CN104471057B - 经修饰的细菌和它们用于治疗癌症或肿瘤的用途 - Google Patents
经修饰的细菌和它们用于治疗癌症或肿瘤的用途 Download PDFInfo
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Abstract
本文提供了一种使用经修饰的细菌以及包含所述经修饰的细菌的治疗性或预防性组合物治疗癌症或肿瘤的方法。所述方法可与其它治疗相组合,例如化学疗法、放射疗法、基因疗法、外科手术或它们的组合。所述方法使经修饰的兼性厌氧性细菌成为条件性的专性厌氧菌。本文还提供了包含必需基因表达盒的经修饰的细菌,其是严格低氧调节的,以及包含其的载体。所述经修饰的细菌在实体瘤/癌症内生长,从而延缓肿瘤/癌症或从正常组织中消除所述肿瘤/癌症。本文还提供了经修饰的细菌在制备治疗癌症的药物中的用途。
Description
对相关申请的交叉引用
本申请要求2012年5月4日提交的美国临时专利申请系列号61/687,975的权益,其特此整体引入作为参考。
1. 技术领域
本文描述了一种使用经修饰的细菌或包含所述经修饰的细菌的组合物治疗癌症或肿瘤的方法。在某些实施方案中,将所述治疗癌症或肿瘤的方法与其它癌症或肿瘤治疗相组合。在某些实施方案中,所述癌症或肿瘤治疗是化学疗法、放射疗法、基因疗法、外科手术或它们的组合。本文描述了一种使经修饰的兼性厌氧性细菌成为条件性的专性厌氧菌的方法。在一个方面,所述经修饰的细菌是严格低氧调节的,且包含必需基因表达盒。本文描述了包含必需基因表达盒的载体,包含所述载体的细胞。本文还描述了包含经修饰的细菌的治疗性和预防性的组合物。在某些实施方案中,所述治疗性和预防性的组合物含有纯化形式的经修饰的细菌。在某些实施方案中,所述治疗性和预防性的组合物不含有其它微生物菌株。在一个方面,所述经修饰的细菌在肿瘤/癌症内生长,从而延缓它的生长。在一个方面,所述肿瘤/癌症是实体瘤/癌症。在一个方面,所述经修饰的细菌从正常组织中快速消除。在某些实施方案中,所述肿瘤/癌症包括、但不限于:乳腺癌、肝癌或成神经细胞瘤。
2. 背景技术
癌症是当今世界上最致命的疾病之一。面对癌症,大多数人认为外科手术、化学疗法或放射疗法是唯一可能的解决方案。但是,并非所有癌症患者都适合于外科手术,并且癌症转移可以造成外科手术治疗的失败。化学疗法或放射疗法可能导致正常器官的巨大损伤和对癌症部位的较小作用。此外,低氧的肿瘤细胞可能表现出细胞周期进展和增殖的抑制,并因此可以相对地耐受许多靶向快速分裂的细胞的抗癌药物。因而,在实体瘤中,低氧区域产生另一个问题,这是因为它们对许多治疗具有抗性[1],并且与更恶性的表型有关[2]。
细菌在癌症治疗中的有意应用可以追溯至十九世纪晚期,甚至存在更早的细菌在治疗癌症中的效力的轶事报告[3, 10, 11]。首先报道的使用细菌(酿脓链球菌(Streptococcus pyrogenes))来治疗不可手术的肉瘤的审慎尝试也证实了该技术的固有危险。尽管可相当大地减少肿瘤和淋巴结,但是患者在治疗的9天内死于感染[3, 10, 11]。另一方面,靶向癌症疗法、基因疗法和癌症疫苗都是基于转染技术。与这些治疗策略有关的最关键的问题是载体的安全性。病毒载体是最广泛地使用的递送载体,但是,它们不容易消除,具有潜在致瘤性,具有有限的效力。因此,具有更大效力和安全操作的非病毒载体(诸如细菌载体)是开发新递送系统的一种有前途的方案。
结果,许多最近的关于癌症的细菌疗法的工作已经聚焦于非致病菌株或将用在模型系统和人类中的细菌减毒的需要。双歧杆菌属(Bifidobacteria)是非致病的专性厌氧菌,且已经被成功地用于靶向肿瘤和用作治疗载体,但是没有表明具有溶瘤作用[8, 12-14]。
3. 发明内容
本文描述了一种经修饰的细菌,其包含严格低氧调节的必需基因表达盒。本文还描述了包含所述经修饰的细菌的组合物。本文还描述了包含所述经修饰的细菌的治疗性和预防性的组合物。在某些实施方案中,所述治疗性和预防性的组合物含有纯化形式的经修饰的细菌。在某些实施方案中,所述治疗性和预防性的组合物不含有其它微生物菌株。
本文提供了一种严格低氧调节的盒,其包含正向厌氧诱导型启动子、必需基因和反向需氧启动子。
本文描述了载体、包含所述载体的细胞。在某些实施方案中,所述载体包含必需基因表达盒。本文描述了一种载体,其包含可操作地连接到必需基因的低氧条件启动子。在一个实施方案中,所述低氧条件启动子包含诱导物结合位点。在一个实施方案中,所述载体还包含由所述诱导物负调节的反义启动子。
本文描述了一种制备所述经修饰的细菌的方法。本文还描述了一种使经修饰的兼性厌氧性细菌成为条件性的专性厌氧菌的方法。在一个方面,所述经修饰的细菌是严格低氧调节的,且包含必需基因表达盒。
本文还描述了一种使用经修饰的细菌或包含所述经修饰的细菌的组合物治疗癌症的方法。所述方法当在体内施用时抑制和减少肿瘤癌症的生长。在某些实施方案中,将所述治疗癌症的方法与其它癌症治疗相组合。在某些实施方案中,所述癌症或肿瘤治疗是化学疗法、放射疗法、基因疗法、外科手术或它们的组合。在一个方面,所述经修饰的细菌在实体瘤/癌症内生长,从而延缓它的生长。在一个方面,所述经修饰的细菌从正常组织快速消除。在某些实施方案中,所述实体瘤/癌症包括、但不限于:乳腺癌、肝癌或成神经细胞瘤。
本文还描述了一种试剂盒,其包含所述经修饰的细菌和药学上可接受的载体。
本文描述了一种从兼性厌氧菌提供专性厌氧菌的方法。在另一个实施方案中,所述兼性厌氧菌是革兰氏阴性细菌。在某些实施方案中,所述兼性厌氧菌包括、但不限于鼠伤寒沙门氏菌(Salmonella typhimurium)。在某些实施方案中,所述经修饰的细菌在抗肿瘤疗法中是有效的。在某些实施方案中,所述必需基因是,例如,天冬氨酸半醛脱氢酶(“asd”)的基因。在某些实施方案中,asd是可操作地连接的,且在低氧条件启动子的控制下。在某些实施方案中,所述细菌的正常功能不受它的基因中的任一个的缺失或突变损害。
在一个实施方案中,所述经修饰的细菌是YB1。新菌株YB1与以前研究的靶向肿瘤的沙门氏菌属菌株VNP20009的对比表明,YB1比VNP20009更有效地靶向和抑制肿瘤生长两者。此外,在乳腺癌动物模型中,YB1比VNP20009远远更快地从正常组织消除。在一个实施方案中,所述经修饰的细菌不是VNP20009。
在一个实施方案中,所述经修饰的细菌在正常组织中没有生活力。在一个实施方案中,通过将必需基因asd置于低氧诱导的启动子控制下,制备所述经修饰的细菌。在一个实施方案中,所述必需基因是asd或二氨基庚二酸(“dapA”)。沙门氏菌属的asd基因编码二氨基庚二酸(DAP)的合成所必需的酶,所述二氨基庚二酸是细菌细胞壁的必需组分,且不存在于哺乳动物系统中[7]。在一个实施方案中,由于仅在低氧条件中表达asd,所述细菌能够在低氧下容易地生长,但是将在正常生长条件下裂解。因此,在某些实施方案中,兼性厌氧革兰氏阴性细菌(包括伤寒沙门氏菌(Salmonella typhi))可以从兼性厌氧菌转化成“专性”厌氧菌,从而使它在正常组织中是安全的。在某些实施方案中,所述经修饰的细菌是鼠伤寒沙门氏菌(Salmonella typhimurium)、猪霍乱沙门氏菌(Salmonella choleraesuis)、肠炎沙门氏菌(Salmonella enteritidis)和鼠伤寒沙门氏菌(S. typhimurium)、大肠杆菌(Escherichia coli)、大肠杆菌K-12(Escherichia. coli K-12)、大肠杆菌O157:H7(Escherichia. coli O157:H7)、志贺氏菌属(Shigella)、痢疾志贺氏菌(Shigella dysenteriae)、弗氏志贺氏菌(Shigella flexneri)、鲍氏志贺氏菌(Shigella boydii)、索氏志贺氏菌(Shigella sonnei)、耶尔森氏菌属(Yersinia)、鼠疫耶尔森氏菌(Yersinia pestis)、假结核耶尔森氏菌(Yersinia pseudotuberculosis)和小肠结肠炎耶尔森氏菌(Yersina enterocolitica)。
在一个实施方案中,本文描述的盒由延胡索酸和硝酸还原基因(“fnr”)调节,该基因参与需氧性生长和厌氧性生长之间的转换[42]。含有FNR结合位点的启动子在低氧下被活化[43]。在一个实施方案中,本文提供的pepT启动子生成了仅在低氧区域中表达的基因疗法载体[43]。在某些实施方案中,使用所述pepT启动子(PpepT)来驱动asd(对低氧条件性的)在经修饰的沙门氏菌属SL7207 (YB-pw)中的表达,从而将细菌生存力限制在低氧区域。在一个实施方案中,用PpepT-asd构建体替代经修饰的细菌中的asd基因(图1B)。在某些实施方案中,所述必需基因在L-天冬酰胺酶II (“ansB”)或甲酸脱氢酶-H (“fdhF”)启动子的控制下。但是,在某些实施方案中,所述经修饰的细菌仍然能够在正常氧水平下生长。在一个实施方案中,为了防止从pepT启动子遗漏,将超氧化物歧化酶(“sodA”)基因的反义启动子(PsodA)(其由FNR负调节[44])添加至所述PpepT-asd构建体以产生PpepT-asd-sodA (图1A),这然后进一步构建了菌株YB1。这有效地抑制沙门氏菌属的生长,如在图5-7中所示,其中YB1仅可以在没有DAP存在下在厌氧条件下生长,但是不可在需氧条件下生长。一种使用ansB启动子的替代性构建体(YB-EW)在厌氧条件下是无效的。在没有DAP存在下,YB1是具有以下组合的唯一菌株:在厌氧条件下生长,但是不在需氧条件下生长。氧水平和细菌浓度的详细滴定表明,在没有DAP存在下,YB1仅在低于0.5%的氧水平是有生活力的(图7)。不同于SL7207,YB1在厌氧条件下仅浸润MDA-MB-231乳腺癌细胞。但是,它更有效地诱导细胞凋亡或细胞死亡,可能是由于asd在低氧条件启动子下的厌氧性表达比野生型启动子更强(图4)。
某些实施方案表明,SL7207、YB1和减毒的沙门氏菌属菌株VNP20009能够浸润在裸鼠中诱导的MDA-MB-231肿瘤,如通过在肿瘤中发现的相当大细菌数目和观察到相当大肿瘤损伤所证实的。尽管休眠的YB1细胞在没有DAP存在下似乎短暂地存在于需氧组织中[45],但是YB1从正常组织有效地清除(图9B和图10)。到感染后3天为止,在肝中几乎不可检测出细菌。VNP20009比YB1更低效地从正常组织清除,且更低效地减小肿瘤大小。SL7207尽管是减毒的疫苗菌株,但是对正常细胞和肿瘤细胞具有类似作用,并到感染后11天为止杀死了所有小鼠,存在明显的相当大量的细菌诱发的肝破坏。尽管SL7207可能不影响免疫活性小鼠,但SL7207向“专性”厌氧性YB1的转化防止细菌杀死小鼠,同时维持和增强肿瘤杀死能力。
