CN110678543B - 体外培养系统及其使用方法 - Google Patents
体外培养系统及其使用方法 Download PDFInfo
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- CN110678543B CN110678543B CN201880035427.1A CN201880035427A CN110678543B CN 110678543 B CN110678543 B CN 110678543B CN 201880035427 A CN201880035427 A CN 201880035427A CN 110678543 B CN110678543 B CN 110678543B
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Abstract
本发明提供了多种体外培养系统。因此,一种培养系统被提供,包含一培养基及一精密切割的组织切片,所述精密切割的组织切片放置在一组织培养插件上,其中所述精密切割的组织切片保持在含有至少50%氧气的一高度氧合的气氛中,及所述培养被旋转搅拌以促进所述组织切片在所述培养基中的间歇浸没。本发明还提供了多种培养一组织的方法及多种使用所述培养系统用于选择治疗一疾病的一药物的方法。
Description
技术领域及背景技术
在一些实施例中,本发明涉及一种体外培养系统及其使用方法。
抗癌治疗方案的现有选择主要基于起源的癌症组织、肿瘤的阶段和等级以及患者的整体健康状况。这种治疗方案对某些患者有效,但是它们是具有毒性的,引起许多可能危及生命的不良反应。
靶向药物疗法的可用性以及识别患者特定肿瘤标记物的可能性已指示个体化的治疗选择,但同时需要广泛使用基因剖析分析(参见例如Dancey等人(2012)细胞期刊148,409-420;及Garraway等人(2013)J.Clin.Oncol.Off.J.Am.Soc.Clin.Oncol.31,1806-1814)。然而,将遗传数据外推到特定的治疗方案是复杂的,并且预测患者的反应是不可靠的。例如,如果患者的肿瘤特征在于具有不止一种可靶向突变的特征,则很难预测哪种潜在药物最有效。当有不止一种药物可用于特定突变时,情况也是如此。因此,选择治疗方法在很大程度上取决于反复试验。
可以使用多种技术来直接测试患者的癌细胞对特定治疗的反应,例如由患者肿瘤和患者来源的异种移植(PDX)模型产生的肿瘤来源细胞系(参见例如Crystal等人(2014)科学期刊346,1480-1486;Clevers等人(2016)细胞期刊165,1586–1597;及Hidalgo等人(2014)Cancer Discov.期刊4,998–1013)。然而,这些模型昂贵且耗时,最重要的是它们没有保留原始的肿瘤的微环境,这可能会对药物敏感性产生显着影响(Straussman等人(2012)自然期刊487,500–504)。
癌症生物学中使用的体外器官培养(EVOC)系统是对患者肿瘤进行精确切割的切片培养物。EVOC已用于各种各样的应用,包含研究药物毒性、病毒吸收、肿瘤对放射线或特定的抗癌药物的敏感性(参见例如Vaira等人(2010)美国国家科学院院刊期刊107,8352–8356;Vickers等人(2004)Chem.Biol.Interact.期刊150,87–96;de Kanter等人(2002)Curr.Drug Metab.期刊3,39–59;Stoff-Khalili等人(2005)Breast Cancer Res.期刊BCR7,R1141-1152;Merz等人(2013)Neuro-Oncol.期刊15,670-681;Gerlach等人(2014)Br.J.Cancer期刊110,479–488;Meijer等人(2013)Br.J.Cancer期刊109,2685–2695;Grosso等人(2013)Cell Tissue Res.期刊352,671–684;Vaira等人(2010)PNAS 107,8352-8356;Roife等人(2016)Clin.Cancer Res.期刊,6月3日,1-10;Maund等人(2014)Lab.Invest.期刊94,208-221;Vickers等人(2004)Toxicol Sci.期刊82(2):534-44;Zimmermann等人(2009)Cytotechnology期刊61(3):145-152);Parajuli等人(2009)InVitro Cell.Dev.Biol.-Animal期刊45:442–450;Koch等人(2014)Cell Communicationand Signaling期刊12:73;Graaf等人Nature Protocols期刊(2010)5:1540-1551;Majumder等人Nat.Commun.期刊6,6169(2015);美国专利申请案公开第US2014/0228246号、第US2010/0203575号和第US2014/0302491号;以及国际专利申请案公开第WO2002/044344号。
发明内容
根据本发明的一些实施例的一个方面,提供了一种培养系统,包含:一培养基;及一精密切割的组织切片,放置在一组织培养插件上,其中所述精密切割的组织切片保持在含有至少50%氧气的一高度氧合的气氛中,及所述培养被旋转搅拌以促进所述组织切片在所述培养基中的间歇浸没。
根据本发明的一些实施例,所述培养是在一组织培养板中。
根据本发明的一些实施例,所述培养系统包含一药物。
根据本发明的一些实施例的一个方面,提供了一种培养一组织的方法,包含以下步骤:在含有至少50%的氧气的一高度氧合的气氛中,将位在一组织培养插件上的一精密切割的组织切片培养在一培养基中;及以一旋转搅拌所述培养,以促进所述组织切片在所述培养基中的间歇浸没。
根据本发明的一些实施例,所述方法还包含:将一药物添加到所述培养基。
根据本发明的一些实施例,提供了一种确定一药物或一批药物的有效性的方法,所述方法包含以下步骤:(i)根据如本发明所述的方法培养一组织;(ii)将所述药物或所述批药物添加到所述培养基;及(iii)确定所述药物或所述批药物对所述组织的作用,其中所述组织对所述药物的敏感性表示所述药物的有效性。
根据本发明的一些实施例,所述组织是一病理组织。
根据本发明的一些实施例,提供了一种对一有需要的对象选择用于治疗一疾病的一药物的方法,所述方法包含以下步骤:
(i)根据如本发明所述的方法培养从所述对象获得的一病理组织;
(iii)将所述药物添加到所述培养基;及
(iii)确定所述药物对所述组织的作用,其中所述组织对所述药物的敏感性表示所述药物对于所述对象治疗所述疾病的有效性。
根据本发明的一些实施例,提供了一种对一有需要的对象治疗一疾病的方法,所述方法包含以下步骤:
(a)根据如本发明所述的方法选择一药物;及
(b)向所述对象施用证实对所述对象的所述疾病的治疗具备有效性的一治疗有效量的所述药物,从而治疗所述对象的所述疾病。
根据本发明的一些实施例,所述药物是一药物组合。
根据本发明的一些实施例,所述组织或所述精密切割的组织切片是刚刚被分离的。
根据本发明的一些实施例,所述组织或所述精密切割的组织切片被保存在4℃。
根据本发明的一些实施例,所述组织或所述精密切割的组织切片被超低温保存。
根据本发明的一些实施例,所述确定的步骤是通过形态评估、生存力评估、增殖评估及/或细胞死亡评估来进行。
根据本发明的一些实施例,所述确定的步骤是通过形态评估来进行。
根据本发明的一些实施例,所述确定的步骤在培养的3至5天内进行。
根据本发明的一些实施例,所述疾病是一癌症。
根据本发明的一些实施例,所述癌症选自于由以下组成的群组:卵巢癌、结肠直肠癌、肺癌、胰腺癌、胃癌、胃食管癌及乳腺癌。
根据本发明的一些实施例,所述病理组织是一癌组织。
根据本发明的一些实施例,所述组织选自于由以下组成的群组:卵巢、结肠直肠、肺、胰腺、胃、胃食管及乳房。
根据本发明的一些实施例,所述组织选自于由以下组成的群组:卵巢、结肠直肠、肺、胰腺、胃、胃食管、乳房、肝脏、软骨组织及骨骼。
根据本发明的一些实施例,所述添加的步骤在所述培养开始后12至24小时进行。
根据本发明的一些实施例,所述药物是一抗发炎药或一抗癌药。
根据本发明的一些实施例,所述药物选自于由以下组成的群组:5-氟尿嘧啶(5FU)、奥沙利铂、伊立替康、顺铂、4-过氧羟基环磷酰胺、多西他赛、阿霉素、诺维本、吉西他滨、吉非替尼、太莫西芬、奥拉帕利、曲美替尼、依维莫司及哌柏西利。
根据本发明的一些实施例,所述药物的浓度高于一细胞系中的所述药物的IC50的剂量。
根据本发明的一些实施例,所述药物浓度来自一剂量试验,其中一剂量依赖性反应被观察到。
根据本发明的一些实施例,所述培养进行至少4天。
根据本发明的一些实施例,所述培养进行至少5天。
根据本发明的一些实施例,所述培养进行至7天。
根据本发明的一些实施例,所述培养在一组织培养板中进行。
根据本发明的一些实施例,所述精密切割的切片为200至300微米。
根据本发明的一些实施例,所述切片被放置在所述细胞培养插件的中间。
根据本发明的一些实施例,所述切片是一个切片。
根据本发明的一些实施例,所述切片与所述组织培养插件直接相接触。
根据本发明的一些实施例,所述组织培养插件是一钛网格插件。
根据本发明的一些实施例,所述组织是一人类组织。
根据本发明的一些实施例,所述高度氧合的气氛含有至少70%的氧气。
根据本发明的一些实施例,所述高度氧合的气氛含有小于95%的氧气。
根据本发明的一些实施例,所述方法与基因剖析结合进行。
除非另有定义,否则本文中使用的所有技术和/或科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。尽管与本文描述的那些类似或等同的方法和材料可以用于本发明的实施例的实践或测试中,但是下面描述了示例性的方法和/或材料。在有冲突的情况下,以专利说明书及其定义为准。另外,材料、方法和实施例仅是说明性的,并不意图必然是限制性的。
附图说明
本文仅通过示例的方式,参考附图描述了本发明的一些实施例。现在具体地具体参考附图,要强调的是,所示出的细节是作为示例并且出于对本发明的实施例的说明性讨论的目的。就这一点而言,结合附图进行的描述对于本领域技术人员而言明白易懂的是可以如何实践本发明的实施例。
在图示中:
图1示出了代表性的组织学显微照片,其示出了体外培养5天后人卵巢癌来源的异种移植的切片的形态。将获得的组织的多个精密切割的切片在6孔板的钛插件(左列)中或直接在6孔板(右列)中孵育;在21%的氧气(下排)或80%的氧气(上排)中放置5天;并用H&E染色。比例尺代表50微米。对于每种情况,一式三份测试组织。
图2示出了代表性的组织学显微照片,其示出了在不同培养基中体外培养5天后人类乳腺癌来源的异种移植的切片的形态。将获得的组织的多个精密切割的切片在DMEM/F12(左图)或M199(右图)培养基中80%氧气中的钛插件上孵育5天;并用H&E染色。比例尺代表50微米。对于每种情况,一式两份测试组织。
图3示出了所开发的体外培养方法预测人乳腺癌来源的异种移植对抗癌药治疗的反应的能力。示出的是由杰克逊实验室(Jackson Laboratories)生成的图表,显示了两种人类乳腺癌来源的异种移植对4-过氧羟基环磷酰胺治疗的体内反应,表明TM00096乳腺癌对治疗有抗性,而TM00098乳腺癌对治疗敏感。y轴表示以立方毫米为单位的肿瘤大小。
代表性的组织学显微照片显示,切片以指示浓度的4-过氧羟基环磷酰胺处理4天,在钛插件上以80%氧气进行体外培养5天后,TM00096(左列)和TM00098(右列)乳腺癌切片的形态。比例尺代表50微米。对于每种情况,一式两份测试组织。
图4示出了开发的体外培养方法预测人结肠直肠癌(CRC)来源的异种移植对抗癌药治疗的反应的能力。示出的是由杰克逊实验室生成的图表,显示了三种CRC来源的异种移植对奥沙利铂治疗的体内反应,表明TM00134CRC对治疗有抗性,而TM00170肿瘤部分敏感,而TM00164 CRC对治疗非常敏感。y轴表示以立方毫米为单位的肿瘤大小。
代表性的组织学显微照片显示,切片以指示浓度的0.2微摩尔/升的奥沙利铂处理4天,在钛插件上以80%氧气进行体外培养5天后,TM00134(左图)、TM00170(中图)和TM00164(右图)CRC切片的形态。用DMSO处理作为对照组。比例尺代表50微米。对于每种情况,一式三份测试组织。
图5示出了在开发的体外培养方法下培养的肿瘤组织切片对不同的抗癌药表现出不同的敏感性。人类结肠直肠癌(CRC)肿瘤组织取自在进行减积手术和腹腔内化疗的手术中切除的腹膜转移病灶。显示的代表性的组织学显微照片示出了肿瘤切片以指示的抗癌药5-氟尿嘧啶(5-Fluouricil)(5-FU)、伊立替康或奥沙利铂处理4天,在钛插件上用80%氧气进行体外培养5天后的形态。以DMSO处理作为对照组。应该注意的是,所述组织对奥沙利铂和伊立替康的治疗呈剂量依赖性,但对5-氟尿嘧啶有抗性。比例尺代表50微米。对于每种情况,一式三份测试组织。
图6示出了从不同个体获得并在开发的体外培养方法下培养的肿瘤组织切片对相同的抗癌药表现出不同的敏感性。人类结肠直肠癌(CRC)肿瘤组织取自在进行减积手术和腹腔内化疗的手术中切除的腹膜转移病灶。显示的代表性的组织学显微照片示出了肿瘤切片以指示的抗癌药:5-氟尿嘧啶(5-FU)或奥沙利铂处理了4天,在钛插件上用80%氧气进行体外培养5天后的形态。以DMSO处理作为对照组。PR表示部分反应;NR表示无反应。应该注意的是,从患者第8号患者获得的肿瘤对奥沙利铂有很强的部分反应并对5-氟尿嘧啶没有反应,另一位患者(第6号患者)对两种药物均部分反应。比例尺代表50微米。对于每种情况,一式两份测试组织。
图7示出了所开发的体外培养方法预测如通过分子谱分析所预测的对靶向疗法的敏感性的能力。显示的代表性的组织学显微照片示出了从两名患者的三阴性乳腺癌肿瘤切片以AZD4547(FGFR抑制剂)处理了4天,在钛插件用80%氧气进行了5天的体外培养后的形态。以DMSO处理作为对照组。应该注意的是,肿瘤带有FGFR1扩增的第1号患者对AZD4547(FGFR抑制剂)敏感,而没带有这种突变的第2号患者则对对治疗有抗性。比例尺代表50微米。对于每种情况,一式两份测试组织。
图8示出了用Ki67染色用于增殖可用于评估组织对不同治疗的敏感性。显示的代表性组织学显微照片示出了从一名患者用指定药物治疗了4天,在钛插件用80%氧气进行了5天的体外培养后的形态(通过H&E染色)和增殖(通过Ki67染色)。由杰克逊实验室(Jackson Laboratories)生成的右图示出了此CRC来源的异种移植对奥沙利铂和5-氟尿嘧啶治疗的体内反应。y轴表示以立方毫米为单位的肿瘤大小。所述患者对5-氟尿嘧啶部分敏感,但体内和体外对奥沙利铂都非常敏感。以DMSO处理用作对照组。比例尺代表50微米。对于每种情况,一式两份测试组织。图9示出了EVOC核心活组织检查的处理。在此示例中,将三个核心活组织检查一个接一个地放置在一个金属托盘中的液体琼脂糖中。添加更多的琼脂糖后,并将托盘冷却。从琼脂糖上切下活检组织,并用触压胶将块体固定在柱塞上,包埋在更多的琼脂糖中(使用与组织切片相同的方法),然后用切片机切片。以类似于组织切片的方式处理和加工活检切片。比例尺代表100微米。
图10示出了组织学显微照片,示出了在开始实验之前可以将组织切成薄片并在培养基中保存长达48小时,而对组织没有任何不利影响或结果没有任何变化。示出的是结肠癌组织,切片后立即或冷藏后48小时用DMSO为对照组或5-氟尿嘧啶(5-FU)处理了4天。在实验结束前18小时添加BrdU;并用抗BrdU抗体对组织进行染色,以鉴定分裂细胞。应该注意的是,用5-FU处理的组织在某种程度上仍然存活,但在这两种情况下,随着细胞死亡增加和BrdU减少,开始对治疗产生反应。比例尺代表50微米。
图11示出了代表性的组织学图像,其显示了体外培养5天后的所示组织;以及总结了所检查的组织,这些组织在至少5天的培养中都保持了组织的结构和活力的表格。将采集的组织的精密切割的切片在钛插件上于DMEM/F12中80%氧气中孵育5天,并用H&E染色,所有实验一式两份地在指定癌症的两个不同病例上进行。
具体实施方案
在一些实施例中,本发明涉及一种体外培养系统及其使用方法。
在详细解释本发明的至少一个实施例之前,应理解的是,本发明的应用并不一定限于以下描述中阐述的或由实施例举例说明的细节。本发明能够具有其他实施例,或者能够以各种方式被实践或执行。
癌症等疾病的个体化治疗选择通常采用基因剖析法,并使用昂贵且费时的模型(例如由患者肿瘤和患者来源异种移植(PDX)产生的肿瘤衍生细胞系)来测试患者细胞对特定治疗的反应。近年来,体外器官培养(EVOC)系统被建议用于多种应用,包含研究药物毒性、病毒吸收(viral uptake)、肿瘤对放射线敏感性或特定抗癌药的敏感性。
在将本发明付诸实践的同时,本发明人现在已经开发了一种EVOC系统,所述系统可以在培养中将一精密切割的组织切片的结构和活力保存至7天,因此可以预测病理组织对各种药物的反应。
如下文和示例部分所述,新开发的EVOC系统基于培养组织的一个切片直接放置在一培养插件(在此示例下,在一可重复使用的钛网格中间)上,其允许切片在培养基中间歇浸没,从而促进营养物和气体在整个切片中的扩散,使用仅添加胎牛血清(FCS)和抗菌剂的标准培养基在高度氧合(80%)的气氛中进行(实施例1,表1,图1-2和图9)。根据此方法培养的各种癌变组织(包含卵巢、结肠直肠、肺、胰腺和乳腺组织)的EVOC系统在培养4至6天后表现出高生存力(实施例1,表1,图11)。
