CN112334487B - 用于诊断和治疗癌症的组合物和方法 - Google Patents
用于诊断和治疗癌症的组合物和方法 Download PDFInfo
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- CN112334487B CN112334487B CN201980040619.6A CN201980040619A CN112334487B CN 112334487 B CN112334487 B CN 112334487B CN 201980040619 A CN201980040619 A CN 201980040619A CN 112334487 B CN112334487 B CN 112334487B
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
公开了一种用于诊断受试对象中的CDH17阳性肿瘤细胞和癌症的方法，包括但不限于以下步骤，从受试对象获得样本；使样本与捕获抗体接触以提供捕获的样本；将捕获的样本与检测抗体或脂质纳米探针(LNP)接触以提供检测样本；确定检测样本中检测抗体或LNP的量；以及基于检测抗体或LNP的量，确定受试对象患有肿瘤的概率。
Description
相关申请的交叉引用
本申请要求根据35U.S.C.§119(e)于2018年5月16日提交的美国临时申请序列号62/672,319的申请日的权益，其全部公开内容通过引用并入本文。
技术领域
本公开总体涉及癌症诊断领域，并且更具体地涉及诊断CDH17阳性癌症的试剂和方法。
背景技术
胃肠道(GI)癌症是世界范围内发病率和死亡率的主要原因。单独的结肠直肠癌(CRC)占所有癌症诊断的大约10％，并且是世界范围内癌症死亡的第二主要原因(Verdaguer 2017)。局部肿瘤的早期检测，最好是在I期，可以对大多数肿瘤进行根治性手术(Siegel 2017)。传统的基于血液的肿瘤标志物分析，如CEA和CA19-9，缺乏早期检测GI癌所需的灵敏度和特异性(Lech 2016)。尽管非侵入性血液检测和液体活检(分析循环肿瘤DNA或ctDNA)最近取得了进展，但仍有必要准确检测更大比例的GI癌和对其进行分期，特别是早期癌症。例如，最近对血浆蛋白和ctDNA标志物进行的血液测试，癌症筛查提高了癌症的检出率(Cohen 2018)。然而，只有大约40％的I期癌症被发现(20％为食管癌)。总体而言，通过液体活检在早期阶段检测癌症仍然很困难，因为尽管使用了极其敏感的技术，这些肿瘤似乎没有向血浆中释放足够数量的ctDNA(Bettegowda 2014，Cohen 2017)。其他经批准的检查，如活检或结肠镜检查，都是侵入性的，在临床护理过程中，活检组织并不总是可以接触到的。因此，毫无疑问，需要一种更好、更灵敏的血液生物标志物测定方法，以便能够及早检测GI癌。
发明内容
以下概述仅是说明性的并且不旨在以任何方式进行限制。除了上述说明性方面、实施例和特征之外，通过参考附图和以下详细描述，其它方面、实施例和特征将变得显而易见。
本公开提供用于诊断受试对象中的肿瘤的方法。在一个实施方案中，该方法包括以下步骤，从受试对象获得样本；使样本与捕获抗体接触以提供捕获的样本；将捕获的样本与检测抗体或脂质纳米探针(LNP)接触以提供检测样本；确定检测样本中检测抗体或LNP的量；以及基于检测抗体或LNP的量，确定受试对象患有肿瘤的概率。捕获抗体可以包括抗CDH17单克隆抗体。抗CD17单克隆抗体可对外泌体、微泡或可溶性CDH17片段具有高度特异性结合活性。
在一个实施方案中，捕获抗体可以是对CD9、CD63、CD81、CD45或其组合具有结合活性的单克隆抗体。在一个实施方案中，检测抗体可包括对CDH17、TROP2、CD63、CD9、CD81、CD45、肿瘤标志物、组织标志物，或其组合，具有亲和力的抗体。在一个实施方案中，该方法中的步骤可以是任何顺序的。在一个实施方案中，该方法中的步骤可以是顺序的。在一个实施方案中，该方法中的两个或更多个步骤可以同时进行。在一个实施方案中，该方法中的两个或更多个步骤可在一个反应容器中发生。
在至少一个实施方案中，该方法可以包括以下步骤，从受试对象获得样本；使样本与捕获抗体接触以提供捕获的样本；将捕获的样本与检测抗体或新的基于脂质的纳米探针(LNP)接触以提供检测样本；确定检测样本中检测抗体或LNP的量；以及基于检测抗体或LNP的量，确定受试对象患有肿瘤的概率。
