含单价、二价或三价金属阳离子。二价阳离子较典型,如Mn2+、Fe2+、Co2+、Ni2+、Cu2+等。优先选择Zn2+作为二价阳离子。
本文公开的多肽有多种形式(如原型的、融合的、糖基化的、非糖基化的、脂化的、非脂化的、磷酸化的、非磷酸化的、十四酰化的、非十四酰化的、单体的、多聚体的、颗粒的、变性的等)。例如,本发明的多肽可包含脂化的N端半胱氨酸。
本文公开的多肽可以通过多种方式制备(如重组表达、从细胞培养中纯化、化学合成等)。优先选择重组表达的蛋白。
本文公开的多肽优先选择经纯化或大体上纯化的形式,即不包含其它多肽(如不包含天然多肽),特别是不含其它大肠杆菌或宿主细胞中的多肽,并且一般纯度至少约50%(按重量),通常纯度至少约90%,即其它表达的多肽占约50%以下,并且更优选低于约10%(如5%)。因此,组合物中的抗原可与进行分子表达的全部生物体分离。
多肽片段中肿瘤相关抗原的抗原表位可以是B细胞抗原表位和/或T细胞抗原表位。可通过经验(如利用PEPSCAN或类似的方法)或预测(如利用Jameson-Wolf抗原指数、基于矩阵的方法、MAPITOPE、TEPITOPE、神经网络、OptiMer&EpiMer、ADEPT、Tsites、亲水性、抗原指数等)的方法来鉴定所述抗原表位。抗原表位是抗原的一部分,可以被抗体或T细胞受体的抗原结合位点识别并结合,并且它们也可被称为“抗原决定簇”。
本文公开的任一多肽可作为疫苗的成分。因此,在另一个实施例中,分离的或重组的多肽将会加入佐剂。
在一个实施例中,融合蛋白包含一个或多个抗原蛋白或肽或抗原蛋白的片段,所述蛋白是肿瘤相关抗原。许多蛋白已被鉴定并连接到某些类型的癌症,这些蛋白被称为肿瘤相关抗原。任何与癌症肿瘤相关的抗原通常都会被利用。在某些实施例中,肿瘤相关抗原为WT1(UniProt知识库,MUC1(P15941),LMP2(P1 3285),HPV16E6(P03126)和E7(P03129),HPV 18(E6-P06463)和E7(P06788),RGL4(Q8IZJ4),EGFRvIII(P0533),HER-2/neu(P04626),MAGE A3(Q53EX0),PSMA(Q04609),CEA(P06731),MelanA/MART(Q16655),gp100(P40967),蛋白酶3(PR1)(P24158),bcr-abl融合,bcr(P11274),ab1(P005 19),酪氨酸酶(P14679),生存素(015392),PSA(P07288),hTERT(014746),EphA2(P29317),PAP(PI5309),ML-IAP(Q96CA5),AFP(P02771),EpCAM(P16422),TMPRSS2/ERG融合,TMPRSS2(015393),ERG(P11308),PAX3(P23760),ALK(Q9UM73),雄激素受体(P10275),细胞周期蛋白B1(P14635),MYCN(P04198),RhoC(P08134),TRP-2(P40126).间皮素(Q13421),PSCA(043653).MAGE A1(P43355),CYP1B1(Q16678),PLAC1(Q9HBJ0),BORIS(Q8NI5I),NY-BR-1(Q9BXX3),RGS5(O15539),SART3(Q15020),碳酸酐酶IX(Q16790),PAX5(Q02548),OY-TES1(Q8NEB7),精子蛋白17(Q15506),LCK(P06239),HMWMAA(Q6UVK1),AKAP-4(Q5JQC9),SSX2(Q16385),XAGE 1(Q9HD64),豆荚蛋白(Q99538),Tie 2(Q02763),VEGFR2(P35968),PDGFR-β(P09619)和Fos相关抗原1(P15407)。
在某些实施例中,将一种或多种α病毒表面膜糖蛋白操作性地连接一种或多种肿瘤相关抗原。在一个实施例中,肿瘤特异性抗原是睾丸癌抗原NY-ESO-1的主要抗原活性区。在某些实施例中,肿瘤特异性抗原包含用于癌症免疫治疗的一系列人TAAs靶标(9)。在一个特定的实施例中,SIVN VGP重组蛋白与NY-ESO-1的主要抗原活性区结合形成融合蛋白。
在某些实施例中,额外的N连接的糖基化位点可被改造为病毒糖蛋白。N连接的多糖与以天冬酰胺-X-丝氨酸/苏氨酸序列形式存在的天冬酰胺侧链连接,其中X可以是除脯氨酸之外的任何氨基酸。
本公开也与编码融合蛋白的核酸构建体有关,所述融合蛋白包含一种或多种肿瘤相关抗原和与SEQ ID NO:1相同的氨基酸序列或其中片段的一种或多种α病毒表面膜糖蛋白。在某些实施例中,所述片段具有40-80、80-150、150-200、200-300、300-400、400-500、500-600、600-700、700-800、800-850和850-900位的氨基酸残基。在某些实施例中,所述片段与SEQ ID NO:2有至少85%、90%、95%、99%的一致性。在某些实施例中,肿瘤相关抗原是全长蛋白。在某些实施例中,肿瘤相关抗原是全长蛋白中的片段。在某些实施例中,所述片段具有5-10、10-20、20-30、30-40、40-80、80-150、150-200、200-300、300-400、400-500和500-600位的氨基酸残基。在某些实施例中,所述片段与野生型肿瘤相关抗原有至少85%、90%、95%、99%的一致性。氨基酸序列间的一致性或同源性可通过任一个如BLOSUM 30、BLOSUM 40、BLOSUM 45、BLOSUM 50、BLOSUM 55、BLOSUM 60、BLOSUM 62、BLOSUM 65、BLOSUM70、BLOSUM 75、BLOSUM 80、BLOSUM 85和BLOSUM 90的著名打分矩阵来计算。
在某些实施例中,肿瘤相关抗原是包含SEQ ID NO:3-11中任一个至少10个连续氨基酸的多肽片段,其中包含至少10个连续氨基酸的多肽片段具有免疫原性,并且所述免疫原性多肽片段包含SEQ ID NO:3-11的多肽的少于1100个的氨基酸。
在一个实施例中,公开了分离的或重组的融合蛋白,其大体上由α病毒表面膜糖蛋白E1、E2和任选地E3、连接肽和至少一种肿瘤相关抗原组成,其中,对受试者给药后,融合蛋白刺激免疫应答。在一个实施例中,融合蛋白包含与SEQ ID NO:1具有至少98%一致性的氨基酸序列。在一个实施例中,融合蛋白至少包含SEQ ID NO:1中至少66-978位的氨基酸残基。在一个实施例中,融合蛋白由与SEQ ID NO:2有至少95%一致性的核酸分子编码。在一个实施例中,融合蛋白还包括删除了SEQ ID NO:1上(i)1-65位;(ii)979-984位或(iii)1-65位及979-984位的氨基酸残基。在一个实施例中,E2包含氨基酸序列,所述氨基酸序列在长度上具有至少300个氨基酸并且与SEQ ID NO:1在66-429位上具有95%序列一致性。在一个实施例中,E1包含氨基酸序列,所述包含氨基酸序列在长度上具有至少300个氨基酸并且与SEQ ID NO:1在449-854位上有95%序列一致性。在一个实施例中,肿瘤相关抗原是包含SEQ ID NO:3-11中任一个至少10个连续氨基酸的多肽片段,其中,多肽片段包含至少10个连续氨基酸具有免疫原性,并且所述免疫原性多肽片段包含SEQ ID NO:3-11中少于1100个的氨基酸。
本领域的技术人员也知道以上所述可应用于病毒抗原。因此,在某些实施例中,癌症相关抗原被病毒抗原所替代。在某些实施例中,融合蛋白包含一种或多种病毒抗原和一种或多种α病毒表面膜糖蛋白。在某些实施例中,病毒抗原是HSV-1糖蛋白B(P06437)、糖蛋白E(P04488)、HIV gag-pol(P04585)、水痘(带状孢疹)糖蛋白B(Q4JR05)或糖蛋白E(Q9J3M8)。
5.2制备VGP-TAA的方法
本文提供了制备融合蛋白的一种方法,包括在诱导多肽表达的条件下,培养被编码融合蛋白的核酸转染后的宿主细胞的步骤。随后,可以从如培养上清液中将多肽纯化。
本发明提供了制备本发明多肽的过程,包括利用化学方法合成至少部分多肽的步骤。
上述的任何及所有蛋白、多肽、杂交多肽、抗原表位和免疫原性片段可以以多种形式中的任意一种存在,包括但不限于重组的、分离的或大体上纯化的(从与自然状态下的这些蛋白、多肽、杂交多肽、抗原表位和免疫原性片段共存的物质中)形式。
一方面,本文公开的融合蛋白由核酸构建体编码,所述核酸构建体包含一种或多种操作性连接一种或多种肿瘤相关抗原的病毒表面膜糖蛋白。融合蛋白是由具有病毒表面膜糖蛋白核苷酸序列的核酸编码形成的重组蛋白,病毒表面膜糖蛋白与一种或多种肿瘤相关抗原操作性相连。在一个实施例中,核酸构建体是表达载体。在一个实施例中,表达载体为非病毒载体、病毒载体或质粒。在某些实施例中,表达载体包含基因或基因片段、启动子、增强子、终止信号、多(聚)腺苷酸尾、连接肽、多聚连接肽、可操作性连接肽、多克隆位点、标记物、终止密码子、内部核糖体进入位点、用于整合的宿主同源序列或其它定义的元素构成。改造核酸构建体的方法在本领域众所周知(参考如《分子克隆:实验手册(MolecularCloning:A Laboratory Manual)》,萨姆布鲁克等人编辑,冷泉港实验室,第二版,冷泉港,纽约,1989)。
在一些实施例中,本发明的核酸在低严格条件下与靶标进行杂交;在其它实施例中,所述核酸在中度严格条件下进行杂交;在优选的实施例中,所述核酸在高严格条件下进行杂交。低严格杂交条件下的一个示范组为50℃和10×SSC缓冲液。中度严格杂交条件下的一个示范组为55℃和1×SSC缓冲液。高严格杂交条件下的一个示范组为68℃和0.1×SSC缓冲液。
本发明包括由这些序列的互补序列组成的核酸(例如用于反义或探测,或作为引物)。
