CN117083294A - 用于检测胶原xviii生物标志物的测定 - Google Patents
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Abstract
本发明提供了采用特异性结合XVIII型胶原的长和/或中等同种型的抗体的免疫测定方法和免疫测定试剂盒。本发明还提供了用于评估患者对抗纤维化药物治疗有响应的可能性和监测患者的肝纤维化的方法。
Description
技术领域
本发明涉及一种用于检测XVIII型的长和/或中等同种型和/或定量测定患者样品中所述同种型的量的免疫测定。本发明还涉及用于在所述免疫测定中使用的抗体并且涉及用于进行所述免疫检测的试剂盒。所述免疫测定、抗体和试剂盒可以用于检测或监测患者的肝纤维化，或用于在患有肝纤维化的患者中评估患者对抗纤维化药物治疗有响应的可能性。
背景技术
慢性肝病(CLD)是导致死亡和发病的主要原因，每年在全世界造成超过200万人死亡。这些CLD相关的死亡中约有100万是由病毒性肝炎引起的，其中丙型肝炎C是主要原因1。CLD病因中常见的是肝纤维化的发展，其最终结局是肝硬化。肝纤维化是长期伤口愈合反应的结果，并且其特征是细胞外基质(ECM)的积累，使得肝脏的ECM组成在质量和数量上与健康肝脏不同。最近的报告表明，纤维化肝脏的ECM成分是患者生存的关键决定因素，这表明了组织剖析患者的价值。纤维病灶主要由胶原组成，所述胶原可以大致分为两组：间质基质和基底膜。基底膜调节细胞功能，而且是生长因子的储存库。基底膜基质的积累与修复性组织反应相关。相反，间质基质的积累与更严重且逐步发展的疾病相关。
在胶原家族中，多聚蛋白XVIII型胶原是独一无二的。XVIII型胶原是位于基底膜中的硫酸乙酰肝素蛋白多糖，在所述基底膜中，其与层粘连蛋白、串珠蛋白、巢蛋白、纤连蛋白、IV型和VI型胶原相互作用，从而在基质环境的柔韧性方面发挥至关重要的作用2,3。存在三种同种型，它们各自的分布存在差异；短同种型主要存在于脉管***和骨骼肌中，而中等和长同种型主要存在于肝脏中，在肝脏中，由肝细胞产生同种型4,5。所有三种同种型都在三螺旋区内携带细胞附着位点和C末端片段内皮抑素，已知其具有抗血管生成和肿瘤生长抑制特性6。尽管如此，所述三种同种型的初级结构确实不同，其中最显著的差异是卷曲结构域。卷曲(Fz)结构域位于长同种型的N末端端部中，是跨膜受体，充当Wnt分子的结合位点，具有调节细胞命运、增殖和迁移的能力。在体外和体内研究中，已经显示Fz结构域用于调节人癌细胞增殖和细胞周期进展7,8。此外，发现Fz决定小鼠中脂肪细胞的成熟度和丰度9。因此，XVIII型胶原的长同种型具有广泛的功能，从而可能影响肝脏病理学和肝细胞功能。
肝纤维化的严重程度通常通过肝活检或瞬时弹性成像来评估。然而，肝活检是本身存在缺陷的模式，其与高昂的经济和劳动力成本相关；瞬时弹性成像尽管是有吸引力的非侵入性替代方案，但并不广泛可用，而且也不提供有关肝纤维化动力学的信息。
因此，本领域需要评估患者中肝纤维化的存在和/或严重程度的新颖方法。特别地，血清学生物标志物可以在临床上用于识别可能在疾病方面有进展或对抗纤维化治疗有响应的个体，这将是非常有用的。
发明内容
本申请人现在已经开发了一种酶联免疫吸附测定(ELISA)生物标志物，所述生物标志物可以准确地量化XVIII型胶原的肝脏特异性同种型，即长同种型和中等同种型，并且已经评估了所述生物标志物在患有轻度至重度肝纤维化的患者中的临床价值。
因此，在第一方面，本发明提供了一种免疫测定方法，其包括：(i)使来自患者的生物流体样品与单克隆抗体接触，所述单克隆抗体特异性结合XVIII型的长和/或中等同种型并且不特异性结合XIIII型的短同种型；以及(ii)检测并确定所述样品中所述单克隆抗体与肽之间的结合量。
如本文所用，术语“结合量”是指患者样品中单克隆抗体与肽之间的结合的定量。所述定量可以例如通过将患者样品中的测量结合值与使用标准样品(所述标准样品含有已知浓度的特异性结合有抗体的肽)中的测量结合值产生的校准曲线进行比较来确定，从而确定患者样品中特异性结合抗体的肽的量。在下文列出的示例中，使用ELISA方法，其中使用分光光度分析来测量患者样品中的结合量以及产生校准曲线时的结合量。然而，可以使用任何合适的分析方法。
在优选的实施例中，所述患者样品来自患有肝纤维化的患者，并且所述方法用于评估患者对抗纤维化药物治疗有响应的可能性。所述方法可以进一步包括：(iii)将步骤(ii)中确定的所述单克隆抗体的结合量与以下值相关联：与治疗响应者相关的值和/或与非响应者相关的值和/或预定的截断值。患者样品可以来自患有慢性肝病的患者。例如，患者样品可以来自患有病毒性肝炎、酒精性肝病或非酒精性脂肪肝病的患者。