在至少一个实施方案中，该方法包括以下步骤，从受试对象获得样本；使样本与捕获抗体接触以提供捕获的样本；确定捕获的样本的量；并且基于所捕获的样本的量，确定受试对象患有肿瘤的概率。
在至少一个实施方案中，该方法包括以下步骤，从受试对象获得样本；用荧光DNA/RNA染色标记样本以提供标记样本；将标记样本与捕获抗体接触以提供捕获样本；确定捕获的样本的量；并且基于所捕获的样本的量，确定受试对象患有肿瘤的概率。
在至少一个实施方案中，捕获抗体可以包括捕获抗CDH17单克隆抗体。在至少一个实施方案中，捕获抗体可以包括对外泌体、微泡或可溶性CDH17片段具有结合活性的单克隆抗体。在一个实施方案中，捕获抗体可以对CDH17或其片段具有结合亲和力。
在至少一个实施方案中，捕获抗体可以包括对CD9、CD63、CD81、CD45或其组合具有结合活性的单克隆抗体。
在至少一个实施方案中，检测抗体可包括对CDH17、TROP2、CD63、CD9、CD81、CD45、肿瘤标志物、组织标志物或其组合具有结合亲和力的抗体。
在至少一个实施方案中，检测步骤通过使用新的基于脂质的纳米探针(LNP)进行。
在至少一个实施方案中，肿瘤是CD17阳性肿瘤。在一个实施方案中，肿瘤包括胃肠系统的癌症。在至少一个实施方案中，肿瘤包括结肠癌。
在至少一个实施方案中，样本包括体液。在一个实施方案中，体液包括血液。
本公开还提供用于测定开发的方法。在一个实施方案中，开发了三个平台并用于最稳健的测定的比较，包括邻近发光、ELISA和流式细胞荧光分析。CDH17捕获和检测抗体用于从一大组抗CDH17抗体中筛选一种或多种优化组合以获得最高水平的灵敏度。为了进一步增加任何诊断测定的灵敏度，产生了功能性定向的重组CDH17捕获抗体。在一个实施方案中，开发了一种新型脂基纳米探针(LNP)的效率，并将其与上述捕获和检测CDH17 EV的方法进行了比较。在一个实施方案中，开发了分别用于检测和定量cCDH17、CDH17 EV和总血CDH17水平的测定方法。
在一个实施方案中，本申请提供用于从患者筛选和诊断生物样本的方法。使用本文描述的新的和优化的测定法对一大组患者和正常血液样本(血浆/血清)进行了诊断和比较。在一个实施方案中，测试来自胃肠炎、胰腺炎和炎性肠病(IBD)患者的血液样本以确定血液中的CDH17在涉及GI组织的非癌炎性疾病中是否增加。在一个实施方案中，被诊断的癌症是结直肠癌(CRC)。在一个实施方案中，临床样本验证的终点是证实GI患者血液中sCDH17、CDH17 EV或总CDH17在统计学上显著增加。在另一个实施方案中，终点包括证明CDH17血浓度随着肿瘤分期的增加和/或治疗后的任何降低而显著增加。
附图说明
结合附图，根据以下描述和所附权利要求书，本公开的前述和其他特征将变得更加完全清楚。应理解，这些附图仅描绘了根据本公开安排的若干实施例并且因此不应被认为是对其范围的限制，将通过使用附图以额外的特性和细节来描述本公开，其中：
图1通过计数CDH17阳性免疫组织化学染色(A)和CDH17特异性血浆标志物(B)，描述了CDH17在l-IV期CRC患者样本中的表达特征；
图2描述了来自I-III期CRC患者的血清样本中CDH17蛋白浓度的测量；
图3使用来自CRC患者血液标本的样本载玻片，说明了个体CRC患者中CDH17阳性循环肿瘤细胞(CTC)的水平随肿瘤分期而增加，并且在手术后5天降低；
图4描述了通过超速离心从肿瘤细胞系培养基中纯化的外泌体上CDH17的表达；
图5说明了用ELISA测定癌细胞培养液(A)和CRC血浆(B)中CDH17的浓度；
图6示出了用于定量液体样本中的CDH17 EV的三种测定平台，荧光ELISA、流式细胞荧光测定法和邻近发光测定法(A、B和C)；捕获的CDH17 EV(D、E和F)；和CDH17 EV上的其他蛋白质(G、H和I)；
图7揭示了对不同CDH17胞外域特异的CDH17单克隆抗体的实例；和
图8描述了通过流式细胞术(上)和/或ELISA(下)定量捕获的CDH17的测定的标准化和灵敏度。标准曲线可以通过使用重组CDH17，以用一种或多种CDH17单克隆抗体捕获在珠上或包覆在孔上来建立。检测剂包括检测抗体，如不同的CH17单克隆抗体。测定的灵敏度为约400至500pg/mL。
具体实施方式