本文描述了YB1在肿瘤中的作用的检查。所述检查表明,它的作为“专性”厌氧菌的设计是有效的,这是因为它被严格限制在低氧的肿瘤区域且保持远离血管。由于预期细菌诱导宿主免疫应答,所以在YB1感染的肿瘤中发现了嗜中性粒细胞。在一个实施方案中,将YB1和嗜中性粒细胞彼此排成一行,其中嗜中性粒细胞作为对抗进一步细菌扩散的屏障。在一个实施方案中,YB1通过将嗜中性粒细胞强烈吸引至肿瘤而增强肿瘤杀死。
在一个实施方案中,本文描述了使用YB1和化学疗法的联合治疗的应用。在一个实施方案中,所述化学疗法包括使用但不限于5-FU的治疗,其增加肿瘤抑制能力。5-FU通过阻断胸苷酸合酶的作用而靶向快速分裂的细胞如癌细胞[46]。当与未治疗的小鼠对比时,YB1显著地延缓肿瘤生长,其有效性大于单独药物5-FU的有效性。在一个实施方案中,YB1和5-FU是更有效的。SL7207具有太高的毒性,并且在观察到对肿瘤生长的影响之前对小鼠是致死的(图13)。
本文描述了一种比使用沙门氏菌属菌株VNP20009的方法改进的抗癌方法。VNP20009源自菌株YS72 [47],其通过亚硝基胍和紫外线照射诱导的随机突变从野生型鼠伤寒沙门氏菌14028产生[20]。该随机诱变策略产生安全的营养缺陷型菌株,其具有受损的肿瘤靶向或杀死能力。VNP20009处于I期临床中,在其中观察到肿瘤靶向和抑制的无效[48]。如果沙门氏菌属的一些未知功能基因在减毒过程中发生突变,VNP20009可能被过度减毒[49]。相反,通过aro转座子插入而产生菌株SL7207,作为YB1的祖先[28]。如在本发明中执行的,通过将必需基因置于低氧条件启动子下而对沙门氏菌属菌株SL7207的精确修饰,已经成功地将该细菌转化成“专性”厌氧菌,由此除去宿主菌株的致死毒性,同时维持它的肿瘤靶向和与VNP20009相比增强它的肿瘤杀死能力(图9C和图13D)。此外,与VNP20009相比,YB1表现出更高的肿瘤栖息偏好,而经工程改造的YB1菌株在正常器官中也表现出更快的根除(图9C)。通过导致更低的毒性和更好的治疗性能,该新颖的策略提供常规减毒技术的一种替代方案,所述常规减毒技术可能损害细菌的肿瘤杀死作用。
在一个实施方案中,本文描述了一种制备经修饰的细菌的方法。类似的方法可以用于制备各种菌株的经修饰的细菌。在一个实施方案中,所述经修饰的细菌是这样的菌株YB1:其为条件性的专性和兼性厌氧菌。首先,YB1作为生孢梭菌(C. sporogenes)具有特异性的肿瘤靶向能力,但是它不总是需要厌氧条件进行培养。简单的DAP补充物可以将YB1恢复成象正常的兼性厌氧性细菌一样有功能。其次,YB1作为鼠伤寒沙门氏菌的菌株可以与大肠杆菌共有相同的质粒复制起点,可以更容易地和更方便地构建基于质粒的药物递送载体和在癌症疗法中控制载体的拷贝数。尽管修饰梭菌属(Chlostridia)来生产基因疗法载体[17, 18]的容易度已经提高[50],但是使用长期确定的技术可以容易地转化沙门氏菌属,并可以类似地开发YB1。YB1-样细菌具有专性厌氧细菌的优点,同时维持趋化性质[5, 22]和沙门氏菌属的靶向转移[25-27]的能力。
在低氧下的条件性沙门氏菌属生长提供常规减毒技术的一种替代方案,所述常规减毒技术需要细菌的突变来损害一些正常功能。经修饰的“专性”厌氧菌YB1代表生产癌症的细菌治疗剂的新方向。
4. 附图说明
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图1A-C. (A)严格低氧调节的必需基因表达盒的构建体(pYB1),其含有有义启动子PpepT、asd基因和反义启动子PsodA;(B)不含反义启动子PsodA的构建体(pYB-pw);和(C)含有不同启动子PansB的构建体(pYB-ew)。
图2A-D. (A)启动子PpepT的DNA序列;(B) asd基因的DNA序列;(C) Asd蛋白的蛋白序列;和(D)启动子PsodA的DNA序列。
图3. 重组工程改造策略用严格低氧调节的且基于染色体的必需基因表达盒替代得自细菌染色体的原始asd基因。
图4A-B. 当YB1面临含有O2 (A)和不含O2 (B)的环境时的情形。
图5A-D. 各种菌株(104个细菌/ml)在不含DAP的LB液体培养基中在需氧或厌氧条件下的生长速率(平均值±sd,每个时间点代表3个单独实验)。(C, D)与在(A, B)中一样,但是含有DAP。
图6. 为了试验响应于氧的asd表达,将菌株YB-myc-EW、YB-myc-PW和YB1在需氧(+O2)或厌氧(-O2)条件下在37℃培养24小时。加入DAP以防止在需氧条件下的细胞裂解。通过OD600测量来定量细菌细胞数目,并分别从那些细菌提取总蛋白。
图7. 将在递减氧水平下的系列稀度的不同突变菌株培养24小时,并观察细菌生长。列:1 SL7207;2 YB-asd;3 YB1;4 YB-pw;5 YB-ew。(进行3个独立实验.)
图8A-C. 乳腺癌细胞中的YB1和SL7207:(A)将体外培养的乳腺癌细胞(MBA-MB-231)分别在厌氧(O2<0.5%: YB1 - O2, SL7207 - O2)或需氧(O2=21%: YB1 + O2, SL7207 +O2)条件下暴露于YB1和SL7207 (1: 500~1000)。温育后2小时,将乳腺癌细胞洗涤,并加入含有艮他霉素(50µg/ml)的新鲜培养基以除去细胞外的细菌。24~48小时以后,收集乳腺癌细胞,使用抗-沙门氏菌属抗体(红色)和鬼笔环肽(指示癌细胞)(绿色)染色,并通过共焦显微术进行观察。给出了合并的和放大的图像。(B, C)在厌氧条件下由沙门氏菌属诱导的癌细胞的细胞凋亡和死亡速率通过膜联蛋白-V/PI染色进行检测,并通过流式细胞术进行测量。*, P<0.05。
图9A-C. YB1、SL7207和VNP20009在携带乳腺肿瘤的裸鼠中的CFU试验。具有MBA-MB-231肿瘤的裸鼠接受YB1、SL7207或VNP20009的暂时静脉注射。在指定的时间点将小鼠实施安死术,并收集血液、心脏、肾、肝、肺、淋巴结、脾和肿瘤组织且匀浆,并评价细菌积累。在SL7207 (A)、YB1 (B)或VNP20009 (C)治疗的小鼠中,显示了随时间过去大多数正常器官和肿瘤的每克的CFU计数(红色线) (平均值±sd,每个时间点代表3个单独实验,每个实验2只小鼠)。*,肿瘤组相对于所有其它组,P<0.05;**P<0.01。
图10 (A-B) .YB1和SL7207在肿瘤和肝中的石蜡切片试验。通过免疫染色在组织石蜡切片中证实了携带乳腺肿瘤的小鼠的肿瘤(A)和肝(B)中的沙门氏菌随时间过去的分布(箭标:沙门氏菌属)。
图11. 低氧区域的YB1定居。给YB1和PBS治疗的荷瘤小鼠腹膜内注射Hypoxyprobe-1,然后处死。将肿瘤样品取出,准备,并用抗-沙门氏菌属或抗-Hypoxyprobe-1抗体显现,如在材料和方法中所述的。横切片显示了低氧区域的概要和肿瘤中的YB1分布。PBS治疗的荷瘤小鼠用作对照。
图12 (A-C) .YB1在肿瘤中的限制。(A)通过分别用抗-沙门氏菌属(绿色)和抗-Hypoxyprobe (红色)抗体染色,指示YB1和低氧区域。通过DAPI染色(紫色)指示DNA。H:低氧区域。V:活的区域。(B)用抗-CD31抗体(红色,箭标)显示肿瘤中的血管。(C)用抗-Gr-1抗体(红色)检测免疫细胞。
图13 (A-D). 沙门氏菌属菌株对肿瘤生长的抑制。(A)注射了YB1、SL7207或PBS的小鼠中的肿瘤体积(开始大小约500-550 mm3)(n=10, 平均值±sd)。SL7207治疗的小鼠到第11天为止死亡。*,YB1组相对于PBS组, P<0.05; ***, P<0.001. (B)分别用YB1、SL7207、YB-asd或PBS治疗的无肿瘤和荷瘤小鼠的存活图(各n=10)。(C)用YB1或PBS治疗荷瘤小鼠(各n=24)。3天以后,将5-FU腹膜内注射(60 mg/kg)给每组的一半小鼠(n=12),并每3-4天重复1次,持续2周。*, YB1+5-FU组相对于PBS组和5-FU组, P<0.05; ***, P<0.001; #, YB1+5-FU组相对于YB1组, P<0.05; ##, P<0.01, ###, P<0.001. (D)菌株YB1和VNP20009的抗肿瘤作用对比。分别用VNP20009、YB1或PBS治疗以后,小鼠中的肿瘤体积(开始大小约360mm3) (n=6, 平均值±sd)。*,YB1组相对于VNP20009组, P<0.05; **, P<0.01。
图14A. 监控使用YB1治疗的原位肝肿瘤生长。将萤光素酶标记的MHCC97L肿瘤种子植入健康裸鼠组的左肝叶中2周以后,通过尾静脉静脉内施用5E+07 CFU YB1。在第0天、第10天、第2周和第3周,在YB1治疗后的不同时间点,通过Xenogen IVIS 100监控肿瘤生长。上图是PBS治疗组。下图是YB1治疗组。在成像之前给每只小鼠腹膜内施用100 ug D-萤光素。
图14B-C. 在肿瘤植入以后3周,在肝癌裸鼠模型中,通过组织学对比原位肿瘤生长,并通过肝成像检查使用和不用YB1治疗的肺转移。(B), 通过组织学对比肝组织中的肿瘤大小;(C), 检查MHCC97L肿瘤细胞的肺转移。彩色信号指示肺转移。上图是PBS对照组。下图是YB1治疗。
图15A-C.'窗口腔室(Window-chamber)' 动物模型。A,在外科手术中的背侧窗口腔室的裸鼠;B,外科手术以后的窗口腔室模型;C,在立体显微术下的窗口腔室的血管分布。
图16A-D.在立体显微术下的肿瘤进展的'窗口腔室'成像。A,血管的透射明视野成像;B,植入3天以后的肿瘤荧光成像;C, D血管的放大图像,并在血管周围发现了肿瘤细胞的生长。
图17A-D.YB1治疗效果的观察。A, 从30分钟至5天,由YB1治疗造成的缩时跟踪肿瘤消退;B,没有YB1治疗时活癌细胞的体内图像;C, D, 12小时(C)和36小时(D)以后,由YB1诱导的癌细胞的细胞凋亡。信号是tdTomato标记的MDA-MB-231癌细胞。箭标指示YB1分布。比例条,100 μm。
图18A-D.在不同时间点的肿瘤浸润免疫细胞。A,肿瘤浸润免疫细胞;B,Ly6G+ 嗜中性粒细胞;C,CD19+ B淋巴细胞;D,CD49b+ 天然杀伤细胞(NK)。
图19A-F.YB1和免疫细胞在肿瘤内的分布的、石蜡包埋的活组织检查。A、B、C和D:用抗-Ly6G抗体(显示为深灰色)染色的石蜡组织切片;Ly6G:嗜中性粒细胞的标记物。E和F:用抗-沙门氏菌抗体(显示为深灰色)染色的组织切片。虚线指示肿瘤坏死区域。
图20. 使用或不用YB1治疗的Hela细胞的细胞增殖测定。将细胞(1x103)接种进96孔板并培养过夜。YB1 (M.O.I=1: 200)温育2h以后,随后将细胞培养24、48、72和96小时,并进行MTT测定。在570 nm测量吸光度。
图21A-E. 在厌氧条件下使用不同癌细胞系的YB1侵入测定。将肺癌A549 (A)、结肠癌Caco-2 (B)、卵巢癌ov443 (C)、骨髓瘤NS1 (D)和成神经细胞瘤SH-SY5Y (E)的癌细胞与YB1 (M.O.I=1: 200)一起共培养1小时,用PBS洗涤3次,并在厌氧条件下另外培养24小时。信号指示细胞内的YB1。