接下来,本发明人示出所开发的EVOC系统可用于预测肿瘤对抗癌药的反应(实施例2)。具体地,本发明人示出了从各种患者来源异种移植(PDX)模型获得的体外癌组织切片对抗癌治疗的敏感性与PDX模型对治疗的体内反应一致(实施例2,表2,图3-4);从患者获得的体外三阴性乳腺癌组织切片对靶向治疗的敏感性与分子谱数据一致(实施例2,图7)。此外,本发明人示出了来自各种患者的人类肿瘤的EVOC系统对不同的抗癌治疗表现出不同的敏感性(实施例2,表3-4,图5-6和8)。重要的是,在开始实验之前,组织可以在培养基中保存至少48小时,而对组织或药物敏感性没有任何不利影响(实施例2,图10)。
综上所述,新开发的EVOC系统保留了组织的微环境、结构、生存能力和遗传异质性。此系统能够以快速、可靠和低成本效益的方式研究人体组织(例如癌症组织)的反应。因此,本教导进一步建议将此开发的EVOC系统用于临床前试验和基础研究,以及一药物总体上用于疾病治疗,尤其是用于个体化治疗的合格功效。
因此,根据本发明的第一方面,提供了一种培养系统,包含:一培养基;及一精密切割的组织切片,放置在一组织培养插件上,其中所述精密切割的组织切片保持在含有至少50%氧气的一高度氧合的气氛中,并且其中所述培养物是旋转搅拌,以促进所述组织切片在所述培养基中的间歇浸没。
根据本发明的另一方面,提供了一种培养一组织的方法,所述方法包含以下步骤:在含有至少50%的氧气的一高度氧合的气氛中,将位在一组织培养插件上的一精密切割的组织切片培养在一培养基中;及以一旋转搅拌所述培养,以促进所述组织切片在所述培养基中的间歇浸没。
如本文所用,术语“培养系统”是指至少一个精密切割的组织切片在体外环境中的插件和培养基。
根据具体的实施例,所述培养系统在培养中至少在2至10天、2至7天、2至5天、4至7天、5至7天或4至5天维持精密切割的组织切片的结构和生存力(viability)。根据一个具体的实施例,所述精密切割的组织切片保持生存力至少5天、6天、7天甚至10天。根据一个具体的实施例,所述精密切割的组织切片保持生存力至少5天。
根据具体的实施例,所述精确切割组织中的至少60%、至少70%、至少80%的细胞在培养4至5天后保持生存力,如通过例如最佳存活面积的形态分析。
如本文所用,短语“最佳存活面积(optimal area of viability)”是指组织的显微视野(例如,以20倍放大率),由病理学家评估,与同一物种的当前的前EVOC(pre-EVOC)样品相比,每单位面积的活细胞数量最多。
因此,根据具体的实施例,培养进行2至10天、2至7天、2至5天、4至7天、5至7或4至5天。
根据一个具体的实施例,所述培养进行至少4天。
根据一个具体的实施例,所述培养进行至少5天。
根据一个具体的实施例,所述培养进行至7天。
如本文所用,术语“组织”是指具有包含一种以上细胞类型的血管化的生物体的固体器官(即,不是血液)的一部分,并保持从其切除的活体组织的至少一些宏观结构。
示例包含但不限于卵巢组织、结肠直肠组织、肺组织、胰腺组织、乳腺组织、脑组织、视网膜、皮肤组织、骨骼、心脏组织和肾组织。根据具体的实施例,所述组织选自由以下组成的群组:卵巢、结肠直肠、肺、胰腺、胃、胃食管和乳腺。根据具体的实施例,所述组织选自由以下组成的群组:卵巢、结肠直肠、肺、胰腺、胃、胃食管、乳腺、肝脏、软骨组织和骨骼。根据具体的实施例,所述组织是从例如但不限于肝脏、骨骼、肺和腹膜的部位获得的转移性癌组织。
根据具体的实施例,所述组织不是一肝脏组织。
根据具体的实施例,所述组织不是一前列腺组织。
根据具体的实施例,所述组织是一哺乳动物组织。
根据一个具体的实施例,所述组织是一人体组织。
根据另一个具体实施例,所述组织是一小鼠或大鼠组织。
根据具体的实施例,所述组织是一健康组织。
根据其他具体实施例,所述组织是一病理组织。所述方法可以采用多个筛选的精密切割的组织切片(例如,每个都在一个单独的插件上),所有这些切片可以来自一个(或多个)病理组织、健康组织或它们的组合(例如,当健康组织取自与病理组织相同的组织来源时作为对照组)。
根据具体的实施例,所述组织是一病理组织。
如本文所用,术语“病理组织”是指引起疾病的一组织。因此,消除这种组织预期将导致如下文进一步定义的治疗。下文详细描述了根据本发明一些实施例的适于治疗的疾病的具体示例。根据具体的实施例,所述病理组织是一发炎的组织、一纤维化的组织或一癌组织。根据一个具体的实施例,所述病理组织是一癌组织。
根据具体的实施例,所述组织通过外科手术或通过活组织检查、腹腔镜检查、内窥镜检查或作为异种移植或其任何组合来获得。
可以在组织提取(即原始组织)之后或将其植入一动物模型(即患者来源的异种移植(PDX)后直接切割和培养组织,每种可能性代表本发明的单独实施例。
本发明的一些实施例的所述组织或所述组织切片可以被刚刚分离或存储例如在4℃下,或者被超低温保存(即冷冻)例如在液态氮。
根据具体的实施例,所述组织或所述组织切片是刚刚被分离的(即,从对象取回后不超过24小时且未经历保存过程),如下文进一步公开的。
根据具体的实施例,在组织取回之后和切割之前,所述组织被超超低温保存。
根据具体的实施例,在切割之前将所述组织解冻。
根据具体的实施例,所述组织切片在切割后被超超低温保存。
根据具体的实施例,在培养之前将所述组织切片解冻。
根据具体的实施例,在组织取回之后和切割之前,所述组织被保存在4℃例如在培养基中。
根据具体实施例,在切割后和培养之前,所述组织切片被保存在4℃例如在培养基中。
根据具体的实施例,在4℃进行保存至120小时、至96小时、至72小时或至48小时。
根据具体的实施例,在4℃进行保存24至48小时。
因此,根据具体的实施例,所述方法进一步包含从对象获得组织或从包含所述组织的动物模型获得组织。
如本文所用,短语“患者来源的异种移植(PDX)”是指通过将原始组织植入一动物体内而产生的组织,所述动物来自与原始组织的供体相关的不同物种。根据具体的实施例,PDX是通过将一人类原始组织(例如癌组织)植入免疫缺陷小鼠中而产生的一组织。
组织抽取后,将所述组织切成多个精密切割的切片。
如本文所用,短语“精密切割的组织切片”是指从具有可再现的、明确定义的厚度(例如,切片之间的厚度变化为±5%)的分离实体组织中获得的活切片。
通常,组织切片是所述组织的一个小模型,其中包含组织在其自然环境中的细胞,并保持三维连接,例如完整组织的细胞间和细胞-基质相互作用,而不选择构成组织或器官的不同细胞类型中的特定细胞类型。精确切割减少了由于切片厚度的变化和切割表面的损伤而导致的误差来源,这两种情况都会导致整个组织切片中气体和营养物质交换不均匀;它提高了再现性;并允许相邻切片在不同实验条件下进行组织学评估和成对比较。
切片可以按不同的方向(如前后、背腹或鼻颞)和厚度切割。组织切片的大小/厚度取决于组织来源和用于切片的方法。根据具体的实施例,精密切割的切片的厚度允许维持培养中的组织结构。
根据具体的实施例,所述精密切割的切片的厚度允许多层内部细胞层完全接触氧气和营养物,使得所述多层内部细胞层暴露于足够的氧气和营养物浓度下。
根据具体的实施例,所述精密切割的切片的厚度允许多层内部细胞层完全接触氧气和营养物,使得所述多层内部细胞层暴露于与多层外部细胞层相同的氧气和营养物浓度下。
根据具体的实施例,所述精密切割的切片在50-1200微米之间、在100-1000微米之间、在100-500微米之间、在100-300微米之间或在200-300微米之间。
根据一个具体的实施例,所述精密切割的切片为200-300微米。
获得组织切片的方法在本领域中是已知的,并且在以下实施例部分作为示例进行了描述以及Roife等人(2016)Clin.Cancer Res.期刊6月3日,1-10;Vickers等人(2004)Toxicol Sci.期刊82(2):534-44;Zimmermann等人(2009)Cytotechnology期刊61(3):145-152);Koch等人(2014)细胞通讯与信号传递期刊12:73;以及Graaf等人Nature Protocols期刊(2010)5:1540-1551,其每一个的内容均通过引用完全并入本文。这样的方法包含但不限于使用振动切片机切片、琼脂糖包埋随后用切片机切片或使用基质切片。
作为非限制性示例,将组织分离并立即放置在可以添加抗生素的生理解剖培养基(例如冰冷的PBS)中。
根据具体的实施例,热缺血时间小于2小时、小于1.5小时或小于1小时。
根据具体的实施例,冷缺血时间小于96小时、小于72小时、小于48小时、小于24小时、小于12小时、小于5小时或小于2小时。
在切片之前,用接触胶将组织固定在切片机上,然后嵌入低熔点琼脂糖凝胶中。随后,将组织切成精密切割的切片。许多合适的组织切片装置可商购获得,例如但不限于CompresstomeTM VF-300(美国北卡罗来纳州的精密仪器公司),Brendel-Vitron组织切片机(亚利桑那州图森市),Krumdieck精密组织切片机(型号:MD4000-01;阿拉巴马州研发)和Leica VT1200S振动刀片式切片机(德国威茨拉尔莱卡市)。根据具体的实施例,所述切片装置填充有冰冷的培养基,例如威廉姆斯培养基E或克雷布斯-亨塞利特缓冲液(KHB)。对于每种类型的组织培养之前,技术人员应知道用于解剖以及用于保存组织和组织切片的培养基和条件。
随后,将组织切片放在装有培养基的一组织培养容器中的一组织培养插件上。可以将一个切片或多个切片放在单个组织培养插件上。根据具体的实施例,将一个切片放置在单个组织培养插件上。
根据具体的实施例,在培养容器中充满培养基直到组织切片的底部(例如,在含有插件的6孔板中的填入4毫升培养基)。
培养物可以在可以为组织培养提供无菌环境的玻璃、塑料或金属容器中。根据具体的实施例,所述培养容器包含培养皿、培养板、烧瓶、培养瓶和小玻璃瓶。所述培养容器例如和/>可从各种制造商处购得。
根据具体的实施例,所述培养容器是一组织培养板,例如6孔板、24孔板、48孔板和96孔板。
根据一个具体的实施例,所述培养容器是一组织培养6孔板。
根据具体的实施例,所述培养容器未预先涂覆有从匹配的组织中提取的蛋白质(例如,当所述组织是癌组织时,则所述培养容器未预先涂覆有阶段和等级匹配的肿瘤提取蛋白质)。这些蛋白质的非限制性示例包含ECM蛋白质,例如胶原蛋白、纤连蛋白、层粘连蛋白、玻连蛋白、钙粘蛋白、细丝蛋白A、波形蛋白、骨桥蛋白、核心蛋白聚糖、生腱蛋白X、基底膜蛋白、细胞骨架蛋白和基质蛋白;及成长因素。
本发明使用的培养基可以是水基介质,其包含诸如盐、营养物、矿物质、维生素、氨基酸、核酸和/或诸如细胞因子、生长因子和激素的蛋白质之类物质的组合,所有这些是细胞增殖所必需的,并且能够维持组织的结构和生存力。例如,培养基可以是合成组织培养基,例如DMEM/F12(可以从例如Biological Industries公司获得),M199(可以例如从Biological Industries公司获得),RPMI(可以例如从Gibco-Invitrogen Corporation公司的产品获得),M199(可以例如从Sigma-Aldrich公司获得),Ko-DMEM(可以例如从Gibco-Invitrogen Corporation公司产品获得),添加必要的添加剂,如下文进一步所述。优选地,本发明的培养基中包含的所有成分基本上是纯的,具有一组织培养等级。
本领域技术人员会知道为每种预期的组织选择培养基。
根据本发明的具体实施例,所述培养基包含血清,例如胎牛血清(FCS,可以从例如Gibco-Invitrogen Corporation公司产品获得)。
根据具体的实施例,所述培养基包含少于10%的血清。
根据具体的实施例,所述培养基包含从与培养组织相同物种获得的小于2%的血清。
根据具体的实施例,所述培养基不含从与培养的组织相同的物种获得的血清。
根据具体的实施例,所述培养基包含少于2%的培养组织(即来自同一对象)的自体血清。
根据具体的实施例,所述培养基没有培养组织(即来自同一对象)的自体血清。
根据具体的实施例,所述培养基包含少于2%的人体血清。
根据本发明的一些实施例,所述培养基不含人体血清。
根据本发明的一些实施例,所述培养基不含任何动物污染物,即动物细胞、液体或病原体(例如感染动物细胞的病毒),即无异源性。
根据本发明的一些实施例,所述培养基可以进一步包含抗生素(例如青霉素、链霉素、庆大霉素)、抗真菌剂(例如两性霉素B),L-谷氨酰胺或NEAA(非必需氨基酸)。
根据一个具体的实施例,所述培养基包含血清和抗生素。
根据一个具体的实施例,所述培养基包含DMEM/F12、5%的FCS,谷氨酰胺,青霉素,链霉素,庆大霉素和两性霉素B。
应当注意的是,可以定期更新培养基,以维持足够水平的添加物并去除可能损坏组织的代谢废物。根据具体的实施例,每12至72小时、每24至72小时、每24至48小时或每12至48小时更新培养基。
根据具体的实施例,所述培养基每12至48小时更新一次。
根据一个具体的实施例,所述培养基在12至24小时后更新一次,然后约每48小时更新一次。
如本文所用,短语“组织培养插件”是指悬浮在用于组织培养的容器中的多孔膜,并且与随后的组织切片的体外培养相容。孔径能够支撑组织切片,而它对培养基则是可渗透的,从而使营养物质分别进入切片和代谢废物从切片离开。根据具体的实施例,所述组织切片被放置在所述组织培养插件上,从而允许培养基进入组织切片的顶表面和底表面。
根据具体的实施例,所述孔径为0.1微米至20微米、0.1微米至15微米、0.1微米至10微米、0.1微米至5微米、0.4微米至20微米、0.4微米至10微米或0.4微米至5微米。
根据具体的实施例,所述孔径为0.4毫米至4毫米、0.4毫米至1毫米、1毫米至4毫米、1毫米至3毫米或1毫米至2毫米。
根据具体的实施例,所述组织培养插件是无菌的。
根据具体的实施例,所述组织培养插件是一次性的。
根据具体的实施例,所述细胞培养插件是可重复使用的和可高压灭菌的。
所述细胞培养插件可以是合成的或天然的,它可以是无机的或聚合的,例如钛、氧化铝、聚四氟乙烯(PTFE)、特氟隆、不锈钢、聚碳酸酯、硝化纤维和纤维素酯。根据具体的实施例,所述细胞培养插件是钛插件。可以与本发明的具体的实施例一起使用的细胞培养插件可以从例如Alabama研发公司、Millipore公司、Costar公司、康宁公司、Nunc公司、Vitron公司和SEFAR公司,包含但不限于MA0036孔板插件、BIOCOATTMTM、 -Cyclopore、/>Anapore、钛-筛网和特氟隆筛网。
根据具体的实施例,所述组织培养插件是钛网格插件,例如但不限于钛MA0036孔板插件(Alabama研发)。
根据具体的实施例,所述组织培养插件未涂覆有机材料,例如胶原蛋白、纤维粘连蛋白或聚乙二醇(PEG)。
根据具体的实施例,所述组织培养插件未涂覆从匹配的组织中提取的蛋白质(例如,当组织是癌组织时,所述组织培养插件未涂覆从阶段和等级匹配的肿瘤提取的蛋白)。
根据具体的实施例,所述组织切片与所述组织培养插件直接接触。
根据具体的实施例,所述组织切片没有通过异源有机材料例如胶原蛋白、纤维粘连蛋白或合成聚合物(其不是培养容器的一部分)例如聚乙二醇(PEG)与培养基分开。
根据具体的实施例,所述组织切片与培养基直接接触。
根据具体的实施例,所述组织切片被置于所述细胞培养插件的中间。因此,例如,当应用钛网格(例如,钛MA0036孔板插件)时,将所述组织切片放置在插件中间的凹处。
随后,所述组织切片在生理温度(例如37℃)在含有至少50%氧气和例如5%二氧化碳的高度氧合增湿的气氛中下培养(或保持)。
根据具体实施例,所述高度氧合气氛包含至少60%、至少70%或至少80%的氧。
根据具体实施例,所述高度氧合气氛包含至少70%的氧。
根据其他具体实施例,所述高度氧合气氛包含小于95%的氧。
根据一个具体的实施例,所述高度氧合气氛包含约80%的氧。
根据一个具体的实施例,在培养过程中,所述培养以旋转的方式搅拌,以促进培养基中组织切片的间歇浸没。
如本文所用,短语“旋转搅拌以促进组织切片在培养基中的间歇浸没”或“以旋转的方式搅拌以促进组织切片在培养基中的间歇浸没”是指搅拌以允许组织切片在培养基中间歇浸没,以促进营养物质和气体扩散在整个培养基中以及通过组织切片。
根据具体的实施例,所述搅拌是轨道的搅拌。
根据具体的实施例,所述搅拌是以一角度的搅拌,例如。所述角度为30度至45度。
根据具体的实施例,所述搅拌是通过一倾斜的旋转器(例如可从Alabama研发公司购买的MD2500孵育单元)进行。
根据具体的实施例,所述搅拌的频率是50至200rpm、50至150rpm或50至100rpm。
根据具体的实施例,所述搅拌的频率为约70rpm。
本发明的组织培养物和方法可以适用于许多应用,包含但不限于:
1.临床前和基础研究,包含:
-研究与健康和疾病有关的机制;
-筛选病理组织(例如肿瘤组织)是否存在特异性标志物;
-筛选和/或开发新型药物,例如抗癌药或新型药物组合;
-确定一批药物的效力;
-研究人体组织的敏感性和抗性的机制。因此,例如,可以利用多种药物和药物组合治疗同一肿瘤来进行详细的机制研究,而这种研究在人类患者中不容易进行。
-研究肿瘤微生物群系:癌症肿瘤中可能存在的细菌、病毒或真菌。
2.测试新药物或药物组合对肿瘤切片的作用,以便优先考虑药物或药物组合以进行进一步的药物开发以及机理研究、临床前体内试验和临床试验
3.预测患者对药物(例如抗癌药)和药物组合的反应,并因此使用此预测为患者量身定制具体的治疗方案(即个体化药物)。
4.当组织切片在培养5天后仍保持结构并具有较高的生存力时,此系统可以对慢性和急性毒性研究(包含组织的代谢活性)进行建模。
5.呈现阳性体外反应的培养可以用作将患者纳入临床试验的标准。因此,这一步骤可以预选具有高反应概率的患者,因此可以提高进行临床试验成功的机会。在这种情况下,体外组织培养以后可能会成为药物合格标准的一部分。
因此,根据具体的实施例,所述培养系统包含一药物。
根据其他具体的实施例,上文描述的本发明的方法包含添加一药物或一药物组合,如下文进一步描述。
如本文所用,短语“药物”是指具有抗病理作用的制剂,包含小分子和生物药物(例如核酸制剂、多肽、抗体、适体等)。通常,药物对于精密切割的组织切片,或者来自人体或组织中精密切割的组织切片是外源的。所述药物可以是监管机构批准用于病理治疗的一药物,也可以是开发中的药物。根据具体的实施例,所述药物是一批药物。