在下面的详细描述中，参考了形成其一部分的附图。在附图中，相似的符号通常标识相似的组件，除非上下文另外指示。在详细描述，附图和权利要求中描述的说明性实施例并不意味着是限制性的。可以利用其他实施例，并且可以进行其他改变，而不偏离本文呈现的主题的精神或范围。将容易理解的是，如本文一般描述的以及在附图中示出的本公开的这些方面可以被布置、取代、组合、分离、以及设计成多种不同的构型，本文明确地考虑了所有这些构型。
本公开内容主要涉及与癌症诊断相关的组合物和方法。
CDH17是在正常GI组织中具有限制性表达的致癌基因和细胞粘附膜蛋白(Liu2009，Wang 2013)。CDH17在结直肠癌(>95％)、胃腺癌(90％)和食管腺癌(82％)患者中高水平且在高比例的肿瘤中表达(Altree-Tacha 2017；Ordonez 2014；Matsusaka 2016；Panarell i 2012；Su 2008)。通过cDNA微阵列测量，CDH17的表达水平似乎在癌前组织中增加，例如胃癌前肠化生(pre-gastric cancer intestinal metaplasia)(IM)和解痉多肽表达化生(spasmolytic polypeptide-expressing metaplasia)(SPEM)(Lee HJ等人，2010)。然而，目前还没有关于CDH17表达水平与GI肿瘤类型和/或分期之间关系的定量研究。作为广泛研究的结果，本公开特别提供了用于以惊人的准确性和灵敏度定量肿瘤中CDH17表达的组合物、试剂和方法。
CDH17在不同类型的GI癌中以高水平表达。使用癌症基因组图谱(TCGA)RNA测序数据(RNA Seq V2)，CDH17在不同类型的恶性肿瘤中的表达水平可以从低到高排序。高水平的CDH17表达与GI癌有关，包括但不限于结直肠癌、胃癌、胰腺癌和食管癌。此外，在乳头状肾细胞癌(PRCC)和胆管癌中发现CDH17表达水平较高。
CDH17在多数GI癌中的表达可用免疫组织化学(IHC)法确定。大约100％的结直肠癌、90％的胃腺癌和82％的食管腺癌表达CDH17。图1-3显示了CRC中CDH17表达水平与癌症I至IV期之间的相关性。
本发明涉及血液中CDH17的灵敏和特异性测定方法的开发。
在一个实施方案中，本文公开的测定方法可用于临床样本验证。癌细胞培养基和患者血液样本均用于开发、验证和优化测定。sCDH17和CDH17EV都可从培养的癌细胞培养基中容易地检测到(图4-5)。然而，在癌细胞培养基或患者血液中，sCDH17和潜在的CDH17在EV膜上的切割形式可能是不同的，即部分CDH17包括一个或多个但不是全部表位。
因此，重点在于鉴定能够从患者样本中捕获所有形式的CDH17的抗体阵列。比较如图6所示的基于邻近的化学发光、ELISA和流式细胞荧光测定法的三个平台，以开发具有sCDH17、CDH17EV和总CDH17的最大灵敏度和动态范围的测定方法。由于步骤较少，邻近发光具有测定时间较短的优点。它还可以实现非常灵敏的测定，只需要很小的分析物体积(Yoshioka 2014)。该测定通过固定的CDH17抗体或LNP(特异性针对EV)捕获sCDH17和/或CDH17EV。使用功能性定向的非竞争性CDH17抗体(图8)或LNP(特异性检测EV)测量捕获的CDH17。由于产量、处理时间和成本的变化，避免了涉及EV提纯的测定，因为这在临床环境中具有挑战性(Contrera-Naranjo 2017)。最稳健的测定可用于临床样本验证。在一个实施方案中，本文开发的测定法定量每体积血浆/血清的CDH17。该测定可用作早期筛选。此外，该测定还可以进一步结合对EV DNA或RNA的相关基因突变的分析，以及对组织起源的CDH17EV膜蛋白的评估。
分析确认的主要步骤包括：
(A)鉴定用于有效捕获和检测CDH17的CDH17抗体。
捕获抗体。针对从癌细胞培养基捕获sCDH17、CDH17 EV和总CDH17的能力，筛选了400多种CDH17单克隆抗体。正常血液(血清/血浆)和阳性患者血液用于以ELISA形式测量CDH17的浓度(图2)。此外，可以使用多克隆抗体和LNP来捕获CDH17EV。癌细胞系包括CDH17阳性CRC(SNU-C1)和PDAC(AsCP1)系，以及CDH17阴性细胞系，如SW480和Jurkat(图4和5)。将捕获抗体或LNP固定到微量滴定板孔上(图6)。为了特异性地测量所捕获的sCDH17，可以通过使用具有300kDa mwco滤器的离心过滤来去除EV(CDH17＝120kDa)。