在此上下文中，术语“与治疗响应者相关的值”意指通过上文所述的方法针对来自已知随后对抗纤维化药物治疗有响应的患者的样品确定的标准化结合量，例如在所述患者中，在用抗纤维化药物进行治疗后肝纤维化减少(例如通过在治疗过程中一个或多个Ishak分数的减少来确定)；并且术语“与非响应者相关的值”意指通过上文所述方法针对来自已知随后对抗纤维化药物治疗没有响应的患者的样品确定的标准化结合量，例如在所述患者中，在用抗纤维化药物进行治疗后肝纤维化增加。
同样在此上下文中，术语“预定的截断值”意指在统计学上经确定用于区分对抗纤维化药物治疗更不可能有响应的患者和对抗纤维化药物治疗更可能有响应的患者的结合量。例如，预定的截断值可以根据先前对来自肝纤维化患者的样品中的结合水平的分析来计算，所述肝纤维化患者随后用抗纤维化药物或安慰剂进行治疗，其中在结合量低于截断值的患者中，安慰剂与抗纤维化药物治疗组之间在肝纤维化减少的患者数量或肝纤维化增加的患者数量方面不存在统计学上显著的差异，和/或其中在具有高于截断值的值的患者中，安慰剂与抗纤维化药物治疗组之间在肝纤维化减少的患者数量和/或肝纤维化增加的患者数量方面存在统计学上显著的差异。
在另一个实施例中，所述方法用于监测患者的肝纤维化，所述方法进一步包括：(iii)将步骤(ii)中确定的所述单克隆抗体的所述结合量与在先前时间点从所述患者获得的值相关联。所述患者可以是患有慢性肝病的患者。例如，患者可以是患有病毒性肝炎、酒精性肝病或非酒精性脂肪肝病的患者。
因此，在这个实施例中，所述方法可以包括量化在第一时间点和至少一个后续时间点从患者获得的至少两个样品中单克隆抗体与肽之间的结合量。
患者可以是接受抗纤维化药物治疗的患者。在这种情况下，所述方法可以进一步用于评估用于治疗肝纤维化的药物的疗效，由此所述方法包括量化在给患者施用药物的时间段期间在第一时间点和至少一个后续时间点从患者获得的至少两个样品中单克隆抗体与肽之间的结合量。
在另一个实施例中，所述方法用于检测患者的肝纤维化。所述方法可以进一步包括：(iii)将步骤(ii)中确定的所述单克隆抗体的所述结合量与以下值相关联：与正常健康受试者相关的值和/或与已知疾病严重程度相关的值和/或预定的截断值。在某些实施例中，所述方法可以用于检测患者的慢性肝病。
在此上下文中，术语“与正常健康受试者相关的值”是指通过上文所述的方法针对来自被认为是健康的(即，没有疾病(并且更具体地说，没有肝纤维化))受试者的样品确定的标准化结合量；并且术语“与已知疾病严重程度相关的值”是指通过上文所述的方法针对来自已知患有已知严重程度的肝纤维化的患者的样品确定的标准化结合量。
同样在此上下文中，术语“预定的截断值”意指在统计学上经确定指示患者发生肝纤维化的高可能性的结合量，因为患者样品中的测量结合值等于或高于统计学截断值，对应于肝纤维化的存在或可能性的至少70％概率、优选地至少80％概率、优选地至少85％概率、更优选地至少90％概率并且最优选地至少95％概率。
在优选的实施例中，所述样品是生物流体。所述生物流体可以是但不限于血液、血清、血浆、尿液或者来自细胞或组织培养物的上清液。优选地，所述生物流体是血液、血清或血浆。
所述免疫测定可以是但不限于竞争性测定或夹心式测定。所述免疫测定可以是例如放射免疫测定或酶联免疫吸附测定(ELISA)。此类测定是本领域技术人员已知的技术。
在优选的实施例中，所述单克隆抗体特异性结合氨基酸序列NLLNLN(SEQ IDNO.1)。所述氨基酸序列存在于XVIII型的长和中等同种型的N末端(并且在XVIII型的短同种型中不存在)，并且相应地所述单克隆抗体特异性结合XVIII型的长和中等同种型的N末端。
在某些实施例中，所述单克隆抗体是针对具有氨基酸序列NLLNLNKDKE(SEQ IDNO.2)的合成肽产生的单克隆抗体。
如本文所用，术语“单克隆抗体”是指完整抗体和其保留完整抗体的结合特异性的片段，例如Fab片段、F(ab’)2片段、单链Fv片段或本领域技术人员已知的其他此类片段。众所周知，完整抗体通常具有两对同一的多肽链的“Y形”结构，每对由一条“轻”链和一条“重”链组成。每个轻链和重链的N末端区域含有可变区，而每个重链和轻链的C末端部分组成恒定区。可变区包含三个互补决定区(CDR)，它们主要负责抗原识别。恒定区允许抗体募集免疫***的细胞和分子。保留结合特异性的抗体片段至少包含CDR和可变区的其余部分的足够部分以保留所述结合特异性。
在本发明的方法中，可以使用包含本领域已知的任何恒定区的单克隆抗体。人恒定轻链被分类为κ和λ轻链。重恒定链被分类为μ、δ、γ、α或ε，并且将抗体的同型分别定义为IgM、IgD、IgG、IgA和IgE。IgG同型具有几个亚类，包括但不限于IgG1、IgG2、IgG3和IgG4。所述单克隆抗体可以优选地具有IgG同型，包括IgGl、IgG2、IgG3或IgG4中的任何一者。