本发明的核酸可用于杂交反应(例如Northern或Southern印迹杂交、或核酸微阵列或“基因芯片”)和扩增反应(例如PCR、SDA、SSSR、LCR、TMA、NASBA等)以及其它核酸技术。
根据本发明的核酸可具有多种形式(例如单链的、双链的、载体、引物、探针、标记物等)。本发明的核酸可以是环形或分支型,但一般都将变为线型。除非是指定的或是被要求的,本发明的任何利用核酸的实施例可采用双链及构成双链的两条互补单链这两种形式。引物和探针一般是单链的,反义核酸也是。
本发明的核酸优选地以纯化或大体上纯化的形式存在,大体上纯化即大体上除去其它核酸(如除去自然存在的核酸)特别是宿主细胞核酸,其一般纯度至少约50%(按重量),并且通常纯度至少约90%。
本发明的核酸可用多种方式从基因组库或cDNA库等中制备,例如通过化学合成(如亚磷酰胺法合成DNA)全部或部分制备,利用核酸酶(如限制性内切酶)酶切更长的核酸,通过连接更短的核酸或核苷酸(如利用连接酶或聚合酶)。
本发明的核酸可连接到固相载体上(如珠、板、过滤器、薄膜、载玻片、微阵列支持物、树脂等)。本发明的核酸可被标记,如放射性或荧光标记或生物素标记。检测技术中利用所述核酸尤其有效,如将核酸作为引物或探针。
术语“核酸”一般指任何长度核苷酸的多聚体形式,包括脱氧核苷酸、核糖核苷酸和/或它们的类似物。核酸包括DNA、RNA以及DNA/RNA杂合体。核酸也包括DNA或RNA的类似物,如包含骨架修饰(如肽核酸(PNAs)或硫代磷酸酯)或碱基修饰的类似物。因此本发明包含mRNA、tRNA、rRNA、核酶、DNA、cDNA、重组核酸、有支链的核酸、质粒、载体、探针和引物等。其中本发明的核酸为RNA形式,它可有或没有5'帽子结构。
本发明的核酸可以是载体的一部分,即为设计用于转导染或转染一种或多种细胞类型的核酸构建体的一部分。例如,载体可为“克隆载体”,其被设计以用于分离、聚集及复制插入的核苷酸,可为“表达载体”,其被设计以用于宿主细胞中核苷酸序列的表达,可为“病毒载体”,其被设计以用于生产重组病毒或病毒样颗粒,或可为“穿梭载体”,其具有多于一种载体的特性。如上所述,优先地选择质粒作为载体。“宿主细胞”包括可作为或已作为外源核酸接受体的单个细胞或细胞培养物。宿主细胞包括单一宿主细胞的后代,并且由于自然的、偶然的或有意的突变和/或改变,所述后代可以不一定与原始亲本细胞(在形态上或在总DNA互补上)完全相同。宿主细胞包括在体内或体外利用本发明的核酸经转染或感染的细胞。
当核酸是DNA时,应了解RNA序列中的“U”会被DNA中的“T”替换。同样,当核酸是RNA时,应了解DNA序列中的“T”会被RNA中的“U”替换。
当术语“互补”或“互补的”的使用与核酸有关时,术语“互补”或“互补的”是指Watson-Crick碱基配对。因此,C的互补为G,G的互补为C,A的互补为T(或U),并且T(或U)的互补为A。也可能可将碱基如I(次黄嘌呤)与嘧啶(C或T)互补配对。
本发明的核酸可用于如:生产多肽,作为杂交探针检测生物样品中的核酸;生成核酸的更多拷贝;生成核酶或反义寡核苷酸;用作单链DNA引物或探针;或用作三链形成寡核苷酸。
本发明提供了生产本发明的核酸的工艺,其中所述核酸全部或部分由化学方法合成。
本发明提供了包含本发明的核苷酸序列的载体(如克隆载体或表达载体)和所述载体转化后的宿主细胞。
根据本发明,核酸扩增可以是定量的和/或实时的。
对于本发明的某些实施例,在长度上优选地包含至少7个核苷酸的核酸(如8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个、25个、26个、27个、28个、29个、30个、31个、32个、33个、34个、35个、36个、37个、38个、39个、40个、45个、50个、55个、60个、65个、70个、75个、80个、90个、100个、110个、120个、130个、140个、150个、160个、170个、180个、190个、200个、225个、250个、275个、300个核苷酸或更长的核苷酸)。
对于本发明的某些实施例,在长度上优选地包含最多500个核苷酸的核酸(如450个、400个、350个、300个、250个、200个、150个、140个、130个、120个、110个、100个、90个、80个、75个、70个、65个、60个、55个、50个、45个、40个、39个、38个、37个、36个、35个、34个、33个、32个、31个、30个、29个、28个、27个、26个、25个、24个、23个、22个、21个、20个、19个、18个、17个、16个、15个核苷酸或更短的核苷酸)。
本发明的引物和探针以及用于杂交的其它核酸在长度上优选地具有10至30个核苷酸(如10个、11个、12个、13个、1.4个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个、25个、26个、27个、28个、29个或30个核苷酸)。
在某些实施例中,编码融合蛋白的公开的核酸构建体包含一种或多种利用可操作性连接肽与一种或多种肿瘤相关抗原连接的α病毒表面膜糖蛋白。在一个实施例中,连接肽是直接连接。在一个实施例中,连接肽是间隔区。通过术语可操作性连接肽,可以了解用保证核酸或蛋白生物处理的方法连接两个核酸构建体或融合蛋白的核苷酸或氨基酸残基序列。若可操作性连接肽是直接连接,则各自编码开放阅读框或开放阅读框的片段的两个核酸被立即靠近放置,因此它们也在开放阅读框内。若可操作性连接肽被间隔区调控,则在编码一种或多种α病毒表面膜糖蛋白和一种或多种肿瘤相关抗原的核苷酸之间插入一系列核苷酸。在某些实施例中,可操作性连接肽包含至少一个多聚连接肽或多克隆位点(MCS)。
核酸构建体的实例在图6及SEQ ID NO:2的序列中显示。通过亚克隆上述多种因子,生成SEQ ID NO:1的部分载体序列。将这些部分序列插入pUC57,然后转移到pFastBac1中。见基因库登陆号AY598466。
在一个实施例中,跨膜区和6K区被去除,并且用柔性连接肽连接E2和E1。E3序列作为ER靶序列并且帮助E2/E1的二聚化。利用另一个柔性连接肽和蛋白酶切位点将TAA加入E1的C-端。从高尔基体分泌时,VGPs三聚体化形成带有TAAs的可溶性突起。在一个实施例中,利用杆状病毒表达系统在昆虫细胞中制造所述蛋白。
在一个实施例中,利用杆状病毒表达系统生产改造的重组α病毒糖蛋白(VGPs),并且所述蛋白有与原病毒相当的靶向特异性。
在某些实施例中,融合蛋白可适当保留糖基化,而不引起不良的免疫应答。
在某些实施例中,融合蛋白可溶解。在某些实施例中,融合蛋白不可溶解。
在某些实施例中,本文公开的方法直接杀死肿瘤细胞。在某些实施例中,本文公开的方法可在病毒入侵时诱发细胞凋亡且不需要病毒复制。在某些实施例中,融合蛋白中的糖蛋白导致细胞凋亡。在某些实施例中,释放其它肿瘤相关抗原实现肿瘤的灭杀。在某些实施例中,肿瘤细胞表面病毒蛋白的存在诱导细胞毒性T细胞和/或NK应答。
在某些实施例中,重组表达载体通过某些运载工具进行转运。运载工具可以是基于RNA或DNA的工具、基于脂质的工具、基于细胞的工具、可生物降解的聚合物微球、脂质体、胶体金颗粒或脂多糖。裸DNA也可通过机械或电技术进行转运,如弹道转移,即利用如基因枪的粒子轰击技术。
在一个实施例中,VGP-TAA融合蛋白用重组表达载体生成。在一个实施例中,辛德毕斯融合糖蛋白利用Sf9昆虫细胞中的杆状病毒表达生成。杆状病毒系统是利用昆虫细胞进行重组蛋白表达的通用且强大的真核表达系统(10),与其它表达载体系统相比有多种优势。由于杆状病毒仅能感染特定的无脊椎动物物种,它们对哺乳动物没有致病性。不同于细菌表达蛋白,杆状病毒系统表达蛋白被加工、折叠、修饰为类似哺乳动物表达系统所产生的蛋白。此外,杆状病毒表达的蛋白很容易扩大规模从而生产大量的重组蛋白。可获得在悬浮培养中生长良好的昆虫细胞系,这样在大规模生物反应器中生成重组蛋白。利用杆状病毒系统针对我们特定的蛋白有另一直接的优势。虽然昆虫细胞和哺乳动物细胞均能产生N连接的糖基化,然而具体的的糖基化途径是不同的。昆虫细胞中产生的N-糖链可以有丰富的甘露糖或寡甘露糖苷(paucimanosidic)的结构,两者末端均有甘露糖残基(11)。哺乳动物细胞中产生的N-糖链可以有丰富的甘露糖结构或以半乳糖和唾液酸为末端的复杂结构(11)。通过基因合成生成编码VGP的基因,并且进行密码子优化以便于在昆虫细胞中表达。重组融合蛋白包含用柔性连接肽连接的pE2的胞外区和E1辛德毕斯糖蛋白,并通过第二个连接肽与TAA连接(见图3)。在一个实施例中,TAA是NY-ESO-1。在其它实施例中,其它TAA插入到编码序列中。在某些实施例中,通过两个或更多的TAAs串联生成构建体,从而产生更有效的免疫应答。
在某些实施例中,可由在刺激免疫应答方面的有多种优势的抗原的表位来引发如T细胞调控的和抗体调控的任一种类型的免疫应答。在某些实施例中,融合蛋白能成功诱导免疫应答,来对抗用传统免疫方法证明太弱的肿瘤相关抗原。在某些实施例中,本文公开的融合蛋白能成功诱导比传统免疫方法高5-10倍、10-20倍、20-30倍、30-50倍、50-100倍、100-500倍和500-1000倍的免疫应答(萨洛亚,拉克希米和巴斯卡兰,国际《药学研究(PharmInvestig)》杂志,2011)。