根据具体的实施例,所述药物是一抗发炎药。
可以与本发明的具体的实施例一起使用的抗发炎药的非限制性实施例包含:阿氯芬酸(Alclofenac);阿氯米松双丙酸酯(Alclometasone Dipropionate);阿孕奈德(Algestone Acetonide);α淀粉酶(Alpha Amylase);安西法尔(Amcinafal);安西非特(Amcinafide);氨芬酸钠(Amfenac Sodium);盐酸氨普立糖(Amiprilose Hydrochloride);阿那白滞素(Anakinra);阿尼罗酸(Anirolac);阿尼扎芬(Anitrazafen);阿扎丙宗(Apazone);巴柳氮二钠(Balsalazide Disodium);苄达酸(Bendazac);苯恶洛芬(Benoxaprofen);盐酸苄达明(Benzydamine Hydrochloride);菠萝蛋白酶(Bromelains);溴哌莫(Broperamole);布地奈德(Budesonide);卡洛芬(Carprofen);环洛芬(Cicloprofen);辛喷他宗(Cintazone);克利洛芬(Cliprofen);丙酸氯倍他索(ClobetasolPropionate);丁酸氯倍他松(Clobetasone Butyrate);氯苯吡咯酸(Clopirac);丙酸氯硫卡松(Cloticasone Propionate);醋酸三氟米松(Cormethasone Acetate);可托多松(Cortodoxone);地夫可特(Deflazacort);地奈德(Desonide);去羟米松(Desoximetasone);双丙酸地塞米松(Dexamethasone Dipropionate);双氯芬酸钾(Diclofenac Potassium);双氯芬酸钠(Diclofenac Sodium);醋酸双氟拉松(DiflorasoneDiacetate);二氟米酮钠(Diflumidone Sodium);二氟尼柳(Diflunisal);二氟泼尼酯(Difluprednate);双酞嗪酮(Diftalone);二甲基亚砜(Dimethyl Sulfoxide);羟西奈德(Drocinonide);恩甲羟松(Endrysone);恩莫单抗(Enlimomab);依诺利康钠(EnolicamSodium);依匹唑(Epirizole);依托度酸(Etodolac);依托芬那酯(Etofenamate);联苯乙酸(Felbinac);非那莫(Fenamole);芬布芬(Fenbufen);芬氯酸(Fenclofenac);苯克洛酸(Fenclorac);芬度柳(Fendosal);苯吡恶二酮(Fenpipalone);芬替酸(Fentiazac);夫拉扎酮(Flazalone);氟扎可特(Fluazacort);氟芬那酸(Flufenamic Acid);氟咪唑(Flumizole);醋酸氟尼缩松(Flunisolide Acetate);氟尼辛(Flunixin);氟尼辛葡甲胺(Flunixin Meglumine);氟可丁丁酯(Fluocortin Butyl);醋酸氟米龙(FluorometholoneAcetate);氟喹宗(Fluquazone);氟比洛芬(Flurbiprofen);氟瑞托芬(Fluretofen);丙酸氟替卡松(Fluticasone Propionate);呋喃洛芬(Furaprofen);呋罗布芬(Furobufen);哈西奈德(Halcinonide);卤倍他索丙酸酯(Halobetasol Propionate);醋酸卤泼尼松(Halopredone Acetate);异丁芬酸(Ibufenac);布洛芬(Ibuprofen);布洛芬铝(IbuprofenAluminum);皮考布洛芬(Ibuprofen Piconol);伊洛达普(Ilonidap);吲哚美辛(Indomethacin);吲哚美辛钠(Indomethacin Sodium);吲哚布洛芬(Indoprofen);吲哚克索(Indoxole);吲四唑(Intrazole);醋酸异氟泼尼龙(Isoflupredone Acetate);伊索克酸(Isoxepac);伊索昔康(Isoxicam);酮洛芬(Ketoprofen);盐酸洛非咪唑(LofemizoleHydrochloride);氯诺昔康(Lomoxicam);氯替泼诺(Loteprednol Etabonate);甲氯灭酸钠(Meclofenamate Sodium);甲氯芬那酸(Meclofenamic Acid);甲氯松二丁酯(MeclorisoneDibutyrate);甲芬那酸(Mefenamic Acid);氨水杨酸(Mesalamine);美西拉宗(Meseclazone);磺庚甲泼尼龙(Methylprednisolone Suleptanate);吗尼氟酯(momiflumate);萘丁美酮(Nabumetone);萘普生(Naproxen);萘普生钠(NaproxenSodium);萘普索(Naproxol);尼马宗(Nimazone);奥沙拉秦钠(Olsalazine Sodium);奥古蛋白(Orgotein);奥帕诺辛(Orpanoxin);奥沙普秦(Oxaprozin);羟基保泰松(Oxyphenbutazone);盐酸瑞尼托林(Paranyline Hydrochloride);戊糖多硫酸钠(Pentosan Polysulfate Sodium);保泰松甘油酸钠(Phenbutazone Sodium Glycerate);吡非尼酮(Pirfenidone);吡罗昔康(Piroxicam);肉桂酸吡罗昔康(PiroxicamCinnamate);吡罗昔康乙醇胺(Piroxicam Olamine);吡洛芬(Pirprofen);泼那扎特(Prednazate);普立非酮(Prifelone);普罗度酸(Prodolic Acid);普罗喹宗(Proquazone);普罗沙唑(Proxazole);枸橼酸普罗沙唑(Proxazole Citrate);利美索龙(Rimexolone);氯马扎利(Romazarit);柳胆来司(Salcolex);沙那西定(Salnacedin);双水杨酸(Salsalate);氯化血根碱(Sanguinarium Chloride);司克拉宗(Seclazone);丝美辛(Sermetacin);舒多昔康(Sudoxicam);舒林酸(Sulindac);舒洛芬(Suprofen);他美辛(Talmetacin);他尼氟酯(Talniflumate);他洛柳酯(Talosalate);特丁非隆(Tebufelone);替尼达普(Tenidap);替尼达普钠(Tenidap Sodium);噻吩昔康(Tenoxicam);替昔康(Tesicam);替昔米德(Tesimide);四氢甲吲胺(Tetrydamine);硫平酸(Tiopinac);特戊酸硫氢可的松(Tixocortol Pivalate);托麦汀(Tolmetin);托麦汀钠(Tolmetin Sodium);三氯奈德(Triclonide);三氟米酯(Triflumidate);齐多美辛(Zidometacin);佐美酸钠(Zomepirac Sodium)。
根据其他具体的实施方案,所述药物是一抗癌药。
如本文所用,短语“抗癌药”是指具有抗肿瘤作用的药剂,包含化学疗法、小分子、生物药物、激素疗法、抗体和靶向疗法。
可以与本发明的具体的实施方案一起使用的抗癌药包含但不限于:阿西维辛(Acivicin);阿柔比星(Aclarubicin);盐酸阿可达佐(Acodazole Hydrochloride);阿克罗宁(Acronine);多柔比星(Adriamycin);阿多来新(Adozelesin);阿地白介素(Aldesleukin);六甲蜜胺(Altretamine);安波霉素(Ambomycin);醋酸阿米坦酮(Ametantrone Acetate);氨鲁米特(Aminoglutethimide);安吖啶(Amsacrine);阿那曲唑(Anastrozole);安曲霉素(Anthramycin);门冬酰胺酶(Asparaginase);曲林菌素(Asperlin);阿扎胞苷(Azacitidine);阿扎替派(Azetepa);阿佐霉素(Azotomycin);巴马司他(Batimastat);苄替哌(Benzodepa);比卡鲁胺(Bicalutamide);盐酸必桑郡(Bisantrene Hydrochloride);双奈法德(Bisnafide Dimesylate);比折来新(Bizelesin);硫酸博莱霉素(Bleomycin Sulfate);布喹那钠(Brequinar Sodium);溴匹立明(Bropirimine);白消安(Busulfan);放线菌素C(Cactinomycin);卡鲁睾酮(Calusterone);卡醋胺(Caracemide);卡贝替姆(Carbetimer);卡铂(Carboplatin);卡莫司汀(Carmustine);盐酸洋红霉素(Carubicin Hydrochloride);卡折来新(Carzelesin);西地芬戈(Cedefingol);苯丁酸氮芥(Chlorambucil);西罗里霉素(Cirolemycin);顺铂(Cisplatin);克拉屈滨(Cladribine);甲磺酸克立那托(Crisnatol Mesylate);环磷酰胺(Cyclophosphamide);阿糖胞苷(Cytarabine);达卡巴嗪(Dacarbazine);放线菌素D(Dactinomycin);盐酸柔红霉素(Daunorubicin Hydrochloride);地西他滨(Decitabine);右奥马铂(Dexormaplatin);地扎呱宁(Dezaguanine);甲磺酸地扎呱宁(DezaguanineMesylate);亚丝醌(Diaziquone);多西他赛(Docetaxel);阿霉素(Doxorubicin);盐酸阿霉素(Doxorubicin Hydrochloride);屈洛昔芬(Droloxifene);枸橼酸屈洛昔芬(Droloxifene Citrate);屈他雄酮丙酸酯(Dromostanolone Propionate);达佐霉素(Duazomycin);依达曲沙(Edatrexate);盐酸依氟乌氨酸(Eflornithine Hydrochloride);依沙芦星(Elsamitrucin);恩洛铂(Enloplatin);恩普氨酯(Enpromate);依匹哌啶(Epipropidine);盐酸表柔比星(Epirubicin Hydrochloride);厄布洛唑(Erbulozole);盐酸依索比星(Esorubicin Hydrochloride);雌莫司汀(Estramustine);磷酸雌莫司汀钠(Estramustine Phosphate Sodium);依他硝唑(Etanidazole);依托泊苷(Etoposide);磷酸依托泊苷(Etoposide Phosphate);艾托卜宁(Etoprine);盐酸法屈唑(FadrozoleHydrochloride);法扎拉滨(Fazarabine);芬维A胺(Fenretinide);氟尿苷(Floxuridine);磷酸氟达拉滨(Fludarabine Phosphate);氟尿嘧啶(Fluorouracil);氟西他滨(Flurocitabine);磷喹酮(Fosquidone);福司曲星(Fostriecin Sodium);吉西他滨(Gemcitabine);盐酸吉西他滨(Gemcitabine Hydrochloride);羟基脲(Hydroxyurea);盐酸伊达比星(Idarubicin Hydrochloride);异环磷酰胺(Ifosfamide);伊莫福新(Ilmofosine);干扰素α-2a(Interferon Alfa-2a);干扰素α-2b(Interferon Alfa-2b);干扰素α-n1(Interferon Alfa-n1);干扰素α-n3(Interferon Alfa-n3);干扰素β-1a(Interferon Beta-I a);干扰素β-1b(Interferon Gamma-I b);异丙铂(Iproplatin);盐酸伊立替康(Irinotecan Hydrochloride);醋酸兰瑞肽(Lanreotide Acetate);来曲唑(Letrozole);醋酸亮丙瑞林(Leuprolide Acetate);盐酸利阿唑(LiarozoleHydrochloride);洛美曲索钠(Lometrexol Sodium);洛莫司汀(Lomustine);盐酸洛索蒽醌(Losoxantrone Hydrochloride);马索罗酚(Masoprocol);美登素(Maytansine);盐酸氮芥(Mechlorethamine Hydrochloride);醋酸甲地孕酮(Megestrol Acetate);醋酸美伦孕酮(Melengestrol Acetate);米尔法兰(Melphalan);美诺立尔(Menogaril);巯嘌呤(Mercaptopurine);甲氨蝶呤(Methotrexate);甲氨蝶呤钠(Methotrexate Sodium);氯苯氨啶(Metoprine);美妥替哌(Meturedepa);米丁度胺(Mitindomide);米托卡星(Mitocarcin);丝裂红素(Mitocromin);米托洁林(Mitogillin);米托马星(Mitomalcin);丝裂霉素(Mitomycin);米托司培(Mitosper);密妥坦(Mitotane);盐酸米托蒽醌(Mitoxantrone Hydrochloride);霉酚酸(Mycophenolic Acid);诺考达唑(Nocodazole);诺加霉素(Nogalamycin);奥马铂(Ormaplatin);奥昔舒仑(Oxisuran);紫杉醇(Paclitaxel);培门冬酶(Pegaspargase);佩里霉素(Peliomycin);奈莫司汀(Pentamustine);硫酸培洛霉素(Peplomycin Sulfate);培磷酰胺(Perfosfamide);哌泊溴烷(Pipobroman);哌泊舒凡(Piposulfan);盐酸吡罗蒽醌(Piroxantrone Hydrochloride);普卡霉素(Plicamycin);普洛美坦(Plomestane);卟吩姆钠(Porfimer Sodium);甲基丝裂霉素(Porfiromycin);泼尼莫司汀(Prednimustine);盐酸甲基苄肼(ProcarbazineHydrochloride);嘌呤霉素(Puromycin);盐酸嘌呤霉素(Puromycin Hydrochloride);吡唑呋喃菌素(Pyrazofurin);利波腺苷(Riboprine);罗谷亚胺(Rogletimide);沙芬戈(Safingol);盐酸沙芬戈(Safingol Hydrochloride);司莫司汀(Semustine);辛曲秦(Simtrazene);磷乙酰天冬氨酸钠(Sparfosate Sodium);司帕索霉素(Sparsomycin);盐酸螺旋锗(Spirogermanium Hydrochloride);螺莫司汀(Spiromustine);螺铂(Spiroplatin);链黑霉素(Streptonigrin);链佐星(Streptozocin);磺氯苯脲(Sulofenur);他利霉素(Talisomycin);紫杉醇(Taxol);替可加兰钠(Tecogalan Sodium);替加氟(Tegafur);盐酸替洛蒽醌(Teloxantrone Hydrochloride);替莫卟吩(Temoporfin);替尼泊苷(Teniposide);替罗昔隆(Teroxirone);睾内酯(Testolactone);硫咪嘌呤(Thiamiprine);硫鸟嘌呤(Thioguanine);塞替派(Thiotepa);噻唑呋林(Tiazofuirin);替拉扎明(Tirapazamine);盐酸拓扑替康(Topotecan Hydrochloride);枸橼酸托瑞米芬(Toremifene Citrate);醋酸曲托龙(Trestolone Acetate);磷酸曲西瑞宾(Triciribine Phosphate);三甲曲沙(Trimetrexate);三甲曲沙葡糖醛酸脂(Trimetrexate Glucuronate);曲普瑞林(Triptorelin);盐酸妥布氯唑(TubulozoleHydrochloride);尿嘧啶氮芥(Uracil Mustard);乌瑞替派(Uredepa);伐普肽(Vapreotide);维替泊芬(Verteporfin);硫酸长春碱(Vinblastine Sulfate);硫酸长春新碱(Vincristine Sulfate);长春地辛(Vindesine);硫酸长春地辛(Vindesine Sulfate);硫酸长春匹定(Vinepidine Sulfate);硫酸长春甘酯(Vinglycinate Sulfate);硫酸长春罗新(Vinleurosine Sulfate);酒石酸长春瑞滨(Vinorelbine Tartrate);硫酸长春罗定(Vinrosidine Sulfate);硫酸长春利定(Vinzolidine Sulfate);伏罗唑(Vorozole);折尼铂(Zeniplatin);净司他丁(Zinostatin);盐酸佐柔比星(Zorubicin Hydrochloride)。其他抗肿瘤药剂包含在抗肿瘤药剂,第52章(Paul Calabresi和Bruce A.Chabner)中公开的那些药剂,以及Goodman和Gilman的“治疗的药理学基础”第1202-1263页,第8版,1990年,McGraw-Hill公司(健康专业部门),以及其引文。