为了具体测量捕获的CDH17EV，使用洗涤和过滤的EV。作为替代方法，使用LNP特异性地测量捕获的CDH17EV，如图6所示。通过使用特异于外泌体标志物例如CD63和CD9的抗体，和/或其它未知直接结合CDH17的EV膜蛋白(例如TROP-2)或通过用细胞渗透DNA/RNA染色例如SYTO-13预标记EV来测量捕获的EV。在鉴定最有效的单个捕获抗体(例如ARB101、ARB102和9C6(SEQ ID No.1-6))之后，测试捕获抗体的组合以鉴定具有较大捕获效率的组合，使得可以改进和优化测定的灵敏度。患者血液样本中独特形式的CDH17可通过免疫印迹和免疫组织化学分析来表征(图3，下组)，而捕获的肽可通过质谱分析来表征。
检测抗体。筛选CDH17抗体以最灵敏地检测捕获的sCDH17和CDH17EV。使用纯化的可溶性重组CDH17-Fc或CDH17his作为标准，可以如图8所示确定不同发展分期的测定灵敏度。该测定的靶标灵敏度为约500pg/ml或更低。候选捕获和检测抗体是具有定位于一个或多个CDH17胞外域的表位的抗体，如图7所示。这些和另外的表位定位的抗体用于粗略估计sCDH17中和可能在CDH17EV上的切割位点。
(B)样本处理；血清与血浆的比较。测定从相同患者(n>10)收集的多组血清和血浆样本的sCDH17和CDH17EV以确定样本收集的一种方法是否允许更大的CDH17产率/检测。
(C)产生重组CDH17捕获抗体以提高测定效率。产生重组CDH17来表征捕获抗体以提高这些测定的效率。为了进一步提高捕获效率和灵敏度，将选择的捕获抗体转化为修饰的重组探针，以使抗体在底物上具有更大的灵活性和功能取向。另一方面，检测抗体还可以掺入至少一个用于生物素化和高亲和力结合HRP-链霉亲和素的Avi-标签，或荧光团-链霉亲和素缀合物。根据关键测定抗体的亲和力，可以考虑亲和力成熟。
实施例
实施例1.用于样本制备和表征的方法
通过标准差示超速离心从CDH17阳性CRC(SNUC1)和PDAC(AsPC1)细胞系的培养基中纯化外泌体(Bow2012)。蛋白检测时，将10ug可溶性外泌体蛋白上样到SDS-PAGE凝胶中，用CDH17和CD63抗体进行印迹和探针检测。为了表征外泌体，用人源化CDH17抗体(mh10C12)或hIgG包覆聚苯乙烯珠(10微米)并与无细胞肿瘤培养基一起孵育。洗涤珠，然后用小鼠CDH17抗体(7C5)或CD63抗体和抗-mIgAlex647染色。针对外泌体标志物CD63的抗体可以检测到50％的CDH17 EV，因为它不是微泡(microvesicle)的标志物。为了进行来自肿瘤细胞系的无细胞培养基的CDH17 ELISA，将SNUC1培养基通过100kDa mwco滤器并测试CDH17的水平。
将正常或CRC血浆样本和可溶性CDH17(1ug/ml)与人源化CDH17抗体或CD68抗体包覆的珠一起孵育，洗涤并用非竞争性小鼠CDH17抗体染色。将正常或CRC血浆样本在用CDH17多克隆或三种人源化CDH17 mAb的集合包覆的孔中孵育，然后用小鼠CDH17 mAb探测。在一些样本中，CDH17容易被多克隆抗体捕获。该发现表明CDH17抗体的性质在用于测定患者样本或癌细胞培养物中的CDH17的任何诊断方法的质量中起重要作用。
为了提高捕获EVs的效率，产生选择的重组CDH17抗体，其均匀且功能性地朝向分析物。这是通过C端多肽标签(AviTag；Avidity LLC)的位点特异性生物素化来实现的，从而使C端能够结合到包覆中和亲和素(neutravadin)的底物上。高亲和力CDH17抗体通过柔性接头锚定以促进快速和高亲和力结合。LNP具有插入到EV膜中的二酰基脂质(DSPE)，聚乙二醇(PEG)间隔区和生物素标签。LNP可以通过生物素与各种底物结合以捕获或检测EV(Wan2017)。
外泌体的测量可以使用流式细胞术，ELISA和邻近生物发光进行测定。
实施例2.循环肿瘤细胞和细胞外囊泡的鉴定方法
采用多种方法对CDH17阳性样本进行定量，包括：组织病理学、免疫组织化学(IHC)、ELISA、免疫印迹、免疫荧光、流式细胞术和邻近生物发光。一般而言，CDH17的水平似乎易于检测，特别是，CDH17阳性IHC计数的水平、血清水平或CTC计数的水平随着肿瘤进展通过每个分期而增加，并且在手术治疗后降低(图3)。相对于起源于肿瘤的循环外泌体，癌症早期的CTC水平可以非常低(Ferreira 2017)。因此，CDH17外泌体可能会被GI肿瘤细胞释放，然后在血液中比CTC更早地被检测到，这使得一种更强大的测定方法可以检测到早期的GI癌症，其可以用来辅助任何GI肿瘤的分期。