在某些实施例中,2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、20个、30个、40个、50个或更多的TAA与VGP共轭。pE2中的E3成分作为分泌所述蛋白的信号肽,帮助E1和E2结合,并通过弗林蛋白酶将其从成熟蛋白上切除(7)。成熟的分泌蛋白形成包含E2和E1异源二聚体复合物的三聚体形式,模仿在SIVN包膜上的三聚体糖蛋白刺突。第二个柔性连接肽能使NY-ESO-1适当折叠而不干扰E2/E1的多聚化。在某些实施例中,TAA包含NY-ESO-1上1-180位的氨基酸残基。在其它实施例中,TAA包含NY-ESO-1上81-180位的氨基酸残基。在某个实施例中,将组氨酸标签(His-tag)加入蛋白的C端用于纯化。通过非变性凝胶电泳和体积排除色谱法测定融合蛋白的多聚体结构。通过ELISA和Western blot分析融合蛋白的特异性。融合蛋白包含多个可被市售抗体检测的抗原性靶标(NY-ESO-1、His-tag、SINV E1和E2)。在某个实施例中,TAA是RGL4。在某个实施例中,TAA是人乳头瘤病毒的E6蛋白。在某个实施例中,TAA是人乳头瘤病毒的E7蛋白。
还公开了包含编码融合蛋白的核酸构建体的细胞。这样的重组细胞可作为体外研究的工具,核酸构建体的运载工具或部分基因治疗方法。
还公开了抗体或能与本文公开的融合蛋白免疫特异性结合的结合片段。在某些实施例中,所述抗体为免疫球蛋白分子和其中能够免疫特异性结合抗原的活性片段。抗体和结合片段可用于受试者的免疫。抗体和结合片段可用于检测抗原的试验中。
5.3免疫原性组合物和药物
本发明的多肽可用作免疫原性组合物的活性成分(免疫原),并且所述组合物可被用作疫苗。根据本发明,疫苗可以是预防疾病的(即防止感染)或治疗疾病的(即治疗感染),但通常是预防疾病的。
免疫原性组合物是药学上可接受的。除抗原外,它们通常包含成分,如它们一般包含一种或多种药学载体、赋形剂和/或佐剂。也公开了一种疫苗,其包含编码融合蛋白的核酸序列,所述融合蛋白包含与一种或多种肿瘤相关抗原操作性相连的一种或多种α病毒表面膜糖蛋白。因此,疫苗可包含核酸构建体或包含如上定义的融合蛋白。此外,疫苗还可用作药物。
疫苗组合物可通过已知方法如混合一种或多种可药学上可接受的载体(亦称赋形剂或包含活性剂的稳定剂)配制。这些赋形剂可允许被注入受试者中,优选地注入脊椎动物中,并且由于赋形剂使用的剂量和浓度对细胞和暴露的个体无毒性,更优选地注入人体中。在某些实施例中,可接受的载体是水性pH缓冲溶液。这些赋形剂、载体和配方的实例可在例如《雷明顿氏制药科学(Remington's Pharmaceutical Sciences)》(马克出版公司,宾夕法尼亚州伊斯顿(Maack Publishing Co,Easton,PA))中找到。生理上可接受的载体的实例包括但不限于:缓冲液,如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸;低分子量(少于10个残基)多肽;蛋白,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸、赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或环糊精;螯合剂,如EDTA;糖醇类,如甘露糖醇或山梨糖醇;成盐反离子,如钠;和/或非离子表面活性剂,如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。
为配置适合有效注射的药学上可接受的组合物,所述组合物应包含有效数量的核酸构建体,所述核酸构建体存在于运载工具中或本文所述的融合蛋白中。载体可用作偶联融合蛋白的支架,以增强诱导免疫应答。载体蛋白可以是任何传统的载体,包括适合呈递免疫决定簇的任何蛋白。合适的载体通常是很大、代谢缓慢的大分子,如蛋白、多糖、聚乳酸、聚乙醇酸、多聚体氨基酸、氨基酸共聚物、脂质聚集体(如油滴或脂质体)和灭活病毒颗粒。本领域的普通技术人员都熟知所述载体。此外,这些载体可用作免疫促进剂(“佐剂”)。可使用佐剂和/或药学载体进行动物免疫。传统的载体蛋白包括但不限于钥孔血蓝素、血清蛋白如转铁蛋白、牛血清白蛋白或人血清白蛋白、卵清蛋白、免疫球蛋白或激素如胰岛素。载体可与佐剂一起存在。疫苗组合物可作预防性和治疗性使用,包括刺激受试者的免疫应答。本文公开的疫苗组合物不诱导任何系统或局部毒性反应或任何其它副作用。
佐剂可存在于疫苗组合物中用于提高特异性免疫应答。因此,特别重要的发现是,当所述佐剂与抗原/核酸构建体和/或运载工具(其中任何一个也可被称为免疫决定簇)结合时,佐剂产生能够诱导强烈特异性免疫应答的疫苗组合物。免疫前,免疫决定簇也可与两个或更多个不同的佐剂混合。大量佐剂已被描述并且用于实验动物体内来产生抗体,如小鼠、大鼠和兔子。由于主要目的是获得强烈的抗体反应,因此所述背景下对副作用的耐受性非常高。为了能在制药中使用且批准使用,特别是应用于人体中,疫苗组合物中包括佐剂在内的成分需要实现良好表征。此外,所述组合物中任何副作用的危险都必须降至最低。在一个实施例中,疫苗组合物包含佐剂。在一个优选的实施例中,疫苗组合物适合注入哺乳动物体内,并且更优选地注入人类受试者中。佐剂的选择可进一步通过其刺激预期免疫应答的类型、B细胞或/和T细胞活化的能力来决定,并且可对疫苗组合物进行配制来对相关淋巴组织优化分布及呈递。
已发现脂多糖及其多种包括脂质A在内的衍生物可作为强大的佐剂,与脂质体或其它脂肪乳结合。弗氏完全佐剂(Freund's complete adjuvant)是大多数实验研究中使用的标准。矿物油可加入至免疫原性组合物中以防止抗原快速分解代谢。许多其它类型的物质可用作免疫原性组合物中的佐剂,包括植物产物如皂苷、动物产物如甲壳素以及大量合成的化合物。
免疫原性组合物也可包含稀释液如缓冲液,抗氧化剂如抗坏血酸,低分子量(少于10个残基)多肽,蛋白,氨基酸,碳水化合物包括葡萄糖、蔗糖或环糊精,螯合剂如EDTA、谷胱甘肽及其它稳定剂和赋形剂。中性缓冲盐或混合了非特异性血清白蛋白的盐溶液是典型合适的稀释液。
组合物的pH值一般为5.0至8.1,并且更常见于6.0至8.0之间,如6.5至7.5,或7.0至7.8。
优选地,组合物是无菌的。优选地,组合物是无热源的,如每剂小于1EU(内毒素单位,标准度量),并且优选地,每剂小于0.1EU。优选地,组合物不含谷蛋白。
5.4剂量
本文公开的疫苗组合物一般以能对受试者充分有益的剂量注入其体内。所述剂量被定义为“治疗有效量”。治疗有效量会通过特定组合物的效能和效价、注射给药的时间和频率、受试者的大小和状态,包括受试者特定的治疗反应来进行测定。此外,测定治疗有效量时,应考虑给药途径。疫苗组合物预期的的治疗有效量为0.1μg/kg至1mg/kg总核酸。合适的剂量包括从约5μg/kg-500mg/kg总DNA,10μg/kg-250μg/kg总DNA或10μg/kg-170μg/kg总DNA。在一个实施例中,对人类受试者(18-50岁,45-75kg)注射了1.2mg-7.2mgDNA。“总DNA”和“总核酸”是指编码不同免疫分子的核酸库。例如,在编码5种不同免疫分子的50mg总DNA中,每种分子有1mg。疫苗可多次注射,如约2-6次。在一个示例方法中,在0、4、12周时,将100μg DNA组合物注入人类受试者(每次100μg)。疫苗组合物的治疗有效量为从约0.1μg/kg至1mg/kg融合蛋白。合适的剂量包括从约5μg/kg-500mg/kg融合蛋白,10μg/kg-250μg/kg融合蛋白或10μg/kg-170μg/kg融合蛋白。在一个实施例中,对人类受试者(18-50岁,45-75kg)注射1.2mg-7.2mg融合蛋白。尽管对儿童可注射一半的剂量(即约0.25ml),人类疫苗一般的注射体积为约0.5ml。
本申请的治疗可包括各种“单位剂量”。单位剂量的定义是指本申请包含的治疗组分的预定数量。临床领域的技术人员熟知给药量、特定的给药途径和配方。单位剂量给药并不是注射一次,而是可以在一段特定时间内持续输注。单位剂量可包含至少0.01mg、0.05mg、0.1mg、0.5mg、1.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg或50.0mg有效成分。可选地,单位剂量包含少于0.01mg、0.05mg、0.1mg、0.5mg、1.0mg、2.5mg、5.0mg、10.0mg、15.0mg、25.0mg或50.0mg有效成分。在至少一个实施例中,单位剂量包含从约0.001mg至约50mg有效成分。在一个或多个实施例中,单位剂量包含从约1mg至约10mg有效成分。
5.5给药
疫苗组合物可以以治疗有效量注入受试者中。有效量可以因许多因素而发生改变,如受试者的状态、体重、性别和年龄。其它因素包括给药方式。药物组合物或兽药组合物可通过多种途径注入个体中,如皮下注射、局部注射、口服和肌肉注射。药物组合物可通过口服和肠外给药。肠外给药方法包括局部注射、动脉注射(直接注入组织)、肌肉注射、皮下注射、骨髓腔内注射、鞘内给药、脑室内给药、静脉注射、腹腔注射或鼻腔给药。也提供了合适的局部的、口服的、系统的和肠外的药物制剂,可与疫苗组合物共同用于疾病预防和治疗。
例如,疫苗组合物可以以口服制剂的形式给药,如片剂、胶囊(每个都有定时释放和缓释的剂型)、丸剂、散剂、颗粒剂、合剂、酊剂、溶液、悬浮液、糖浆和乳化剂或注射给药。同样,疫苗组合物也可以以静脉注射(药丸和输液)、腹膜内注射、皮下注射、局部封包或不封包或肌肉注射的形式给药,制药行业的普通技术人员都熟知所有的使用形式。包含本文所述的任何成分的有效但无毒的疫苗剂量可用作预防制剂或治疗制剂。此外,还包括适合配制注射用免疫原性肽组合物的本领域技术人员所熟知的任何及所有传统的剂型,如冻干粉形式和溶液,悬浮液或如需要可包括传统药学上可接受的载体、稀释液、防腐剂、佐剂和缓冲液成分等的乳化剂形式。
优选地,疫苗组合物的给药途径包括但不限于系统给药,如静脉注射或皮下注射、皮内注射、肌肉注射、鼻腔给药、口服给药、直肠给药、阴道给药、肺部给药及一般任何形式的黏膜给药。