抗癌药物的非限制性示例包含:阿巴瑞克(abarelix),阿地白介素(aldesleukin),阿地白介素(aldesleukin),阿仑单抗(alemtuzumab),阿利维A酸(alitretinoin),别嘌醇(allopurinol),六甲蜜胺(altretamine),氨磷汀(amifostine),阿那曲唑(anastrozole),三氧化二砷(arsenic trioxide),门冬酰胺酶(asparaginase),阿扎胞苷(azacitidine),奥斯替尼(AZD9291),AZD4547,奥拉帕尼(AZD2281),贝伐单抗(bevacuzimab),贝沙罗汀(bexarotene),博莱霉素(bleomycin),硼替佐米(bortezomib),白消安(busulfan),卡鲁睾酮(calusterone),卡培他滨(capecitabine),卡铂(carboplatin),卡莫司汀(carmustine),塞来昔布(celecoxib),西妥昔单抗(cetuximab),顺铂(cisplatin),克拉屈滨(cladribine),氯法拉滨(clofarabine),环磷酰胺(cyclophosphamide),阿糖胞苷(cytarabine),达拉菲尼(dabrafenib),达卡巴嗪(dacarbazine),放线菌素D(dactinomycin),放线菌素D(actinomycin D),达依泊汀α(Darbepoetin alfa),达依泊汀α(Darbepoetin alfa),柔红霉素脂质体(daunorubicinliposomal),柔红霉素(daunorubicin),地西他滨(decitabine),地尼白介素(Denileukindiftitox),右雷佐生(dexrazoxane),右雷佐生(dexrazoxane),多西他赛(docetaxel),阿霉素(doxorubicin),屈他雄酮丙酸酯(dromostanolone propionate),埃利奥B溶液(Elliott's B Solution),表柔比星(epirubicin),阿法依泊汀(Epoetin alfa),厄洛替尼(erlotinib),雌莫司汀(estramustine),依托泊苷(etoposide),依西美坦(exemestane),非格司亭(Filgrastim),氟尿苷(floxuridine),氟达拉滨(fludarabine),氟尿嘧啶5-FU(fluorouracil 5-FU),氟维司琼(fulvestrant),吉非替尼(gefitinib),吉西他滨(gemcitabine),吉妥单抗(gemtuzumab ozogamicin),醋酸戈舍瑞林(goserelinacetate),醋酸组氨瑞林(histrelin acetate),羟基脲(hydroxyurea),替伊莫单抗(Ibritumomab Tiuxetan),伊达比星(idarubicin),异环磷酰胺(ifosfamide),甲磺酸伊马替尼(imatinib mesylate),干扰素α-2a(interferon alfa 2a),干扰素α-2b(Interferonalfa-2b),伊立替康(irinotecan),来那度胺(lenalidomide),来曲唑(letrozole),亚叶酸钙(leucovorin),醋酸亮丙瑞林(Leuprolide Acetate),左旋咪唑(levamisole),洛莫司汀(lomustine),洛莫司汀(CCNU),氮芥(meclorethamine),氮芥(nitrogen mustard),醋酸甲地孕酮(megestrol acetate),米尔法兰(melphalan),美法仑(L-PAM),巯嘌呤(mercaptopurine 6-MP),美司钠(mesna),甲氨蝶呤(methotrexate),丝裂霉素C(mitomycin C),密妥坦(mitotane),米托蒽醌(mitoxantrone),苯丙酸诺龙(nandrolonephenpropionate),奈拉滨(nelarabine),诺非单抗(Nofetumomab),奥普瑞白介素(Oprelvekin),奥普瑞白介素(Oprelvekin),奥沙利铂(oxaliplatin),紫杉醇(paclitaxel),帕博西尼(palbociclib)帕利夫明(palifermin),帕米磷酸二钠(pamidronate),培加酶(pegademase),培门冬酶(pegaspargase),非格司亭(Pegfilgrastim),培美曲塞二钠(pemetrexed disodium),喷司他丁(pentostatin),哌泊溴烷(pipobroman),普卡霉素(plicamycin mithramycin),卟吩姆钠(porfimer sodium),甲基苄肼(procarbazine),奎纳克林(quinacrine),拉布立酶(Rasburicase),利妥昔单抗(Rituximab),沙格司亭(sargramostim),索拉非尼(sorafenib),链佐星(streptozocin),苹果酸舒尼替尼(sunitinib maleate),他莫昔芬(tamoxifen),替莫唑胺(temozolomide),替尼泊苷(teniposide VM-26),睾内酯(testolactone),硫鸟嘌呤(thioguanine 6-TG),塞替派(thiotepa),塞替派(thiotepa),拓扑替康(topotecan),托瑞米芬(toremifene),托西莫单抗(Tositumomab),曲美替尼(Trametinib),曲妥珠单抗(Trastuzumab),维甲酸(tretinoin ATRA),尿嘧啶氮芥(Uracil Mustard),戊柔比星(valrubicin),长春碱(vinblastine),长春瑞滨(vinorelbine),唑来磷酸盐(zoledronate)及唑来膦酸(zoledronic acid)。
根据具体实施例,抗癌药物选自尤以下组成的群组:吉非替尼(Gefitinib),拉帕替尼(Lapatinib),阿法替尼(Afatinib),BGJ398,CH5183284,林西替尼(Linsitinib),PHA665752,克唑替尼(Crizotinib),舒尼替尼(Sunitinib),帕唑帕尼(Pazopanib),伊马替尼(Imatinib),芦可替尼(Ruxolitinib),达沙替尼(Dasatinib),BEZ235,PI3K抑制剂(Pictilisib),依维莫司(Everolimus),MK-2206,曲美替尼(Trametinib/AZD6244),威罗菲尼(Vemurafinib)/达拉菲尼(Dabrafenib),CCT196969/CCT241161,巴拉塞替(Barasertib),VX-680,Nutlin3,帕博西尼(Palbociclib),BI 2536,巴多索隆(Bardoxolone),伏立诺他(Vorinostat),Navitoclax(ABT263),硼替佐米(Bortezomib),维莫德吉(Vismodegib),奥拉帕尼(AZD2281),辛伐他汀(Simvastatin),5-氟尿嘧啶(5-Fluorouricil),伊立替康(Irinotecan),表柔比星(Epirubicin),顺铂(Cisplatin)及奥沙利铂(Oxaliplatin)。
根据具体的实施方案,所述抗癌药选自由以下组成的群组:4-过氧羟基环磷酰胺、5-氟尿嘧啶(5FU)、奥沙利铂、伊立替康、多西他赛、顺铂、曲美替尼、哌柏西利及AZD4547。
根据具体的实施方案,所述抗癌药选自由以下组成的群组:5-氟尿嘧啶(5FU)、奥沙利铂、伊立替康、顺铂、4-过氧羟基环磷酰胺、多西他赛(Decetaxel)、阿霉素、诺维本、吉西他滨(Gemcitanime)、吉非替尼、太莫西芬、奥拉帕利、曲美替尼、依维莫司和哌柏西利。
应当理解,本文所述的培养系统和方法可以用于测试药物组合的差异化效应。
因此,根据具体的实施方案,所述药物是一药物组合。
通过在不同的药物浓度上培养几种癌组织(相同或不同类型)并评估达到剂量依赖性反应的范围,可以得出本发明的培养系统和方法中药物的具体浓度。通常,此剂量依赖性范围反映了藉以培养的癌组织预期的反应或显示没反应的光谱,从而产生预测结果的范围。
根据具体的实施方案,本发明的培养系统和方法中的所述药物浓度至少与一细胞系(例如,相同组织类型和/或物种的细胞系)中的所述药物的IC50剂量相同。
根据具体的实施方案,本发明的培养系统和方法中的所述药物浓度高于一细胞系(例如,相同组织类型和/或物种的细胞系)中的所述药物的IC 50剂量。
根据具体的实施方案,本发明的培养系统和方法中的所述药物浓度为一细胞系(例如,相同组织类型和/或物种的细胞系)中的所述药物的IC50剂量的至少2倍、至少3倍、至少5倍、至少10倍、至少25倍、至少50倍、至少100倍。
根据具体的实施方案,本发明的培养系统和方法中的所述药物浓度为一细胞系(例如,相同组织类型和/或物种的细胞系)中的所述药物的IC50剂量的至少10倍。
可以与本发明的一些实施方案一起使用的抗癌药的具体的浓度在下文的表5至6中示出。
表5:具体的抗癌药浓度范围
表6:具体的抗癌药浓度
药物 | 浓度 |
5-FU | 80微摩尔/升 |
奥沙利铂 | 10微摩尔/升 |
伊立替康 | 30微摩尔/升 |
顺铂 | 20微摩尔/升 |
4-羟基环磷酰胺 | 10微摩尔/升 |
多西他赛 | 20微摩尔/升 |
阿霉素 | 5微摩尔/升 |
太莫西芬 | 10微摩尔/升 |
奥拉帕利 | 20微摩尔/升 |
曲美替尼 | 1微摩尔/升 |
吉西他滨 | 5微摩尔/升 |
根据具体的实施方案,来自一个组织的多个组织切片被制备并在几个培养容器(例如一多孔板)中培养,从而允许测试多种药物和药物组合。
根据具体的实施例,本发明的方法包含:
(i)根据本发明的方法确定多种(例如至少2种)药物的有效性;
(ii)根据步骤(i)确定显示为有效的药物的药物组合的有效性,其中所述组织对一种药物组合的增加的敏感性表明所述药物组合的有效性。
如本文所用,术语“增加的敏感性”是指与组合中的每种药物诱导的有效性相比,药物组合诱导的有效性增加,这可以是累加作用或协同作用。根据具体的实施方案,所述作用是协同作用。
根据具体的实施方案,与组合中所述多种药物中的每种药物诱导的有效性相比,所述增加至少1.5倍、至少2倍、至少3倍、至少5倍、至少10倍或至少20倍。
根据其他具体的实施方案,与组合中的所述多种药物中的每种诱导的有效性相比,所述增加为至少5%、至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少为80%、至少90%或大于100%。
如所提到的,根据具体的实施例,所述组织或组织切片可以被存储在即4℃或被超低温保存并根据需要解冻,从而允许系列地测试几种药物和多个药物组合。
因此,例如,根据具体的实施例,本发明的方法包含:
(i)根据本发明的方法确定至少两种药物的有效性;
(ii)根据本发明的方法(例如,在冷冻保存和解冻之后)培养从得自对象的病理组织中获得的一另外的组织切片;
(iii)根据步骤(i)加入确定对对象的疾病有效的多个药物的多个组合;和
(iv)确定所述多个药物的组合对所述组织切片的有效性,其中所述组织切片对所述多个药物的组合增加的敏感性表明所述多个药物的组合在对象中所述疾病的治疗的有效性。
可以在各个时间点将药物或药物组合添加到培养中。根据具体的实施方案,在培养开始后的2至48小时、2至36小时、2至24小时、12至48小时、12至36小时或12至24小时将药物添加到培养中。
根据一个具体的实施方案,在培养开始后12至24小时将药物或药物组合添加到培养中。
根据一个具体的实施方案,在培养开始后12至36小时将药物或药物组合添加到培养中。
根据一个具体的实施方案,在培养开始后12至48小时将药物或药物组合添加到培养中。
在药物或药物组合存在下的培养可以从第一次添加药物开始就可以在整个培养期间内进行,也可以在时间上加以限制。替代地或另外地,可以将药物或药物组合多次添加到培养中,例如当培养基更新时。
选择与药物或药物组合的药物浓度和孵育时间完全在本领域技术人员的能力范围内。
根据具体的实施方案,与药物或药物组合的药物浓度和孵育时间导致对组织的可检测作用,如下文进一步所述。
用于体外测试的药物浓度的选择在组织上可检测到的有效性完全在本领域技术人员的能力范围内。优选地,所使用的浓度应在所选参数的线性范围内。
测试药物浓度的数量可以在同一试验中是至少1、至少2、至少3、至少5、至少6、1至10、2至10、3至10、5至10、1至5、2至5及3至5种不同的浓度。
每个测试药物浓度的样品重复次数可以是2、3、4、5或6次重复。
培养后,可以确定药物或药物组合对组织的作用,从而确定一药物的有效性。
因此,根据本发明的另一方面,提供一种确定一药物或一批药物的有效性的方法,所述方法包含以下步骤:
(i)在含有至少50%的氧气的一高度氧合的气氛中,将位在一组织培养插件上的一精密切割的组织切片培养在一培养基中;及以一旋转搅拌所述培养,以促进所述组织切片在所述培养基中的间歇浸没。
(ii)将所述药物或所述批药物添加到所述培养基
(iii)确定所述药物或所述批药物对所述组织的作用,其中所述组织对所述药物的敏感性表示所述药物的有效性。
根据具体的实施方案,所述确定步骤在预定的培养时间之后进行。所述培养时间可以变化,并且将导致可察觉效果的培养时间的确定完全在本领域技术人员的能力范围内。
根据具体的实施方案,所述确定的步骤在培养的2至10天、2至7天、2至5天、3至10天、3至7天、3至5天或4至5天内进行。
根据一个具体的实施方案,所述确定的步骤在培养的3至5天内进行。
根据另一个具体实施方案,所述确定的步骤在培养的4至5天内进行。
确定由药物或药物组合引起的作用的方法在本领域中是已知的,并且包含例如:
可行性评估使用例如MTT试验,所述试验基于活细胞对黄色盐MTT(3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四氮唑溴化物)还原的选择性能力(Sigma,Aldrich公司,圣路易斯市,美国密苏里州)生成紫蓝色不溶的三苯基甲脂沉淀;WST测定法或ATP吸收测定法;
使用例如BrDu试验(细胞增殖ELISA BrdU比色试剂盒(罗氏公司,曼海姆,德国)或Ki67染色进行增殖评估;
细胞死亡评估使用例如TUNEL分析(罗氏,曼海姆,德国)、Annexin V分析(膜联蛋白V(Annexin V)细胞凋亡试剂盒(Clontech Laboratories公司,美国加州))、LDH分析、活化的半胱天冬酶-3(Activated Caspase 3)分析,活化的半胱天冬酶-8(Activated Caspase 8)分析和一氧化氮合酶测定
衰老评估使用例如衰老相关的半乳糖苷酶测定法(Dimri GP,Lee X等人,1995年,一种生物标记物,可识别体内培养物中和衰老的皮肤中的衰老人类细胞。美国国家科学院院刊92:9363-9367)和端粒酶缩短测定法;
细胞代谢评估使用例如葡萄糖摄取测定;
各种RNA和蛋白质检测方法(可检测表达水平和/或活性);以及
形态评估使用苏木精-伊红(H&E)染色;
根据具体的实施方案,所述确定的步骤是通过形态学评估、生存力评估、增殖评估和/或细胞死亡评估来实现。
根据具体的实施例,所述确定的步骤是通过形态评估来实现的。
使用H&E染色的形态评估可以提供有关细胞含量、大小和密度、活细胞/死细胞的比例、患病(例如肿瘤)细胞/健康细胞的比例、免疫细胞浸润、纤维化、核的大小和密度及完整性、凋亡小体和有丝分裂形态。根据具体的实施方案,所述药物对组织的有效性通过形态评估,例如通过一病理学家确定。
通常,每个测定的结果均以数字形式表示,其中高分与药物敏感性相关,低分与药物抗性相关。
如本文所用,短语“对药物的敏感性”或“对药物组合的敏感性”是指药物或药物组合诱导细胞变化的能力,例如细胞活力、增殖率、分化、细胞死亡、坏死、凋亡、衰老、特定基因的转录和/或转译速率和/或蛋白质状态的变化,例如磷酸化、去磷酸化、易位及其任何组合。根据具体的实施方案,与不存在药物的情况相比,细胞的变化通过细胞活力降低、增殖速率降低、细胞死亡增加和/或异常形态来反映。
根据一个具体的实施方案,所述细胞变化由细胞活力降低反映。
根据一个具体的实施方案,所述细胞变化由异常形态反映。
根据具体的实施方案,与不存在药物的情况相比,所述变化为至少1.5倍、至少2倍、至少3倍、至少5倍、至少10倍或至少20倍。
根据其他具体实施方式,与不存在所述药物的情况相比,所述变化为至少5%、至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少99%或至少100%。
根据具体的实施方案,药物所确定的有效性表示一批药物的效力,即,药物敏感性表示该批次有效。
如本文所用,术语“效力”是指基于与相关生物特性相关联的药物的属性,对药物的生物活性的测量(即,药物敏感性)。
根据本发明的具体实施方式,所述方法包含将组织对药物的敏感性和所述组织对所述药物的参考标准批次的敏感性比较,以确定所述批次的相对效力。
如本文所用,术语“相对效力”是指相对于具有已知效力的药物的参考标准(RS),对一批药物的效力的定性测量。
根据具体的实施例,相对于参考标准(RS)的已知效能来确定一批药物的效能。
如本文所用,短语“参考标准”或“RS”是指一标准化药物,其用作药物的测量基础。RS提供了可校准的生物有效性水平,可以药物的新制剂进行比较。