抗体的CDR可以使用本领域已知的方法、诸如Kabat等人所述的方法来确定。如示例中所述，可以由B细胞克隆生成抗体。抗体的同型可以通过对人IgM、IgG或IgA同型或人IgG1、IgG2、IgG3或IgG4亚类具有特异性的ELISA来确定。生成的抗体的氨基酸序列可以使用标准技术来确定。例如，可以从细胞中分离出RNA，并且使用RNA通过逆转录来生成cDNA。然后使用扩增抗体重链和轻链的引物对cDNA进行PCR。例如，对所有VH(可变重链)序列的前导序列具有特异性的引物可以与结合至位于先前确定的同型的恒定区中的序列的引物一起使用。可以使用与κ或λ链的3’末端结合的引物以及退火至Vκ或Vλ前导序列的引物来扩增轻链。可以生成全长重链和轻链并对其进行测序。
所述单克隆抗体或其片段可以优选地包含选自以下的一个或多个互补决定区(CDR)：
CDR-H1：DYWIH(SEQ ID NO.3)
CDR-H2：EINPSDGRSNYNEKFKT(SEQ ID NO.4)
CDR-H3：DLGFAD(SEQ ID NO.5)
CDR-L1：RSSQSIVYSNGNTYLQ(SEQ ID NO.6)
CDR-L2：KVSNRFS(SEQ ID NO.7)
CDR-L3：FQGSHVPFT(SEQ ID NO.8)。
优选地，所述抗体或其片段包含上文列出的CDR序列中的至少2、3、4、5或6个。
优选地，所述单克隆抗体或其片段具有包含以下CDR序列的轻链可变区：
CDR-L1：RSSQSIVYSNGNTYLQ(SEQ ID NO.6)
CDR-L2：KVSNRFS(SEQ ID NO.7)以及
CDR-L3：FQGSHVPFT(SEQ ID NO.8)。
优选地，所述单克隆抗体或其片段具有包含CDR之间的框架序列的轻链，其中所述框架序列与以下轻链序列中的CDR之间的框架序列大体上同一或大体上相似(其中CDR以粗体显示并加下划线，并且框架序列以斜体显示)：
优选地，所述单克隆抗体或其片段具有包含以下CDR序列的重链可变区：
CDR-H1：DYWIH(SEQ ID NO.3)
CDR-H2：EINPSDGRSNYNEKFKT(SEQ ID NO.4)以及
CDR-H3：DLGFAD(SEQ ID NO.5)。
优选地，所述单克隆抗体或其片段具有包含CDR之间的框架序列的重链，其中所述框架序列与以下重链序列中的CDR之间的框架序列大体上同一或大体上相似(其中CDR以粗体显示并加下划线，并且框架序列以斜体显示)：
如本文所用，如果抗体的CDR之间的框架氨基酸序列与另一抗体的CDR之间的框架氨基酸序列具有至少70％、80％、90％或至少95％的相似性或同一性，则所述框架氨基酸序列大体上同一或大体上相似。相似或同一的氨基酸可以是相邻的或非相邻的。
所述框架序列可以含有一个或多个氨基酸取代、***和/或缺失。氨基酸取代可能是保守的，这意味着取代的氨基酸具有与原始氨基酸相似的化学特性。技术人员将了解哪些氨基酸共享相似的化学特性。例如，以下几组氨基酸共享相似的化学特性，诸如大小、电荷和极性：第1组，Ala、Ser、Thr、Pro、Gly；第2组，Asp、Asn、Glu、Gln；第3组，His、Arg、Lys；第4组，Met、Leu、Ile、Val、Cys；第5组，Phe、Thy、Trp。
诸如CLUSTAL程序的程序可以用于比较氨基酸序列。这一程序比较氨基酸序列，并且通过在任一序列中适当***空格来找到最佳比对。有可能计算氨基酸的同一性或相似性(同一性加上氨基酸类型的保守性)以实现最佳比对。如BLASTx的程序将比对相似序列的最长延伸，并且为拟合指定值。因此，有可能获得一种比较，其中发现数个相似的区域，每个区域具有不同的分数。本发明预期这两种类型的分析。同一性或相似性优选地在框架序列的整个长度上计算。
在某些优选的实施例中，所述单克隆抗体或其片段可以包含以下轻链可变区序列：
和/或以下重链可变区序列：
(CDR为粗体并加下划线；框架序列为斜体)。
在第二方面，本发明提供了一种单克隆抗体，其特异性结合XVIII型的长和/或中等同种型，并且不特异性结合XIIII型的短同种型。
在优选的实施例中，所述单克隆抗体特异性结合氨基酸序列NLLNLN(SEQ IDNO.1)。
所述单克隆抗体可以是针对具有氨基酸序列NLLNLNKDKE(SEQ ID NO.2)的合成肽产生的单克隆抗体。
根据第二方面的单克隆抗体的进一步优选的实施例和特征将从用于根据第一方面的方法中的优选单克隆抗体的以上讨论中显而易见。特别地，根据第二方面的单克隆抗体可以优选地包含一个或多个如上所述的互补决定区(CDR)、框架序列和/或可变区序列。
在第三方面，本发明提供了一种免疫测定试剂盒，其包括：(a)单克隆抗体，其特异性结合XVIII型的长和/或中等同种型，并且不特异性结合XIIII型的短同种型；以及(b)以下中的至少一者：
-链霉亲和素包被的孔板；
-单克隆抗体特异性结合的生物素化肽；
-用于在夹心式免疫测定中使用的次级抗体；
