CN115280148A - 测定肽酰甘氨酸α-酰胺化单加氧酶(PAM)的方法及其用于诊断目的的用途 - Google Patents
测定肽酰甘氨酸α-酰胺化单加氧酶(PAM)的方法及其用于诊断目的的用途 Download PDFInfo
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- CN115280148A CN115280148A CN202180016860.2A CN202180016860A CN115280148A CN 115280148 A CN115280148 A CN 115280148A CN 202180016860 A CN202180016860 A CN 202180016860A CN 115280148 A CN115280148 A CN 115280148A
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Abstract
本发明涉及一种通过测定受试者的体液样品中肽酰甘氨酸α‑酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法。
Description
本发明涉及用于测定体液样品中PAM和/或其同工型和/或其片段的水平的方法,以及其用于诊断目的的用途。
背景技术
生物活性肽激素实现作为信号分子的功能。大多数生物活性肽激素是由较大的无活性前体肽合成的。在它们的生物合成期间,这些肽经历了若干共翻译和翻译后修饰,包括信号肽的切割、特定内肽酶主要在碱性残基对处对前体肽原的内蛋白酶解切割、通过羧肽酶去除碱性残基、二硫键的形成以及N-糖基化和O-糖基化(Eipper等人,1993.Protein Science 2(4):489–97)。超过一半的已知神经和内分泌肽需要额外的修饰步骤才能获得完整的生物活性,包括形成c末端α-酰胺基团(Guembe等人,1999.J Histochem Cytochem 47 (5):623–36)。肽激素生物合成的这个最后步骤涉及双功能酶肽酰甘氨酸α-酰胺化单加氧酶(PAM)的作用。PAM特异性识别其底物中的c末端甘氨酸残基,在两步酶促反应中从肽的c末端甘氨酸残基切割乙醛酸,导致形成c末端α-酰胺化肽激素,其中产生的α-酰胺基团起源于所切割的c末端甘氨酸(Prigge等人,2004.Science 304(5672):864-67)。这种酰胺化反应在酰胺化产物胞吐之前发生在分泌颗粒的内腔中(Martinez和Treston 1996.Molecular and Cellular Endocrinol 123:113-17)。α-酰胺化肽是例如肾上腺髓质素、P物质、加压素、神经肽Y、胰淀素、降钙素、神经激肽A等。然而,之前已经证明PAM也可以催化从非肽特性的甘氨酸化底物形成α-酰胺,例如N-脂肪酰基-甘氨酸,其通过PAM转化为初级脂肪酸酰胺(PFAM)如油酰胺。经鉴定和纯化的肽酰-甘氨酸酰胺化活性表明依赖于铜和抗坏血酸盐(Emeson等人,1984.Journal of Neuroscience:2604–13;Kumar等人,2016.J Mol Endocrinol 56(4):T63-76;Wand等人,1985.Neuroendocrinology 41:482–89)。
在人类中,PAM基因位于染色体5q21.1,长度为160kb,含有25个已知外显子(Gaier 等人,2014.BMC Endocrine Disorders 14)。已知通过选择性剪接产生至少6种同工型(SEQID 1-6)。发现PAM酶在几乎所有哺乳动物细胞类型中均有不同水平的表达,其中在气道上皮、内皮细胞、脑室管膜细胞、成人心房、脑、肾、垂体、胃肠道和生殖组织中均有显著表达。(Chen等人,2018.Diabetes Obes Metab 20增刊2:64-76;Oldham等人,1992.Biochem Biophys Res Commun 184(1):323–29;Schafer等人,1992.J Neurosci 12(1):222–34)。
然而,在垂体、茎和下丘脑中描述了最高的人PAM活性。15岁以下健康儿童的血浆酰胺化活性显著高于健康成人(Wand等人,1985Metabolism 34(11):1044–52)。
由PAM cDNA编码的已知最大的PAM同工型1(SEQ ID No.1)的前体蛋白(1-973个氨基酸)绘示于图1中。N末端信号序列(氨基酸1-20)确保新生PAM多肽进入内质网分泌腔的方向并且随后被共翻译切割。之后,PAM-肽原由用于生物合成完整膜蛋白和分泌蛋白的相同机制加工,包括切割前区(氨基酸21-30),确保正确折叠、二硫键形成、磷酸化和糖基化(Bousquet-Moore等人,2010.J Neurosci Res 88(12):2535-45)。
如图1中所绘示,PAM cDNA进一步编码两种不同的酶活性。第一种酶活性被命名为肽酰-甘氨酸α-羟基化单加氧酶(PHM;EC 1.14.17.3),是一种能够催化C末端甘氨酸残基转化为α-羟基-甘氨酸的酶。第二种活性被命名为肽酰-α-羟基-甘氨酸α-酰胺化裂解酶(PAL;EC 4.3.2.5),它是一种能够催化α-羟基-甘氨酸转化为α-酰胺并随后释放乙醛酸的酶。这些单独的酶活性的顺序作用导致总体肽酰-甘氨酸α酰胺化活性。第一酶活性(PHM)直接位于前区上游(在同工型1(SEQ ID No.7)的氨基酸31-494内)。第二催化活性(PAL)位于同工型1中外显子16之后的氨基酸495-817(SEQ ID No.8)内。