根据一个具体实施方案,所述RS的特征在于有效治疗疾病(例如炎性疾病、癌症)的活性成分的最佳效力和质量。
计算效力和相对效力在本领域中是已知的。根据具体的实施方案,使用适合于生物测定的软件,例如平行线分析软件,例如PLA(Stegmann Systems GmbH公司)和Gen5数据分析软件(BioTek公司),来计算相对效价。
本发明实施例的方法和/或系统的实现可以包含手动、自动或其组合来执行或完成所选择的任务。此外,根据本发明的方法和/或系统的实施例的实际仪器和设备,可以使用操作系统通过硬件、软件、固件或它们的组合来实现几个选择的任务。
根据具体的实施方案,所确定的药物或药物组合的有效性表示药物用于治疗一疾病的适用性。
正如本发明人所示,所开发的EVOC系统可以预测肿瘤对抗癌药和联合治疗的反应(以下实施例部分中的实施例2),本发明还考虑了本文所述的培养系统和方法在预测特定对象对治疗方案的反应的用途,从而为所述特定对象选择合适的治疗方案,并根据所述选择对所述对象进行治疗。
因此,根据本发明的一个方面,提供了一种对一有需要的对象选择用于治疗一疾病的一药物的方法,所述方法包含:
(i)在含有至少50%的氧气的一高度氧合的气氛中,将位在一组织培养插件上的一精密切割的组织切片培养在一培养基中;及以一旋转搅拌所述培养,以促进所述组织切片在所述培养基中的间歇浸没;
(ii)将所述药物添加到所述培养基;及
(iii)确定所述药物对所述组织的作用,其中所述组织对所述药物的敏感性表示所述药物对于所述对象治疗所述疾病的有效性。
根据本发明的另一方面,提供了一种对一有需要的对象治疗一疾病的方法,该方法包含:
(a)根据本文所述方法选择一药物或多个药物的一组合;及
(b)向所述对象施用证实对所述对象的所述疾病的治疗具备有效性的一治疗有效量的一药物,从而治疗所述对象的所述疾病。
如本文所用,短语“对象”是指被诊断出患有疾病或处于罹患疾病的风险中的哺乳动物对象(例如,人)。还考虑了兽医用途。所述对象可以是任何性别和任何年龄的人,包含新生儿、婴儿、少年、青少年、成人和老年人。
术语“治疗”是指抑制或中止一病理(疾病、病症或病状)的发展和/或造成一病理的减轻、缓解或消退。本领域技术人员将理解,各种方法和测定可用于评估病理的发展,并且类似地,各种方法和测定可用于评估病理的减少、缓解或消退。
确定一药物或一药物组合的治疗有效量在本领域技术人员的能力范围内。所述剂量可以根据所选择的药物、所采用的剂型和所采用的给药途径而变化。具体的制剂、给药途径和剂量可以由个别医师根据患者的状况来选择。(参见,例如,Fingl等人,1975年,在“治疗学的理论基础”,第1章,第1页中)。
根据具体的实施方案,所述疾病是一炎症疾病,其可以是慢性炎症疾病的急性炎症疾病。
与过敏反应有关的炎症疾病
过敏反应的非限制性示例包含:
II型过敏反应,包含但不限于类风湿性疾病、类风湿性自身免疫性疾病、类风湿性关节炎(Krenn V.等人,Histol Histopathol期刊2000年7月;15(3):791)、脊柱炎、强直性脊柱炎(Jan Voswinkel等人,关节炎研究2001;3(3):189)、全身性疾病、全身自身免疫性疾病、系统性红斑狼疮(Erikson J.等人,Immunol Res期刊1998年;17(1-2):49)、硬化、全身性硬化(Renaudineau Y等人,Clin Diagn Lab Immunol.期刊1999年3月;6(2):156);ChanOT.等人,Immunol Rev期刊1999年六月;169:107)、腺体疾病、腺体自身免疫性疾病、胰腺自身免疫性疾病、糖尿病、I型糖尿病(Zimmet P.Diabetes Res Clin Pract期刊1996年十月;34增刊S125)、甲状腺疾病、自身免疫甲状腺疾病、格雷夫斯病(Orgiazzi J.EndocrinolMetab Clin North Am期刊2000年六月;29(2):339)、甲状腺炎、自发性自身免疫性甲状腺炎(Braley-Mullen H.和Yu S,J Immunol期刊2000年12月15日;165(12):7262)、桥本氏甲状腺炎(Toyoda N.等人,Nippon Rinsho期刊1999年8月;57(8):1810)、粘液水肿、特发性粘液水肿(Mitsuma T.Nippon Rinsho.期刊1999年八月;57(8):1759);自身免疫性生殖疾病、卵巢疾病、卵巢自身免疫性疾病(Garza KM.等人,J Reprod Immunol期刊1998年2月;37(2):87)、自身免疫性抗精子不育症(Diekman AB.等人,Am J Reprod Immunol.期刊2000年3月;43(3):134)、反复胎儿流失(Tincani A.等人,Lupus期刊1998年;7增刊2:S107-9)、神经退行性疾病、神经系统疾病、神经系统自身免疫性疾病、多发性硬化(Cross AH.等人,JNeuroimmunol期刊2001年1月1日;112(1-2):1)、阿尔茨海默氏病(Oron L.等人,J NeuroTransm增刊.期刊1997年;49:77)、重症肌无力(Infante AJ.及Kraig E,Int Rev Immunol期刊1999年;18(1-2):83)、运动神经病变(Kornberg AJ.J Clin Neurosci.期刊2000年5月;7(3):191)、格林-巴利综合征、神经病变和自身免疫性神经病变(Kusunoki S.Am,J MedSci.期刊2000年4月;319(4):234)、肌无力疾病、兰伯特-伊顿肌无力综合征(Takamori M.,Am J Med Sci.期刊2000年4月;319(4):204)、副肿瘤性神经系统疾病、小脑萎缩、副肿瘤性小脑萎缩、非副肿瘤性渐冻人综合征、小脑萎缩症、进行性小脑萎缩症、脑炎、拉斯穆森脑炎、肌萎缩性侧索硬化症、薛登汉氏舞蹈症、吉尔德拉图雷特综合征(Gilles de laTourette syndrome)、多发性内分泌病、自身免疫性多发性内分泌病(Antoine JC.和Honnorat J.,Rev Neurol期刊(Paris)2000年1月;156(1):23);神经病变、免疫障碍性神经病变(Nobile-Orazio E.等人,Electrophaphalogr Clin Neurophysiol期刊增刊1999年;50:419);神经性肌强直、后天性神经性肌强直、先天多发性关节挛缩症(Vincent A.等人,Ann NY Acad Sci.期刊1998年5月13日;841:482)、心血管疾病、心血管自身免疫性疾病、动脉粥样硬化(Matsuura E.等人,Lupus.期刊1998年;7增刊2:S135)、心肌梗塞(VaaralaO.Lupus.期刊1998年;7增刊2:S132)、血栓形成(Tincani A.等人,Lupus期刊1998年;7增补2:S107-9)、肉芽肿病、韦格纳肉芽肿病、动脉炎、高安氏动脉炎和川崎综合征(PraprotnikS.等人,Wien Klin Wochenschr期刊2000年8月25日;112(15-16):660);抗VIII因子自身免疫疾病(Lacroix-Desmazes S.等人,Semin Thromb Hemost.期刊2000年;26(2):157);血管炎、坏死性小血管性血管炎、显微镜下多发性血管炎、查格-施特劳斯氏综合征、肾小球肾炎、少免疫性局灶性坏死性肾小球肾炎、新月型肾小球肾炎(Noel LH.,Ann Med Interne期刊(Paris)2000年5月;151(3):178);抗磷脂综合征(Flamholz R.等人,J Clin Apheresis期刊1999年;14(4):171);心力衰竭、心力衰竭中的激动剂样β-肾上腺素受体抗体(Wallukat G.等人,Am J Cardiol.期刊1999年6月17日;83(12A):75H)、血小板减少性紫癜(Moccia F.,Ann Ital Med Int.期刊1999年4月-6月;14(2):114);溶血性贫血、自身免疫性溶血性贫血(Efremov DG.等人,Leuk Lymphoma期刊1998年1月;28(3-4):285)、胃肠道疾病、胃肠道自身免疫性疾病、肠道疾病、慢性炎症性肠道疾病(Garcia Herola A.等人,Gastroenterol Hepatol.期刊2000年1月;23(1):16)、腹腔疾病(Landau YE.及ShoenfeldY.,Harefuah期刊2000年1月16日;138(2):122)、肌肉组织自身免疫性疾病、肌炎、自身免疫性肌炎、干燥综合征(Feist E.等人,Int Arch Allergy Immunol期刊2000年9月;123(1):92);平滑肌自身免疫病(Zauli D.等人,Biomed Pharmacother期刊1999年6月;53(5-6):234)、肝病、肝自身免疫病、自身免疫性肝炎(Manns MP.,J Hepatol期刊2000年8月;33(2):326))和原发性胆汁性肝硬化(Strassburg CP.等人,Eur J Gastroenterol Hepatol.期刊1999年6月;11(6):595);
IV型或T细胞介导的过敏反应,包含但不限于类风湿性疾病、类风湿性关节炎(Tisch R,McDevitt HO.,美国国家科学院院刊1994年1月18日;91(2):437)、系统性疾病、全身性自身免疫疾病、系统性红斑狼疮(Datta SK.,Lupus期刊1998年;7(9):591)、腺体疾病、腺体自身免疫性疾病、胰腺疾病、胰腺自身免疫性疾病、1型糖尿病(Castano L.和Eisenbarth GS.,Ann.Rev.Immunol.期刊8:647);甲状腺疾病、自身免疫性甲状腺疾病、格雷夫斯病(Sakata S.等人,Mol Cell Endocrinol期刊1993年3月;92(1):77);卵巢疾病(Garza KM.等人,J Reprod Immunol期刊1998年2月;37(2):87)、前列腺炎、自身免疫性前列腺炎(Alexander RB.等人,Urology期刊1997年12月;50(6):893)、多腺综合征、自身免疫多腺综合征、I型自身免疫多腺综合征(Hara T.等人,Blood.期刊1991年3月1日;77(5):1127)、神经系统疾病、自身免疫神经系统疾病、多发性硬化症、神经炎、视神经炎(Soderstrom M.等人,J Neurol Neurosurg Psychiatry期刊1994年5月;57(5):544)、重症肌无力(Oshima M.等人,Eur J Immunol期刊1990年12月;20(12):2563)、全身肌强直综合症(Hiemstra HS.等人,美国国家科学院院刊2001年3月27日;98(7):3988)、心血管疾病、恰加斯病中的心脏自身免疫性疾病(Cunha-Neto E.等人,J Clin Invest期刊1996年10月15;98(8):1709)、自身免疫性血小板减少性紫癜(Semple JW.等人,Blood期刊1996年5月15;87(10):4245)、抗辅助性T淋巴细胞自身免疫(Caporossi AP.等人,Viral Immunol期刊1998年;11(1):9)、溶血性贫血(Sallah S.等人,Ann Hematol期刊1997年3月;74(3):139)、肝病、肝自身免疫性疾病、肝炎、慢性活动性肝炎(Franco A.等人,Clin ImmunolImmunopathol期刊1990年3月;54(3):382)、胆汁性肝硬化、原发性胆汁性肝硬化(JonesDE.,Clin Sci(Colch)期刊1996年11月;91(5):551)、肾病、肾自身免疫性疾病、肾炎、间质性肾炎(Kelly CJ.,J Am Soc Nephrol期刊1990年8月;1(2):140)、结缔组织疾病、耳朵疾病、自身免疫结缔组织疾病、自身免疫性耳朵疾病(Yoo TJ.等人,Cell Immunol期刊1994年8月;157(1):249)、内耳疾病(Gloddek B.等人,Ann NY Acad Sci期刊1997年12月29日;830:266)、皮肤病(skin diseases)、皮肤病(cutaneous diseases)、皮肤病(dermaldiseases)、大疱性皮肤病、寻常型天疱疮、类大泡性天疱疮和落叶状天疱疮;
迟发型过敏反应包含但不限于接触性皮炎和药疹。
自身免疫性疾病
包含但不限于心血管疾病、类风湿性疾病、腺体疾病、胃肠道疾病、皮肤疾病、肝病、神经病变、肌肉疾病、肾病、与生殖有关的疾病、结缔组织疾病和全身性疾病。
自身免疫性心血管疾病的示例包含但不限于动脉粥样硬化(Matsuura E.等人,Lupus.期刊1998年;7增刊2:S135)、心肌梗塞(Vaarala O.,Lupus.期刊1998年;7增刊2:S132)、血栓形成(Tincani A.等人,Lupus.1998年;7增刊2:S107-9)、韦格纳肉芽肿病、高安氏动脉炎、川崎综合征(Praprotnik S.等人,Wien Klin Wochenschr期刊2000年8月25;112(15-16):660)、抗VIII因子自身免疫性疾病(Lacroix-Desmazes S.等人,Semin ThrombHemost.期刊2000年;26(2):157)、坏死性小血管血管炎、显微镜下多发性血管炎、查格-施特劳斯氏综合征、少免疫性局灶性坏死性和新月型肾小球肾炎(Noel LH.Ann Med Interne期刊(Paris)2000年5月;151(3):178)、抗磷脂综合征(Flamholz R.等人,J ClinApheresis期刊1999年;14(4):171)、抗体引起的心力衰竭(Wallukat G.等人,Am JCardiol.期刊1999年6月17;83(12A):75H)、血小板减少性紫癜(Moccia F.,Ann Ital MedInt.期刊1999年4月-6月;14(2):114;Semple JW.等人,Blood期刊1996年5月15日;87(10):4245)、自身免疫性溶血性贫血(Efremov DG.等人,Leuk Lymphoma期刊1998年1月;28(3-4):285;Sallah S.等人,Ann Hematol期刊1997年3月;74(3):139)、恰加斯病的心脏自身免疫性疾病(Cunha-Neto E.等人,J Clin Invest期刊1996年10月15日;98(8):1709)和抗辅助性T淋巴细胞自身免疫(Caporossi AP.等人,Viral Immunol期刊1998年;11(1):9)。
自身免疫性类风湿疾病的示例包含但不限于类风湿关节炎(Krenn V.等人,Histol Histopathol期刊2000年7月;15(3):791;Tisch R,McDevitt HO.美国国家科学院院刊1994年1月18日;91(2):437)和强直性脊柱炎(Jan Voswinkel等人,Arthritis Res期刊2001;3(3):189)。
自身免疫性腺疾病的示例包含但不限于胰腺疾病、I型糖尿病、甲状腺疾病、格雷夫斯病、甲状腺炎、自发性自身免疫性甲状腺炎、桥本甲状腺炎、特发性粘液水肿、卵巢自身免疫性、自身免疫性抗精子不育症、自身免疫性前列腺炎和I型自身免疫性多腺综合征。疾病包含但不限于胰腺自身免疫性疾病、1型糖尿病(Castano L.和Eisenbarth GS.,Ann.Rev.Immunol.期刊8:647;Zimmet P.,Diabetes Res Clin Pract期刊1996年10月;34增刊:S125)、自身免疫性甲状腺疾病、格雷夫斯病(Orgiazzi J.,Endocrinol Metab ClinNorth Am期刊2000年6月;29(2):339;Sakata S.等人,Mol Cell Endocrinol期刊1993年3月;92(1):77)、自发性自身免疫性甲状腺炎(Braley-Mullen H.和Yu S,J Immunol期刊2000年12月15;165(12):7262)、桥本氏甲状腺炎(Toyoda N.等人,Nippon Rinsho期刊1999年8月;57(8):1810)、特发性粘液性水肿(Mitsuma T.,Nippon Rinsho.期刊1999年8月;57(8):1759)、卵巢自身免疫(Garza KM.等人,J Reprod Immunol期刊1998年2月;37(2):87)、自身免疫抗精子不育(Diekman AB.等人,Am J Reprod Immunol.期刊2000年3月;43(3):134)、自身免疫性前列腺炎(Alexander RB.等人,Urology期刊1997年12月;50(6):893)和I型自身免疫性多腺综合征(Hara T.等人,Blood.期刊1991年3月1日;77(5):1127)。
自身免疫性胃肠疾病的示例包含但不限于慢性炎症性肠疾病(Garcia Herola A.等人,Gastroenterol Hepatol.期刊2000年1月;23(1):16)、腹腔疾病(Yandau YE.和Shoenfeld Y.,Harefuah期刊2000年1月16;138(2):122)、结肠炎、回肠炎和克罗恩氏病。
自身免疫性皮肤病的示例包含但不限于自身免疫性大疱性皮肤病,例如但不限于寻常性天疱疮、大疱性天疱疮和叶状天疱疮。
自身免疫性肝病的示例包含但不限于肝炎、自身免疫性慢性活动性肝炎(FrancoA.等人,Clin Immunol Immunopathol期刊1990 3月;54(3):382)、原发性胆汁性肝硬化(Jones DE.,Clin Sci(Colch)期刊1996年11月;91(5):551;Strassburg CP.等人,Eur JGastroenterol Hepatol.期刊1999年6月;11(6):595)和自身免疫性肝炎(Manns MP.,JHepatol期刊2000年8月;33(2):326)。