-单克隆抗体特异性结合的校准肽；
-抗体生物素化试剂盒；
-抗体HRP标记试剂盒；
-抗体放射性标记试剂盒；以及
-测定可视化试剂盒。
在优选的实施例中，所述单克隆抗体特异性结合氨基酸序列NLLNLN(SEQ IDNO.1)。所述单克隆抗体可以是针对具有氨基酸序列NLLNLNKDKE(SEQ ID NO.2)的合成肽产生的。特别地，所述单克隆抗体优选地是如上所述的根据本发明第二方面的单克隆抗体。
在某些实施例中，所述校准蛋白可以是包含氨基酸序列NLLNLNKDKE(SEQ IDNO.2)的肽。
在某些实施例中，所述生物素化肽可以包含NLLNLNKDKE-L-生物素(SEQ IDNO.13)，其中L是任选的接头。
附图说明
图1：对PRO-C18L测定的特异性测试。针对PRO-C18L肽(标准肽)和具有从PRO-C18LN末端序列改变的一个氨基酸的去选择肽来测试PRO-C18L抗体的反应性。数据显示为抑制曲线，其中y轴为光密度(OD)并且x轴为肽含量(ng/ml)。
图2：在所有患者(A)中和在被分为低于或高于基线处的PRO-C18L中位值的所有患者中，从基线(BL)到第52周(W52)，安慰剂(PL)或法格列酮(farglitazar)治疗的(T)患者中PRO-C18L的百分比变化。图形显示为带有图基须(Tukey whiskers)的箱形图。p＜0.05的显著性用*(A)或精确值(B)表示。
图3：根据基线PRO-C18L的三分位组(tertiles)以及是否用安慰剂(PL)或法格列酮(T)进行治疗来划分的患者组中回归者、稳定者或进展者的比例。根据第52周Ishak评分中相应的一个或多个减少或增加，患者被表征为回归者、稳定者或进展者。显著的p值用精确值表示。在PRO-C18L三分位组1(T1)中，PL组有16％回归者、58％稳定者和26％进展者，而T组有13％回归者、25％稳定者和7％进展者。在PRO-C18L三分组3(T3)中，PL组有7％回归者、60％稳定者和33％进展者，而T组有22％回归者、59％稳定者和19％进展者。
图4：高PRO-C18L(高于2.56ng/ml的中位值)与高PRO-C3的关联系数。
具体实施方式
示例
在以下示例中描述了目前公开的实施例，这些示例旨在帮助理解本公开，并且不应当被解释为以任何方式限制在随后的权利要求中定义的本公开的范围。提出以下示例以便向本领域普通技术人员提供如何制备和使用所述实施例的完全公开和说明，并且不意图限制本公开的范围，也不意图表示以下实验是所进行的全部或仅有的实验。已经努力确保关于所使用的数字(例如量、温度等)的准确性，但是应当考虑一些实验误差和偏差。除非另有说明，否则份数是重量份，分子量是重均分子量，温度是摄氏度，并且压力等于或接近大气压。
在以下示例中，采用了以下材料和方法。
材料和方法
试剂
用于实验的所有试剂都是来自Merck公司(Whitehouse Station，NJ，USA)和Sigma-Aldrich公司(St.Louis，MO，USA)的高质量化学物质，以及从GenScript公司(Piscataway，NJ，USA)购买的所有合成肽。定义用于抗体产生和验证的肽的序列如下：
1.用于抗体产生的标准肽NLLNLNKDKE(SEQ ID NO.2)。与XVIII型胶原的长和中等同种型的10个氨基酸N末端序列相比，这种肽的最后四个氨基酸不同。XVIII型胶原的长和中等同种型(在23个氨基酸的信号肽切割后形成)的10个氨基酸N末端氨基酸序列是24NLLNLNWLWF33(SEQ ID NO.14)。当测试针对大鼠、小鼠和牛的序列同源性时，发现这种N末端序列对于人XVIII型胶原是独特的，但是也发现其是不溶的，因此不适合抗体产生。因此，将可溶的序列NLLNLNKDKE(SEQ ID NO.2)用于抗体产生，并通过随后的测试来确认所产生的抗体与XVIII型胶原的长和中等同种型(以及因此与N末端序列NLLNLN(SEQ ID NO.1))的特异性结合。如本文所用，术语“PRO-C18L”可互换地用于指代标准肽/序列NLLNLNKDKE(SEQID NO.2)和N末端表位/序列NLLNLN(SEQ ID NO.1)两者，所述N末端表位/序列存在于标准肽和XVIII型胶原的长和中等同种型中，并且与本文所述的抗体特异性结合。
2.用于包被和筛选的生物素缀合肽NLLNLNKDKE-K-生物素(SEQ ID NO.15)。
3.与钥孔血蓝蛋白(KLH)缀合以用于免疫反应的免疫原性肽NLLNLNKDKEKK-GGC-KLH(SEQ ID NO.16)。
单克隆抗体产生