本文所述疫苗可以一次、两次、三次、四次、五次或更多次给药。疫苗给药超过一次可以提高产生的免疫应答。以与之前不同的给药形式进行疫苗给药可以进一步提高疫苗的疗效。加强注射包括同源的加强注射或异源的加强注射。同源的加强注射是在第一次和随后的给药中,疫苗有相同的构建体和融合蛋白,更具体的说,是有相同的运载工具。异源的加强注射是相同的构建体或融合蛋白存在于不同的载体中。
优选地,哺乳动物作为疫苗接受体,并且在一个更优选的实施例中,哺乳动物的受试者选自由以下组成的群组:牛、猪、马、绵羊、山羊、美洲驼、小鼠、大鼠、猴、狗、猫和人。
在一个实施例中,疫苗组合物进一步包含第二活性成分,所述第二活性成分为抗体、化疗药物、抗过敏药、细胞因子、补体因子和免疫系统的共刺激分子。
5.6治疗和预防的方法
还公开了一种用于诱导受试者的免疫应答的方法,包括向受试者注入本文所述的疫苗。免疫应答包括以下种类的应答:MHC-I依赖应答(dependent response)、MHC-I和/或MHC-II依赖应答、T细胞依赖应答、CD4 T细胞依赖应答、CD4+ T细胞依赖应答、CD8+ T细胞依赖应答和B细胞依赖免疫应答。所述方法用于动物的基因免疫,或治疗所需受试者的临床症状。
正如本文所述,“治疗(treatment')”包括治疗性治疗和预防或防治性治疗两者,其目的为阻止或减缓目标病理状况或失调。需要治疗的对象包括已失调的、即将失调的或要预防失调的对象。术语“治疗(therapy')”、“治疗的(therapeutic')”、“治疗(treatment')”或“治疗的(treating')”包括减少、减轻、抑制或消除症状或病情发展的能力或措施。治疗的预期效果包括预防疾病的发生或复发、减轻症状、减少直接或间接的疾病病理性后果、抑制转移、减缓病程的发展速度、改善或缓解疾病状态、控制疾病或改善预后。在一些实施例中,本申请的方法和组合物用于延迟疾病或失调的进展或减缓疾病或失调的发展。
根据本申请,治疗包括癌症或其它肿瘤性失调的治疗方法,包括向需要治疗的患者注入本申请的肽、核酸和抗体组合物。在至少一个实施例中,治疗进一步包括向所述患者注入化疗药物,如前药形式的药物。两种成分可一起给药如以复方药片的形式,或分开给药。给药还可为序贯给药或同时给药。“序贯”给药表明成分在不同时间或时间点给药,尽管如此,但是可以重叠。同时给药表明成分在同一时间给药。
本申请治疗中,应用有效量或优选的治疗有效量进行给药。“有效量”是指为达到预期的治疗或预防结果而采用的在必要的药量和时间上有效的剂量。有效量可因治疗中同时应用的药物或前药而改变。本申请的“治疗有效量”可因如个体的疾病状态、年龄、性别、体重和蛋白诱导预期治疗结果的能力等因素而改变。治疗有效量包括蛋白的治疗有益作用超过其任何有毒或有害作用的剂量。治疗有效量也包括能充分赋予益处如临床受益的剂量。
本发明还提供了一种提高哺乳动物免疫应答的方法,包括本发明的有效剂量成分的给药步骤。免疫应答优选地是预防性的并且优选地涉及抗体和/或细胞调控的免疫。所述方法可引起回忆应答。
本发明还提供了可用作药物的本发明的多肽,如用于引起哺乳动物的免疫应答。
本发明还提供了本发明的多肽在生产用于引起哺乳动物免疫应答的药物中的使用。
本发明还提供了一种预填充了本发明的免疫原性组合物的运载装置。
通过这些用途和方法引起哺乳动物的免疫应答,哺乳动物可抵御包括HIV、带状疱疹和疱疹在内的潜在病毒感染。
哺乳动物优选地是人,但可以是如牛、猪、鸡、猫或狗的动物,因为大肠杆菌同样可在这些物种中产生问题。当疫苗起预防性作用时,所述人优选地是儿童(如幼儿或婴儿)或青少年;当疫苗起治疗性作用时,所述人优选地是青少年或成年人。用于儿童的疫苗也可用于成人,如分析安全性、剂量、免疫原性等。本发明的疫苗可同时用于儿童和成人。因此人类患者可小于1岁、1-5岁、5-15岁、15-55岁或至少55岁。优选为老年人(如≧50岁、≧60岁和优选的≦65岁)、年轻人(如≦5岁)、住院病患、医护人员、武装部队、军事人员、怀孕妇女、患慢性疾病或免疫缺陷的患者接种疫苗。然而,疫苗不仅仅只适合用于这些群体中,可在更广泛的人群中使用。
检测治疗性治疗疗效的一种方法包括在本发明组合物给药后,监测大肠杆菌的感染情况。检测预防性治疗疗效的一种方法包括在组合物给药后,监测对抗发明成分中抗原的系统的(如监测产生IgG1和IgG2a的水平)和/或粘膜的(如监测产生IgA的水平)免疫应答。一般情况下,抗原特异性血清抗体应答是在免疫接种后但在攻毒前(pre-challenge)检测,而抗原特异性粘膜抗体应答是在免疫接种后及攻毒后(post-challenge)检测。
另一种评价本发明组合物免疫原性的方法为利用免疫印迹和/或微阵列重组表达蛋白从而筛选患者血清或粘膜分泌物。蛋白和患者样品中的阳性反应表明患者已对有问题的蛋白产生了免疫应答。所述方法也可用于鉴定免疫显性抗原和/或抗原中的表位。
还公开了一种通过α病毒表面膜糖蛋白处理以刺激人类T细胞生长的方法。
还公开了一种通过α病毒表面膜糖蛋白处理以激活人类造血细胞的方法(包括T细胞、NK细胞、B细胞、树突细、调节性T细胞、巨噬细胞、红细胞和所有其它细胞)。
还公开了一种通过α病毒表面膜糖蛋白处理以释放原本无反应性的T细胞的方法。
还公开了一种通过α病毒表面膜糖蛋白处理以克服T细胞断点抑制(BreakpointInhibiiton)的方法。
还公开了一种通过α病毒表面膜糖蛋白处理以治疗癌症的方法。
5.6.1联合治疗
在某些实施例中,融合蛋白可与至少一种其它治疗剂用于联合治疗。融合蛋白和治疗剂可相加作用或更优选地协同作用。在一个优选的实施例中,包含融合蛋白的组合物与另一治疗剂同时给药,所述治疗剂与融合蛋白的组合物部分相同或不同。在另一个实施例中,包含融合蛋白的组合物在另一个治疗剂之前或之后给药。由于利用融合蛋白进行治疗的多数失调是慢性失调,在一个实施例中,联合治疗为包含融合蛋白的成分与包含另一治疗剂的成分间的交替给药,如将特定药物的毒性最小化。每种药物或治疗剂的给药持续时间可以是一个月、三个月、六个月或一年。在某些实施例中,当融合蛋白与另一治疗剂同时给药,并且所述治疗剂产生包括但不限于毒性的潜在副作用时,可按低于其产生副作用的阈值的有益剂量给药。
在某一个实施例中,融合蛋白给药伴随着检验点疗法或化疗。在某一个实施例中,融合蛋白与CTLA4、PD1或PDL1的抗体共同给药。
本融合蛋白可与放射治疗或一种或多种化疗药物联合使用。放射治疗中的射线可以是γ射线或X射线。若想了解放射治疗的概况,可参照海尔曼(Heilman)《肿瘤学原理和实践(Principles and Practice of Oncology)》,第12章《放射治疗癌症的原理(Principlesof Radiation Therapy Cancer)》,德维塔等人编辑,第二版,J.B.Lippencott Company,费城)。有效的化疗药物包括甲氨蝶呤、紫杉醇、巯嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素、氮烯唑胺、甲基苄肼、依托泊甙、喜树碱、博来霉素、阿霉素、去甲氧基柔红霉素、柔红霉素、更生霉素、光神霉素、米托葱醌、天冬酰胺酶、长春碱、长春新碱、长春瑞滨、特素和多西他赛。在一个具体实施例中,包含融合蛋白的组合物还包含一种或多种化疗药物,和/或其给药与放射治疗同时进行。在另一个具体实施例中,化学治疗或放射治疗在本组合物给药之前或之后进行,优选地在包含融合蛋白的组合物给药后至少1小时、5小时、12小时、1天、1周、1个月、更优选地几个月(如达到3个月)进行。
任何有用、已用于或现在正用于预防、治疗和/或管理失调如癌症的有效治疗物可在本发明的组合物和方法中使用。治疗物(如治疗制剂或预防制剂)包括但不限于肽、多肽、共轭物、核酸分子、小分子、拟似药、合成药、无机分子和有机分子。癌症治疗的非限制性实例包括化疗、放射治疗、激素治疗和/或生物或免疫疗法及手术。在某些实施例中,本发明的预防性和/或治疗性有效疗法包括应用联合治疗。
癌症治疗剂的实例包括但不限于:阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、六甲蜜胺、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林菌素、阿扎胞苷、阿替派、氮霉素、巴马司他、苯佐替派、比卡鲁胺、盐酸比生群、二甲磺酸双奈法德、双磷酸盐(如氨羟二磷酸二钠(阿可达(Aredria))、氯磷酸钠(sodium clondronate)(Bonefos;骨膦)、唑来膦酸(择泰)、阿仑唑奈(福善美)、羟乙膦酸钠、伊班膦酸盐、英卡膦酸钠、利塞膦酸盐和替鲁膦酸盐)、比折来新、硫酸博来霉素、布喹那钠、溴匹立明、白消安、放线菌素C、卡鲁睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡米诺霉素、卡折来新、西地芬戈、苯丁酸氮芥、西罗霉素、顺铂、克拉屈滨、克立那托甲磺酸盐、环磷酰胺、阿糖胞苷、氮烯咪胺、更生霉素、盐酸柔红霉素、地西他滨、右奥马铂、地扎呱宁、甲磺酸地扎呱宁、地吖醌、多西他赛、阿霉素、盐酸阿霉素、屈洛昔芬、柠檬酸屈洛昔芬、屈他雄酮丙酸酯、偶氮霉素、依达曲沙、依氟鸟氨酸盐酸盐、EphA2抑制剂、依沙芦星、恩洛铂、恩普氨酯、依匹哌啶、盐酸表柔比星、厄布洛唑、依索比星盐酸盐、雌二醇氮芥、雌二醇氮芥磷酸钠、依他硝唑、依托泊苷、磷酸依托泊苷、氯苯乙嘧胺、盐酸法倔唑、法扎拉滨、芬维A胺、氟尿苷、磷酸氟达拉滨、氟尿嘧啶、氟卡他滨(fluorocitabine)、磷喹酮、福司曲星钠、吉西他滨、盐酸吉西他滨、羟基脲、盐酸伊达比星、异环磷酰胺、ihnofosine、白细胞介素II(包括重组白细胞介素II或rIL2)、干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素α-n3、干扰素β-Ia、干扰素γ-I B、异丙铂、盐酸伊立替康、醋酸兰瑞肽、来曲唑、醋酸亮丙瑞林、盐酸利阿唑、洛美曲索钠、洛莫司汀、盐酸洛索蒽醌、马索罗酚、美登素、盐酸氮芥、抗CD2抗体、醋酸甲地孕酮、醋酸美仑孕酮、美法仑、美诺立尔、巯嘌呤、甲氨蝶呤、甲氨喋呤钠、氯苯氨啶、美妥替哌、米丁度胺、米托卡星、丝裂红素、丝林霉素、丝裂马菌素、丝裂霉素、丝裂帕菌素、米托坦、盐酸米托蒽醌、霉酚酸、诺考达唑、诺加霉素、奥马铂、亚磺酰吡啶、紫杉醇、培门冬酶、佩里霉素、戊氮芥、硫酸培洛霉素、培磷酰胺、哌血生、哌泊舒凡、盐酸吡罗蒽醌、普卡霉素、普洛美坦、卟吩姆钠、紫菜霉素、松龙苯芥、盐酸丙卡巴肼、嘌呤霉素、盐酸嘌呤霉素、吡唑呋喃菌素、异戊烯腺苷、罗谷亚胺、沙芬戈、沙芬戈盐酸盐、司莫司汀、双曲秦、磷乙酰天冬氨酸钠、稀疏霉素、盐酸螺旋锗、螺莫司汀、螺铂、链黑菌素、链脲菌素、磺氯苯脲、他利霉索、替可加兰钠、替加氟、替洛蒽醌盐酸盐、替莫泊芬、替尼泊苷、替罗昔隆、睾内脂、硫咪嘌呤、硫鸟嘌呤、噻替哌、噻唑呋林、替拉扎明、枸橼酸托瑞米芬、曲托龙、磷酸曲西立滨、三甲曲沙、三甲曲沙葡萄糖醛酸盐、曲普瑞林、盐酸妥布氯唑、尿嘧啶齐末、尿烷亚胺、伐普肽、维替泊芬、硫酸长春碱、硫酸醛基长春碱、去乙酰长春酰胺、硫酸长春碱酰胺、硫酸长春匹定、硫酸长春甘酯、硫酸环氧长春碱、酒石酸长春瑞滨、硫酸长春罗定、硫酸长春利定、伏氯唑、折尼拉汀、净司他丁和盐酸佐柔比星。
