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CN103608681A - 用于检测肿瘤细胞的类固醇受体测定 - Google Patents

用于检测肿瘤细胞的类固醇受体测定 Download PDF

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CN103608681A
CN103608681A CN201280016743.7A CN201280016743A CN103608681A CN 103608681 A CN103608681 A CN 103608681A CN 201280016743 A CN201280016743 A CN 201280016743A CN 103608681 A CN103608681 A CN 103608681A
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D.A.奇亚内塞
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Abstract

本发明公开了用于对表达类固醇受体(特别是雌激素受体)的循环肿瘤细胞进行检测、计数和分析的方法。这些方法可用于癌症筛查和分期、用于开发治疗方案、以及用于监测治疗应答、癌症复发等。还提供了便利此类循环肿瘤细胞的检测、计数和分析的测试试剂盒。

Description

用于检测肿瘤细胞的类固醇受体测定
技术领域
本发明涉及肿瘤学和诊断性检验的领域，更具体地，涉及用于癌症筛查、以及用于预测和监测化学疗法治疗应答、癌症复发等的方法。
背景技术
据估测，每年存在至少数十万新乳腺癌病例。这些病例目前通过外科手术方式来证实，诸如收集肿瘤或乳房切除术组织，将这样的组织切片石蜡块，并使用免疫组织化学方法辅助证实类固醇受体蛋白在这样的组织中的存在。由于外科手术，这样的方法不能用于贯穿疗程监测疾病状态的进展。多年来，这些方法已经被改进，使得可以评估所述组织的不同特征，诸如黄体酮受体和HER/2-neu状态，以及证实雌激素受体的表位的存在。但是，在所有情况下，该评估需要外科手术。此外，对于在她们的早期治疗中切除其乳房组织的患者而言，这些方法完全是不可用的。
循环肿瘤细胞(“CTC”)存在于患有转移性乳腺癌的患者的血液中，且可以在患者的疗程中进行收集。可以针对它们的HER/2-neu状态来分析这些细胞。但是，迄今为止，没有用4确定此类CTC的雌激素受体的N和C末端区域的表位的存在的方法。在下述发明中发现了这些方法。
附图说明
图1显示了雌激素受体α阳性的CTC的患者样品的图像。
具体实施方式
本发明包括用于表征来自转移性癌症患者的循环肿瘤细胞的方法，所述方法包括以下步骤：
a)从所述患者获得生物样本(血液和骨髓)；
b)使所述生物样本与配体接触混合，所述配体与循环肿瘤细胞特异性地反应，以基本上排除其它样品组分，并且允许此类结合的循环肿瘤细胞与所述生物样本的其它样品组分分离；
c)使步骤(b)的样品与至少一种试剂接触，所述试剂特异性地结合步骤(b)的样品；
d)使步骤(c)的样品与药剂接触，所述药剂对细胞中的类固醇受体具有结合亲和力；以及
e)分析所述样品以确定表达类固醇受体的循环肿瘤细胞的存在。
本文中使用的术语生物样品包括但不限于：全血、尿、血清、血浆、痰、脑脊液、羊水、洗出液和骨髓。优选的生物样品是全血、尿、血浆、痰和骨髓，更优选全血、尿、血浆、痰，最优选全血。
术语“配体”表示结合CTC的细胞表面标志物的蛋白，其包括但不限于：粘附分子诸如E钙粘着蛋白、N钙粘着蛋白、以及针对EpCAM的单克隆抗体等。优选的配体包括EpCAM抗体。此外，所述配体可以包含“磁性应答颗粒”。磁性应答颗粒是便利磁性分离的物质。通常，这样的颗粒是金属或有机金属组合物。它们可以任选地涂有聚合物，优选生物起源的聚合物诸如BSA。可检测的标记可以结合配体和磁性应答颗粒的复合物，所述可检测的标记包括但不限于荧光标记。磁性应答颗粒的更详细描述参见标题为“Magnetic Separation Apparatus and Mehtods Employing an Internal magneticCapture Gradient and an EXtemal Transport Force(采用内部磁性捕获梯度和外部运输力的磁性分离仪器和方法)”的美国专利号5,985,153，其以引用方式全文并入本文。
术语“其它样品组分”表示生物样品中的除了循环肿瘤细胞以外的组分。此类组分包括但不限于：白血细胞、正常红血细胞、白细胞、内皮细胞、无核细胞等。
术语“试剂”表示区分不同类型的细胞的物质。试剂的例子包括但不限于：染料诸如DAPI、溴化乙锭和吖啶橙，和探针例如CD45、CD41、PAC-1、CD4、CD8、CD56、CD146、CD34、CD38、细胞角蛋白等。
术语“药剂”表示针对类固醇受体的特定区域的抗体。如果针对来自雌激素阳性的乳腺癌患者的CTC分析生物样品，使用针对雌激素受体的N-末端和C-末端区域的抗体。针对N-末端区域的抗体包括但不限于：ID5、CF11、E115(rb mono)、SP-1(rb mono)、ER119.3等。优选的N-末端区域抗体是ID5和E115(rb mono)。针对C-末端区域的抗体包括但不限于：H222、F10、TE111.5D11。优选针对C-末端区域H222的抗体。关于在本发明中可用的其它单克隆抗体，参见M.Pavao等人，Esuogen receptorantibodies：speciEcity and utility in the detection，localization，and analyses ofestrogen receptorαandβ；Steroids66(2001)1-16。