具体实施方式
由于沙门氏菌属与埃希氏菌属(Escherichia)密切相关并且具有广宿主范围,所以它的基因组信息是清楚的,并且与大肠杆菌具有许多共同特征。与革兰氏阳性细菌(例如梭菌属(Clostridium))相比,沙门氏菌属易于遗传操作,这是因为它具有薄膜,对药物选择敏感。它在细胞内存活和增殖;因此,它可以将遗传材料(DNA、mRNA、微RNA等)递送进细胞质中,而不干扰细胞核。最重要的是,使用细菌载体的转染可以避免(随机的)基因组整合。因而,它可以将异位mRNA直接递送进宿主细胞中,并利用宿主细胞的翻译机制来合成对应的外源蛋白。另一方面,由于它是兼性厌氧的,所以易于在体外培养它,并然后将其发送至肿瘤内的靶低氧区域。因而,沙门氏菌可以在研究和药疗法中充当细菌“武器”和“载体”。此外,多年来已经证实减毒的沙门氏菌在人类中是安全的。
由于它们的靶向实体瘤的对常规治疗具有抗性的低氧区域的能力,厌氧细菌在癌症疗法中提供一个重要的治疗机会[1, 3, 16]。如果要使沙门氏菌属(兼性厌氧性细菌)在抗癌疗法中成为一种成功的治疗剂,那么需要解决在宿主中的细菌毒力[11]。在大多数情况下,生成减毒形式并用作试验治疗剂[24, 29, 34, 40]。但是,使细菌减毒所需的突变也可能损害它的肿瘤靶向和杀死能力。这被提出作为VNP20009在临床试验中的较差性能的一个可能原因[11]。近年来,沙门氏菌突变体的系统研究[41]如下部分地解决了该问题:鉴别几种减毒的突变体细菌,其具有轻度或中度的肿瘤适合性降低。没有检查这些突变体实现的肿瘤杀死[41]。
在一个实施方案中,本文描述了一种将厌氧细菌转化成条件“专性”厌氧菌的方法。在一个方面,所述方法是严格低氧调节的,并且包括:用必需基因表达盒转化细菌。在一个方面,所述方法包含兼性厌氧革兰氏阴性细菌,包括、但不限于鼠伤寒沙门氏菌。在正常组织中,在需氧条件下,不表达必需基因asd,不合成二氨基庚二酸(DAP),并且所述细菌将在生长过程中裂解,除非由环境供给DAP。在荷瘤裸鼠中,所述经修饰的细菌抑制肿瘤生长,而不影响小鼠。相比而言,原始的沙门氏菌属菌株对小鼠是致死的。
已经开发了几种减毒的沙门氏菌属菌株用于肿瘤靶向研究。几个研究组[29-33]已经使用了SL7207,其具有aroA基因中的缺陷,并且是类似的减毒菌株[28]的衍生物,尽管它可以影响无免疫应答的小鼠的健康[29, 33]。purI和msbB中的缺失产生VNP20009 [21,34],其已经被用于基因靶向的前体药物疗法中[35],并针对口服递送进行了试验[36],并进入了临床试验中[37, 38]。菌株A1 [39]和它的衍生物A1-R [24]是亮氨酸-精氨酸营养缺陷型和A1-R靶向转移模型[26]。在鸟苷5′-二磷酸-3′-二磷酸合成中的缺陷减毒沙门氏菌属(菌株ΔppGpp) [40],其已经被表明作为针对CT-26肿瘤和转移的可诱导载体是有效的[23]。肿瘤中的不同营养环境可以补偿这些细菌中的代谢缺陷,由此允许在肿瘤中的有效生长,但是不在正常组织中生长[20, 39]。
但是,减少在正常组织中的毒力的减毒可能损害细菌在肿瘤中的功能。一项大规模研究使用转座子文库和定制的微阵列以鉴定一组沙门氏菌属突变体,其在正常组织中具有降低的适合性或减毒[41]。他们的目的是,鉴定保留它们在肿瘤内的适合性的减毒菌株。鉴定出了两类减毒菌株,即具有肿瘤适合性的微小下降或中等下降的那些。STM3120(一种剧烈减毒的SPI-3突变体)具有肿瘤适合性的微小下降,并且在PC-3肿瘤中是有效的,并且在口服施用中稍微有效[41]。一种aroA突变体(类似于SL7207)具有中等下降的肿瘤适合性。但是,该研究检查了细菌在肿瘤中的适合性,没有检查肿瘤杀死能力。
在一个实施方案中,本文描述了一种经修饰的细菌,其包含严格低氧调节的必需基因表达盒。通过使用重组技术,将该盒引入兼性厌氧革兰氏阴性细菌(包括、但不限于鼠伤寒沙门氏菌)的基因组中。然后产生了条件性的“专性”厌氧菌菌株YB1。当在体内施用时,应用该菌株YB1以进一步抑制和减少实体瘤癌症的生长。
4.1 制备低氧靶向的沙门氏菌属菌株(YB1)的方法
通过重组技术实现了构建体对得自亲本鼠伤寒沙门氏菌菌株SL7207的必需基因asd的替换,在所述构建体中,该基因是在低氧靶向的启动子控制下的(图3)。在得到的YB1菌株中,FNR有关的厌氧能力的启动子PpepT控制asd转录,而需氧启动子PsodA促进反义asd 的转录,所述反义asd在需氧条件下阻断Asd表达的任何泄漏(图1A)。如果没有转录asd且在环境中没有供给DAP,那么在细菌生长过程中发生YB1细菌的裂解。
构建了几种其它的菌株变体(YB-asd–不含asd基因的SL7207;YB1-pw–与YB1一样,但是不含有asd的反义启动子;YB1-ew–与YB1一样,但是含有用更弱的ansB启动子替代的PpepT启动子) (图1B, C)。试验了在高和低氧水平下Asd表达的调节。通过myc标记的asd的免疫印迹,证实了Asd蛋白水平的变化。结果(图6)表明,如预期的那样,YB1 (YB1-myc)菌株中的Asd表达受氧控制:在厌氧条件下检测到非常强的Asd表达,而在需氧条件下没有观察到这样的表达(YB1+O2和YB1-O2)。但是,在需氧或厌氧条件下(EW+O2和EW-O2),在含有弱PansB启动子的菌株YB1-ew (YB-myc-ew)中没有观察到Asd表达。在不含反义启动子的YB1-pw (YB-myc-pw)菌株中,在需氧条件下观察到泄漏的Asd表达(PW+O2和PW-O2)。
试验了所有突变体在LB液体培养基中的生长(图5A-D)。在没有DAP存在下,在经工程改造的菌株中,仅YB1表现出在厌氧培养条件下的生长与在需氧环境中的抑制的组合。SL7207和YB-pw在所有条件下表现出生长。YB-asd和YB-ew仅在添加DAP后才表现出生长。
使用氧水平和细菌浓度的系列减小来确立条件范围,在所述条件下,YB1和其它菌株可以在有或没有DAP存在下存活。在不含DAP的LB琼脂板上,YB1仅在氧水平下降至0.5%以下时才生长。菌株YB-asd和YB-ew在没有DAP存在下不生长,而SL7207和YB-pw在所有条件下生长(图7)。
4.2 YB1的侵入癌细胞的能力
在低于0.5%的氧浓度或需氧条件下,将乳腺癌细胞系MDA-MB-231样品与YB1或SL7207一起温育。除去细胞外细菌并进一步培养以后,共焦显微术表明,SL7207和YB1两者已经在厌氧条件下侵入乳腺癌细胞(图8A, YB1-O2, SL7207-O2)。与此相比,在需氧条件下(图8A, YB1+O2, SL7207+O2),YB1不可存活,且在乳腺癌细胞中仅观察到SL7207。在厌氧条件下,通过使用膜联蛋白V/PI测定,用每种细菌处理的MDA-MB-231样品表现出濒死的或细胞凋亡的细胞的数目相对于空白对照的增加(图8B),其中YB1稍微更有效地造成细胞死亡或细胞凋亡(P<0.05) (图8C)。
4.3 SL7207、YB1和VNP20009在体内在肿瘤和正常组织中的积累
给3组4周龄裸鼠接种乳腺癌细胞,并且当肿瘤体积达到500-550 mm3时,经由尾静脉注射单剂SL7207或YB1或VNP20009。在不同的时间点,将小鼠实施安死术,并将大多数器官和肿瘤收集,匀浆,并在含有抗生素和DAP的LB琼脂板上培养。使用CFU/克作为细菌对组织的定居程度的相对量度。
对于SL7207接种的小鼠,除了在血液中高得多的水平以外(1.3E+03 CFU/克),在6小时时在所有组织中发现了1E+02至1E+04 CFU/克的细菌(图9A)。细菌水平在所有组织中增加,随后到第3天为止发生不受控制的感染(图9A)。SL7207的肿瘤与肝比率在第3天时为2.78:1。小鼠在第7天开始死亡。在第11天,肝中的SL7207水平达到3.8E+09 CFU/克(图9A),并且此后所有小鼠死亡。
对于YB1注射的小鼠,在接种后6小时,在所有组织中的细菌水平与SL7207接种的小鼠大约相同(图9B),并且细菌在70%的小鼠的血液中消除。1天以后,YB1从血液消除,且随后所有正常组织中的水平快速下降。在肿瘤中,YB1水平到第3天为止增加至~1E+08 CFU/克的平台(图9B)。YB1 CFU/克的肿瘤与肝比率在第3天为~7,000:1,且在第7天为~20,000:1(图9B)。到第26天为止,YB1从心脏、肾、肺、淋巴结和脾完全消除。在试验的6只小鼠中的5只中,YB1也从肝消除,在一只小鼠中剩余1.3E+03 CFU/克。YB1表现出相对于其它器官而言在肿瘤中的显著偏好(在第5天和第11天,P<0.05;在第7天和第26天,P<0.01)。在整个实验过程中,在骨髓内没有检测出YB1。
还通过CFU试验评价了VNP20009在不同器官中的积累。象YB1一样,VNP20009也表现出如以前所报道[21, 47]的肿瘤偏好(P<0.05)。到第5天为止,在肿瘤中的分布达到~3E+08 CFU/克的平台(图9C)。最佳肿瘤与肝比率是在第5天的~3,900:1 (图9C)。与SL7207菌株相比,VNP20009表现出在正常器官中的快速清除,但是消除速度慢于YB1在肝(P<0.05)、肾(P<0.05)、脾(P<0.05)、肺、淋巴结和心脏中的消除速度(图9)。
肿瘤和肝的切片的免疫染色证实了沙门氏菌属细菌在这些组织中的分布。YB1和SL7207两者靶向肿瘤,从第3天起存在大量细菌(图10A)。在肝中,YB1下降,并且到第7天为止几乎根除,对肝结构几乎没有影响(图10B)。对于SL7207治疗的小鼠,持续的细菌积累和肝损伤是显而易见的(图10B)。
4.4 YB1向肿瘤中的低氧区域和坏死区域的靶向
将Hypoxyprobe™-1 (盐酸哌莫硝唑)用作低氧标记物来证实沙门氏菌属在肿瘤中的分布。当将乳腺癌肿瘤切片免疫染色时,发现了低氧区域和坏死区域(图11),这与以前的报道相一致。在荷瘤小鼠中注射沙门氏菌以后,大多数细菌积累在Hypoxyprobe™-1标记的区域中(图12A)。低氧区域在肿瘤中的形成可能是由于血管发育的瓦解。YB1定居的区域几乎没有血管或没有血管,如CD31染色所示(图12B),这提示细菌在肿瘤的低氧区域中的定居。使用GR-1抗体的染色以检查对细菌侵入的免疫应答揭示了Gr-1+宿主嗜中性粒细胞向乳腺肿瘤中的渗透,它们在此处似乎形成在YB1周围的屏障(图12C)。
4.5 YB1在体内抑制肿瘤生长
由于YB1体外侵入MDA-MB-231乳腺癌细胞从而造成细胞的细胞凋亡,测量了它的体内效应。在YB1治疗的小鼠中的肿瘤生长(在细菌接种时的肿瘤体积为~500-550 mm3)与PBS治疗的小鼠相比最初被抑制,然后被延迟(在第3天,P<0.05;从第5天至第21天,P<0.001)(图13A)。在SL7207治疗的小鼠中几乎没有看到进一步的肿瘤生长,这是因为细菌毒性造成第7-11天之间的死亡(图13A)。用YB1治疗的小鼠(具有或没有肿瘤)和YB-asd治疗的无肿瘤小鼠存活了超过25天,用PBS治疗的小鼠(具有或没有肿瘤)也是如此(图13B)。SL7207治疗的小鼠在第5和7天开始死亡,所有小鼠(分别没有或具有肿瘤)到第8和11天为止濒临死亡。SL7207治疗的荷瘤小鼠具有稍微更好的存活率(图13B)。