癌症治疗剂的其它实例包括但不限于:20-epi-1,25-二羟维生素D3、5-乙炔基尿嘧啶、阿比特龙、阿柔比星、酰基富烯、腺环戊醇、阿多来新、阿地白介素、ALL-TK拮抗剂、六甲蜜胺、氨莫司汀、艾美多、氨磷汀、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、阿那曲唑、穿心莲内酯、血管生成抑制剂、拮抗剂D、拮抗剂G、安雷利克斯、抗背部化形态发生蛋白-1、前列腺癌的抗雄激素、抗雌激素、抗瘤酮、反义寡核苷酸、甘氨酸阿非迪霉素、细胞凋亡基因调节剂、细胞凋亡调节剂、脱嘌呤核酸、ara-CDP-DL-PTBA、精氨酸脱氨酶、奥沙那宁、阿他美坦、阿莫司汀、海洋环肽(axinastatin)1、海洋环肽2、海洋环肽3、阿扎司琼、阿扎毒素(azatoxin)、重氮酪氨酸、巴卡亭III衍生物、班兰诺、巴马司他、Bcl-2抑制剂、Bcl-2家族抑制剂(包括ABT-737、BCR-ABL拮抗剂)、苯并二氢卟吩、苯甲酰基星形孢菌素、β-内酰胺类衍生物、β-阿立辛(beta-alethine)、β可来霉素B(betaclamycin)、桦木酸、bFGF抑制剂、比卡鲁胺、比生群、双氮丙啶基精胺、双奈法德、双曲群A、比折来新、比锐来特、溴匹立明、布多替钛、丁硫氨酸亚砜胺、钙泊三醇、钙感光蛋白C、喜树碱衍生物、金丝雀痘IL-2、卡培他滨、甲酰氨基三唑、羧胺三唑、CaRest M3、CARN 700、软骨源性抑制剂、卡折来新、酪蛋白激酶抑制剂、栗树精胺、杀菌肽B、西曲瑞克、二氢卟酚(chlorlns)、磺胺氯喹嗯啉、西卡前列素、顺式卟啉、克拉屈滨、氯米芬类似物、克霉唑、碰撞霉素(Collismycin)A、碰撞霉素B、考布他汀A4、考布他汀类似物、康纳京尼、卡那贝西汀(crambescidin)816、克里斯奈托(crisnatol)、念珠藻环肽8、念珠藻环肽A衍生物、卡拉新A、环戊蒽醌类、环普兰姆、西匹霉素、十八烷基磷酸阿糖胞苷(cytarabine ocfosfate)、溶细胞因子、磷酸己烷雌酚、达昔单抗、地西他滨、脱氢膜海鞘素B、地洛瑞林、地塞米松、右异环磷酰胺、右丙亚胺、右维拉帕米、地吖醌、代代宁B、地多西、二乙基降精胺、二氢-5-氮杂胞嘧啶核苷、二氢紫杉醇、二恶霉素、二苯基螺莫司汀、多西他赛、多可沙诺、多拉司琼、去氧氟尿苷、屈洛昔芬、屈大麻酚、倍癌霉素SA、依布硒啉、依考莫司汀、依地福新、依决洛单抗、依氟鸟氨酸、榄香烯、乙嘧替氟、表阿霉素、爱普列特、雌莫司汀类似物、雌激素激动剂、雌激素拮抗剂、依他硝唑、磷酸依托泊苷、依西美坦、法倔唑、法扎拉滨、维甲酰酚胺、非格司亭、非那雄胺、夫拉平度、氟卓斯汀、夫斯特隆、氟达拉滨、盐酸氟道诺霉素、福酚美克、福美司坦、福司曲星、福莫司汀、钆特沙弗林、硝酸镓、加洛他滨、加尼瑞克、明胶酶抑制剂、吉西他滨、谷胱甘肽抑制剂、HMG-CoA还原酶抑制剂(如阿托伐他汀、西立伐他汀、氟伐他汀、来适可、立普妥、洛伐他汀、瑞舒伐他汀和辛伐他汀)、庚二醇二氨基磺酸酯、调蛋白、六亚甲基二乙酰胺、金丝桃素、伊班膦酸、去甲氧柔红霉素、吲哚昔酚、伊决孟酮、伊莫福新、伊洛马司他、咪唑并吖啶酮(imidazoacridones)、咪喹莫特、免疫刺激肽、胰岛素样生长因子-1受体抑制剂、干扰素激动剂、干扰素、白细胞介素、碘苄胍、碘阿霉素、甘薯醇、4-伊罗普拉、伊索拉定、异苯胍唑、异高软海绵素B、伊他司琼、杰斯普拉克立德、卡哈拉利得F、片螺素-N-三乙酸酯、兰瑞肽、雷拉霉素、来格司亭、香菇多糖硫酸酯、来普他汀、来曲唑、白血病抑制因子、白细胞α-干扰素、亮脯利特+雌激素+黄体酮、亮丙瑞林、左旋咪唑、LFA-3T1P、利阿唑、线性多胺类似物、亲脂性二糖肽、亲脂性铂化合物、立索克林酰胺7、洛铂、蚯蚓磷脂、洛美曲索、氯尼达明、洛索蒽醌、洛伐他汀、罗唑利宾、勒托替康、镥替沙林、立索茶碱、裂解肽、美坦辛、麦洛坦汀A、马马司他、马索罗酚、乳腺丝抑蛋白、基质溶解因子抑制剂、基质金属蛋白酶抑制剂、美诺立尔、美巴龙、美替瑞林、蛋氨酸酶、甲氧氯普胺、MIF抑制剂、米非司酮、米替福新、米立司亭、错配双链RNA、米托胍腙;二溴卫矛醇、丝裂霉素类似物、米托萘胺、丝裂毒素成纤维细胞生长因子-皂草素、米托蒽醌、莫法罗汀、莫拉司亭、单克隆抗体、人绒毛膜促性腺激素、单磷酰脂A+分枝杆菌细胞壁sk、莫哌达醇、多重耐药基因抑制剂、多肿瘤抑制基因1治疗剂、芥末抗癌剂、印度洋海绵(mycaperoxide)B、分枝杆菌细胞壁提取物、美瑞泡仁、N-乙酰基地那林、N取代苯甲酰胺、那法瑞林、纳格瑞替、纳洛酮+喷他佑辛、纳帕维(napavin)、萘特非、那托司亭、奈达铂、奈莫柔比星、奈立膦酸、中性内肽酶、尼鲁米特、丽沙霉素、一氧化氮调节剂、氮氧自由基抗氧化剂、里挫林、O6-苄基鸟嘌呤、奥曲肽、奥克恩、寡核苷酸、奥那司酮、昂丹司琼(ondansetron)、昂丹司琼(ondansetron)、奥拉新、口服细胞因子诱导剂、奥马铂、奥沙特隆、奥赛利铂、厄诺霉素、紫杉醇、紫杉醇类似物、紫杉醇衍生物、帕诺明、十六酰基根霉素、帕米膦酸、人参三醇、帕诺米芬、帕拉贝新、帕折普汀、培门冬酶、培得星、戊聚糖多硫酸钠、喷司他丁、喷唑(pentrozole)、全氟溴烷、培磷酰胺、紫苏醇、苯连氮霉素、乙酸苯酯、磷酸酶抑制剂、溶链菌制剂、盐酸毛果芸香碱、吡柔比星、吡曲克辛、普来司汀(placetin)A、普来司汀(placetin)B、纤溶酶原激活物抑制剂、铂络合物、铂化合物、铂-三胺络合物、卟吩姆钠、紫菜霉素、泼尼松、丙基双吖啶酮、前列腺素J2、蛋白酶体抑制剂、基于蛋白A的免疫调节剂、蛋白激酶C抑制剂、蛋白激酶C抑制剂、微藻、蛋白酪氨酸磷酸酶抑制剂、嘌呤核苷磷酸化酶抑制剂、红紫素、吡唑啉吖啶、吡哆酸化血红蛋白聚氧乙烯偶联物、Raf拮抗剂、雷替曲塞、雷莫司琼、Ras法尼基蛋白转移酶抑制剂、Ras抑制剂、Ras-GAP抑制剂、脱甲基化瑞替普汀、依替膦酸铼Re186、根瘤菌素、核酶、RII维甲酰胺、罗谷亚胺、罗希吐碱、罗莫泰德、罗喹美克、鲁滨吉隆B1、鲁泊塞、沙芬戈、圣特平、SarCNU、肌肉叶绿醇A、沙莫司亭、Sdi 1模拟物、司莫司汀、衰老源性抑制因子1、正义寡核苷酸、信号转导抑制剂、信号转导调节剂、单链抗原结合蛋白、西佐喃、索布佐生、硼卡钠、苯乙酸钠、索佛罗、生长调节素结合蛋白、索纳明、膦门冬酸、穗霉素D、螺莫司汀、斯耐潘定、海绵抑制素1、角鲨胺、干细胞抑制剂、干细胞分裂抑制剂、斯替皮米德、基质溶解素抑制剂、索非罗新、强效血管活性肠肽拮抗剂、磺化偏端霉素、苏拉明、苦马豆碱、合成糖胺聚糖、他莫司汀、5-氟尿嘧啶、亚叶酸、他莫西芬甲碘化物、牛碘莫司汀、他扎罗汀、替可加兰钠、替加氟、碲哌喃鎓、端粒酶抑制剂、替莫泊芬、替莫唑胺、替尼泊苷、四氯十氧化物、替唑明、噻立拉斯汀、噻可拉林、血小板生成素、血小板生成素模拟物、胸腺法新、胸腺生成素受体激动剂、胸腺曲南、促甲状腺激素、锡乙基初紫红素、替拉扎明、二氯化二茂钛、托普升替、托瑞米芬、全能干细胞因子、转译抑制剂、维甲酸、三乙酰尿苷、曲西立滨、三甲曲沙、曲普瑞林、托烷司琼、妥罗雄脲、酪氨酸激酶抑制剂、酪氨酸磷酸化抑制剂、UBC抑制剂、乌苯美司、泌尿生殖窦源性生长抑制因子、尿激酶受体拮抗剂、伐普肽、凡瑞林B、载体系统、红细胞基因治疗剂、沙利度胺、维拉雷琐、藜芦胺、维尔啶、维替泊芬、长春瑞滨、维萨汀、伏氯唑、扎诺特隆、折尼铂、亚苄维和净司他丁斯酯。
在某些实施例中,与融合蛋白结合的治疗剂为免疫调节剂。免疫调节剂的非限制性实例包括蛋白制剂,如细胞因子、肽模拟物和抗体(如人的、人源化的、嵌合的、单克隆的、多克隆的、Fvs、ScFvs、Fab或F(ab)2片段或抗原表位结合片段)、核酸分子(如反义核酸分子和三重螺旋)、小分子、有机化合物和无机化合物。特别是免疫调节剂包括但不限于甲氨蝶呤、来氟米特、环磷酰胺、癌得星、依木兰、环孢霉素A、二甲胺四环素、硫唑嘌呤、抗生素(如FK506(他克莫司)、甲强龙(MP)、皮质甾类、类固醇、吗替麦考酚酯、雷帕霉素(西罗莫司)、咪唑立宾、脱氧精胍菌素、布喹那、丙二腈酰胺(malononitriloamindes)(如来氟米特)。在一个实施例中,免疫调节剂为化疗药物。在一个替代实施例中,免疫调节剂为不同于化疗药物的免疫调节剂。在一些实施例中,根据本发明使用的治疗剂不是免疫调节剂。