如图2中所绘示,两种活性可以在一个多肽内一起编码为膜结合蛋白(同工型1、2、5、6;对应于SEQ ID No.1、2、5和6)以及在一个多肽内编码为缺乏跨膜结构域的可溶性蛋白(同工型3和4;对应于SEQ ID No.3和4)。虽然在分泌囊泡与质膜融合后,同工型1、2、5和6保留在外质膜中,随后内吞作用和再循环或降解,但缺乏TMD(氨基酸864-887)的可溶性PAM同工型(同工型3和4)与肽激素共同分泌(Wand等人,1985 Metabolism 34(11):1044–52)。此外,激素原转化酶可以通过在分泌途径期间连接PAL与TMD的柔性区域(外显子25/26)内的切割将膜结合PAM蛋白转化为可溶性PAM蛋白(Bousquet-Moore等人,2010.J Neurosci Res 88(12):2535-45)。PHM亚基可以通过激素原转化酶从分泌途径内的可溶性或膜结合的PAM上切割下来,所述转化酶处理外显子16区域中的双碱性氨基酸切割位点。此外,在内吞作用期间,全长PAM蛋白也可以由于α分泌酶和γ分泌酶的作用而转化为可溶形式(Bousquet- Moore等人,2010.J Neurosci Res 88(12):2535-45)。来自晚期内体的膜结合PAM可以进一步以外泌体囊泡的形式分泌。
在若干人体组织和体液中测定了PHM和PAL活性以及全长PAM的活性。然而,当允许在相同的隔室、体液或体外实验装置中进行单独的反应时,可溶形式的分离的PHM和PAL活性也会导致从c末端甘氨酸化底物形成c末端α酰胺化产物。迄今为止,尚未完全了解PHM羟基化产物如何转移到PAL。有证据表明,羟基化产物释放到溶液中并且不会直接从PHM转移到PAL(Yin等人,2011.PLoS One 6(12):e28679)。迄今为止尚不清楚循环中PAM的来源。
PHM的部分反应绘示于图2中。PHM是一种铜依赖性单加氧酶,负责在α-碳原子处对c末端甘氨酸进行立体特异性羟基化。在羟基化反应期间,抗坏血酸盐被认为是天然存在的还原剂,而新形成的羟基基团中的氧被证明来源于分子氧。PAL的部分反应绘示于图2中。PAL的催化作用涉及通过蛋白质骨架衍生的基底从PHM形成的羟基-甘氨酸中提取质子,以及羟基基团氧对二价金属的亲核攻击,从而导致乙醛酸的裂解和c末端酰胺的形成。
因此,术语“酰胺化活性”、“α-酰胺化活性”、“肽酰-甘氨酸α-酰胺化活性”或“PAM活性”是指PHM和PAL的连续酶活性,导致从肽或非肽特性的甘氨酸化底物形成肽或非肽特性的α酰胺化产物,与本发明剪接变体或剪接变体混合物或翻译后修饰的PAM酶或可溶性的分离的PHM或PAL活性或可溶性PHM和膜结合PAL或所有提到的形式的组合无关。换言之,术语“酰胺化活性”、“α-酰胺化活性”、“肽酰-甘氨酸α-酰胺化活性”或“PAM活性”可以描述为位于人PAM cDNA编码的肽原中氨基酸31至817内的酶活性的顺序作用,与本发明剪接变体或其混合物无关。
在健康样本或患有若干疾病的那些的若干人体组织和体液中分析了PAM活性。过去所做的工作总结如下:
人类体液中PAM活性的检测主要涉及使用放射性标记的合成三肽,例如125I-D-TyrValGly、125I-N-乙酰基-TyrValGly或类似修饰的三肽,以及由于γ闪烁而对酰胺化产物进行量化(Kapuscinski等人,1993.Clinical Endocrinology 39(1):51–58;Wand等人, 1985 Metabolism 34(11):1044–52;Tsukamoto等人,1995.Internal Medicine 34(4): 229–32;Wand等人,1987 Neurology 37:1057–61;Wand等人,1985 Neuroendocrinol 41: 482–89)。此外,P物质-Gly或截短形式的神经肽Y-Gly被用作PAM活性测定法的底物(Gether等人,1991 Mol Cell Endocrinol 79(1-3):53–63; 等人,1990 Pain43:163–68; Jeng等人,1990 Analytical Biochemistry 185(2):213–19)。
Wand等人(Wand等人,1985 Metabolism 34(11):1044-52)最初证明了人体循环中α-酰胺化活性的存在。他们报告没有性别差异,但在某些疾病状态下PAM活性存在一些差异:甲状腺功能减退成人以及甲状腺髓样癌患者中的血浆PAM活性增加。PAM在甲状腺髓样癌、嗜铬细胞瘤和胰岛肿瘤的组织中的活性显示升高,表明内分泌肿瘤组织中酰胺化肽的形成增加(Gether等人,1991 Mol Cell Endocrinol 79(1-3):53–63;Wand等人,1985 Neuroendocrinol 41:482–89)。
与健康对照受试者相比,患有多发性内分泌肿瘤1型(MEN-1)和恶性贫血的患者显示血浆PAM活性降低(Kapuscinski等人,1993.Clin Endocrinol 39(1):51–58)。
Wand及其同事证实了在人脑脊液(CSF)中存在酰胺化活性(Wand等人,1985 Neuroendocrinol 41:482–89)。在患有阿尔茨海默病(AD)的患者中,与健康对照相比,血浆PAM活性显示未发生改变,而与来自正常样本的活性相比,CSF PAM活性显著降低(Wand等 人,1987 Neurology 37:1057–61)。此外,在WO2015/103594中,提出与健康对照相比,通过质谱法检测到的AD患者的CSF中PAM蛋白的存在减少。此外,PAM的酰胺化产物之一ADM-NH2被证明在患有流行性和偶发性阿尔茨海默病的患者中减少(WO2019/154900)。然而,迄今为止,没有报告循环PAM活性与AD的预测、诊断或进展有直接关联。