尽管YB1治疗的小鼠的肿瘤生长减小与PBS治疗的小鼠相比是显著的,但肿瘤仍然在生长。与PBS治疗相比,用治疗剂5-FU对荷瘤小鼠的治疗仅表现出肿瘤生长的小下降(P>0.05)。但是,当将5-FU施用给YB1感染的荷瘤小鼠时,与单独治疗相比观察到肿瘤大小的大得多的下降(YB1+ 5-FU组相对于PBS组或5-FU组表现出在第4天的P<0.05和从第6天至第15天的P<0.001;YB1+ 5-FU组相对于YB1组表现出在第6、8天的P<0.05,在第10、12天的P<0.01,和在第15天的P<0.001) (图13C)。
4.6 菌株YB1和VNP20009在肿瘤消退和靶向中的对比
为了进一步评价YB1菌株的抗肿瘤作用,我们将它与众所周知的肿瘤靶向菌株VNP20009进行了对比。还经由尾静脉将单剂的VNP20009或YB1注射给携带乳腺肿瘤的小鼠(在细菌接种时的肿瘤体积为~360 mm3)。每2天测量肿瘤大小。与PBS治疗组相比,YB1 (P<0.01)和VNP20009 (P<0.05)两者都可以延迟肿瘤生长。但是,YB1表现出比VNP20009更强的肿瘤抑制(P<0.05) (图13D)。
4.7 裸鼠模型中的肝癌的YB1治疗
在MHCC97-L肝癌模型中,单剂的YB1治疗表现出肝癌生长和转移的显著抑制(图14)。对比了使用YB1治疗和PBS治疗的组之间的肿瘤生长,其通过Xenogen IVIS成像系统来监控(图14A)。在组织学检查以后证实了远端肺转移(图14C)。成像结果表明,在10天的YB1治疗以后,肿瘤大小开始缩小。3周以后,所有治疗小鼠的肿瘤大小都表现出急剧减小。一些小鼠甚至表现出肿瘤的完全消除(图14)。
5. 实施例
5.1 克隆和装配严格低氧调节的必需基因表达盒
在这里使用或生成的细菌和质粒提供在表1中,且使用的引物提供在表2中。通过使用引物对asd-C-F和asd-C-R、pepT-F和pepT-R进行PCR(在95℃预热5分钟,继之以30个在95℃变性30秒、在60℃退火30秒、在72℃延伸1分钟的循环,最后在72℃延伸10分钟,然后冷却至室温),从SL7207的染色体克隆asd基因和pepT基因的启动子,而使用asd-C-F和asd-C-myc-R引物对生成asd-myc。通过使用寡核苷酸对ansB-F和ansB-R、sodA-F和sodA-R的退火过程(将10µM正向引物和反向引物混合,并在95℃加热5分钟,并在室温放置30分钟),产生PansB和PsodA (ansB和sodA的启动子)构建体。使用引物cm-F和cm-R通过PCR从ploxp-cm-loxp模板扩增抗生素标记物[51]。在用HindIII、XhoI、NotI和PstI消化的pBluescript IISK (pBSK)的主链上构建asd表达载体的质粒。用T4连接酶连接以后,产生质粒pYB1 (pBSK-cm-PpepT-asd-PsodA)、pYB1-myc (pBSK-cm-PpepT-asd-myc-PsodA)、pYB-pw (pBSK-cm-PpepT-asd)、pYB-myc-pw (pBSK-cm-PpepT-asd-myc)、pYB-ew (pBSK-cm-PansB-asd-PsodA)和pYB-myc-ew (pBSK-cm-PansB-asd-myc-PsodA)。
5.2 氧敏感的沙门氏菌突变体(YB1)的构建
使用λ-Red重组系统(质粒pSim6) [52],以用SL7207中的cm-PpepT-asd-sodA遗传回路(genetic circuit)替代asd基因。作为第一步,在PCR反应中用ploxp-cm-loxp模板产生靶asd基因,电穿孔进重组感受态细胞中,并在氯霉素Luria-Bertani (LB)板上选择。通过质粒p705cre-Km的转化经由位点特异性的Cre/loxP介导的重组除去抗生素抗性基因,从而产生菌株YB-asd。接着,从质粒pYB1扩增cm-PpepT-asd-sodA遗传回路,并在重组以后,选择正确的菌落,并通过PCR确认,从而得到菌株YB1。分别用质粒pYB1-myc、pYB-pw、pYB-pw-myc、pYB-ew和pYB-ew作为模板,类似地构建菌株YB1-his、YB-pw和YB-ew (图3)。
5.3 在不同环境中的YB1
通过用诱导型启动子控制必需基因asd,将兼性厌氧革兰氏阴性细菌转变成“专性”厌氧菌,而不在其它方面干扰该细菌的功能。该新种类的“专性”厌氧菌是可逆的。它具有2个阶段:在厌氧条件下,它可以作为正常的兼性厌氧革兰氏阴性细菌生长和生活;在需氧条件下,它具有2个选择。在加入化学试剂二氨基庚二酸(DAP)的情况下,YB1可以执行兼性厌氧革兰氏阴性细菌的完整功能,但是在没有DAP的情况下,它会在短时间段内裂解和死亡。因此,氧和DAP是控制YB1的“专性”厌氧能力的2种重要因素(图4)。
为了试验沙门氏菌属菌株和突变体在需氧和厌氧条件下的生长,将细菌菌株在LB培养基中在37℃在220 rpm摇动下培养过夜。通过在液体培养基中摇动来实现需氧条件,并将厌氧培养物在厌氧管或厌氧罐(Mitsubishi Gas Chemical Company)中培养。将沙门氏菌属菌株SL7207、YB-asd、YB1、YB-pw和YB-ew的过夜培养物计数,并以5E+04菌落形成单位(CFU)/ml稀释进样品中,其中将每种菌株分成在LB液体培养基中的2个组(含有或不含DAP)。从0小时至24小时,对于需氧培养物,每30分钟测量OD600,对于厌氧培养物,每小时测量OD600。对于LB琼脂板测定,应用厌氧罐以通过AnaeroPacks的组合产生不同的氧浓度,并通过测氧计进行监控。将各滴的10个系列稀释物(从5E+06 CFU/ml的高浓度至5E+01 CFU/ml,其中每滴含有10µl细菌培养物)添加给板,将所述板在厌氧罐中在37℃培养2天。结果显示在图5和7中。
5.4 细菌菌株体外对乳腺癌细胞的侵入
制备沙门氏菌属和MDA-MB-231细胞,并在厌氧(O2<0.5%)或需氧条件下以1000~500:1的比率共培养2小时。然后将细胞用PBS洗涤,并在补充了艮他霉素的培养基中培养,以除去细胞外的细菌。24小时以后,将细胞在低聚甲醛(4%)中固定,并用抗-沙门氏菌抗体(1:500, Abcam)在4℃染色过夜。加入Cy3缀合的第二抗体,并在室温温育1小时。然后,施加FITC缀合的鬼笔环肽(1:1000)来指示细胞边界。在共焦显微镜下观察图像。用膜联蛋白V-PI试剂盒(Biovision),根据生产商的说明书,检测细菌在厌氧条件下诱导的癌细胞的细胞凋亡和死亡。如通过流式细胞术证实的,膜联蛋白V+/PI- 细胞是细胞凋亡的,且膜联蛋白V+/PI+ 细胞是死亡的。结果显示在图8中。
5.5 在乳腺癌裸鼠模型的治疗中的细菌菌株
将5E+05 MDA-MB-231细胞接种在4周龄裸鼠的脂垫处。通过下式计算肿瘤体积:4/3×π×(h×w2)/8,h = 高度,且w = 宽度。当肿瘤生长至约500-550 mm3时(15-19天),将小鼠分组用于实验。如果肿瘤达到4000 mm3 (直径20 mm) [53],将小鼠实施安死术。
为了测量细菌接种对小鼠存活和肿瘤生长的影响,将2组各10只小鼠用YB1 (5E+07 CFU)、SL7207 (5E+07 CFU)治疗,并给PBS组的6只小鼠通过尾静脉(i.v.)注射100µl的体积。每2-3天用测径器测量肿瘤大小(开始体积为约500-550 mm3) (图13 A)。记录小鼠存活率(图13 B)。对于VNP20009和YB1对比试验,给每组的另外6只小鼠施用相同剂量(5E+07CFU),但是具有更小的肿瘤开始大小(约360 mm3) (图13 D)。
为了测量接种以后的细菌分布,用与上面相同的方法治疗小鼠,并在指定的时间点处死(对于每个时间点,YB1组和SL7207组的共6只小鼠;对于每个时间点,VNP20009组的5只小鼠),并将组织称重,匀浆,在PBS中系列稀释,并与所需抗生素和DAP一起铺板。生长2天以后,计数CFU。将YB1和SL7207治疗的实验重复3次,每个实验每个时间点2只小鼠;将VNP20009治疗的实验重复2次,每个实验每个时间点2-3只小鼠(图9)。
在48只荷瘤小鼠中试验YB1和5-FU的可能协同效应,将所述小鼠分成4个组,每组12只小鼠,并用PBS、PBS+5-FU (60mg/Kg)、单剂的YB1 (5E+07 CFU)或单量的YB1 (5E+07CFU)+5-FU治疗。对于5-FU-治疗组,从细菌注射以后第3天开始,每4天腹膜内(i.p)注射5-FU (图13C)。
5.6 在肝癌裸鼠模型的治疗中的YB1
使用4-6周龄雄性裸鼠。将6E+05的MHCC97L细胞皮下地注射进每只小鼠的右胁腹中。一旦肿瘤达到0.8-1 cm的直径,就将它们通过外科手术取出,并以1-2 mm3的体积切入管中。然后,将肿瘤种子植入另一个健康裸鼠组[54]的左肝叶中保持另外2周。应用5E+07CFU的YB1剂量来治疗小鼠。在第0天、第10天、第2周和第3周,在YB1治疗以后的不同时间点,通过Xenogen IVIS 100监控肿瘤生长。在成像之前,给每只小鼠腹膜内施用100 ug D-萤光素。结果显示在图14中。
5.7 使用长期现场活体动物成像系统(Chronic live intravital animalimaging system)('窗口腔室')以直接观察YB1的抗肿瘤作用
背侧皮肤皱褶窗口腔室是一个复杂的动物模型,其可以观察小鼠中的某些区域与周围宿主组织的动态相互作用。该长期模型提供肿瘤植入以后2-3周过程中的肿瘤进展、治疗和血管发生的可重复分析[55, 56]。
5.7.1构建'窗口腔室' 动物模型
在外科手术中,首先,将麻醉的小鼠放在恒温毯上以维持体温。其次,用70%乙醇将小鼠的大部分皮肤灭菌。第三,将背侧皮肤轻轻拉松,并用2个窗口腔室夹子连接。第四,用18G针在螺杆位置将皮肤的两侧穿3个孔。第五,穿过3个孔将螺杆插入并固定在前窗口腔室(图15A)。第六,将前层皮肤用蚊式止血钳夹住并切割,并保持相对层完整。第七,用29G注射器将约20ul肿瘤细胞悬浮液注射在筋膜面层和真皮之间。第八,将玻璃盖玻片放在窗口上,并用固定环固定(图15B, 15C)。为了避免感染,每天通过腹膜内注射给每只小鼠施用500mg链霉素。该程序改编自Palmer的规程[56]。
5.7.2 用'窗口腔室' 模型观察肿瘤形成
肿瘤植入3天以后,再次将小鼠麻醉,并置于立体显微镜下(图16A-D)。发现肿瘤块局部化在血管周围,以供给营养物和氧。放大图显示了单个肿瘤细胞的细节(图16D)。
5.7.3 用‘窗口腔室’模型观察YB1的抗肿瘤作用
当荷瘤小鼠模型准备好时,如附图16所示,经由尾静脉静脉内地注射5E+07 CFUYB1。治疗后30分钟,发现YB1局部化在肿瘤区域内(图17A)。12小时以后,肿瘤显示出消退,并且该效应持续5天,直到整个肿瘤区域被消除(图17A)。在12小时和36小时以后,可以观察到癌细胞的细胞凋亡(图17C, D)。