用100μg乳化免疫原皮下免疫六至七周龄的Balb/C小鼠，所述乳化免疫原由PRO-C18L钥孔血蓝蛋白(KLH)缀合的抗原肽(NLLNLNKDKEKK-GGC-KLH(SEQ ID NO.16)，即免疫原性肽)与Stimune免疫原性佐剂(SPECOL，cat#7925000，Invitrogen)混合组成。每两周重复一次免疫，直到发现血清效价稳定为止。选择具有最高血清效价和最佳肽抑制的小鼠进行融合。因此，在休息至少三周之后，对所选小鼠腹膜内给予50-100μg乳化免疫原(取决于抗体效价)与100μl 0.9％NaCl溶液混合的最终增强。在最后一次增强后三天，处死小鼠，分离脾细胞并与SP2/0骨髓瘤细胞融合以产生杂交瘤用于进一步培养，这个过程先前已经描述10。使用半培养基法并采用有限稀释法将杂交瘤接种在96孔微量滴定板上，以确保单克隆性。此外，亚克隆至少重复两次，以进一步确保单克隆性。在使用链霉亲和素包被的板的直接竞争性ELISA中筛选上清液对标准肽、无义肽(LHDSNPYPRR(SEQ ID NO.17))和去选择肽(NALNLNWLWF(SEQ ID NO.18))的反应性和特异性，以确认与标准肽的结合以及与无义肽和去选择肽类缺乏结合。为了确认IgG同种型，在克隆分型***HRP试剂盒cat.No.5300-05(Southern Biotech,Birmingham,AL,USA)中进一步测试克隆。
对产生的抗体进行测序并确定CDR。
链的序列如下：
CDR加下划线且为粗体
恒定区斜体：
重链：氨基酸序列(514aa)
轻链：氨基酸序列(219aa)
克隆的特征
使用HiTrap亲和柱(GE Healthcare Life Science,Little Chalfont,Buckinghamshire,UK)来纯化所选克隆，并且根据制造商说明，使用Roche PeroxidaseLabelling Kit(cat.no.11829696001)(Roche Diagnostics GmbH,Mannheim,Germany)用辣根过氧化物酶(HRP)来标记所选克隆。使用不同的人生物材料(诸如血清或血浆)与EDTA、肝素或柠檬酸盐来评估克隆的天然反应性和亲和力。
PRO-C18L竞争性ELISA程序
为了测量血清或血浆样品中PRO-C18L的血清学水平，使用以下程序：
1.在来自Roche Diagnostics GmbH(Mannheim,Germany)的96孔链亲和素包被的微量滴定板cat.no.11940279上涂上100μl生物素化肽(生物素缀合肽)，所述生物素化肽溶于含有10％山梨醇的50mM PBS-BTB中并且在测定缓冲液(50mM PBS-BTB,8g NaCl,pH 7.4)中稀释。在20℃的黑暗中，在300rpm的摇动装置上培养30分钟。
2.在洗涤缓冲液(20mM Tris,50mM NaCl,pH 7.2)中洗涤5次。
3.将20μl标准肽、对照品或样品一式两份加入适当的孔中，然后加入100μl在测定缓冲液(50mM PBS-BTB,8g NaCl,pH 7.4)中稀释的HRP标记抗体。在4℃中培养过夜并以300rpm的转速摇动。
4.在洗涤缓冲液(20mM Tris,50mM NaCl,pH 7.2)中洗涤5次。
5.加入100μl四甲基联苯胺(TMB)(cat.no.4380H,Kem-En-Tec,Taastrup,Denmark)，并且在20℃下孵育15分钟。
6.最后，加入停止溶液(1％ H2SO4)。
7.以650nm作为参考，读取450nm处的吸光度。这是在ELISA微孔板阅读器(VerseMax,Molecular Devices,Sunnyvale,CA,USA)上完成的。
通过标准肽的2倍稀释来制备标准曲线。
技术验证
为了确定测量的线性，在人的血清和血浆样品的2倍稀释液中确定100％样品的回收百分比。同样，抗体特异性被计算为100％校准肽(标准肽，NLLNLNKDKE(SEQ ID NO.2))、无义肽(LHDSNPYPRR(SEQ ID NO.17))和去选择肽(NALNLNWLWF(SEQ ID NO.18))的回收百分比。检测下限(LLOD)被确定为21个空白(缓冲液)的平均值+3x标准偏差(SD)。检测上限(ULOD)被确定为标准A的10次测量的平均值-3x SD。为了评估测定内和测定间变化，在双联测定中测量了8个质量控制(QC)样品的10次独立运行，并计算为平均方差系数(CV％)。通过测量掺有标准肽的健康人血清样品来评估测量的准确性，并计算为分析物理论收集量的回收百分比。干扰被测量为掺有显著浓度的血红蛋白、脂血症和生物素的人血清样品的回收百分比。线性、准确度和干扰的可接受范围为±20％。
分析物和试剂稳定性
将三份血清和血浆人体样品进行五个冷冻-解冻循环，以确定分析物的稳定性，其中第一次循环作为参考。此外，通过将三份血清和三份血浆样品在4℃和20℃下孵育2小时、4小时、24小时和48小时来测试分析物稳定性，并针对非应激样品参考进行测试。所有样品测试均作为双联测定进行。通过将HRP标记的抗体在20℃和37℃下孵育七天来测试试剂稳定性，并针对无应激试剂进行测试。分析物和试剂稳定性测试的可接受范围为±20％。