自身免疫性神经疾病的示例包含但不限于多发性硬化症(Cross AH.等人,JNeuroimmunol期刊2001年1月1日;112(1-2):1)、阿尔茨海默氏病(Oron L.等人,J NeuralTransm期刊增刊1997年;49:77)、重症肌无力(Infante AJ.和Kraig E,Int Rev Immunol期刊1999年;18(1-2):83;Oshima M.等人,Eur J Immunol期刊1990年12月;20(12):2563)、神经病变、运动神经病变(Kornberg AJ.,J Clin Neurosci.期刊2000年5月;7(3):191);格林-巴利综合征和自身免疫性神经病变(Kusunoki S.,Am J Med Sci.期刊2000年4月;319(4):234)、肌无力、兰伯特-伊顿肌无力综合征(Takamori M.,Am J Med Sci.期刊2000年4月;319(4)):204);副肿瘤性神经疾病、小脑萎缩、副肿瘤性小脑萎缩和僵硬综合症(Hiemstra HS.等人,美国国家科学院院刊2001年3月27日;98(7):3988);非副肿瘤性僵硬综合症、进行性小脑萎缩症、脑炎、拉斯穆森氏脑炎、肌萎缩性侧索硬化症、薛登汉氏舞蹈症、吉尔德拉图雷特综合症和自身免疫性多发性内分泌病(Antoine JC.和Honnorat J.,Rev Neurol期刊(Paris)2000年1月;156(1):23);免疫障碍性神经病变(Nobile-Orazio E.等人,Electrophapharr Clin Neurophysiol期刊增刊1999年;50:419);获得性神经性肌强直、多发性先天性关节炎(Vincent A.等人,Ann NY Acad Sci.期刊1998年5月13;841:482)、神经炎、视神经炎(Soderstrom M.等人,J Neurol Neurosurg Psychiatry期刊1994年5月;57(5):544)和神经退行性疾病。
自身免疫性肌肉疾病的示例包含但不限于肌炎、自身免疫性肌炎和原发性干燥综合征(Feist E.等人,Int Arch Allergy Immunol期刊2000年9月;123(1):92)和平滑肌自身免疫性疾病(Zauli D等人,Biomed Pharmacother期刊1999年6月;53(5-6):234)。
自身免疫性肾病的示例包含但不限于肾炎和自身免疫性间质性肾炎(Kelly CJ.,J Am Soc Nephrol期刊1990年8月;1(2):140)。
与生殖有关的自身免疫疾病的示例包含但不限于反复的胎儿流失(Tincani A.等人,Lupus期刊1998年;7增刊2:S107-9)。
自身免疫性结缔组织疾病的示例包含但不限于耳部疾病、自身免疫性耳部疾病(Yoo TJ.等人,Cell Immunol期刊1994年8月;157(1):249)和内耳自身免疫性疾病(Gloddek B.等人,Ann N Y Acad Sci期刊,1997年12月29日;830:266)。
自身免疫性系统疾病的示例包含但不限于系统性红斑狼疮(Erikson J.等人,Immunol Res期刊1998年;17(1-2):49)和系统性硬化症(Renaudineau Y.等人,Clin DiagnLab Immunol.期刊1999年3月;6(2):156;Chan OT.等人,Immunol Rev期刊1999年6月;169:107)。
传染性疾病
传染病的示例包含但不限于慢性传染病、亚急性传染病、急性传染病、病毒性疾病、细菌性疾病、原生动物疾病、寄生虫病、真菌病、支原体病和朊病毒病。
根据具体的实施方案,所述疾病是癌症。
术语“癌症”和“癌性的(cancerous)”描述了哺乳动物中典型特征是细胞生长不受调控的生理状况。如本文所用,术语“癌症”和“癌性的”是指任何实体肿瘤、癌症转移和/或实体癌前病变。
癌症的示例包含但不限于癌(carcinoma)、母细胞瘤、肉瘤和淋巴瘤。此类癌症的更具体示例包含鳞状细胞癌、肺癌(包含小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞状癌)、神经胶质瘤、黑色素瘤癌、腹膜癌、肝细胞癌、胃癌(gastric)、胃食管癌或胃癌(stomachcancer)(包含胃肠道癌)、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝癌(hepatoma)、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、涎腺癌、软组织肉瘤、肾脏癌(kidney或renal cancer)、前列腺癌、外阴癌、甲状腺癌、肝癌(hepaticcarcinoma)、卡波济氏肉瘤类癌(Kaposi's sarcoma carcinoid carcinoma)和各种类型的头颈癌。
癌前病变在本领域中是充分表征和已知的(例如,参见Berman JJ.和Henson DE.,2003年,癌前病变分类:元数据方法,BMC Med Inform Decis Mak.期刊3:8”)。癌前病变的示例包含但不限于后天性小癌前病变,具有核异型的后天性大病变,由遗传性增生综合症进展为癌症的癌前病变,以及后天弥漫性增生和弥漫性化生。小癌前病变的非限制性示例包含HGSIL(宫颈高度鳞状上皮内病变)、AIN(肛门上皮内瘤变)、声带发育不良、(结肠)异常隐窝、PIN(前列腺上皮内瘤变)。
具有核异型的后天性大病变的非限制性示例包含肾小管腺瘤、AILD(伴蛋白异常的血管免疫母细胞性淋巴结病)、非典型脑膜瘤、胃息肉、大斑块状副银屑病(large plaqueparapsoriasis)、骨髓增生异常(myelodysplasia)、原位乳头移行细胞癌(papillarytransitional cell carcinoma in-situ)、难治性贫血伴过度成纤维细胞(refractoryanemia with excess blasts)、以及施耐德乳头状瘤(Schneiderian papilloma)。遗传性增生综合症进展为癌症的癌前病变的非限制性示例包含非典型痣综合征、C细胞腺瘤病和MEA。后天弥漫性增生和弥漫性化生的非限制性实例包含骨骼的佩吉特氏病(Paget'sdisease)和溃疡性结肠炎。
根据具体的实施方案,所述癌症选自:卵巢癌、结肠直肠癌、肺癌、胰腺癌、胃癌、胃食管癌和乳腺癌。
根据具体的实施方案,所述癌症是一转移性癌症。
由于可用各种其他技术来预测患者对治疗方案的反应,因此本发明的方法可以与本领域已知的其他方法组合,例如但不限于基因剖析,从患者肿瘤产生的肿瘤来源细胞系和患者来源的异种移植(PDX)模型,也将在下面的“示例”部分中进行介绍。
根据具体的实施方案,所述方法与基因剖析结合进行。
如本文所用,术语“基因剖析”是指使用任何合适的剖析技术例如但不限于DNA测序、RNA测序和微阵列技术的生物样品中的一组基因的分子特征。
如本文所用,术语“约”是指±10%
术语“包含(comprises、comprising、includes、including),“具有(having)”及其共轭词意指“包含但不限于”。
术语“由...组成(consisting of)”是指“包含并限于”。
术语“基本上由……组成(consisting essentially of)”是指所述组合物、方法或结构可包含另外的成分、步骤和/或部分,但前提是所述另外的成分、步骤和/或部分不会实质性地改变所要求的成分、方法或结构的基本和新颖特征。
如本文所使用的,单数形式“一(a、an)”,和“所述(the)”包含复数引用,除非上下文另外明确指出。例如,术语“一种化合物”或“至少一种化合物”可以包含多种化合物,包含其混合物。
在整个申请中,本发明的各种实施例可以以范围格式呈现。应当理解,范围格式的描述仅是为了方便和简洁,而不应被解释为对本发明范围的不灵活的限制。因此,应该认为范围的描述已经详细公开了所有可能的子范围以及该范围内的各个数值。例如,对范围从1到6的描述应被认为具有具体公开的子范围,例如从1到3,从1到4,从1到5,从2到4,从2到6。从3到6等,以及该范围内的单个数字,例如1、2、3、4、5和6。这与范围的广度无关。
每当在本文中表示数值范围时,其意图包含在表示范围内的任何引用数字(分数或整数)。短语“在第一指示数字和第二指示数字之间的范围(ranging/ranges between)”和“从第一指示数字到第二指示数字的范围(ranging/ranges from)”在本文中可互换使用,并且意在包含第一和第二指示数字以及它们之间的所有小数和整数。
如本文所用,术语“方法”是指用于完成给定任务的方式、手段、技术和过程,包含但不限于化学、药理、生物学、生物化学和医学领域的从业人员已知的方式、手段、技术和程序或从已知的方式、手段、技术和程序容易开发的方式、手段、技术和程序。
当提到特定的序列表时,应理解为该参考还包含基本上与其互补序列相对应的序列,包含由于例如测序错误、克隆错误或导致碱基替换(碱基缺失或碱基添加)的其他改变而引起的微小序列变化,条件是这种变异的频率小于50个核苷酸中的1个、或者小于100个核苷酸中的1个、或者小于200个核苷酸中的1个、或者小于500个核苷酸中的1个、或者小于1000个核苷酸中的1个、或者小于5,000个核苷酸中的1个、或者小于10,000个核苷酸中的1个。
应当理解,为清楚起见在单独的实施例的上下文中描述的本发明的某些特征也可以在单个实施例中组合提供。相反,为简洁起见,在单个实施例的上下文中描述的本发明的各种特征,也可以单独地或以任何合适的子组合或在本发明的任何其他所述的实施例中合适地提供。在各种实施例的上下文中描述的某些特征不应被认为是那些实施例的必要特征,除非该实施例没有那些要素就不能工作。
上文描述的和本文权利要求书中要求保护的本发明的各种实施例和方面在以下实施例中得到实验支持。
实施例
现在参考以下实施例,这些实施例与以上描述一起以非限制性方式示出了本发明的一些实施方案。
通常,本文所用的命名和本发明中所用的实验室方法包括分子、生化、微生物学和重组DNA技术。这些技术在文献中有详尽的解释。参见,例如,“分子克隆:实验室手册”,Sambrook等人,(1989)。“分子生物学的当前方案”,第I-III卷,Ausubel,R.M.,编辑(1994);Ausubel等人,“分子生物学的最新研究方法”,约翰威立出版社,马里兰州巴尔的摩(1989);Perbal,“分子克隆实用指南”,约翰威立出版社,纽约(1988年);Watson等人,“重组DNA”,Scientific American Books出版社,纽约;Birren等人编辑“基因组分析:实验室手册系列”,第一卷1-4,冷泉港实验室出版社,纽约(1998);美国专利第4,666,828号;第4,683,202号;第4,801,531号;第5,192,659号和第5,272,057号;“细胞生物学:实验室手册”,卷I-III,Cellis,J.E.编辑(1994);Freshney,Wiley-Liss,纽约(1994),第三版,“动物细胞的培养-基本技术手册”;“免疫学的当前方案”,第I-III卷,Coligan J.E.编辑(1994);Stites等人编辑,“基础和临床免疫学”(第8版),Appleton&Lange,诺沃克,CT(1994年);Mishell及Shiigi编辑,“细胞免疫学的选择方法”,W.H.Freeman&Co.,纽约(1980);可利用的免疫测定法在专利和科学文献中有广泛的描述,例如参见美国专利第3,791,932号;第3,839,153号;第3,850,752号;第3,850,578号;第3,853,987号;第3,867,517号;第3,879,262号;第3,901,654号;第3,935,074号;第3,984,533号;第3,996,345号;第4,034,074号;第4,098,876号;第4,879,219号;第5,011,771号和第5,281,521号;“寡核苷酸合成”,Gait,M.J.编辑(1984);“核酸杂交”,Hames,BD.和Higgins S.J.编辑(1985);“转录和翻译”,Hames,BD.和Higgins S.J.编辑(1984);“动物细胞培养”,Freshney,R.I.编辑(1986年);“固定化的细胞和酶”,IRL出版社,(1986年);“分子克隆实用指南”,Perbal,B.,(1984年)及“酶学方法”,第1-317卷,学术出版社;“PCR方案:方法和应用指南”,学术出版社,圣地亚哥,加利福尼亚(1990);Marshak等人,“蛋白质纯化和表征的策略-实验室课程手册”CSHL出版社(1996);所有这些文献均通过引用并入本文,如同在此完全阐述一样。本文档中提供了其他的一般参考。据信其中的过程在本领域中是众所周知的,并且为读者提供方便。其中包含的所有信息均通过引用并入本文。
材料和方法
组织切片:从小鼠PDX模型(Nod Scid Gamma小鼠,美国杰克逊实验室和/或哈兰实验室)获得健康和癌性组织(源自肺、结肠、乳腺或胰腺的肝癌、肺癌、结肠癌、乳腺癌、胰腺癌的组织或癌转移组织);人体活检和手术切除的组织;和人类来源的异种移植(卵巢癌,胰腺的PDX)。获得后,将新鲜组织立即置于冰冷的磷酸盐缓冲盐水(PBS,BiologicalIndustries公司,以色列贝特哈梅克基布兹)或冰冷的培养基(RPMI BiologicalIndustries公司)中。使用70%乙醇清洁精密组织切片机(CompresstomeTM VF-300:Precisionary Instruments Inc.公司,美国北卡罗来纳州),用无菌水冲洗两次,然后安装新刀片(Double Edge Blades 32017759Belgar公司,以色列耶路撒冷,)并定位到位。
组织保留在冰上,直到转移到预先清洁的组织切片器中;然后将组织从PBS中取出,并用接触胶将其轻轻附着在柱塞上,并稳定在3%的低凝胶琼脂糖中加热至50℃,然后在使用前冷却至凝固(琼脂糖,低凝胶A0701 Sigma-Aldrich公司,3%在0.9克NaCl中)。将带有组织的柱塞插入组织切片器中的指定位置,并在浴槽中加入添加了青霉素和链霉素的冰冷的Williams培养基E。为使介质在浴槽中保持低温,构造了一个位于浴槽中的空心冷却盘管。然后使用标准浸没泵将冰冷的水泵送通过盘管。将组织切成约250微米的切片。从一块1公分的组织中制备约30-40片。立即将两到三片切片置于一次性塑料组织学盒中,并固定在4%PFA中。
培养程序:将组织切片分别直接放置在6孔板(Corning CC-3516Getter,Petach-Tikva,以色列)中,直接放置在钛插件(MA0036孔插件,Alabama R&D公司,美国阿拉巴马州)顶部或PEG上或放置在钛插件上的PEG。每个孔包含4.5毫升的DMEM/F12或M199培养基,其中添加了青霉素(100IU/毫升)、链霉素(100微克/毫升)、庆大霉素(G1397 50微克/毫升,Sigma-Aldrich公司),5%胎牛血清(FCS,10270106Gibco,Sigma-Aldrich公司,以色列Rehovot)、两性霉素B(A-4888 2.5微克/毫升,Sigma-Aldrich公司)和谷氨酰胺(L-谷氨酰胺03-020-1B,100微升/毫升,Biological Industries公司)。培养板在37℃的潮湿培养箱中以5%二氧化碳及21%或80%氧气孵育(使用氧气室:BioSpherix C274,美国纽约州;氧气控制器:Biospherix ProOx C21,美国纽约州;及氧气98%,Maxima Air Innovations,Ashdod,以色列)。
将整个培养箱置于的轨道振动器(TOU-120N,MRC,Holon,以色列)上,以70rpm的速度搅拌。过夜孵育后,将培养基替换为新鲜培养基。在所示的孔中,新鲜培养基包含抗癌药:4-过氧羟基环磷酰胺(sc-206885,ENCO,Petach Tikva,以色列)、5-氟尿嘧啶(5FU,A10042,Adooq Biotag公司,Kfar Yona,以色列)、奥沙利铂(O9512,Sigma-Aldrich公司)、伊立替康(A10479-200,Adooq Biotag公司,Kfar Yona,以色列)、多西他赛(01885,Sigma-Aldrich公司)、顺铂(Sigma-Aldrich公司)、曲美替尼(A11029,Adooq Biotag公司,Kfar Yona,以色列)、CDK4/6抑制剂哌柏西利(PZ0199,Sigma-Aldrich公司)或FGFR抑制剂AZD4547(A11075-5,Adooq Biotag公司)。每48小时用新鲜的药物/DMSO更换培养基4-6天。
功能测定:培养结束前18至24小时,将BrdU添加到培养基(最终浓度:10μM/毫升)中,用于随后用抗BrdU抗体(BRDU+抗BRDU B5002,Sigma-Aldrich公司和94-MS-1058-P,Eldan公司,以色列Petach Tikva)和/或anti Ki67(94-RM-9106-S,Eldan公司,以色列Petach Tikva)染色。培养结束时,将组织置于两个玻璃盖玻片之间,置于一次性塑料组织学盒中,并在4%的聚甲醛(PFA)中固定过夜。切片后进行石蜡化,封闭并切成5微米切片进行苏木精-伊红(H&E)染色以及其他IHC染色,例如Ki67染色。
实施例1
维持健康和肿瘤组织切片的结构和功能的体外器官培养条件
为了在体外器官培养(EVOC)中获得至少5天的组织结构和功能,检验了几个条件。所述多个条件包括:
1.与直接将切片浸入培养基中相比,将组织切片培养在不同的表面,例如(如钛插件)上培养组织切片;