在一些实施例中,与融合蛋白共同使用的治疗剂为血管生成抑制剂。血管生成抑制剂的非限制性实例包括蛋白、多肽、肽、共轭物、抗体(如人的、人源的、嵌合的、单克隆的、多克隆的、Fvs、ScFvs、Fab片段、F(ab)2片段及其抗原结合片段)如结合TNF-α的抗体、核酸分子(如反义分子或三重螺旋)、有机分子、无机分子和能够减少或抑制血管生成的小分子。血管生成抑制剂的其它实例可在美国公开第2005/0002934 A1号中第277-282段找到,通过引用将其全文结合在此。在其它实施例中,根据本发明使用的治疗剂不是血管生成抑制剂。
在一些实施例中,与融合蛋白共同使用的治疗剂为抗炎药。抗炎药的非限制性实例包括任何抗炎药,其包含能够用于治疗炎症疾病的药物,本领域的技术人员对其非常熟悉。抗炎药的非限制性实例包括非甾体类抗炎药(NSAIDs)、甾体类抗炎药、抗胆碱药(如硫酸阿托品、硝酸甲基阿托品和异丙托溴铵(ATROVENT.TM.)、β2-激动剂(如马布特罗(abuterol)(VENTOLIN.TM.和PROVENTIL.TM)、比托特罗(TORNALATE.TM.)、左旋沙丁胺醇(XOPONEX.TM.)、奥西那林(ALUPENT.TM.)、吡布特罗(MAXAIR.TM.)、特布他林(terbutlaine)(BRETHAIRE.TM.和BRETHINE.TM.)、舒喘灵(PROVENTIL.TM.、REPETABS.TM.和VOLMAX.TM.)、福莫特罗(FORADIL AEROLIZER.TM.)和沙美特罗(SEREVENT.TM.和SEREVENT DISKUS.TM.))和甲基黄嘌呤(如茶碱(UNIPHYL.TM.、THEO-DUR.TM.、SLO-B1D.TM.和TEHO-42.TM.))。NSAIDs的实例包括但不限于阿司匹林、布洛芬、塞来昔布(CELEBREX.TM.)、双氯芬酸(VOLTAREN.TM.)、依托度酸(LODINE.TM.)、非诺洛芬(NALFON.TM.)、消炎痛(INDOCIN.TM.)、酮咯酸(TORADOL.TM.)、奥沙普秦(DAYPRO.TM.)、萘布美酮(RELAFEN.TM.)、舒林酸(CLINORIL.TM.)、托美丁(TOLECTIN.TM.)、罗非考昔(VIOXX.TM.)、甲氧萘丙酸(ALEVE.TM.、NAPROSYN.TM.)、苯酮苯丙酸(ACTRON.TM.)和萘布美酮(RELAFEN.TM.)。所述NSAIDs通过抑制环氧合酶(如COX-1和/或COX-2)发挥作用。甾体类抗炎药的实例包括但不限于糖皮质激素、地塞米松(DECADRON.TM.)、皮质甾类(如甲强龙(MEDROL.TM.))、可的松、氢化可的松、泼尼松(PREDNISONE.TM.和DELTASONE.TM.)、泼尼松龙(PRELONE.TM.和PEDIAPRED.TM.)、曲安奈德、柳氮磺胺吡啶和廿烷酸类抑制剂(如前列腺素、血栓素和白三烯)。在其它实施例中,根据本发明使用的治疗剂不是抗炎剂。
在某些实施例中,使用的治疗剂为烷化剂、亚硝基脲类、抗代谢物和蒽环类、拓扑异构酶II抑制剂或有丝分裂抑制剂。烷化剂包括但不限于白消安、顺铂、卡铂、苯丁酸氮芥、环磷酰胺、异环磷酰胺、氨烯咪胺、二氯甲基二乙胺、美法仑和替莫唑胺。亚硝基脲类包括但不限于卡氮芥(BCNU)和环己亚硝脲(CCNU)。抗代谢物包括但不限于5-氟尿嘧啶、卡培他滨、氨甲喋呤、吉西他滨、阿糖胞苷和氟达拉滨。蒽环类药物包括但不限于柔红霉素、阿霉素、表柔比星、去甲氧基柔红霉素和米托蒽醌。拓扑异构酶II抑制剂包括但不限于托泊替康、伊立替康、依托泊苷(VP-16)和替尼泊甙。有丝分裂抑制剂包括但不限于紫杉烷类(紫杉醇、多西他赛)和长春花生物碱(长春碱、长春新碱和长春瑞滨)。
在一些实施例中,融合蛋白与放射治疗结合使用,其中放射治疗包括使用X射线、γ射线和其它辐射源来杀死癌症干细胞和/或癌细胞。在特定的实施例中,放射治疗应用外照射放疗或远距放射疗法,其中辐射直接来自于远程放射源。在其它实施例中,放射治疗应用内部治疗或近距治疗,其中放射源置于体内,靠近癌症干细胞、癌细胞和/或肿瘤块。
5.7癌症的种类
根据本发明可以预防、治疗和/或管理任何类型的癌症。根据本发明可预防、治疗和/或管理的癌症的非限制性实例包括:白血病,比如但不限于急性白血病、急性淋巴细胞白血病、急性髓细胞白血病,如成髓细胞、前髓细胞、粒单核细胞、单核细胞,和红白血病及骨髓增生异常综合征;慢性白血病,比如但不限于慢性髓细胞(粒细胞)白血病、慢性淋巴细胞白血病、毛细胞白血病;真性红细胞增多症;淋巴瘤,比如但不局限于霍奇金病、非霍奇金病;多发性骨髓瘤,比如但不限于郁积型多发性骨髓瘤、非分泌型骨髓瘤、骨硬化性骨髓瘤、浆细胞白血病、孤立性浆细胞瘤和髓外浆细胞瘤;华氏巨球蛋白血症;意义未明的单克隆丙种球蛋白病;良性单克隆丙种球蛋白病;重链病;树突状细胞癌,包括浆细胞样树突状细胞癌、NK细胞淋巴瘤(也被称为皮肤NK/T细胞淋巴瘤和无颗粒型(CD4+/CD56+)皮肤肿瘤);嗜碱性白血病;骨骼和结缔组织肉瘤,比如但不限于骨肉瘤、成骨肉瘤、软骨肉瘤、尤文肉瘤(Ewing's sarcoma)、恶性巨细胞瘤、骨纤维肉瘤、脊索瘤、骨膜肉瘤、软组织肉瘤、血管肉瘤(血管内皮瘤)、纤维肉瘤、卡波济氏肉瘤(Kaposi's sarcoma)、平滑肌肉瘤、脂肪肉瘤、淋巴管肉瘤、神经鞘瘤、横纹肌肉瘤和滑膜肉瘤;脑肿瘤,比如但不限于神经胶质瘤、星形细胞瘤、脑干胶质瘤、室管膜瘤、少突胶质细胞瘤、非胶质来源肿瘤、听神经瘤、颅咽管瘤、成神经管细胞瘤、脑膜瘤、松果体细胞瘤、松果体母细胞瘤和原发性脑淋巴瘤;乳腺癌,包括但不限于导管癌、腺癌、乳腺小叶(小细胞)癌、乳管内癌、乳腺髓样癌、乳腺黏液癌、管状乳腺癌、乳头乳腺癌、派杰氏病(Paget's disease)和炎性乳腺癌;肾上腺癌,比如但不限于嗜铬细胞瘤和肾上腺皮质癌;甲状腺癌,比如但不限于乳头状或滤泡状甲状腺癌、甲状腺髓样癌和甲状腺未分化癌;胰腺癌,比如但不限于胰岛素瘤、胃泌素瘤、胰高血糖素瘤、血管活性肠肽瘤、生长抑素分泌肿瘤和类癌瘤或胰岛细胞瘤;垂体肿癌,比如但限于库兴氏病(Cushing'sdisease)、垂体催乳素瘤、肢端肥大症和尿崩症;眼癌,比如但不限于眼黑色素瘤如虹膜黑色素瘤、脉络膜黑色素瘤、和睫状体黑色素瘤和视网膜母细胞瘤;阴道癌,如鳞状细胞癌、腺癌和黑色素瘤;外阴癌,如鳞状细胞癌、黑色素瘤、腺癌、基底细胞癌、肉瘤和派杰氏病;宫颈癌,比如但不限于鳞状细胞癌和腺癌;子宫癌,比如但不限于子宫内膜癌和子宫肉瘤;卵巢癌,比如但不限于上皮性卵巢癌、交界瘤、生殖细胞肿瘤和间质瘤;食管癌,比如但不限于鳞癌、腺癌、腺样囊性癌、粘液表皮样癌、腺鳞癌、肉瘤、黑色素瘤、浆细胞瘤、疣状癌和燕麦细胞(小细胞)癌;胃癌,比如但不限于腺癌、真菌样(息肉样)、溃疡、浅表扩散、弥漫性扩散、恶性淋巴瘤、脂肪肉瘤、纤维肉瘤和癌肉瘤;结肠癌;直肠癌;肝癌,比如但不限于肝细胞癌和肝母细胞瘤;胆囊癌,如腺癌;胆管癌,比如但不限于乳头状型、结节型和弥漫型;肺癌,如非小细胞肺癌、鳞状细胞癌(表皮样癌)、腺癌、大细胞癌和小细胞肺癌;睾丸癌,比如但不限于生殖细胞瘤、精原细胞瘤(未分化精原细胞瘤,经典(典型)精原细胞瘤,精母细胞精原细胞瘤)、非精原细胞瘤、胚胎癌、畸胎瘤癌和绒毛膜癌(卵黄囊瘤);前列腺癌,比如但不限于前列腺上皮内瘤、腺癌、平滑肌肉瘤和横纹肌肉瘤;刑事癌(penal cancers);口腔癌,比如但不限于鳞状细胞癌;基底细胞癌;唾液腺癌,比如但不限于腺癌、粘液表皮样癌和腺样囊性癌;咽癌,比如但不限于鳞状细胞癌和疣状皮肤癌;皮肤癌,比如但不限于基底细胞癌、鳞状细胞癌和黑素瘤、浅表扩散性黑色素瘤、结节性黑色素瘤、小痣恶性黑色素瘤和肢端黑色素瘤;肾癌,比如但不限于肾细胞癌、腺癌、肾上腺瘤、纤维肉瘤、移行细胞癌(肾盂和/或输尿管);维尔姆斯瘤(Wilms'tumor);膀胱癌,比如但不限于移行细胞癌、鳞状细胞癌、腺癌和肉瘤。此外,癌症包括粘液肉瘤,骨肉瘤,内皮肉瘤、淋巴管内皮肉瘤、间皮瘤、滑膜肉瘤、成血管细胞瘤、上皮癌、囊腺癌、支气管癌、汗腺癌、皮脂腺癌、乳头状癌和乳头状腺癌(若想全面了解这些疾病,可参考菲什曼等人,1985,《药学(Medicine)第二版,J.B.Lippincott Co.,费城,和墨菲等人,1997,《明智的决定:癌症诊断、治疗和恢复全集(Informed Decisions:The Complete Book of Cancer Diagnosis,TreaPnent,and Recovery)》,维京企鹅(Viking Penguin),企鹅(美国)出版集团(Penguin Books U.S.A.,Inc.),美国)。
预防性和/或治疗性的有效疗法对各种癌症或其它异常增生性疾病的预防和/或管理也是有用的,包括但不限于以下疾病:癌症,包括:膀胱、乳腺、结肠、肾、肝、肺、卵巢、胰腺、胃、子宫颈、甲状腺和皮肤的癌症;包括鳞状细胞癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、伯基特淋巴瘤(Burkitt's lymphoma);髓系造血肿瘤,包括急性和慢性髓细胞性白血病和前髓细胞性白血病;间质来源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;其它肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、神经母细胞瘤和神经胶质瘤;中枢和外周神经系统的肿瘤,包括星形细胞瘤、神经母细胞瘤,神经胶质瘤和神经鞘瘤;间质来源的肿瘤,包括纤维肉瘤、横纹肌肉瘤和骨肉瘤;其它肿瘤,包括黑色素瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌和畸胎瘤。在一些实施例中,根据本发明的方法可预防、治疗和/或管理与细胞凋亡异常有关的癌症。这些癌症可包括但不限于滤泡性淋巴瘤、p53突变的癌症、激素依赖性乳腺癌、前列腺癌、卵巢癌和癌前期病变如家族性腺瘤性息肉病和骨髓增生异常综合征。在特定的实施例中,根据本发明的方法可预防、治疗和/或管理恶性肿瘤或增殖异常性变化(如组织转化和发育异常)或皮肤、肺、肝、骨、脑、胃、结肠、乳腺、前列腺、膀胱、肾脏、胰腺、卵巢和/或输尿管过度增生性疾病。在其它具体的实施例中,根据本发明的方法可预防、治疗和/或管理肉瘤、黑色素瘤或白血病。在某些实施例中,受试者患有急性髓细胞性白血病(AML)。在某些其它实施例中,受试者患有骨髓增生异常综合征(MDS)。在其它实施例中,受试者患有慢性骨髓单核细胞性白血病(CMML)。在其它具体的实施例中,根据本发明的方法可预防、治疗和/或管理骨髓增生异常综合征。