已经报道CDH17作为细胞外囊泡膜蛋白从培养的GI肿瘤细胞系中释放(Mathivanan S.2010，Demory B 2013，Xu R 2015)。携带CDH17(CDH17EV)的细胞外囊泡包括外泌体(30-100nm)和微泡(100-1000nm)。实际上，在GI癌细胞的组织培养基中容易检测到CDH17EV，如图3-5所示。通过使用抗CDH17抗体和ELISA鉴定分子量小于100kDa的CDH17(sCDH17)的可溶性推测脱落形式。由于完整的CDH17分子具有7个三级胞外域(图7)和120kDa(图4)，肿瘤细胞培养基中的这一sCDH17似乎缺少结构域6(D6，图7)，因为它不结合D6特异性抗体。在GI肿瘤细胞的培养基中也检测到大于100kDa的CDH17，其可归类为CDH17EV。
使用来自正常和CRC患者的少量血浆样本的测定分析表明，患者血液同时含有sCDH17和CDH17EV(图2-3)。通常，患者的血液可具有几乎1ug/ml的CDH17，但正常血液中的CDH17的量接近背景。癌症患者血液中CDH17EV或sCDH17的表征表明，在来自培养的癌细胞的培养基中有效捕获CDH17的某些抗体可能不会捕获来自一些患者血液的CDH17。因此，鉴定可有效捕获患者血液中所有形式的CDH17的CDH17抗体是筛选患者样本的先决条件。
尽管先前有几项研究表明，肿瘤相关的CDH17可能是一种有用的早期生物标志物，但CDH17血液测定尚未被开发或验证(Lee 2010，Panarelli 2012)。这可能是因为患者血液中CDH17的裂解形式(脱落和囊泡相关)尚未被表征，并且不能获得合适的捕获和检测探针。为了开发诊断测定，已经生成了一组400多个CDH17抗体，这些抗体的表位定位于所有7个CDH17胞外域(见下文)。
在正常个体中，血液中的基线CDH17可以是次纳摩尔的或可忽略的(图1-3)。其他提出的标志物，如E-钙粘蛋白的正常血浓度可能很高，可能只显示患者的血液增加了2倍(Weib 2011)。CDH17测定可以通过使用针对表型捕获的EV的组织特异性抗体进一步发展，并允许确定肿瘤的来源(图3)。该结果可进一步发展为预后分析，以用捕获的CDH17EV中突变肿瘤基因的分析指导治疗。例如，可分析CDH17外泌体或总EV中KRAS和NRAS密码子12和13、BRAF p.V600、miRNA和其他肿瘤驱动突变DNA/RNA以用于预后或预测性评估(Sepulveda2017，Ogata-Kawata 2014，Hao 2017)。最近，随着在几个不同的平台上显示出检测肿瘤相关蛋白、DNA和RNA的能力，开发基于血液的细胞外囊泡(EV)测定的力度有所增加(Soung2017)。最后，对CDH17血浓度的测定也将用作靶向CDH17的任何临床研究的药效学标志物。
目前，没有基于血液的测定法可用于测量血清或细胞培养物中的CDH17水平。这一障碍可能是由于缺乏高亲和力表位定位的CDH17抗体所致，而其可能是以高灵敏度定量检测sCDH17、CDH17EV和总CDH17水平所必需的。新型脂质纳米探针(LNP)(Wan 2017；图7)可以被认为是用于捕获和检测CDH17EV的整合部分。这种测定法包括新的经修饰的重组CDH17抗体，以使得能够更有效地结合sCDH17并从血清/血浆中高度亲和地捕获循环CDH17EV(图2-3)。此外，该测定可能会进一步发展，以鉴定CDH17EV的起源组织和基因突变，以帮助选择当前和新出现的针对GI癌症患者的靶向治疗方法。
实施例3.CDH17EV测定平台
为了量化CDH17 EV相对于EV总量的比例，EV将被LNP捕获，如图3所示。然后使用特异性和高亲和力的CDH17抗体及其第二试剂如抗Ig过氧化物酶(ELISA)、抗Ig藻红蛋白(流式细胞荧光测定法)或CDH17抗体缀合珠(邻近发光)对CDH17的水平进行定量。为了定量捕获的CDH17EV，EV将与结合不同的非重叠表位(CDH17 mAb2)的CDH17抗体结合(图3)。这两种方法在定量检测CDH17EV方面各显示出比较优势。第一种方法使用LNP探针和二级试剂，如链酶亲和素过氧化物酶(SA-HRP；ELISA)、链霉亲和素藻红蛋白(SA-PE；流式细胞荧光测定法)或链霉亲和素缀合的珠(邻近发光(proximity luminescence))。第二种方法使用CDH17mAb2作为其一线抗体(first line of Ab)和二级检测试剂。为了定量CDH17 EV上的其它蛋白质，将用人源化CDH17特异性抗体(huCDH17 mAB)捕获CDH17 EV。针对抗原的特异性小鼠抗体(例如TROP2)将被允许结合。其结合将用抗鼠IgHRP(ELISA)或抗鼠IgPE(流式细胞荧光法)检测。对于邻近发光，CDH17可以用CDH17 mAb2偶联珠捕获，第二蛋白质可以用蛋白-A/G珠检测(邻近发光)。