5.8 YB1干扰的肿瘤微环境中的免疫应答的表征
将YB1施用给荷瘤小鼠以后,先天性免疫系统被活化(图12C)。为了研究细节,将不同时间点的肿瘤解剖,并分解成单个细胞,并通过FACS进一步分析(图18A-D)。结果指示,在YB1治疗以后,免疫细胞的总百分比在第10天增加至PBS对照组的2倍(图18A)。此外,大多数活化的免疫细胞是嗜中性粒细胞(图18B, C, D)。石蜡切片提示,YB1被共同局部化并被嗜中性粒细胞包围(图19A-F)。
5.9. 在其它体外肿瘤模型的治疗中的YB1
5.9.1 子宫颈癌细胞系Hela的细胞增殖测定
将1E+03 Hela细胞接种在96孔板中,并在培养箱中培养过夜。在补充DAP的情况下与YB1 (2E+05 CFU)共培养2h以后,将细胞用PBS洗涤3次,随后培养另外24、48、72和96小时。进行MTT测定来评价YB1的抗癌作用(图20)。
5.9.2 在厌氧条件下对肺癌、结肠癌、卵巢癌、骨髓瘤和成神经细胞瘤的YB1侵入测定
将肺癌A549、结肠癌Caco-2、卵巢癌ov443、骨髓瘤NS1和成神经细胞瘤SH-SY5Y的癌细胞系分别接种在6孔板中并培养。将2E+07 CFU的YB1在厌氧条件下与不同癌症系共培养24小时。结果指示,YB1在厌氧条件下具有侵入所有这些细胞系的能力(图21A-C)。
5.9.3 YB1在大鼠模型中的安全性试验
将15只Buffalo大鼠(各约200 g)分成3组(每组5只大鼠),以试验YB1的最大耐受剂量。通过阴茎静脉注射,用5E+09 CFU (中剂量组使用5E+08 CFU;低剂量组使用5E+07CFU)攻击在高剂量组中的每只大鼠。在治疗后1天内,杀死在高剂量组中的所有大鼠。在其它组中在3周内没有观察到大鼠死亡。此外,在3周的治疗以后,在肝或脾内不存在YB1的痕迹。结果指示,就通过静脉内注射在Buffalo大鼠中施用而言,5E+08 CFU或更低的YB1是安全的,这是在小鼠模型中的10倍。
6. 人治疗
6.1 制剂
本文提供的经修饰的细菌可以以常规制剂形式(诸如注射剂和悬浮液)施用给患者。通过常用的方法,使用常规的有机或无机添加剂,诸如选自填充物或稀释剂、粘合剂、崩解剂、润滑剂、调味剂、防腐剂、稳定剂、助悬剂、分散剂、表面活性剂、抗氧化剂或加溶剂的赋形剂,可以制备合适的制剂。
可以选择的赋形剂是本领域技术人员已知的,且包括、但不限于:填充物或稀释剂(例如,蔗糖、淀粉、甘露糖醇、山梨糖醇、乳糖、葡萄糖、纤维素、滑石、磷酸钙或碳酸钙等)、粘合剂(例如,纤维素、羧甲基纤维素、甲基纤维素、羟甲基纤维素、羟丙基甲基纤维素、聚丙基吡咯烷酮、聚乙烯吡咯烷酮、明胶、阿拉伯树胶、聚乙二醇或淀粉等)、崩解剂(例如,羟基乙酸淀粉钠、交联甲羧纤维素钠等)、润滑剂(例如,硬脂酸镁、轻质无水硅酸、滑石或十二烷基硫酸钠等)、调味剂(例如,柠檬酸或薄荷醇等)、防腐剂(例如,苯甲酸钠、亚硫酸氢钠、羟苯甲酸甲酯或对羟苯甲酸丙酯等)、稳定剂(例如,柠檬酸、柠檬酸钠或乙酸等)、助悬剂(例 如,甲基纤维素、聚乙烯吡咯烷酮或硬脂酸铝等)、分散剂(例如,羟丙基甲基纤维素等)、表面活性剂(例如,十二烷基硫酸钠、泊洛沙姆、聚山梨醇酯等)、抗氧化剂(例如,乙二胺四乙酸(EDTA)、丁化羟基甲苯(BHT)等)和加溶剂(例如,聚乙二醇、SOLUTOL®、GELUCIRE®等)。在药物组合物中的本文提供的经修饰的细菌的有效量可以是在将发挥期望作用的水平。
在另一个实施方案中,本文提供了组合物,其包含有效量的本文提供的经修饰的细菌和药学上可接受的载体或媒介物,其中药学上可接受的载体或媒介物可以包含赋形剂、稀释剂或其混合物。在一个实施方案中,所述组合物是药物组合物。
可以将组合物配制成在剂量单位中含有每日剂量或每日剂量的方便份额。一般而言,根据药物化学中已知的方法制备所述组合物。通过将本文提供的经修饰的细菌与合适的载体或稀释剂混合,并将正确量的混合物填充在胶囊中,可以制备胶囊。
6.2 使用方法
通过本文提供的方法可以治疗的实体瘤癌症包括、但不限于肉瘤、癌和淋巴瘤。在具体实施方案中,根据所述方法可以治疗的癌症包括、但不限于乳房、肝、成神经细胞瘤、头、颈、眼、口、喉、食管、食管、胸、骨、肺、肾、结肠、直肠或其它胃肠道器官、胃、脾、骨骼肌、皮下组织、前列腺、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血液、淋巴结、肾、肝、胰和脑或中枢神经系统的癌症。
在特定实施方案中,本文提供的治疗癌症的方法抑制、减轻、减少、阻止或稳定与癌症有关的肿瘤。在其它实施方案中,本文提供的治疗癌症的方法抑制、减轻、减少、阻止或稳定与癌症有关的肿瘤中的血流量、代谢或水肿或其一种或多种征状。在具体实施方案中,本文提供的治疗癌症的方法造成肿瘤、肿瘤血流量、肿瘤代谢或肿瘤周围水肿的消退,和/或与癌症有关的一种或多种征状的消退。在其它实施方案中,本文提供的治疗癌症的方法维持肿瘤的大小,从而使得它不增加,或使得它的增加小于在施用标准疗法以后的肿瘤增加,如通过本领域技术人员可得到的常规方法测量的,诸如直肠指诊、超声(例如,经直肠(transrectal)超声)、CT扫描、MRI、动态反差增强MRI或PET扫描。在具体实施方案中,本文提供的治疗癌症的方法减小肿瘤大小。在某些实施方案中,本文提供的治疗癌症的方法减少肿瘤的形成。在某些实施方案中,本文提供的治疗癌症的方法根除、除去或控制原发性的、局部性的和/或转移性的与癌症有关的肿瘤。在一些实施方案中,本文提供的治疗癌症的方法降低与癌症有关的转移的数目或大小。
在某些实施方案中,与施用经修饰的细菌之前的肿瘤大小(例如,体积或直径)相比,本文提供的治疗癌症的方法使受试者中的肿瘤大小(例如,体积或直径)减小至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、80%、85%、90%、95%、99%或100%,如通过本领域众所周知的方法评估的,例如,CT扫描、MRI、DCE-MRI或PET扫描。在特定实施方案中,与施用经修饰的细菌之前受试者中的肿瘤大小(例如,直径)相比,本文提供的治疗癌症的方法使受试者中的肿瘤体积或肿瘤大小(例如,直径)减小在以下范围内的量:约5%至20%、10%至20%、10%至30%、15%至40%、15%至50%、20%至30%、20%至40%、20%至50%、30%至60%、30%至70%、30%至80%、30%至90%、30%至95%、30%至99%、30%至100%、或之间的任意范围,如通过本领域众所周知的方法评估的,例如,CT扫描、MRI、DCE-MRI或PET扫描。
在某些实施方案中,与施用经修饰的细菌之前的肿瘤灌注相比,本文提供的治疗癌症的方法使受试者中的肿瘤灌注减小至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、80%、85%、90%、95%、99%或100%,如通过本领域众所周知的方法评估的,例如,MRI、DCE-MRI或PET扫描。在特定实施方案中,与施用经修饰的细菌之前的肿瘤灌注相比,本文提供的治疗癌症的方法使受试者中的肿瘤灌注减小在以下范围内的量:约5%至20%、10%至20%、10%至30%、15%至40%、15%至50%、20%至30%、20%至40%、20%至50%、30%至60%、30%至70%、30%至80%、30%至90%、30%至95%、30%至99%、30%至100%或之间的任意范围,如通过本领域众所周知的方法评估的,例如,MRI、DCE-MRI或PET扫描。
在特定方面,本文提供的治疗癌症的方法抑制或减少受试者中的肿瘤代谢,如通过本领域众所周知的方法评估的,例如,PET扫描。在具体实施方案中,与施用经修饰的细菌之前的肿瘤代谢相比,本文提供的治疗癌症的方法将受试者中的肿瘤代谢抑制或减少至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、80%、85%、90%、95%或100%,如通过本领域众所周知的方法评估的,例如,PET扫描。在特定实施方案中,与施用经修饰的细菌之前的肿瘤代谢相比,本文提供的治疗癌症的方法将受试者中的肿瘤代谢抑制或减少在以下范围内的量:约5%至20%、10%至20%、10%至30%、15%至40%、15%至50%、20%至30%、20%至40%、20%至50%、30%至60%、30%至70%、30%至80%、30%至90%、30%至95%、30%至99%、30%至100%、或之间的任意范围,如通过本领域众所周知的方法评估的,例如,PET扫描。
6.3 患者群体
在一些实施方案中,根据本文提供的方法治疗其癌症的受试者是患有癌症或者被诊断出癌症的人。在其它实施方案中,根据本文提供的方法治疗其癌症的受试者是易患癌症或者易感癌症的人。在一些实施方案中,根据本文提供的方法治疗其癌症的受试者是处于发展癌症的危险中的人。
在一个实施方案中,根据本文提供的方法治疗其癌症的受试者是人婴儿。在另一个实施方案中,根据本文提供的方法治疗其癌症的受试者是人幼儿(toddler)。在另一个实施方案中,根据本文提供的方法治疗其癌症的受试者是人儿童。在另一个实施方案中,根据本文提供的方法治疗其癌症的受试者是成年人。在另一个实施方案中,根据本文提供的方法治疗其癌症的受试者是中年人。在另一个实施方案中,根据本文提供的方法治疗其癌症的受试者是老年人。
在某些实施方案中,根据本文提供的方法治疗其癌症的受试者具有转移至身体的其它区域(诸如骨、肺和肝)的癌症。在某些实施方案中,根据本文提供的方法治疗其癌症的受试者处于癌症缓解中。在一些实施方案中,根据本文提供的方法治疗其癌症的受试者具有癌症的复发。在某些实施方案中,根据本文提供的方法治疗的受试者正在经历一个或多个与癌症有关的肿瘤的复发。
在某些实施方案中,根据本文提供的方法治疗其癌症的受试者是约1至约5岁、约5-10岁、约10至约18岁、约18至约30岁、约25至约35岁、约35至约45岁、约40至约55岁、约50至约65岁、约60至约75岁、约70至约85岁、约80至约90岁、约90至约95岁、或约95至约100岁、或之间的任意年龄的人。在具体实施方案中,根据本文提供的方法治疗其癌症的受试者是18岁或以上的人。在特定实施方案中,根据本文提供的方法治疗其癌症的受试者是1岁至18岁之间的人儿童。在特定实施方案中,根据本文提供的方法治疗其癌症的受试者是12岁至18岁之间的人。在特定实施方案中,所述受试者是男人。在另一个实施方案中,所述受试者是女人。在一个实施方案中,所述受试者是没有怀孕或没有在母乳喂养的女人。在一个实施方案中,所述受试者是怀孕的或将要/可能怀孕的女人,或者是正在母乳喂养的女人。