临床评估
患者样品
PRO-C18L ELISA在多中心II期临床研究的群体中进行了测试，所述研究调查了法格列酮(过氧化物酶体增殖物激活受体γ激动剂，用于感染丙型肝炎患者的潜在抗纤维化化合物)(NCT00244751)的有效性，如前所述11。血浆样品可在200名患者的亚群中获得，所述患者接受了52周的日剂量法格列酮或匹配安慰剂治疗。肝活检可在基线和52周后进行，并由中心经验丰富的组织病理学家进行检查，使用Ishak改良的组织学活性指数进行分级和分期。这项研究是根据《赫尔辛基宣言》进行的，并遵循了所有相关国家的道德准则。所有患者均提供书面知情同意书。基线患者特征如下表1所示。
表1：患者基线特征
HAI，组织活性指数。BMI，体重指数。AST，天冬氨酸转氨酶。SD，标准偏差。IQR，四分位数范围。
所述群体因患有慢性丙型肝炎且由于先前的抗病毒治疗失败而难以治疗而被选择。最初的研究得出的结论是，法格列酮没有任何影响，因为根据Ishak评分，从基线到研究结束，疾病进展或消退的受试者比例是相同的11。然而，在关于同一群体的后来的出版物中，发现III型胶原形成的标志物可以识别治疗响应者，这表明纤维化的血清学测量提供了疾病活性的更动态的量化12。
生物标志物测量
在来自上述患者的EDTA血浆中一式两份测量PRO-C18L。ELISA和测量是在NordicBioscience公司(Herlev,Denmark)开发和测量的，如上所述。
统计分析
所使用的测试：卡方、T检验、单因素方差分析
使用MedCalc 19.3版(MedCalc Software Ltd,Ostend,Belgium)和GraphPadPrism第8版(GraphPad Software,La Jolla,CA,USA)来执行图形和统计分析。数据显示为图基箱线图。P<0.05的p值被认为是统计学上显著的。
结果
克隆选择和质量保证
为了从产生的克隆中选择最佳抗体：评估天然反应性、特异性和稳定性。选择用于ELISA开发的抗体被命名为NBH133A1-2B4，并且被确定为IgG2a亚型。为了确保抗体特异性，使用上述竞争性ELISA程序来测试其对标准肽、无义肽(LHDSNPYPRR(SEQ ID NO.17))和去选择肽(NALNLNWLWF(SEQ ID NO.18))的反应性。标准肽以剂量依赖的方式抑制信号(图1)，而对无义肽(数据未显示)或去选择肽没有反应性(图1)。此数据表明所选单克隆抗体对PRO-C18L N-末端表位具有高特异性。
ELISA技术说明
PRO-C18L ELISA的技术评估是通过在以上方法部分中描述的不同验证步骤进行评估的，并且结果概括在下表2中。
表2：PRO-C18L测定的技术验证
IC50为11.7ng/ml。检测下限和上限为1.7ng/ml和282.5ng/ml。测定内和测定间变化为8％和11％，分别低于10％和15％的可接受标准极限。血清和血浆两者中的稀释回收率(从未稀释到1:4稀释)均在100±20％的可接受标准范围内。在血清中校准肽(标准肽)的尖峰测试中，发现平均回收率为109％；生物片段与合成标准物的结合亲和力相同，从而确认N末端结合和高测定特异性。在用四个冷冻/解冻循环测试分析物之后，血清和EDTA血浆中的分析物回收率分别为94％和105％。此外，将血清、肝素血浆和EDTA血浆在4℃和20℃下储存48小时不会影响分析物回收率，血清回收率为85％和116％，肝素血浆回收率为82％和109％，并且EDTA血浆回收率为102％和90％。血清和血浆中的低或高水平的生物素、脂血或血红蛋白均未检测到干扰，其中回收率在92％-121％的范围内。这些结果共同证明PRO-C18L是技术上稳健的测定。
PRO-C18L的临床验证
为了测试PRO-C18L作为纤维化生物标志物的潜力，对127名用法格列酮或安慰剂治疗的HCV患者进行了纵向研究。表1中测试的人口统计资料显示，治疗组和安慰剂组之间的分布没有显著差异。
首先，对安慰剂患者与接受法格列酮治疗的患者在PRO-C18L从基线(BL)到第52周(W52)的变化进行了评估，发现安慰剂的PRO-C18L水平增加，而治疗患者的PRO-C18L水平降低(p＝0.05)，如图2A所示。为了进一步测试更高的PRO-C18L基线水平(高于中位值)是否与更多的治疗响应一致，以类似的方式对高于和低于PRO-C18L中位值(2.56ng/ml)进行了测试：在治疗患者与安慰剂患者中，从BL到W52的δPRO-C18L。尽管随着治疗，高于基线PRO-C18L的中位值水平比低于中位值的治疗患者在视觉上下降得更多(图2B)，这表明对平均值的调节，但结果并不显著。然而，这些结果表明PRO-C18L受到治疗的调节。