实施例4.选择用于临床样本验证的测定平台和方案。
在ELISA中选择最佳捕获和检测抗体后，将抗体和LNP用于邻近发光和流式细胞术平台中。三个平台分别用于比较癌细胞培养基、阳性血样本、正常血样和重组可溶性CDH17。根据它们的性能，即灵敏度、稳定性、再现性，选择一个或两个平台用于临床样本验证测定。非优化测定法的灵敏度接近400pg/ml。用于测定验证的靶标标准包括高灵敏度(≤20pg/ml)、特异性(相对于正常血清≥50倍)、再现性、动态范围(超过4log)、高通量和最小执行时间(1-2小时)。
临床样本验证的主要终点是具有统计学上显著的值，其区分来自GI癌症患者的血液样本中sCDH17、CDH17 EV或总CDH17水平的增加，例如CDH17血浓度的显著增加、肿瘤分期的改变和治疗后的显著降低(图3)。预期需要持续优化sCDH17、CDH17 EV和总CDH17的标准。在本文中，可以使用多于一个测定平台以确保每个血液样本的稳健测定结果。
本公开不限于本申请中描述的特定实施例，其旨在作为各个方面的说明。在不脱离其精神和范围的情况下，可以进行许多修改和变化，这对于本领域技术人员而言是显而易见的。除了本文列举的那些之外，本公开范围内的功能等同的方法和装置对于本领域技术人员而言从前述描述中将是显而易见的。这样的修改和变化旨在落入所附权利要求的范围内。本公开仅受所附权利要求的条款以及这些权利要求所赋予的等同物的全部范围的限制。应当理解，本公开不限于特定的方法、试剂、化合物、组合物或生物系统，其当然可以变化。还应当理解的是，本文使用的术语仅用于描述具体实施方案的目的，而不意图是限制性的。
虽然已经参照其实施例具体示出和描述了本公开，但是本领域技术人员将理解，在不脱离本公开的精神和范围的情况下，可以在形式和细节上进行前述和其他改变。
表格
表1.测定CDH17阳性EV的特征性试剂
序列表
CDH17捕获和检测抗体的实例：
SEQ ID NO：1
Lic3可变重链结构域的人源化氨基酸序列(ARB101，CDH17捕获)DIVLTQTPLSLTVSLGDQASISCRSSQSIVHSNGNTYLGWYLQRPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPLTFGAGTKLELKRAD
SEQ ID NO：2
Lic3可变轻链结构域的人源化氨基酸序列(ARB101，CDH17捕获)QVQLQESGGGLVKPGGSLKLSCAASGFSFSDYYMYWVRQAPEKRLEWVASISFDGTYTYYTDRVKGRFTISRDNAKNNLYLQ MSSLKSEDTAMYYCARDRPAWFPYWGQGTLVTVSA
SEQ ID NO：3
10C12(CDH17)可变重链结构域的人源化氨基酸序列(ARB102，CDH17捕获)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAVIDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQ MNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSA
SEQ ID NO：4
10C12(CDH17)可变轻链结构域的人源化氨基酸序列(ARB102，CDH17捕获)
DIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATY YCLQYASSPFTFGGGTKVEIK
SEQ ID NO：5(7)
9C6(CDH17)可变重链结构域的人源化氨基酸序列(CDH17检测)