在一些实施方案中,在除了经修饰的细菌以外的疗法的任何不良作用或无耐受力发展之前,给根据本文提供的方法治疗其癌症的受试者施用经修饰的细菌或其药物组合物或联合治疗。在一些实施方案中,根据本文提供的方法治疗其癌症的受试者是难治的患者。在特定实施方案中,难治的患者是用标准疗法(例如,外科手术、放射、抗雄激素疗法和/或药物疗法诸如化学疗法)难治的患者。在某些实施方案中,当癌症尚未显著根除和/或一种或多种征状尚未显著减轻时,患有癌症的患者是治疗难治的。使用本领域接受的“难治”在这样的背景下的含义,通过本领域已知的用于测定癌症治疗的有效性的任意方法,可以在体内或在体外确定患者是否是难治的。在各种实施方案中,当一个或多个与癌症有关的肿瘤尚未减小或已经增加时,患有癌症的患者是难治的。在各种实施方案中,当一个或多个肿瘤转移和/或扩散至其它器官时,患有癌症的患者是难治的。
在一些实施方案中,根据本文提供的方法治疗其癌症的受试者是这样的人:其已经被证实是经修饰的细菌治疗以外的疗法难治的,但是不再接受这些疗法。在某些实施方案中,根据本文提供的方法治疗其癌症的受试者是这样的人:其已经接受一种或多种常规抗癌疗法,诸如外科手术、药物疗法诸如化学疗法、抗-雄激素疗法或放射。在这些患者中包括难治的患者、对于常规疗法而言太年轻的患者、和尽管用现有疗法进行治疗但是具有复发性肿瘤的患者。
6.4 剂量
在一个方面,本文提供的用于治疗癌症的方法包括:施用单位剂量的经修饰的细菌。所述剂量可以以经确定为有效的频率施用(例如,每天1次、每天2次或每天3次,每隔1天1次,每周1次或2次,每2周1次或每月1次)。在某些实施方案中,本文提供的用于治疗癌症的方法包括:给有此需要的受试者施用单位剂量的经修饰的细菌,所述单位剂量可以由本领域技术人员确定。
在一些实施方案中,如下将单位剂量的经修饰的细菌或其药物组合物施用给受试者:每天1次,每天2次,每天3次;每隔1天(即,隔日)1次、2次或3次;每2天1次、2次或3次;每3天1次、2次或3次;每4天1次、2次或3次;每5天1次、2次或3次;每周1、每2周或每月1次、2次或3次,且所述剂量可以口服地施用。
6.5 联合治疗
本文中提供了用于治疗癌症的联合治疗,其包括:将经修饰的细菌与一种或多种其它疗法联合地施用给有此需要的受试者。在具体实施方案中,本文中提供了用于治疗癌症的联合治疗,其包括:将有效量的经修饰的细菌与有效量的其它疗法联合地施用给有此需要的受试者。
本文中使用的术语“联合”在施用经修饰的细菌的背景下是指,在施用一种或多种用于治疗癌症的其它疗法(例如,试剂、外科手术或放射)之前、同时或之后施用经修饰的细菌。术语“联合”的使用不限制给受试者施用经修饰的细菌和一种或多种其它疗法的次序。在具体实施方案中,经修饰的细菌的施用和一种或多种其它疗法的施用之间的时间间隔可以是约1-5分钟、1-30分钟、30分钟至60分钟、1小时、1-2小时、2-6小时、2-12小时、12-24小时、1-2天、2天、3天、4天、5天、6天、7天、1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、15周、20周、26周、52周、11-15周、15-20周、20-30周、30-40周、40-50周、1个月、2个月、3个月、4个月5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、1年、2年、或二者之间的任意时间段。在某些实施方案中,间隔小于1天、1周、2周、3周、4周、1个月、2个月、3个月、6个月、1年、2年或5年施用经修饰的细菌和一种或多种其它疗法。
在一些实施方案中,本文中提供的联合治疗包括:每天施用经修饰的细菌,和每周1次、每2周1次、每3周1次、每4周1次、每月1次、每2个月(例如,大约8周) 1次、每3个月(例如,大约12周) 1次、或每4个月(例如,大约16周) 1次地施用一种或多种其它疗法。在某些实施方案中,给受试者循环施用经修饰的细菌和一种或多种其它疗法。循环疗法包括:施用经修饰的细菌一段时间,随后施用一种或多种其它疗法一段时间,并重复该序贯施用。在某些实施方案中,循环疗法还可以包括一段停止,其中不施用经修饰的细菌或其它疗法一段时间(例如,2天、3天、4天、5天、6天、7天、1周、2周、3周、4周、5周、10周、20周、1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、2年或3年)。在一个实施方案中,施用的循环的数目是1-12个循环、2-10个循环或2-8个循环。
在一些实施方案中,本文提供的治疗癌症的方法包括:施用作为单一试剂的经修饰的细菌一段时间,然后与其它疗法联合施用经修饰的细菌。在某些实施方案中,本文提供的治疗癌症的方法包括:施用单独的其它疗法一段时间,然后与所述其它疗法联合施用经修饰的细菌。
在一些实施方案中,与单独的所述经修饰的细菌或所述一种或多种其它疗法的施用相比,根据本文所提供的方法的经修饰的细菌和一种或多种其它疗法的施用具有加性效应。在一些实施方案中,与单独的所述化合物或所述一种或多种其它疗法的施用相比,根据本文所提供的方法的经修饰的细菌和一种或多种其它疗法的施用具有协同效应。
本文中使用的术语“协同”表示施用与一种或多种其它疗法(例如,试剂)组合的经修饰的细菌的效应,所述组合比任意2种或更多种单一疗法(例如,试剂)的加性效应更有效。在具体实施方案中,联合治疗的协同效应允许使用更低剂量(例如,最适度以下的剂量)的经修饰的细菌或其它疗法和/或以更低频率给受试者施用经修饰的细菌或其它疗法。在某些实施方案中,利用更低剂量的经修饰的细菌或其它疗法和/或以更低频率施用经修饰的细菌或所述其它疗法的能力,减小与分别给受试者施用经修饰的细菌或所述其它疗法有关的毒性,而不降低经修饰的细菌或所述其它疗法分别在癌症治疗中的功效。在一些实施方案中,协同效应导致提高的经修饰的细菌和每种所述其它疗法在癌症治疗中的功效。在一些实施方案中,经修饰的细菌和一种或多种其它疗法的组合的协同效应避免或减小与任何单一疗法的使用有关的不利的或不希望的副作用。
可以将经修饰的细菌和一种或多种其它疗法的组合在相同药物组合物中施用给受试者。可替代地,可以将经修饰的细菌和一种或多种其它疗法在分开的药物组合物中同时地施用给受试者。可以将经修饰的细菌和一种或多种其它疗法在分开的药物组合物中依次施用给受试者。还可以将经修饰的细菌和一种或多种其它疗法通过相同或不同的施用途径施用给受试者。
本文提供的联合治疗包括:将经修饰的细菌与常规的或已知的治疗癌症的疗法联合地施用给有此需要的受试者。用于癌症或与其有关的状况的其它疗法的目的在于,控制或缓解一种或多种征状。因此,在一些实施方案中,本文中提供的联合治疗包括:给有此需要的受试者施用疼痛缓解剂、或目的在于减轻或控制一种或多种与癌症有关的征状或与癌症有关的状况的其它疗法。
可以与经修饰的细菌联合使用的抗癌剂的具体例子包括:激素剂(例如,芳香酶抑制剂、选择性雌激素受体调节剂(SERM)和雌激素受体拮抗剂)、化学治疗剂(例如,微管拆散(dissembly)阻断剂、抗代谢物、拓扑异构酶抑制剂和DNA交联剂或损伤剂)、抗血管生成剂(例如,VEGF拮抗剂、受体拮抗剂、整联蛋白拮抗剂、血管靶向剂(VTA)/血管破坏剂(VDA))、放射疗法和常规外科手术。
可以与经修饰的细菌联合使用的激素剂的非限制性例子包括:芳香酶抑制剂、SERMs和雌激素受体拮抗剂。作为芳香酶抑制剂的激素剂可以是甾体类或非甾体类。非甾体类激素剂的非限制性例子包括来曲唑、阿那曲唑、氨鲁米特、法倔唑和伏罗唑。甾体类激素剂的非限制性例子包括阿诺新(依西美坦)、福美坦和睾内酯。作为SERMs的激素剂的非限制性例子包括他莫昔芬(作为Nolvadex®注册商标/销售)、阿非昔芬(afimoxifene)、阿佐昔芬、巴多昔芬(bazedoxifene)、氯米芬、femarelle、拉索昔芬、奥美昔芬、雷洛昔芬和托瑞米芬。作为雌激素受体拮抗剂的激素剂的非限制性例子包括氟维司群。其它激素剂包括、但不限于阿比特龙和洛那立生(lonaprisan)。
可以与经修饰的细菌联合使用的化学治疗剂的非限制性例子包括微管拆散(disasssembly)阻断剂、抗代谢物、拓扑异构酶抑制剂以及DNA交联剂或损伤剂。作为微管拆散(dissemby)阻断剂的化学治疗剂包括、但不限于:紫杉烯(taxene)(例如,紫杉醇(作为TAXOL®注册商标/销售)、多西他赛、abraxane、拉罗他赛、奥他赛和替司他赛);埃博霉素(例如,伊沙匹隆);和长春花生物碱(例如,长春烯碱、长春碱、长春地辛和长春新碱(作为ONCOVIN®注册商标/销售))。
作为抗代谢物的化学治疗剂包括、但不限于:叶酸盐抗代谢物(例如,甲氨蝶呤、氨蝶呤、培美曲塞、雷替曲塞);嘌呤抗代谢物(例如,克拉屈滨、氯法拉滨(clofarabine)、氟达拉滨、巯嘌呤、喷司他丁、硫鸟嘌呤);嘧啶抗代谢物(例如,5-氟尿嘧啶、卡培他滨(capcitabine)、吉西他滨(GEMZAR®)、阿糖胞苷、地西他滨、氟尿苷、替加氟);和脱氧核糖核苷酸抗代谢物(例如,羟基脲)。
作为拓扑异构酶抑制剂的化学治疗剂包括、但不限于:I类(喜树属(camptotheca))拓扑异构酶抑制剂(例如,托泊替康(作为HYCAMTIN®注册商标/销售)伊立替康、卢比替康和贝洛替康(belotecan));II类(鬼臼属)拓扑异构酶抑制剂(例如,依托泊苷或VP-16和替尼泊苷);蒽环类(例如,多柔比星、表柔比星、盐酸多柔比星脂质体(Doxil)、阿柔比星、氨柔比星、柔红霉素、伊达比星、吡柔比星、戊柔比星和佐柔比星);和蒽二酮(anthracenediones)(例如,米托蒽醌和匹克生琼(pixantrone))。
作为DNA交联剂(或DNA损伤剂)的化学治疗剂包括、但不限于:烷化剂(例如,环磷酰胺、氮芥、异环磷酰胺(作为IFEX®注册商标/销售)、曲磷胺、苯丁酸氮芥、美法仑、泼尼莫司汀、苯达莫司汀、乌拉莫司汀、雌莫司汀、卡莫司汀(作为BiCNU®注册商标/销售)、洛莫司汀、司莫司汀、福莫司汀、尼莫司汀、雷莫司汀、链佐星、白消安、甘露舒凡、曲奥舒凡、卡波醌、N,N',N'-三亚乙基硫代磷酰胺、三亚胺醌、曲他胺);烷化样试剂(例如,卡铂(作为PARAPLATIN®注册商标/销售)、顺铂、奥沙利铂、奈达铂、四硝酸三铂(triplatintetranitrate)、沙铂、吡铂(picoplatin));非经典的DNA交联剂(例如,丙卡巴肼、达卡巴嗪、替莫唑胺(作为TEMODAR®注册商标/销售)、六甲蜜胺、二溴甘露醇);和嵌入剂(例如,放线菌素、博来霉素、丝裂霉素和普卡霉素)。
可以与化合物联合施用给受试者的其它疗法的非限制性例子包括:
(1)抑制素诸如洛伐他汀(lovostatin)(例如,作为MEVACOR®注册商标/销售);
(2)mTOR抑制剂诸如西罗莫司,其也被称作雷帕霉素(例如,作为RAPAMUNE®注册商标/销售)、坦罗莫司(temsirolimus)(例如,作为TORISEL®注册商标/销售)、evorolimus(例如,作为AFINITOR®注册商标/销售)和地磷莫司(deforolimus);
(3)法尼基转移酶抑制剂诸如替匹法尼(tipifarnib);
(4)抗纤维化剂诸如吡非尼酮;
(5)加入聚乙二醇的干扰素诸如PEG-干扰素α-2b;