治疗癌症的一个主要目标是能够以充足合适的治疗水平靶向肿瘤,而无全身毒性。
在某些实施例中,治疗癌症的方法包括:(i)减少癌细胞;(ii)癌细胞不再增加;(iii)降低癌细胞的活力;(iv)减少受试者中癌细胞的生长。
在某些实施例中,用本公开的方法进行治疗的受试者已被诊断患有所述病并且已接受治疗。在某些实施例中,用本公开的方法进行治疗的受试者已被诊断患有癌症并且已接受癌症治疗。
在某些实施例中,受试者处于癌症缓解期。在某些实施例中,受试者癌症复发。在某些实施例中,受试者癌症治疗失败。
5.8试剂盒
本文提供了包含用于处理本文描述条件的材料的制品和试剂盒。制品可包括如本文描述的具有标签的化合物容器。合适的容器包括,例如瓶子、玻璃小瓶和试管。容器可以由多种材料制成,如玻璃或塑料。容器中容纳可有效治疗或预防癌症的疫苗的组合物。容器上的标签可表明所述组合物可用于治疗特定情况,也可指明给药说明。
在一个或多个实施例中,本发明可提供包含治疗有效量疫苗的试剂盒。根据本公开的一个或多个实施方案,可以理解在一个或多个试剂盒中可包括疫苗的任何实施例。
5.9免疫应答
本领域技术人员可利用任何方法比较受试者中多肽引发的免疫应答与全长蛋白引发的免疫应答。下面的实例中使用了一个简单的方法:对模型受试者(如小鼠)进行免疫,然后向其注入致死剂量的大肠杆菌。为了进行适当的比较,本领域技术人员会自发地选择相同的佐剂,如弗氏完全佐剂。在此测试中,例如,如果多肽提供至少70%全长蛋白提供的保护、至少80%全长蛋白提供的保护、至少85%全长蛋白提供的保护、至少90%全长蛋白提供的保护、至少95%全长蛋白提供的保护、至少97%全长蛋白提供的保护、至少98%全长蛋白提供的保护或至少99%全长蛋白提供的保护,则本发明的免疫原性多肽片段可在受试者中引起大体相似的免疫应答(即引发抵抗致命攻击的大体相同的保护)。
本发明的组合物可引起细胞介导的免疫应答和体液免疫应答两者。所述免疫应答会优先诱导持久的(如中和)抗体和细胞介导的当再接触抗原时能快速响应的免疫。
CD4和CD8细胞被普遍认为是启动和/或增强细胞介导的免疫和体液免疫的两类T细胞。CD8 T细胞可表达CD8共受体并且通常被称为细胞毒性T淋巴细胞(CTL)。CD8 T细胞能够识别或与MHCⅠ类分子呈递的抗原相互作用。
CD4 T细胞可以表达CD4共受体并且通常被称为T辅助细胞。CD4 T细胞能够识别与MHCⅡ类分子结合的抗原肽。在与MHCⅡ类分子相互作用时,CD4细胞可以分泌细胞因子等因子。
这些分泌的细胞因子可以激活B细胞、细胞毒性T细胞、巨噬细胞和参与免疫应答的其它细胞。
6实例
6.1制备融合蛋白
在一个实施例中,在Sf9昆虫细胞中利用杆状病毒表达以产生辛德毕斯融合蛋白。由于杆状病毒只能感染特定的无脊椎动物,它们对哺乳动物无致病性。与细菌蛋白表达不同,杆状病毒系统中表达的蛋白质可被加工、折叠和修饰,类似于哺乳动物表达系统中产生的蛋白。此外,杆状病毒表达的蛋白很容易扩展规模从而生产大量的重组蛋白。昆虫细胞系在悬浮培养中生长良好,可在大规模生物反应器中生产重组蛋白。尽管昆虫和哺乳动物细胞均能形成N连接的糖基化,但是特定的糖基化路径不同。昆虫细胞中产生的N糖链能有丰富的甘露糖或微量甘露糖苷结构,两者都有末端甘露糖残基。哺乳动物细胞中产生的N糖链能有丰富的甘露糖结构或复杂的结构,末端为半乳糖和唾液酸。树突状细胞特异性细胞间黏附分子-3结合非整合素(DC-SIGN)需要其包膜糖蛋白具有高甘露糖的糖基化才能将SINV与树突状细胞(DC)受体结合。哺乳动物细胞中产生的病毒若没有额外的酶法修饰将不会结合DC-SIGN。因此,昆虫细胞中产生的融合蛋白能实现TAA有效靶向DC。
编码VGP的基因是通过基因合成及针对昆虫细胞表达进行密码子优化而产生的。重组融合蛋白是由通过柔性连接肽连接并通过第二个连接肽连接至TAA的pE2和E1辛德毕斯糖蛋白的胞外结构域构成(见图4)。在一个实施例中,TAA为NY-ESO-1。在某个实施例中,其它TAA被插入编码序列中。可替代地,构建体是由两个或更多个TAA串联而成,由此产生较强的免疫应答。pE2中的E3成分充当蛋白质分泌的信号肽,帮助E1和E2的结合,并且被弗林蛋白酶自然地从成熟蛋白中切除。α病毒糖蛋白是作为成熟的分泌蛋白产生,形成E1和E2异源二聚体复合物的三聚体,类似在SIVN包膜上观察到的三聚体糖蛋白刺突。第二个柔性连接肽使NY-ESO-1适当折叠而不干扰E2/E1的多聚化。此外,由于NY-ESO-1的前80个氨基酸富含甘氨酸且严重缺乏T细胞抗原,故在一个实施例中,构建体中只包括氨基酸残基81-180。在某些实施例中,TAA包含NY-ESO-1上1-180、81-100、100-150和150-180位的氨基酸残基。在所述蛋白质的C末端加上了组氨酸标签(His-tag)用于纯化目的。利用非变性凝胶和尺寸排阻色谱法分析新蛋白以确定其多聚体结构。此外,还应用了ELISA和对所述蛋白质具有特异性的western印迹分析。所述蛋白质具有多个抗原靶标(NY-ESO-1、His-tag以及SINV E1和E2),可用市售抗体进行检测。
本文提供一种病毒糖蛋白复合物,所述病毒糖蛋白复合物是一种重组蛋白,由辛德毕斯病毒E3、E2和E1蛋白的胞外结构域连接至来源于抗原肿瘤相关抗原NY-ESO-1的截短肽组成。辛德毕斯病毒结构蛋白E3、E2、6K和E1的氨基酸序列(NCBI网站参考序列NP_062890.1)。从编码序列中除去了E2和E1蛋白的跨膜结构域。E2和E1蛋白由柔性甘氨酸/丝氨酸连接肽(GGGGSGGGGSGGGGSGGGG)代替6K区进行连接。NY-ESO-1的氨基酸序列(NCBI网站参考序列NP_001318.1)。由于NY-ESO-1的N末端有极丰富的甘氨酸并且严重缺乏T细胞抗原,故在一个实施例中,所述蛋白质的前78个氨基酸已被去除。在一个实施例中,辛德毕斯的E3/E2/E1序列通过TEV切割位点(ENLYFQ)和第二个甘氨酸/丝氨酸连接肽(GGGGGSGGGGSGGGGS)与截短的含102个氨基酸的NY-ESO-1蛋白连接。在一个实施例中,在重组蛋白的C末端加上了6x-His标签用于纯化目的。由Genscript(Piscataway,NJ)合成编码所述重组蛋白的DNA序列,并且针对在Sf9细胞中表达进行密码子优化。使用DH10Bac细胞株产生重组杆状病毒质粒。利用Cellfectin II,以杆状病毒质粒转染Sf9昆虫细胞并在Sf-900II培养基中于27℃孵育5-7天。离心后,收集上清液并称为P1病毒原液。细胞进一步用P1感染以产生高滴度P2原液。用P2病毒转染Sf9细胞并于72小时后收集培养基。上清液针对包含蛋白酶抑制剂的50mM Tris、150mM NaCl(pH 8.0)进行透析,并用镍柱纯化蛋白质,并且用抗His western印迹进行分析。
6.2受体结合分析
SINV与肿瘤细胞受体(层粘连蛋白受体)和树突细胞(DC-SIGN)受体两者结合。融合蛋白维持病毒表面E2/E1异源二聚体的三聚体的构象,并与这些相同的受体结合。利用蛋白质A微球和DC-SIGN Fc融合蛋白对DC-SIGN的结合情况进行测定。融合蛋白最大限度结合覆盖有DC-SIGN的珠,然后在流式细胞仪上利用荧光标记二抗的VGP(抗His或抗NY-ESO-1)进行检测。分析多种蛋白浓度下的结合情况,并与其它靶向DC-SIGN的方法(如抗DC-SIGN抗体)进行比较。使用配备了96孔板读数器的流式细胞仪以高通量方式进行检测。病毒蛋白靶向与DC-SIGN抗体的亲和力相似的DC。此外,在人体(表达DC-SIGN)和小鼠体内(L-SIGN)分析融合蛋白与DC的结合情况。用受体阻断抗体和甘露聚糖、甘露糖多糖来证明相互作用的特异性。对于层粘连蛋白受体结合,通过可不同程度表达层粘连蛋白受体的多个肿瘤细胞系分析结合情况。可通过加入层粘连蛋白受体的抗体或过量的层粘连蛋白即受体的天然配体来阻断所述结合。融合蛋白优选地结合这些细胞而不是旁观者细胞,并且能有效地将肿瘤相关抗原传递到DC进行处理和呈递。
6.3体外分析
SINV通过招募NK细胞和激活针对病毒编码的肿瘤相关抗原的T细胞来提高免疫系统对肿瘤细胞的应答。通过利用病毒将抗原通过DC-SIGN受体传递到DC来达到这些效果的后者。为了引起强烈的T细胞反应,必须首先通过检测在病毒、细菌或寄生虫中常见的病原相关分子模式(PAMPs)来激活DC。活化的DC表达更高水平的MHC分子及共刺激分子B7-1和B7-2。因此,有必要评估重组融合蛋白是否具有足够的免疫原性来诱导DC的活化,或是否有必要将其与佐剂结合。
通过人外周血单个核细胞(PBMC),利用磁珠选择获得单一特定的免疫细胞类型,然后评价VGP/NY-ESO-1的直接作用。可通过流式细胞分析细胞表面活性标志物并通过ELISA检测细胞因子的分泌来测定DC和NK细胞的活化情况。利用肿瘤患者体内的T细胞来分析调控肿瘤特异性应答的能力。这些患者已暴露于肿瘤抗原,并且与健康供体相比,他们体内的肿瘤特异性T细胞的比例升高。用重组融合蛋白过夜处理患者的DC,其间,所述蛋白质被吸附、加工,相关的表位被呈递到细胞表面。DC与患者的T细胞共培养数天,在这期间对T细胞的抗原特异性应答进行分析。通过流式细胞仪,利用CFSE标记的T细胞对T细胞的增殖进行测量。用ELISPOT法检测活化的NY-ESO-1特异性T细胞。NY-ESO-1特异性T细胞通过识别DC呈递的特异性表位来产生IFN-γ,其被包被ELISPOT板上孔的抗体所捕获用于检测。这些分析表明融合蛋白产生的肽被树突细胞加工和呈递,且人体内可激活T细胞应答。