术语“类固醇受体”具有它的常规含义。优选的类固醇受体是黄体酮、睾酮和雌激素受体。特别优选的类固醇受体是雌激素受体的所有亚型，尤其是雌激素受体α。
除非在本文中另外定义，与本发明相关使用的科学和技术术语应当具有本领域普通技术人员通常理解的含义。
用磁性颗粒通过免疫磁性捕获从外周血分离循环肿瘤细胞是从血液样品的稳定化和抗凝固开始的多步骤方法。接下来用与上皮特异性的单克隆抗体缀合的强磁性颗粒进行靶细胞的免疫磁性捕获和分离。用染料和荧光染料缀合的抗体(其对细胞生物学上重要的靶罕见事件细胞和抗原是特异性的)对靶细胞和/或其它表征标志物进行的荧光标记，被用于鉴别和表征细胞群体。最后，通过荧光显微术用适合罕见事件鉴别和分析的窗口通过在筒中的磁性局部化而使细胞显影，用软件测量从靶罕见事件细胞的显微分析产生的荧光信号。
此外，本发明包括用于针对表达类固醇受体的循环肿瘤细胞的存在筛选患者样品的测试试剂盒，所述测试试剂盒包括：
a)配体，其与循环肿瘤细胞特异性地反应，以基本上排除其它样品组分，并且允许此类结合的循环肿瘤细胞与所述生物样本的其它样品组分分离；
b)至少一种试剂，其特异性地结合患者的循环肿瘤细胞和其它样品组分中的一者或两者；
c)药剂，其对患者的循环肿瘤细胞中的类固醇受体具有结合亲和力。
为了更好地理解本发明，给出以下实例。这些实例只是用于例证的目的，不应解释为以任何方式限制本发明的范围。
实例
血液样品的抗凝固和保存：使用商购可得的
Figure BDA0000390662970000041
试管收集血液样品用于该测定。该试管含有EDTA钠(一种抗凝血剂)和血液防腐剂，它们会稳定化样品中的靶细胞，从而增强测定的检测完整循环肿瘤细胞的能力。该收集试管会通过使细胞在室温稳定化多达96小时的时段而便利样品为了分析向远距离实验室的运输。文献详述了防腐剂用于预防循环肿瘤细胞的片段化的用途的重要性，所述片段化在患有实体组织癌症(诸如乳腺癌)的患者的外周血中观察到。这些保存方法也与在雌激素受体蛋白在这些罕见事件细胞上的检测相容。
靶细胞的强磁性捕获：使用与抗-EpCAM抗体克隆VU-1D9结合的铁磁流体作为商购可得的
Figure BDA0000390662970000042
上皮细胞试剂盒的一部分，以局部化得自外周血的循环肿瘤细胞。该试剂盒会富集罕见事件细胞，从7.5毫升含有大约30,000.000至50.000.000个有核血细胞的血液样品中的少至5个细胞，达到含有约2,000至3000个白细胞的小于0.5毫升的工作容积，并且得到的靶细胞富集大于15,000倍。该减小的体积然后允许用荧光试剂染色，以鉴别和表征捕获的罕见事件细胞。
捕获的细胞的染色标准的
Figure BDA0000390662970000043
试剂盒构型含有基于皂苷的试剂，以渗透化处理完整细胞的细胞膜和核膜，从而允许标记细胞内蛋白和核蛋白。染料4'6'二脒基苯基吲哚被用作AT碱基对，其为当与细胞核结合时会在紫外范围内发荧光的DNA特异性的染料。这被该系统用于鉴别分离的样品中存在的有核细胞。使用与荧光染料(诸如藻红蛋白或荧光素)缀合的抗-细胞角蛋白单克隆抗体作为上皮特异性的标志物，以鉴别血液组分群体中的罕见事件肿瘤细胞。使用对CD45(一种白细胞共同抗原)特异性的荧光缀合物从分析中排除污染性的白血细胞。
雌激素受体特异性的试剂：获取针对雌激素受体α的N-末端和C-末端区域的商购可得的单克隆抗体，与藻红蛋白缀合，并针对在不含雌激素的培养条件中生长的培养的MCF-7乳腺癌细胞系进行滴定。经证实，抗体克隆H222、SP-1、1D5和E115在处理过的MCF-7细胞在正常供体血液样品内的模型系统中起作用。还证实了这些克隆在具有晚期乳腺癌的患者样品中是阳性的，如在
Figure BDA0000390662970000044
系统上所确定的。
分析：在
Figure BDA0000390662970000051
Analyzer II上分析了所有供体和患者样品，所述
Figure BDA0000390662970000052
Analyzer II是一种自动化的成像系统，其扫描在分析室中局部化的细胞，如在美国专利号7,011,794(其以引用方式全文并入本文)中所述。处理图像，并呈现候选循环肿瘤细胞图像用于操作员评价。所有细胞被确定为DAPI和细胞角蛋白阳性的以及CD45阴性的。然后根据使用的试剂，将被鉴别为循环肿瘤细胞的细胞评分为雌激素受体或其它类固醇受体阳性的或阴性的。使用荧光信号的核定位作为形态学标准，与在石蜡切片的免疫组织化学中使用的分析相匹配。
在模型系统中评价的所有对雌激素受体α特异性的市售抗体都被证实在患者样品中具有反应性。用与藻红蛋白缀合的E115兔单克隆抗体(Epitomics Inc.)以及针对HER/2-neu肿瘤标志物的荧光素缀合的单克隆抗体(如得自University of Texas的单克隆抗体Her-81所定义)，评价了乳腺癌患者组。用经过MCF-7细胞处理的供体血液进行10个样品运行，作为测定对照。对照样品都是CTC阳性的，处理过的细胞的雌激素受体的阳性率平均值为78％±16％。乳腺癌患者数据总结在表1中。图1是从患者样品得到的、CellTracks
Figure BDA0000390662970000053
的典型CTC图像的汇总。
表1：小规模乳腺癌患者组的总结
乳腺癌组n=28
9个患者为CTC阳性 32％
9个样品中的6个为ER阳性 67％
9个样品中的3个为HER2阳性 33％
9个样品中的3个为ER/HER2双重阳性 33％