(6)CNS刺激剂诸如哌甲酯(作为RITALIN®注册商标/销售);
(7)HER-2拮抗剂诸如抗-HER-2抗体(例如,曲妥珠单抗(trastuzumab))和激酶抑制剂(例如,拉帕替尼(lapatinib));
(8) IGF-1拮抗剂诸如抗-IGF-1抗体(例如,AVE1642和IMC-A11)或IGF-1激酶抑制剂;
(9)EGFR/HER-1拮抗剂诸如抗-EGFR抗体(例如,西妥昔单抗(cetuximab)、帕尼单抗(panitumamab))或EGFR激酶抑制剂(例如,厄洛替尼(erlotinib);吉非替尼(gefitinib));
(10)SRC拮抗剂诸如波舒替尼(bosutinib);
(11)细胞周期蛋白依赖性激酶(CDK)抑制剂诸如塞利西利(seliciclib);
(12)Janus激酶2抑制剂诸如来妥替尼(lestaurtinib);
(13)蛋白酶体抑制剂诸如硼替佐米(bortezomib);
(14)磷酸二酯酶抑制剂诸如阿那格雷;
(15)肌苷一磷酸脱氢酶抑制剂诸如噻唑呋林;
(16)脂氧合酶抑制剂诸如马索罗酚;
(17)内皮缩血管肽拮抗剂;
(18)类视黄醇受体拮抗剂诸如维A酸或阿利维A酸;
(19)免疫调节剂诸如来那度胺(lenalidomide)、泊马度胺(pomalidomide)或沙利度胺;
(20)激酶(例如,酪氨酸激酶)抑制剂诸如伊马替尼、达沙替尼(dasatinib)、厄洛替尼、尼洛替尼(nilotinib)、吉非替尼、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、拉帕替尼或TG100801;
(21)非类固醇抗炎药诸如塞来考昔(作为CELEBREX®注册商标/销售);
(22)人粒细胞-集落刺激因子(G-CSF)诸如非格司亭(作为NEUPOGEN®注册商标/销售);
(23)亚叶酸或亚叶酸钙;
(24)整联蛋白拮抗剂诸如整联蛋白α5β1-拮抗剂(例如,JSM6427);
(25)核因子κβ(NF-κβ)拮抗剂诸如OT-551,其也是抗氧化剂。
(26)hedgehog抑制剂诸如CUR61414、环杷明(cyclopamine)、GDC-0449和抗-hedgehog抗体;
(27)组蛋白脱乙酰酶(HDAC)抑制剂诸如SAHA (也被称作伏林司他(vorinostat)(作为ZOLINZA注册商标/销售))、PCI-24781、SB939、CHR-3996、CRA-024781、ITF2357、JNJ-26481585或PCI-24781;
(28)类视黄醇诸如异维A酸(例如,作为ACCUTANE®注册商标/销售)
(29)肝细胞生长因子/散射因子(HGF/SF)拮抗剂诸如HGF/SF单克隆抗体(例如,AMG 102);
(30)合成的化学药剂诸如抗瘤酮;
(31)抗糖尿病剂诸如罗格列酮(rosaiglitazone)(例如,作为AVANDIA®注册商标/销售)
(32)抗疟疾和的杀阿米巴的药物诸如氯喹(例如,作为ARALEN®注册商标/销售);
(33)合成的缓激肽诸如RMP-7;
(34)血小板-衍生生长因子受体抑制剂诸如SU-101;
(35)Flk-1/KDR/VEGFR2、FGFR1和PDGFRβ的受体酪氨酸激酶抑制剂,诸如SU5416和SU6668;
(36)抗炎剂诸如柳氮磺吡啶(例如,作为AZULFIDINE®注册商标/销售);和
(37)TGF-β反义疗法。
本发明的范围不受本文描述的具体实施方案限制。实际上,除了描述的那些以外,本领域技术人员从前述描述和附图将明白本发明的各种修改。这样的修改意图落入所附权利要求的范围内。
在本文中引用的所有参考文献整体引入本文作为参考并用于所有目的,达到如同明确地且单独地指出每篇单独的出版物或专利或专利申请为所有目的整体引入作为参考的相同程度。
参考文献
序列表
<110> 黄建东
于斌
杨梅
石蕾
<120> 经修饰的细菌和它们用于治疗癌症或肿瘤的用途
<130> 10030/002893-US1
<140> 13/871,716
<141> 2013-04-26
<150> 61/687,975
<151> 2012-05-04
<160> 21
<170> PatentIn version 3.5
<210> 1
<211> 37
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 1
atttgcggcc gcgtaaacgc aacggatggc tgaccgc 37
<210> 2
<211> 35
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 2
cccaagcttc ttttcgtgac aacattatta ataag 35
<210> 3
<211> 50
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 3
cccaagcttt ggagcgaaac cgatgaaaaa tgttggtttt atcggctggc 50
<210> 4
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 4
ccgctcgagc tacgccaact ggcgcagcat tcga 34
<210> 5
<211> 67
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 5
ccgctcgagc tacagatctt cttcgctaat cagtttctgt tcttccgcca actggcgcag 60
cattcga 67
<210> 6
<211> 69
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 6
atttgcggcc gcttttttga cctgcctcaa actttgtaga tctccaaaat atattcacgt 60
tgtaaattg 69
<210> 7
<211> 73
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 7
cccaagcttc gctacgcatt atcccttagc tctgtatggg aaatttgacg ttaaacaatt 60
tacaacgtga ata 73
<210> 8
<211> 62
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 8
gacgaaaagt acggcattga taatcatttt caatatcatt taattaacta taatgaacca 60
ac 62
<210> 9
<211> 70
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 9
tcgagttggt tcattatagt taattaaatg atattgaaaa tgattatcaa tgccgtactt 60
ttcgtctgca 70
<210> 10
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 10
atttgcggcc gcccgatcat attcaataac cct 33
<210> 11
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 11
atttgcggcc gcgactagtg aacctcttcg aggg 34
<210> 12
<211> 87
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 12
gtatggtgaa ggatgcgcca caggatactg gcgcgcatac acagcacatc tctttgcagg 60
aaaaaaccga tcatattcaa taaccct 87
<210> 13
<211> 91
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 13
atggcggcgc tgacgcgcct tatccggcct acagaaccac acgcaggccc gataagcgct 60
gcaatagccg actagtgaac ctcttcgagg g 91
<210> 14
<211> 73
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 14
gctggcggcg gcagtgcgca tcattcaggg ttccgcgacc gtggcgtgtt agggttttcc 60
cagtcacgac gtt 73
<210> 15
<211> 74
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 15
tgcaattagc gcattaatca cgtctctatc gatacgactg gacatggttt gagcggataa 60
caatttcaca cagg 74
<210> 16
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 16
gattctggtc gcttgtctgg 20
<210> 17
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列描述:合成的引物
<400> 17
acattccagt ttgccgactt 20
<210> 18
<211> 237
<212> DNA
<213> 肠沙门氏菌(Salmonella enterica)
<400> 18
gtaaacgcaa cggatggctg accgctgcgg ggtttgtggt taaccacctt aatcactctt 60
aatgagggcg gtcattctac ggcaaaccac cgtgatcgcc aatccttgtt gcgaattact 120
gacttagctt tatagtcaga aagcgtgtca aagtgaaata ttcttgtttg cagggataaa 180
agtgacctga cgcaatattt gtcttttctt gcttattaat aatgttgtca cgaaaag 237
<210> 19
<211> 1107
<212> DNA
<213> 肠沙门氏菌(Salmonella enterica)
<400> 19
atgaaaaatg ttggttttat cggctggcgc ggaatggtcg gctctgttct catgcaacgc 60
atggtagagg agcgcgattt cgacgctatt cgccctgttt tcttttctac ctcccagttt 120