尽管我们相信VGP治疗的最重要作用需要通过激活免疫系统,仍不应忽视通过层粘连蛋白受体直接靶向肿瘤的作用。在进入肿瘤细胞和无病毒复制的情况下,SINV可诱导肿瘤细胞的凋亡。在体外研究VGP对肿瘤细胞生长和存活的影响。表达不同程度的层粘连蛋白受体的多种肿瘤细胞系可用于分析蛋白和肿瘤之间的相互作用对治疗疗效的影响(如果确实存在任何影响)。
6.4体内刺激分析
在试图治疗生长活跃的肿瘤前,证明用VGP/NY-ESO-1能诱导体内肿瘤特异性免疫应答十分重要。正常小鼠从未遇到NY-ESO-1,其被免疫系统识别为外来抗原。通过向小鼠腹腔注射VGP/NY-ESO-1对其进行免疫,可导致NY-ESO-1特异性T细胞的激活和增殖以及融合蛋白特异性T细胞和NK细胞的激活。VGP/NY-ESO-1显示出比单独VGP、单独NY-ESO-1和抗DC-SIGN/NY-ESO-1(对照)更强的免疫原性,即可确定该治疗的效果。检查点抑制剂抗CTLA-4和PD-1具有强大的免疫治疗潜力并且与公开的治疗协同作用甚至产生更强的免疫应答。对向本文公开的治疗联合加入和未加入这些阻断抗体的疗效进行了评估。
基于已知的MHC结合偏好,用特定品系小鼠的MHC分子对NY-ESO-1和VGP的抗原表位进行呈递。可替代地,可用已知NY-ESO-1抗原表位的转基因小鼠来表达人MHC分子。血、脾脏和引流淋巴结的样品可用于检验免疫刺激。MHC四聚体染色可用于验证NY-ESO-1和VGP特异性T细胞数量的扩增。这些细胞存在于原小鼠体内,但数量很少,低于检测阈值。在成功的免疫接种中,这些细胞增殖且易于通过流式细胞仪进行检测。此外,应用流式细胞仪并通过观察表面标记物如CD62L和CD69来分析这些四聚体细胞的活化状态,CD62L和CD69分别只存在于原细胞和活化细胞中。VGP特异性T细胞的活性被认为是脱靶效应,其进一步增强对肿瘤的免疫应答,因为这些抗原也会靶向肿瘤自身。
ELISPOT检测可用于确定这些NY-ESO-1特异性T细胞有效应功能。采集于免疫小鼠脾脏和淋巴结的CD8+T细胞与抗原提呈细胞在预加入NY-ESO-1的培养基中共培养。这些抗原表位的特异性活化T细胞可在应答中产生细胞因子,如干扰素γ,其被包被孔底部的抗体捕获进行检测。通过细胞毒性试验来分析这些活化T细胞的效应功能。类似于ELISPOT检测,免疫小鼠体内的CD8+T细胞与抗原呈递细胞在预加入相关肽的培养基中共培养。可替代地,利用转导慢病毒的同源小鼠细胞系来表达NY-ESO-1。激活的CD8+CTL直接杀死这些NY-ESO-1呈递细胞,通过检测裂解细胞中的胞内蛋白来测量其细胞毒性,如上清液中的乳酸脱氢酶。
通过流式细胞术分析所述疗法对其它免疫细胞群的影响。具体而言,分析了治疗对几种免疫细胞类型(CD4+和CD8+T细胞、DC、NK细胞、B细胞、巨噬细胞)彼此间百分比及对总细胞数的影响。通过分析血清来评价小鼠针对重组蛋白产生的抗体。浆细胞产生对NY-ESO-1和VGP的特异性抗体。在某些实施例中,当用多个剂量给药时,这些抗体可干扰治疗的效果。在某些实施例中,这些抗原靶向肿瘤本身,使其更具抗原性,因此这些抗体有助于清除肿瘤。
在进入肿瘤模型前,检查合适的剂量策略(蛋白数量、给药量、给药次数)以产生强大的抗肿瘤免疫应答。此外,通过ELISA检测小鼠血清和组织中的VGP来评价剂量以及体内蛋白的运输和稳定性。
为了适当地激活T细胞,通过检测病原体相关分子模式(PAMPs)激活DC。在某些实施例中,向VGP/NY-ESO-1中加入佐剂以提高其免疫原性。
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本发明不限于此处所述的具体实施例的范围。实际上,通过以上描述和附图,本领域技术人员将会熟悉除本文描述以外的本发明的各种修改。这种修改意在属于所附权利要求的范围。
在整个申请中,引用了专利、专利申请和出版物,其中公开的、特别是包括所有公开的化学结构,都通过引用的方式并入本文。上述出版物或文件的引文并不允许承认上述任何一项都与现有技术有关,也不构成对这些出版物或文件的内容或日期的任何承认。本文中引用的所有参考文献都是以相同的程度引用的,正如每一单独的出版物、专利申请或专利,都是明确且单独被引用的。
上述书面说明书被认为足以使本领域技术人员实践本发明。除本发明所示和描述的本发明的各种修改外,本领域的技术人员将会熟悉本发明的多种修改,且属于所附权利要求的范围。
Claims (31)
1.一种分离的或重组的融合蛋白,大体上由α病毒表面膜糖蛋白E1、E2和任选地E3;连接肽;以及至少一种肿瘤相关抗原组成,其中当给予受试者时,所述融合蛋白刺激免疫应答。
2.如权利要求1所述的融合蛋白,包含与SEQ ID NO:1具有至少98%一致性的氨基酸序列。
3.如权利要求1所述的融合蛋白,至少包含在SEQ ID NO:1的66-978位处的氨基酸残基。
4.如权利要求2所述的融合蛋白,进一步包含缺失SEQ ID NO:1上(i)1至65位;(ii)979-984位;或(iii)1-65和979-984位处的氨基酸残基。
5.如权利要求1所述的融合蛋白,所述融合蛋白是由与SEQ ID NO:2具有至少95%一致性的核酸分子编码。
6.如权利要求1所述的融合蛋白,其中E2包含至少300个氨基酸长度并且与SEQ ID NO:1的66-429位具有至少95%序列一致性的氨基酸序列。
7.如权利要求1所述的融合蛋白,其中E1包含至少300个氨基酸长度并且与SEQ ID NO:1的449-854位具有至少95%序列一致性的氨基酸序列。
8.如权利要求1所述的融合蛋白,其中所述肿瘤相关抗原是多肽片段,所述多肽片段是SEQ ID NOs:3-11中任一序列上的至少10个连续氨基酸,其中所述多肽片段包含至少10个连续氨基酸具有免疫原性,并且所述免疫原性多肽片段包含具有SEQ ID NOs:3-11的多肽的少于1100个氨基酸。
9.一种包含如权利要求1至8所述的融合蛋白的疫苗,所述疫苗能够在受试者体内通过NK细胞、T细胞或记忆T细胞来引起免疫应答。
10.一种组合物,包含如权利要求1至8所述的融合蛋白和药学上可接受的载体。
11.如权利要求10所述的组合物,进一步包含佐剂。
12.一种表达载体,包含编码如权利要求1至8所述的融合蛋白的核酸分子。
13.一种包含如权利要求12所述的表达载体的细胞,其中所述细胞表达融合蛋白。
14.如权利要求1所述的融合蛋白,其中所述肿瘤相关抗原是在《临床肿瘤研究》2009;15:5323-5337中描述的美国国家癌症研究所(NCI)有关癌症抗原优先级排序试点项目的表3中所列出的蛋白质的多肽片段。
15.如权利要求1至8所述的融合蛋白,所述融合蛋白被表达为一个连续的基因产物。
16.如权利要求1至8所述的融合蛋白,所述融合蛋白能够形成二聚体或三聚体。
17.如权利要求1至8所述的融合蛋白,其中所述至少一种肿瘤相关抗原经内部插入所述α病毒表面膜糖蛋白E1或E2中。
18.如权利要求1至8所述的融合蛋白,其中所述至少一种肿瘤相关抗原在末端连接到所述α病毒表面膜糖蛋白E1或E2。
19.如权利要求1至8所述的融合蛋白,所述融合蛋白进一步结合至衣壳蛋白。
20.如权利要求1至8所述的融合蛋白,其中所述α病毒表面膜糖蛋白为辛德毕斯α病毒蛋白。
21.一种用于在受试者中诱导或调节免疫应答的方法,包括向所述受试者给予融合蛋白,其中所述融合蛋白大体上由通过至少一个连接肽结合至一种或多种肿瘤相关抗原的α病毒表面膜糖蛋白E1和/或E2组成。
22.一种治疗受试者中包括艾滋病、带状疱疹和疱疹在内的潜伏病毒感染的方法,包括向所述受试者给予融合蛋白,其中所述融合蛋白大体上由通过至少一个连接肽结合至一种或多种病毒抗原的α病毒表面膜糖蛋白E1和/或E2组成。
23.如权利要求21或22所述的方法,其中E2包含至少300个氨基酸长度并且与SEQ IDNO:1的66-429位具有至少95%序列一致性的氨基酸序列。
24.如权利要求21或22所述的方法,其中E1包含至少300个氨基酸长度并且与SEQ IDNO:1的449-854位具有至少95%序列一致性的氨基酸序列。
25.一种产生融合蛋白的方法,包括在表达载体中表达所述融合蛋白,所述表达载体包含编码以下的核苷酸构建体:(a)α病毒表面膜糖蛋白E1和/或E2;(b)至少一种肿瘤相关抗原或病毒抗原,其中所述肿瘤相关抗原或病毒抗原可操作地连接到所述α病毒表面膜糖蛋白E1和/或E2,其中当给予受试者时,所述融合蛋白刺激免疫应答。
26.一种用于治疗受试者的癌症的方法,包括向有需要的所述受试者给予融合蛋白,其中所述融合蛋白大体上由α病毒表面膜糖蛋白E1、E2以及至少一个连接肽组成,其中当对所述受试者给予时,所述融合蛋白刺激免疫应答。
27.如权利要求25所述的方法,其中所述肿瘤相关抗原是多肽片段,所述多肽片段是SEQ ID NOs:3-11中任一序列上的至少10个连续氨基酸,其中所述多肽片段包含至少10个连续氨基酸具有免疫原性,并且所述免疫原性多肽片段包含具有SEQ ID NOs:3-11的多肽的少于1100个氨基酸。
28.如权利要求25所述的方法,其中所述融合蛋白是在哺乳动物细胞系统中产生。
29.如权利要求25所述的方法,其中所述融合蛋白是在昆虫细胞中产生。
30.如权利要求25所述的方法,其中所述融合蛋白是在杆状病毒载体中表达并且所述融合蛋白是在昆虫细胞中表达。
31.如权利要求21至24和26至30所述的方法,进一步包括给予额外治疗。
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