Claims (12)

1. 一种用于表征来自转移性癌症患者的循环肿瘤细胞的方法，包括以下步骤：
a) 从所述患者获得生物样本（血液和骨髓）；
b) 使所述生物样本和与循环肿瘤细胞特异性地反应的配体接触混合，以基本上排除其它样品组分，并且允许此类结合的循环肿瘤细胞与所述生物样本的其它样品组分分离；
c) 使步骤(b)的样品与至少一种试剂接触，所述试剂特异性地结合步骤(b)的样品；
d) 使步骤(c)的样品与药剂接触，所述药剂对细胞中的类固醇受体具有结合亲和力；以及
e) 分析所述样品以确定表达类固醇受体的循环肿瘤细胞的存在。
2. 根据权利要求1所述的方法，还包括确定表达类固醇受体的循环肿瘤细胞的数目的步骤。
3. 根据权利要求1所述的方法，其中所述与循环肿瘤细胞特异性地反应的药剂偶联到所述循环肿瘤细胞中的所述类固醇受体的N-末端和C-末端区域中的任一者或两者。
4. 根据权利要求1所述的方法，其中所述试剂选自：DAPI、细胞角蛋白和CD45 neg。
5. 根据权利要求1所述的方法，其中所述配体特异性地结合到所述肿瘤细胞上的上皮细胞粘附表位。
6. 根据权利要求1所述的方法，其中所述配体包含磁性应答颗粒。
7. 根据权利要求1所述的方法，其中通过至少一种选自下列的方法来分析步骤(e)中的样品：多参数流式细胞计量术、免疫荧光显微术、激光扫描细胞计量术、明视野基础图像分析、波谱成像分析、人工细胞分析、CELLSTRACKS®分析和自动化的细胞分析。
8. 根据权利要求6所述的方法，还包括使步骤(b)的产物经受磁场。
9. 根据权利要求6所述的方法，其中所述磁性应答颗粒是胶体的。
10. 根据权利要求1所述的方法，其中所述药剂是选自下列的抗体：ID5、CF11、E115（rb mono）、ER119.3和SP-1（rb mono）。
11. 根据权利要求1所述的方法，其中所述药剂是选自下列的抗体：H222、F10和TE111.5D11。
12. 一种用于针对表达类固醇受体的循环肿瘤细胞的存在筛选患者样品的测试试剂盒，包括：
a) 配体，其与循环肿瘤细胞特异性地反应，以基本上排除其它样品组分，并且允许此类结合的循环肿瘤细胞与所述生物样本的其它样品组分分离；
b) 至少一种试剂，其特异性地结合患者的循环肿瘤细胞和其它样品组分中的任一者或两者；
c) 药剂，其对所述患者的循环肿瘤细胞中的类固醇受体具有结合亲和力。
CN201280016743.7A 2011-04-01 2012-03-30 用于检测肿瘤细胞的类固醇受体测定 Pending CN103608681A (zh)

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