ggacaggcgg cgcccacctt cggcgacacc tccaccggca cgctacagga cgcttttgat 180
ctggatgcgc taaaagcgct cgatatcatc gtgacctgcc agggcggcga ttataccaac 240
gaaatttatc caaagctgcg cgaaagcgga tggcagggtt actggattga cgcggcttct 300
acgctgcgca tgaaagatga tgccattatt attctcgacc cggtcaacca ggacgtgatt 360
accgacggac tgaacaatgg cgtgaagacc tttgtgggcg gtaactgtac cgttagcctg 420
atgttgatgt cgctgggcgg tctctttgcc cataatctcg ttgactgggt atccgtcgcg 480
acctatcagg ccgcctccgg cggcggcgcg cgccatatgc gcgagctgtt aacccaaatg 540
gggcagttgt atggccatgt cgccgatgaa ctggcgacgc cgtcttccgc aattcttgat 600
attgaacgca aagttacggc attgacccgc agcggcgagc tgccggtgga taactttggc 660
gtaccgctgg cgggaagcct gatcccctgg atcgacaaac agcttgataa cggccaaagc 720
cgcgaagagt ggaaaggcca ggcggaaacc aacaagatcc tcaatactgc ctctgtgatc 780
ccggttgatg gtttgtgcgt gcgcgtcggc gcgctgcgct gtcacagcca ggcgttcacc 840
attaagctga aaaaagaggt atccattccg acggtggaag aactgctggc ggcacataat 900
ccgtgggcga aagtggtgcc gaacgatcgt gatatcacta tgcgcgaatt aaccccggcg 960
gcggtgaccg gcacgttgac tacgccggtt ggtcgtctgc gtaagctgaa catggggcca 1020
gagttcttgt cggcgtttac cgtaggcgac cagttgttat ggggcgccgc cgagccgctg 1080
cgtcgaatgc tgcgccagtt ggcgtag 1107
<210> 20
<211> 368
<212> PRT
<213> 肠沙门氏菌(Salmonella enterica)
<400> 20
Met Lys Asn Val Gly Phe Ile Gly Trp Arg Gly Met Val Gly Ser Val
1 5 10 15
Leu Met Gln Arg Met Val Glu Glu Arg Asp Phe Asp Ala Ile Arg Pro
20 25 30
Val Phe Phe Ser Thr Ser Gln Phe Gly Gln Ala Ala Pro Thr Phe Gly
35 40 45
Asp Thr Ser Thr Gly Thr Leu Gln Asp Ala Phe Asp Leu Asp Ala Leu
50 55 60
Lys Ala Leu Asp Ile Ile Val Thr Cys Gln Gly Gly Asp Tyr Thr Asn
65 70 75 80
Glu Ile Tyr Pro Lys Leu Arg Glu Ser Gly Trp Gln Gly Tyr Trp Ile
85 90 95
Asp Ala Ala Ser Thr Leu Arg Met Lys Asp Asp Ala Ile Ile Ile Leu
100 105 110
Asp Pro Val Asn Gln Asp Val Ile Thr Asp Gly Leu Asn Asn Gly Val
115 120 125
Lys Thr Phe Val Gly Gly Asn Cys Thr Val Ser Leu Met Leu Met Ser
130 135 140
Leu Gly Gly Leu Phe Ala His Asn Leu Val Asp Trp Val Ser Val Ala
145 150 155 160
Thr Tyr Gln Ala Ala Ser Gly Gly Gly Ala Arg His Met Arg Glu Leu
165 170 175
Leu Thr Gln Met Gly Gln Leu Tyr Gly His Val Ala Asp Glu Leu Ala
180 185 190
Thr Pro Ser Ser Ala Ile Leu Asp Ile Glu Arg Lys Val Thr Ala Leu
195 200 205
Thr Arg Ser Gly Glu Leu Pro Val Asp Asn Phe Gly Val Pro Leu Ala
210 215 220
Gly Ser Leu Ile Pro Trp Ile Asp Lys Gln Leu Asp Asn Gly Gln Ser
225 230 235 240
Arg Glu Glu Trp Lys Gly Gln Ala Glu Thr Asn Lys Ile Leu Asn Thr
245 250 255
Ala Ser Val Ile Pro Val Asp Gly Leu Cys Val Arg Val Gly Ala Leu
260 265 270
Arg Cys His Ser Gln Ala Phe Thr Ile Lys Leu Lys Lys Glu Val Ser
275 280 285
Ile Pro Thr Val Glu Glu Leu Leu Ala Ala His Asn Pro Trp Ala Lys
290 295 300
Val Val Pro Asn Asp Arg Asp Ile Thr Met Arg Glu Leu Thr Pro Ala
305 310 315 320
Ala Val Thr Gly Thr Leu Thr Thr Pro Val Gly Arg Leu Arg Lys Leu
325 330 335
Asn Met Gly Pro Glu Phe Leu Ser Ala Phe Thr Val Gly Asp Gln Leu
340 345 350
Leu Trp Gly Ala Ala Glu Pro Leu Arg Arg Met Leu Arg Gln Leu Ala
355 360 365
<210> 21
<211> 60
<212> DNA
<213> 大肠杆菌(Escherichia coli)
<400> 21
acgaaaagta cggcattgat aatcattttc aatatcattt aattaactat aatgaaccaa 60
Claims (13)
1.一种使经修饰的兼性厌氧鼠伤寒沙门氏菌(Salmonella typhimurium)成为专性厌氧菌的方法,其中所述兼性厌氧鼠伤寒沙门氏菌包含严格低氧调节的必需基因表达盒,其中所述表达盒包含:(a)被FNR激活并且包含FNR结合位点的与必需基因asd可操作地连接的低氧条件启动子pepT;和(b)由FNR负调节的反义启动子sodA,
且所述专性厌氧菌当在体内施用时抑制和减少实体瘤癌症的生长。
2.根据权利要求1所述的方法,其中所述专性厌氧菌在二氨基庚二酸(DAP)不存在下被诱导。
3.根据权利要求1所述的方法,其中所述低氧条件启动子是正向厌氧诱导型启动子,以及所述反义启动子是反向需氧启动子。
4.根据权利要求1所述的方法,其中所述严格低氧调节的必需基因表达盒是基于染色体的。
5.一种载体,其包含:(a)被FNR激活并且包含FNR结合位点的与必需基因asd可操作地连接的低氧条件启动子pepT;和(b)由FNR负调节的反义启动子sodA。
6.一种细菌,其包含根据权利要求5所述的载体,其中所述细菌是鼠伤寒沙门氏菌。
7.经修饰的包含严格低氧调节的必需基因表达盒的细菌在药物制备中的用途,所述药物用于治疗实体瘤癌症,其中所述表达盒包含:(a)被FNR激活并且包含FNR结合位点的与必需基因asd可操作地连接的低氧条件启动子pepT;和(b)由FNR负调节的反义启动子sodA,其中所述细菌是鼠伤寒沙门氏菌。
8.根据权利要求7所述的用途,其中所述药物与第二种癌症疗法联合施用。
9.根据权利要求8所述的用途,其中所述第二种癌症疗法是用5-氟尿嘧啶(5-FU)治疗。
10.根据权利要求7-9中任一项所述的用途,其中所述实体瘤癌症是乳腺、肝、肺、皮肤、肾、前列腺、神经系统或膀胱的肿瘤。
11.根据权利要求6所述的细菌在药物制备中的用途,所述药物用于治疗实体瘤癌症,其中所述实体瘤癌症是乳腺、肝、肺、皮肤、肾、前列腺、神经系统或膀胱的实体瘤癌症。
12.根据权利要求10所述的用途,其中所述药物与第二种癌症疗法联合施用。
13.根据权利要求12所述的用途,其中所述第二种癌症疗法是用5-FU治疗。
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US20220023358A1 (en) * | 2018-11-08 | 2022-01-27 | Synlogic Operating Company, Inc. | Combination therapies of microorganisms and immune modulators for use in treating cancer |
CN111358811A (zh) * | 2018-12-26 | 2020-07-03 | 深圳先进技术研究院 | 细菌-光热纳米颗粒复合物及制备方法和应用 |
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CN114525295A (zh) * | 2020-11-05 | 2022-05-24 | 中国科学院深圳先进技术研究院 | 构建严格厌氧沙门氏菌的方法,所构建的严格厌氧沙门氏菌及其应用 |
WO2022094867A1 (zh) * | 2020-11-05 | 2022-05-12 | 深圳先进技术研究院 | Pp2严格厌氧沙门氏菌菌株构建及其在肿瘤治疗方面应用 |
WO2022094865A1 (zh) * | 2020-11-05 | 2022-05-12 | 中国科学院深圳先进技术研究院 | "自体裂解"沙门氏菌菌株、其制备方法及其在肿瘤治疗中的应用 |
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