2.与含有80%氧气的高度氧合气氛相比,在21%氧气和5%二氧化碳的标准组织培养条件下孵育组织;
3.在每个孔中培养1个切片,与每个孔中培养几个切片相比;
4.使用不同的培养基,例如DMEM/F12和M199;
5.在有或没有钛插件的PEG上培养。
结果总结在下表1中。
为此,与21%氧气的标准组织培养条件相比,在含有80%氧气的高度氧合气氛下孵育组织显着提高了组织活力(图1示出了人类卵巢癌来源的异种移植的代表性培养)。此外,与直接将组织直接插入组织培养孔板中以使切片完全浸入培养基中相比,将组织支撑在允许培养基/空气界面的钛插件上时,组织可以更好地存活(图1示出了人类卵巢癌来源的异种移植的代表性培养)。此外,DMEM/F12是比M199更好的培养基(图2示出了人类卵巢癌来源的异种移植的代表性培养物)。
表1:不同培养条件下人体组织体外器官培养(EVOC)的总结
*实验一式两份或一式三份,以提高测定的稳定性。生存力百分比是通过对至少两个不同的独立观察者独自采取的最佳生存力区域进行形态学分析的主观评估。
**组织是从手术中获得并直接培养。
***PDX–患者来源异种移植,CRC-结肠直肠癌
上表1中提供的EVOC的组织全部来自手术。然而,开发的检测方法可适用于从肿瘤组织中通过核心活检(core biopsy)取出的小型活检组织(图9)。具体而言,将组织以两个步骤嵌入琼脂糖中:首先将液体琼脂糖置于一个小的金属托盘中,将核心活检样品置于琼脂糖上,然后将琼脂糖添加至活检样品的顶部。冷却托盘,将带有活组织检查的琼脂糖整体切出。在第二步中,将琼脂糖块通过接触胶(clue)固定到柱塞上,并以类似于组织切片的方式被琼脂糖包围。
总体而言,建立了来自代表多种组织的不同来源的EVOC,其在至少5天的培养中维持了组织的结构和活力(图1、2和11)。重要的是,所有组织均由病理学家检查,并被认为具有与患者常规病理组织相同形态的完全存活能力。
总之,在含有80%氧气的高度氧合气氛下,在DMEM/F12培养基中的钛插件中间直接培养一个组织切片,并在轨道摇动下搅动所述培养,以促进组织切片在培养基中的间歇浸没,以维持至少培养5天的组织结构和活力。此新开发的EVOC系统在以下的实施例中使用。
实施例2
开发的EVOC可用于预测肿瘤对抗癌药的反应
已开发的EVOC可以预测患者来源的异种移植对治疗的体内反应:从杰克逊实验室购买了几种已知的抗癌药体内反应的小鼠患者来源的异种移植(PDX)模型。从小鼠切除肿瘤,按照上文材料和方法以及实施例1中所述进行培养,并测试组织切片对抗癌剂的敏感性。总共测试了来自3种肿瘤类型(乳腺癌、肺癌和结肠直肠癌)的7个PDX模型,在所有测试模型中,开发的EVOC系统均能够正确预测肿瘤对药物治疗的敏感性(下表2和图3至图4)。另外,在EVOC系统中观察到明显的剂量依赖性反应。
因此,如在下面的图3至图4和表2中所示,对体内治疗具有抗性的肿瘤也对体外治疗具有抗性,即使施加非常高的剂量。相反地,采用体内对肿瘤敏感的治疗,在低药物浓度下,体外检测到细胞死亡,并且药物敏感性随着药物浓度的增加而增加。
表2:PDX小鼠模型对全身药物治疗的体内反应与相同肿瘤的体外反应的比较。
*体内数据由杰克逊实验室生成。
*5-FU:5-氟尿嘧啶;4-HA:4-过氧羟基环磷酰胺;
CR:完全反应;PR:部分反应;NR:无反应。
开发的EVQC证明,人类肿瘤对不同的抗癌治疗具有不同的敏感性:在手术切除过程中从患者肿瘤中切除的患者肿瘤组织按照上述的材料和方法和实施例1所述的方式直接培养,以及组织切片对抗癌药的敏感性进行了测试。最常见的抗癌方案用于每种肿瘤类型,例如,对于人类结肠直肠癌,标准治疗方法是5-氟尿嘧啶、奥沙利铂和/或伊立替康。图5显示了对高剂量5-氟尿嘧啶具有抗性但对伊立替康和奥沙利铂相对敏感的肿瘤的示例。用Ki67染色法检测细胞增殖也可以用来评估组织切片的生存力和对抗癌药物的敏感性。因此,图8展示了一个结肠直肠癌的示例,发现对5-氟尿嘧啶部分敏感,但通过Ki67染色对奥沙利铂治疗非常敏感。
综上所述,开发的EVOC系统清楚地表明,患者肿瘤对一种抗癌药物敏感,但对另一种药物具有抗性。此外,从不同患者产生的EVOC对相同的抗癌治疗有不同的反应(图6和下表3至表4)。此外,对于每种抗癌治疗,观察到剂量依赖性反应(如表3至表4)。
表3:从8名患者获得的人类结肠直肠癌的体外反应。
0-完全反应;1-强烈的部分反应;2-中度部分反应;3-部分反应较弱;和4-无反应。
表4:用于联合治疗的人类结肠直肠癌的体外反应。
0-完全反应;1-强烈的部分反应;2-中度部分反应;3-部分反应较弱;及4-无反应。
开发的EVOC可以预测对靶向治疗的敏感性,如同通过分子谱分析(molecularprofiling)所预测的那样:作为个体化药物的一种手段,可以通过外显子组测序来检测患者的肿瘤组织是否存在可操作的基因突变。获得的肿瘤之一来自患有三阴性乳腺癌的患者,该患者发现其具有潜在地可靶向的体细胞遗传变化,包括FGFR1的扩增和CDK6的扩增。从图7中可以看出,虽然从该患者(患者1)获得的肿瘤对CDK4/6抑制剂哌柏西利具有体外抗性,但它对FGFR抑制剂AZD4547表现出高度敏感性。最重要的是,从另一名没有FGFR1扩增的患者(患者2)获得的乳腺癌在开发的EVOC系统中对FGFR抑制具有抗性。
组织可以在培养之前保存48小时:手术切除的患者肿瘤组织按上述材料和方法及实施例1所述直接培养,或在4℃的培养基中保存48小时后培养;组织切片对抗癌药物的敏感性为经过测试。图10示出了一个结肠癌组织的示例,在两种情况下(即在直接培养或4℃下48小时后培养)均发现以类似方式对5-氟尿嘧啶部分敏感。
综上所述,在开始实验之前,组织可以在培养基中保存至少48小时,而对组织或药物敏感性没有任何不利影响。
综上所述,新开发的EVOC使研究人类癌症组织反应的过程变得快速,具有成本效益并且对许多癌症组织都具有普遍性。培养4-7天后,所有测试的癌组织,包括卵巢、结肠直肠、肺、胰腺和乳腺组织均表现出高生存能力。
尽管已经结合本发明的具体实施方式描述了本发明,但是显然,对于本领域技术人员而言,许多替代、修改和变化是显而易见的。因此,旨在涵盖落入所附权利要求书的精神和广泛范围内的所有这样的替代、修改和变化。
在此具体引用本出版物中提及的所有出版物,专利和专利申请的全部内容,并以其全文并入本出版物中,就像每个单独的出版物、专利或专利申请均在附图上分别和单独地指出是相同的。通过引用并入本文。此外,在本申请中对任何参考文献的引用或标识均不应解释为承认该参考文献可作为本发明的现有技术。在使用章节标题的程度上,不应将其解释为必然的限制。
参考资料
1.Dancey,J.E.,Bedard,P.L.,Onetto,N.和Hudson,T.J.,癌症治疗决策的遗传基础,细胞期刊148,409-420(2012)。
2.Garraway,L.A.,基因组学驱动的肿瘤学:新兴范式的框架,J.Clin.Oncol.Off.J.Am.Soc.Clin.Oncol.期刊31,1806-1814(2013)。
3.Crystal,A.S.等人,获得性耐药的患者来源模型可以识别有效的癌症药物组合,科学期刊346,1480-1486(2014)。
4.Liu,X.等人,ROCK抑制剂和饲养细胞诱导上皮细胞的条件重编程,Am.J.Pathol.期刊180,599-607(2012)。
5.Daniel,V.C.等人,小细胞肺癌的主要异种移植模型显示了体外培养物施加的基因表达的不可逆变化,Cancer Res.期刊69,3364-3373(2009)。
6.Clevers,H.,用类器官对发育和疾病进行建模,细胞期刊165,1586-1597(2016)。
7.Hidalgo,M.等人,患者来源的异种移植模型:用于转化癌症研究的新兴平台。Cancer Discov.期刊4,998-1013(2014)。
8.Straussman,R.等人,肿瘤微环境通过HGF分泌引起对RAF抑制剂的先天抗性,自然期刊487,500-504(2012)。
9.Olson,O.C.和Joyce,J.A.,微环境介导的对抗癌疗法的抗性,Cell Res.期刊23,179-181(2013)。
10.Vaira,V.等人,用于人类肿瘤药效分析的器官型培养的临床前模型,美国国家科学院院刊107,8352-8356(2010)。
11.Vickers,A.E.M.&Fisher,R.L.,器官切片用于评估人类药物毒性,Chem.Biol.Interact.期刊150,87-96(2004)。
12.de Kanter,R.,Monshouwer,M.,Meijer,D.K.F.和Groothuis,G.M.M.,精确切割的器官切片作为研究异源生物的毒性和代谢的工具,特别是针对非肝组织,Curr.DrugMetab.期刊3,39-59(2002)。
13.Stoff-Khalili,M.A.等人,组织切片模型系统中乳腺癌靶向转录策略的临床前评估,Breast Cancer Res.期刊BCR 7,R1141-1152(2005)。
14.Merz,F.等人,人胶质母细胞瘤的器官切片培养显示出不同的治疗敏感性,Neuro-Oncol.期刊15,670-681(2013)。
15.Gerlach,M.M.等人,头颈部鳞状细胞癌的切片培养物:药物敏感性和耐药机制的新型测试系统,Br.J.Cancer期刊110,479-488(2014)。
16.Meijer,A.等人,Nutlin-3对表达野生型p53的癌细胞对DR5选择性TRAIL的敏感性高于rhTRAIL,Br.J.Cancer期刊109,2685-2695(2013)。
17.Grosso,S.H.G.等人,乳腺癌组织切片作为评价雷帕霉素反应的模型,CellTissue Res.期刊352,671-684(2013)。
18.Majumder,B.等人,使用捕获肿瘤异质性的体外平台预测对抗癌药物的临床反应,Nat.Commun.期刊6,6169(2015)。
19.Roife,D.等人,病人异种移植物的体外测试反映了胰腺导管腺癌患者的临床结果,Clin.Cancer Res.期刊2016年6月3日;DOI:10.1158/1078-0432.CCR-15-2936。
20.Maund,SL.等人,前列腺良恶性组织培养模型的优化与综合表征,Lab.Invest.期刊94,208-221(2014)。
21.Siolas,D.,Hannon,G.,患者肿瘤细胞移植:将临床样本转化为小鼠模型,Cancer Res.期刊73:5315-5319(2013)。
22.Vaira,V.等人,用于人类肿瘤药效分析的器官型培养的临床前模型,PNAS期刊107,8352-8356(2010)。
23.van der Kuip,H.等人,乳腺癌组织的短期培养,以研究抗癌药物紫杉醇在完整肿瘤环境中的活性,BMC Cancer期刊6,86-90。
24.Salmon,E.等人,基质结构决定了T细胞在人肺肿瘤基质中的优先定位和迁移,Clin.Invest.期刊122,899-910(2012)。
Claims (27)
1.一种培养系统,其特征在于,所述培养系统包含:
一培养基;及
一精密切割的癌症组织的切片,放置在一钛网格组织培养插件上,
其中所述精密切割的癌症组织的切片保持在含有80%±10%的氧气的一高度氧合的气氛中培养,及所述培养被旋转搅拌以促进癌症组织的切片在所述培养基中的间歇浸没,其中所述癌症组织不是肝脏组织。
2.如权利要求1所述的培养系统,其特征在于:所述培养是在一组织培养板中。
3.如权利要求1所述的培养系统,其特征在于:所述培养系统包含一药物。
4.一种培养一癌症组织的方法,其特征在于,所述方法包含以下步骤:
在含有80%±10%的氧气的一高度氧合的气氛中,将位在一钛网格组织培养插件上的精密切割的癌症组织的切片培养在一培养基中;及
以一旋转搅拌培养,以促进所述癌症组织的切片在所述培养基中的间歇浸没,其中所述癌症组织不是肝脏组织。
5.如权利要求4所述的方法,其特征在于:所述方法还包含:将一药物添加到所述培养基。
6.如权利要求3所述的培养系统、或如权利要求5所述的方法,其特征在于:所述药物是一药物组合。
7.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织或所述精密切割的癌症组织的切片是刚刚被分离的。
8.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织或所述精密切割的癌症组织的切片被保存在4℃。
9.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织或所述精密切割的癌症组织的切片被超低温保存。
10.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织选自于由以下组成的群组:卵巢、结肠直肠、肺、胰腺、胃、胃食管及乳房。
11.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织选自于由以下组成的群组:卵巢、结肠直肠、肺、胰腺、胃、胃食管、乳房、软骨组织及骨骼。
12.如权利要求5所述的方法,其特征在于:所述添加的步骤在所述培养开始后12至24小时进行。
13.如权利要求3所述的培养系统、或如权利要求5所述的方法,其特征在于:所述药物是一抗发炎药或一抗癌药。
14.如权利要求3所述的培养系统、或如权利要求5所述的方法,其特征在于:所述药物选自于由以下组成的群组:5-氟尿嘧啶(5FU)、奥沙利铂、伊立替康、顺铂、4-过氧羟基环磷酰胺、多西他赛、阿霉素、诺维本、吉西他滨、吉非替尼、太莫西芬、奥拉帕利、曲美替尼、依维莫司及哌柏西利。
15.如权利要求3所述的培养系统、或如权利要求5所述的方法,其特征在于:所述药物的浓度高于一细胞系中的所述药物的IC50的剂量。
16.如权利要求3所述的培养系统、或如权利要求5所述的方法,其特征在于:所述药物浓度来自一剂量试验,其中一剂量依赖性反应被观察到。
17.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述培养进行至少4天。
18.如权利要求4所述的方法,其特征在于:所述培养进行至少5天。
19.如权利要求4所述的方法,其特征在于:所述培养进行至7天。
20.如权利要求4所述的方法,其特征在于:所述培养在一组织培养板中进行。
21.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述精密切割的切片为200至300微米。
22.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织选自于由以下组成的群组:卵巢癌、肺癌、胰腺癌、结肠直肠癌及乳腺癌。
23.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述切片被放置在所述钛网格组织培养插件的中间。
24.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述切片是一个切片。
25.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述切片与所述钛网格组织培养插件直接相接触。
26.如权利要求1所述的培养系统、或如权利要求4所述的方法,其特征在于:所述癌症组织是一人类组织。
27.如权利要求4至26任一项所述的方法,其特征在于:所述方法与基因剖析结合进行。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6158582A (ja) * | 1984-08-29 | 1986-03-25 | Advance Res & Dev Co Ltd | 連続還流細胞培養装置 |
CN101268184A (zh) * | 2005-06-15 | 2008-09-17 | 开普森特神经技术有限公司 | 制备器官型细胞培养物的方法 |
CN101316609A (zh) * | 2005-09-02 | 2008-12-03 | 麦克斯塞特公司 | 用电穿孔向细胞负载抗原 |
WO2009034108A1 (en) * | 2007-09-11 | 2009-03-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | An in vitro beating heart model |
CN101712946A (zh) * | 2009-09-27 | 2010-05-26 | 南通大学附属医院 | 构建生殖结节器官培养尿道体外发育模型的方法 |
WO2011109651A2 (en) * | 2010-03-03 | 2011-09-09 | The Johns Hopkins University | Expression vectors for classifying cells as cell cycling or hypoxic and methods of use |
WO2011150398A1 (en) * | 2010-05-28 | 2011-12-01 | Garnet Biotherapeutics, Inc | Compositions and methods of using living and non-living bioactive devices with components derived from self- renewing colony forming cells cultured and expanded in vitro |
WO2012093173A1 (en) * | 2011-01-06 | 2012-07-12 | Capsant Neurotechnologies Ltd | Tumour cell and tissue culture |