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTHYWMHWVRQRPGKGLEWMGEIDPFDSYTYYNQKFKGRVTMTVDTSSDTA YMELSSLRSEDTAVYYCARPLPGTGWYFDVWGQGTTVTVSS
SEQ ID NO：6(8)
9C6(CDH17)轻链可变结构域的人源化氨基酸序列(CDH17检测)
EIVLTQSPTTLSLSPGERATLSCSASSSISSTYLHWYQQKPGFPPRLLIYGTSNLASGIPACFSGSGSGTDFTLTISSLEAEDFAVYYCQQG SSLPFTFGQGTKLEIK
序列表
<110> 艾贝乐医药科技有限公司
<120> 用于诊断和治疗癌症的组合物和方法
<130> ARTI1924PCT
<141> 2019-05-16
<150> 62/672,319
<151> 2018-05-16
<160> 6
<170> SIPOSequenceListing 1.0
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<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 1
Asp Ile Val Leu Thr Gln Thr Pro Leu Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Ala Asp
115
<210> 2
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 2
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 3
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 3
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 4
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 4
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Gly Tyr
20 25 30
Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly Ala Ile Lys Arg Leu Ile
35 40 45
Tyr Thr Thr Ser Thr Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 5
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr His Tyr
20 25 30
Trp Met His Trp Val Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asp Pro Phe Asp Ser Tyr Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Ser Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Leu Pro Gly Thr Gly Trp Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 6
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 6
Glu Ile Val Leu Thr Gln Ser Pro Thr Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Ile Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Phe Pro Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Cys Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Ala Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ser Ser Leu Pro