为了进一步评估PRO-C18L作为肝纤维化的生物标志物，根据从BL到W52的δIshak将患者分为回归者、稳定者或进展者。回归者和进展者分别被表征为从BL到W52具有一个或多个Ishak分数的减少或增加，而稳定者的Ishak没有变化。为了评估PRO-C18L的预测值，根据基线处的PRO-C18L水平，将安慰剂组和法格列酮治疗组进一步分为三分位组。在三分位组3(该三分位组由PRO-C18L基线水平最高的患者组成)的患者组中，与安慰剂组相比，法格列酮治疗组在回归者和进展者的比例上显示出显著差异(图3)，而在三分位组1(该三分位组由PRO-C18L基线水平最低的患者组成)的患者组中没有发现这种差异，这表明在基线处具有高PRO-C18L水平的患者更有可能对治疗有响应。
最后，为了评估PRO-C18L是否与PRO-C3(在早期对同样的患者的研究中发现其可以预测治疗响应者)不同，使这两个标志物在其初步截断水平(PRO-C3为20.2ng/ml，并且PRO-C18L为2.56ng/ml)上相互对照(图4)。没有发现关联性(correlation)，这表明PRO-C18L在同一人群中识别出额外的治疗响应者。
在本说明书中，除非另有明确指示，否则“或”一词在当满足所述条件中的任一个或两个时返回真值的运算符意义上使用，，其与要求仅满足一个条件的运算符‘独占或’不同。“包含”一词用于表示“包括或由……组成”。上文所承认的所有先前的教导均由此以引用的方式并入。本文中对任何先前公布的文件的承认均不应视为供认或声明在本文件发布之日，其教导是澳大利亚或其他地方的公知常识。
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Claims (21)
1.一种免疫测定方法，包括：
(i)使患者样品与单克隆抗体接触，所述单克隆抗体特异性结合XVIII型胶原的长和/或中等同种型，并且不特异性结合XIIII型胶原的短同种型；以及
(ii)检测并确定所述样品中所述单克隆抗体与肽之间的结合量。
2.根据权利要求1所述的方法，其中所述患者样品来自患有肝纤维化的患者，并且所述方法用于评估所述患者对抗纤维化药物治疗有响应的可能性，所述方法进一步包括：
(iii)将步骤(ii)中确定的所述单克隆抗体的所述结合量与以下值相关联：与治疗响应者相关的值和/或与非响应者相关的值和/或预定的截断值。
3.根据权利要求1所述的方法，其中所述方法用于监测患者的肝纤维化，所述方法进一步包括：
(iii)将步骤(ii)中确定的所述单克隆抗体的所述结合量与在先前时间点从所述患者获得的值相关联。
4.根据权利要求3所述的方法，其中所述患者样品来自接受抗纤维化药物治疗的患者。
5.根据任一前述权利要求所述的方法，其中所述患者样品来自患有慢性肝病的患者。
6.根据任一前述权利要求所述的方法，其中所述患者样品来自患有病毒性肝炎、酒精性肝病或非酒精性脂肪肝病的患者。
7.根据权利要求1所述的方法，其中所述方法用于检测患者的肝纤维化，所述方法进一步包括：
(iii)将在步骤(ii)中确定的所述单克隆抗体的所述结合量与以下值相关联：与正常健康受试者相关的值和/或与已知疾病严重程度相关的值和/或预定的截断值。
8.根据任一前述权利要求所述的方法，其中所述样品是生物流体。
9.根据权利要求8所述的方法，其中所述生物流体是血液、血清或血浆。
10.根据任一前述权利要求所述的方法，其中所述免疫测定是竞争性测定或夹心式测定。
11.根据任一前述权利要求所述的方法，其中所述免疫测定是放射免疫测定或酶联免疫吸附测定。
12.根据任一前述权利要求所述的方法，其中所述单克隆抗体特异性结合氨基酸序列NLLNLN(SEQ ID NO.1)。
13.根据任一前述权利要求所述的方法，其中所述单克隆抗体是针对具有氨基酸序列NLLNLNKDKE(SEQ ID NO.2)的合成肽产生的。
14.一种单克隆抗体，其特异性结合XVIII型胶原的长和/或中等同种型，并且不特异性结合XIIII型胶原的短同种型。
15.根据权利要求14所述的单克隆抗体，其中所述单克隆抗体特异性结合氨基酸序列NLLNLN(SEQ ID NO.1)。
16.根据任一前述权利要求所述的单克隆抗体，其中所述单克隆抗体是针对具有氨基酸序列NLLNLNKDKE(SEQ ID NO.2)的合成肽产生的。
17.一种免疫测定试剂盒，包括：(a)单克隆抗体，其特异性结合XVIII型胶原的长和/或中等同种型，并且不特异性结合XIIII型胶原的短同种型；以及(b)以下中的至少一者：
-链霉亲和素包被的孔板；
-单克隆抗体特异性结合的生物素化肽；
-用于在夹心式免疫测定中使用的次级抗体；
-单克隆抗体特异性结合的校准肽；
-抗体生物素化试剂盒；
-抗体HRP标记试剂盒；
-抗体放射性标记试剂盒；以及
-测定可视化试剂盒。
18.根据权利要求17所述的免疫测定试剂盒，其中所述单克隆抗体特异性结合氨基酸序列NLLNLN(SEQ ID NO.1)。