JP2014505675A (ja) * | 2010-12-16 | 2014-03-06 | アルト,エックハルト,ユー. | 組織サンプルから細胞および細胞濃縮マトリックスを濃縮回収する方法および装置 |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL154600B (nl) | 1971-02-10 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van specifiek bindende eiwitten en hun corresponderende bindbare stoffen. |
NL154598B (nl) | 1970-11-10 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van laagmoleculire verbindingen en van eiwitten die deze verbindingen specifiek kunnen binden, alsmede testverpakking. |
NL154599B (nl) | 1970-12-28 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van specifiek bindende eiwitten en hun corresponderende bindbare stoffen, alsmede testverpakking. |
US3901654A (en) | 1971-06-21 | 1975-08-26 | Biological Developments | Receptor assays of biologically active compounds employing biologically specific receptors |
US3853987A (en) | 1971-09-01 | 1974-12-10 | W Dreyer | Immunological reagent and radioimmuno assay |
US3867517A (en) | 1971-12-21 | 1975-02-18 | Abbott Lab | Direct radioimmunoassay for antigens and their antibodies |
NL171930C (nl) | 1972-05-11 | 1983-06-01 | Akzo Nv | Werkwijze voor het aantonen en bepalen van haptenen, alsmede testverpakkingen. |
US3850578A (en) | 1973-03-12 | 1974-11-26 | H Mcconnell | Process for assaying for biologically active molecules |
US3935074A (en) | 1973-12-17 | 1976-01-27 | Syva Company | Antibody steric hindrance immunoassay with two antibodies |
US3996345A (en) | 1974-08-12 | 1976-12-07 | Syva Company | Fluorescence quenching with immunological pairs in immunoassays |
US4034074A (en) | 1974-09-19 | 1977-07-05 | The Board Of Trustees Of Leland Stanford Junior University | Universal reagent 2-site immunoradiometric assay using labelled anti (IgG) |
US3984533A (en) | 1975-11-13 | 1976-10-05 | General Electric Company | Electrophoretic method of detecting antigen-antibody reaction |
US4098876A (en) | 1976-10-26 | 1978-07-04 | Corning Glass Works | Reverse sandwich immunoassay |
US4879219A (en) | 1980-09-19 | 1989-11-07 | General Hospital Corporation | Immunoassay utilizing monoclonal high affinity IgM antibodies |
US5011771A (en) | 1984-04-12 | 1991-04-30 | The General Hospital Corporation | Multiepitopic immunometric assay |
US4666828A (en) | 1984-08-15 | 1987-05-19 | The General Hospital Corporation | Test for Huntington's disease |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US4801531A (en) | 1985-04-17 | 1989-01-31 | Biotechnology Research Partners, Ltd. | Apo AI/CIII genomic polymorphisms predictive of atherosclerosis |
US5272057A (en) | 1988-10-14 | 1993-12-21 | Georgetown University | Method of detecting a predisposition to cancer by the use of restriction fragment length polymorphism of the gene for human poly (ADP-ribose) polymerase |
US5192659A (en) | 1989-08-25 | 1993-03-09 | Genetype Ag | Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes |
US5281521A (en) | 1992-07-20 | 1994-01-25 | The Trustees Of The University Of Pennsylvania | Modified avidin-biotin technique |
US20030152909A1 (en) * | 1994-11-16 | 2003-08-14 | Mitrani Eduardo N. | In vitro micro-organs, and uses related thereto |
US7345031B2 (en) * | 2000-04-12 | 2008-03-18 | International Medical Innovations, Inc. | Pharmaceutical dopamine glycoconjugate compositions and methods of their preparation and use |
WO2002044344A2 (en) | 2000-11-28 | 2002-06-06 | Curis, Inc. | Basal cell carcinoma cultures, methods related thereto and their use |
US20090239247A1 (en) * | 2002-12-13 | 2009-09-24 | Harris Adrian L | MN and Hypoxia |
US20050130254A1 (en) * | 2003-12-16 | 2005-06-16 | Park Sung-Soo | Drug testing system with bio-artificial liver |
US9175254B2 (en) * | 2006-07-07 | 2015-11-03 | University Of Miami | Enhanced oxygen cell culture platforms |
ES2624177T3 (es) * | 2006-07-07 | 2017-07-13 | University Of Miami | Plataformas de cultivo celular potenciadas en oxigeno |
CA2850274A1 (en) | 2011-10-04 | 2013-04-11 | Mitra Biotech Private Limited | Ecm composition, tumor microenvironment platform and methods thereof |
US20140302491A1 (en) | 2011-10-28 | 2014-10-09 | The Board Of Trustees Of The Leland Stanford Junior University | Ex Vivo Culture, Proliferation and Expansion of Primary Tissue Organoids |
GB2504996A (en) * | 2012-08-17 | 2014-02-19 | Univ Keele | Embryonic stem cell culture method |
WO2018185760A1 (en) | 2017-04-05 | 2018-10-11 | Yeda Research And Development Co. Ltd. | Ex-vivo culture system and methods of using same |
-
2018
- 2018-04-03 WO PCT/IL2018/050390 patent/WO2018185760A1/en unknown
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-
2022
- 2022-11-17 JP JP2022184484A patent/JP2023022119A/ja active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6158582A (ja) * | 1984-08-29 | 1986-03-25 | Advance Res & Dev Co Ltd | 連続還流細胞培養装置 |
CN101268184A (zh) * | 2005-06-15 | 2008-09-17 | 开普森特神经技术有限公司 | 制备器官型细胞培养物的方法 |
CN101316609A (zh) * | 2005-09-02 | 2008-12-03 | 麦克斯塞特公司 | 用电穿孔向细胞负载抗原 |
WO2009034108A1 (en) * | 2007-09-11 | 2009-03-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | An in vitro beating heart model |
CN101712946A (zh) * | 2009-09-27 | 2010-05-26 | 南通大学附属医院 | 构建生殖结节器官培养尿道体外发育模型的方法 |
WO2011109651A2 (en) * | 2010-03-03 | 2011-09-09 | The Johns Hopkins University | Expression vectors for classifying cells as cell cycling or hypoxic and methods of use |
WO2011150398A1 (en) * | 2010-05-28 | 2011-12-01 | Garnet Biotherapeutics, Inc | Compositions and methods of using living and non-living bioactive devices with components derived from self- renewing colony forming cells cultured and expanded in vitro |
JP2014505675A (ja) * | 2010-12-16 | 2014-03-06 | アルト,エックハルト,ユー. | 組織サンプルから細胞および細胞濃縮マトリックスを濃縮回収する方法および装置 |
WO2012093173A1 (en) * | 2011-01-06 | 2012-07-12 | Capsant Neurotechnologies Ltd | Tumour cell and tissue culture |
Non-Patent Citations (7)
Title |
---|
Ev viva organ culture as potential prioritization tool for breast cancer targeted therapy;GRINSHPUN ALBERT 等;《CANCER BIOLOGY & THERAPY》;20180322;第19卷(第8期);1-4 * |
Ex vivo tumor culture systems for functional drug testing and therapy response prediction;Titia G Meijer等;《future science》;20170327;第3卷(第2期);第5-9页"器官型肿瘤组织切片"段落和表1, * |
Organ slices for the evaluation of human drug toxicity;Alison E.M. Vickersdeng;《Chemico-Biological Interactions》;20041101;第150卷;第89页左栏第3段 * |
Tumor slice culture system to assess drug response of primary breast cancer;Kishan A. T. Naipal等;《BMC Cancer》;20160209;第16卷;第1页摘要,第2-3页方法,第8页左栏第2段-右栏第3段 * |
体外髁突软骨培养方法的建立;李松等;《临床口腔医学杂志》;20051030;第21卷(第10期);607-609 * |
利鲁唑对体外培养人脐静脉内皮细胞及小鼠视网膜新生血管形成的影响;吴海星;张学东;;中国组织工程研究与临床康复;20080812(33);6416-6420 * |
李志丹,王强,侯铁舟,李相如,王红,陶洪.体外器官培养人牙胚的实验观察.世界最新医学信息文摘.(01),503-505. * |
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WO2018185760A1 (en) | 2018-10-11 |
US11920162B2 (en) | 2024-03-05 |
EP4317971A2 (en) | 2024-02-07 |
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EP3607050B1 (en) | 2023-08-30 |
RU2019134857A (ru) | 2021-04-30 |
JP2020516243A (ja) | 2020-06-11 |
ES2963461T3 (es) | 2024-03-27 |
JP2023022119A (ja) | 2023-02-14 |
SI3607050T1 (sl) | 2024-02-29 |
US20200224171A1 (en) | 2020-07-16 |
CN110678543A (zh) | 2020-01-10 |
IL269821B1 (en) | 2023-10-01 |
EP3607050A1 (en) | 2020-02-12 |
BR112019020953A2 (pt) | 2020-05-05 |
AU2018248137A1 (en) | 2019-11-21 |
HRP20231499T1 (hr) | 2024-03-01 |
IL269821A (en) | 2019-11-28 |
AU2018248137B2 (en) | 2024-03-07 |
CA3058168A1 (en) | 2018-10-11 |
EP4317971A3 (en) | 2024-04-17 |
IL269821B2 (en) | 2024-02-01 |
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FI3607050T3 (fi) | 2023-11-20 |
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