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
Claims (10)
1.捕获抗体和检测抗体在制备诊断受试对象中CDH17阳性肿瘤的方法中使用的试剂中的用途，其中，所述方法包括：
使来自所述受试对象的样本与捕获抗体接触以提供捕获的样本，其中所述捕获抗体对外泌体、微泡或可溶性CDH17片段具有结合亲和力；
将所述捕获的样本与检测抗体或脂质纳米探针（LNP）接触以提供检测样本；
确定所述检测样本中所述检测抗体或脂质纳米探针（LNP）的量；和
基于所述检测抗体或LNP的量确定患所述CDH17阳性肿瘤的所述受试对象的概率，
其中，所述捕获抗体包括对CD9、CD63、CD81、CD45或其组合具有结合亲和力的单克隆抗体，其中，所述捕获抗体包括由SEQ ID NO. 1组成的可变重链结构域的人源化氨基酸序列和由SEQ ID NO. 2组成的可变轻链结构域的人源化氨基酸序列；或由SEQ ID NO. 3组成的可变重链结构域的人源化氨基酸序列和由SEQ ID NO. 4组成的可变轻链结构域的人源化氨基酸序列、或由SEQ ID NO. 5组成的可变重链结构域的人源化氨基酸序列和由SEQ IDNO. 6组成的可变轻链结构域的人源化氨基酸序列。
2.捕获抗体和检测抗体在制备诊断受试对象中CDH17阳性肿瘤的方法中使用的试剂中的用途，其中，所述方法包括：
使来自所述受试对象的样本与捕获抗体接触以提供捕获的样本，其中所述捕获抗体对外泌体、微泡或可溶性CDH17片段具有结合亲和力；
确定所述捕获的样本的量；和
基于所述捕获的样本的量确定患有所述CDH17阳性肿瘤的受试对象的概率，
其中，所述捕获抗体包括对CD9、CD63、CD81、CD45或其组合具有结合亲和力的单克隆抗体，其中，所述捕获抗体包括由SEQ ID NO. 1组成的可变重链结构域的人源化氨基酸序列和由SEQ ID NO. 2组成的可变轻链结构域的人源化氨基酸序列；或由SEQ ID NO. 3组成的可变重链结构域的人源化氨基酸序列和由SEQ ID NO. 4组成的可变轻链结构域的人源化氨基酸序列；或由SEQ ID NO. 5组成的可变重链结构域的人源化氨基酸序列和由SEQ IDNO. 6组成的可变轻链结构域的人源化氨基酸序列。
3.捕获抗体在制备诊断受试对象中CDH17阳性肿瘤的方法中使用的试剂中的用途，其中，所述方法包括：
用荧光DNA/RNA染料标记来自所述受试对象的样本以提供标记的样本；
使所述标记的样本与捕获抗体接触以提供捕获的样本，其中所述捕获抗体对外泌体、微泡或可溶性CDH17片段具有结合亲和力；
确定所述捕获的样本的量；和
基于所述捕获的样本的量确定患有所述CDH17阳性肿瘤的受试对象的概率，
其中，所述捕获抗体包括对CD9、CD63、CD81、CD45或其组合具有结合亲和力的单克隆抗体，其中，所述捕获抗体包括由SEQ ID NO. 1组成的可变重链结构域的人源化氨基酸序列和由SEQ ID NO. 2组成的可变轻链结构域的人源化氨基酸序列；或由SEQ ID NO. 3组成的可变重链结构域的人源化氨基酸序列和由SEQ ID NO. 4组成的可变轻链结构域的人源化氨基酸序列；或由SEQ ID NO. 5组成的可变重链结构域的人源化氨基酸序列和由SEQ IDNO. 6组成的可变轻链结构域的人源化氨基酸序列。
4.根据权利要求1-3任一项所述的用途，其中，所述接触所述捕获的样本包括使所述捕获的样本与脂质纳米探针（LNP）接触。
5.根据权利要求1-3任一项所述的用途，其中，所述CDH17阳性肿瘤包括胃肠系统的癌症。
6.根据权利要求5所述的用途，其中，所述CDH17阳性肿瘤包括结肠癌。
7.根据权利要求1-3任一项所述的用途，其中，所述样本包括体液。
8.根据权利要求7所述的用途，其中，所述体液包括外周血、尿、骨髓、胸膜液、腹膜液或肠液。
9.根据权利要求8所述的用途，其中，所述外周血为血清或血浆。
10.根据权利要求8或9所述的用途，其中，所述体液的体积小于10 mL。
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| CN102483414A (zh) * | 2008-10-09 | 2012-05-30 | 香港大学 | 作为肝癌诊断标记和治疗靶标的钙黏着蛋白-17 |
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