19.根据权利要求17至18中任一项所述的免疫测定试剂盒，其中所述单克隆抗体是针对具有氨基酸序列NLLNLNKDKE(SEQ ID NO.2)的合成肽产生的。
20.根据权利要求17至19中任一项所述的免疫测定试剂盒，其中所述校准蛋白是包含氨基酸序列NLLNLNKDKE(SEQ ID NO.2)的肽。
21.根据权利要求17至20中任一项所述的免疫测定试剂盒，其中所述生物素化肽包含NLLNLNKDKE-L-生物素(SEQ ID NO.13)，其中L是任选的接头。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB2019578.0A GB202019578D0 (en) | 2020-12-11 | 2020-12-11 | Assay for detecting Collagen XVIII biomarkers |
| GB2019578.0 | 2020-12-11 | ||
| PCT/EP2021/085308 WO2022123058A1 (en) | 2020-12-11 | 2021-12-10 | Assay for detecting collagen xviii biomarkers |
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| CN117083294A true CN117083294A (zh) | 2023-11-17 |
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| EP (1) | EP4259652A1 (zh) |
| JP (1) | JP2023554313A (zh) |
| KR (1) | KR20230145319A (zh) |
| CN (1) | CN117083294A (zh) |
| AU (1) | AU2021396552A1 (zh) |
| GB (1) | GB202019578D0 (zh) |
| WO (1) | WO2022123058A1 (zh) |
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| GB201306792D0 (en) * | 2013-04-15 | 2013-05-29 | Nordic Bioscience As | PIIINP Neo-epitope assay |
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- 2020-12-11 GB GBGB2019578.0A patent/GB202019578D0/en not_active Ceased
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2021
- 2021-12-10 AU AU2021396552A patent/AU2021396552A1/en active Pending
- 2021-12-10 JP JP2023535351A patent/JP2023554313A/ja active Pending
- 2021-12-10 KR KR1020237023167A patent/KR20230145319A/ko unknown
- 2021-12-10 EP EP21839072.2A patent/EP4259652A1/en active Pending
- 2021-12-10 WO PCT/EP2021/085308 patent/WO2022123058A1/en active Application Filing
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| Publication number | Publication date |
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| GB202019578D0 (en) | 2021-01-27 |
| JP2023554313A (ja) | 2023-12-27 |
| EP4259652A1 (en) | 2023-10-18 |
| WO2022123058A1 (en) | 2022-06-16 |
| AU2021396552A1 (en) | 2023-07-06 |
| KR20230145319A (ko) | 2023-10-17 |
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