使用1-12P物质-Gly(SP-Gly)作为底物分析了下背部疼痛患者的CSF中的酰胺化活性( 等人,1990 Pain 43:163–68)。患有多发性硬化症(MS)的患者的PAM活性显示在CSF中增加,而在血清中则显著降低(Tsukamoto等人,1995.Internal Medicine 34(4): 229–32;WO2010/005387)。PAM的血浆活性与2型糖尿病之间的关联在(WO2014/118634)中进行了描述。
尽管关于人类体液和疾病或疾病进展中的PAM活性进行了一些研究,但没有关于用免疫测定法测量的人类体液中、特别是在循环中的PAM浓度的信息。本发明的令人惊讶的发现是以受试者体液中PAM的总量或活性来测定PAM的水平,用于疾病或不良事件的诊断、预后、预测或监测。
发明内容
本申请的主题是一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,
其中所述受试者中的疾病选自:痴呆、心血管病症、肾脏疾病、癌症、炎性或感染性疾病和/或代谢疾病,
其中所述不良事件选自:心脏事件、心血管事件、脑血管事件、癌症、糖尿病、感染、严重感染、败血症样全身感染、败血症和全因死亡。
本申请的一个实施方式涉及一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,所述方法包括以下步骤:
·测定所述受试者的体液样品中PAM和/或其同工型和/或其片段的水平,
·将所述测定量与预定阈值进行比较,
·其中如果所述测定量低于或高于所述预定阈值,则所述受试者被诊断为患有疾病,或
·其中如果所述测定量低于或高于所述预定阈值,则预示疾病的结果,或
·其中如果所述测定量低于或高于所述预定阈值,则预测所述患者患上疾病或发生不良事件的风险,或
·其中监测所述受试者的疾病或不良事件。
本申请的一个优选实施方式涉及一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中PAM和/或其同工型和/或其片段的水平是所述受试者的体液样品中PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度或者PAM和/或其同工型和/或其片段的活性。
本申请的另一个实施方式涉及一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中PAM和/或其同工型和/或其片段的活性选自以下序列:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQ ID No.6、SEQ ID No.7、SEQID No.8和SEQ ID No.10。
本领域技术人员应理解,如序列表中所示的PAM同工型序列(SEQ ID No.1至6)含有N末端信号序列(氨基酸1-20),其在蛋白质分泌之前被切断。因此,在一个优选的实施方式中,所述PAM同工型序列(SEQ ID No.1至6)和/或其片段不含N末端信号序列。
本申请的另一个实施方式涉及一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度用免疫测定法来检测。
本申请的另一个具体实施方式涉及一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中使用肽-Gly作为底物来检测PAM和/或其同工型和/或其片段的活性。
本申请的另一个优选实施方式涉及一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素(kisspeptin)、MIF-1、转移抑制素(metastin)、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽(deltorphin)I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
本申请的一个实施方式涉及一种通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中所述PAM和/或其同工型和/或其片段选自:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQID No.5、SEQ ID No.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
本申请的另一个实施方式涉及一种通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中确定受试者患上疾病的风险,其中所述受试者是健康受试者。
本申请的另一个实施方式涉及一种通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中所述疾病选自阿尔茨海默病、结直肠癌和胰腺癌。
本申请的另一个具体实施方式涉及一种使用测定法来测定体液样品中PAM和/或其同工型和/或其片段的水平的方法,其中所述测定法包含结合于PAM的两个不同区域的两种结合剂,其中所述两种结合剂针对长度为至少5个氨基酸、优选至少4个氨基酸的表位,其中所述两种结合剂针对包含在以下PAM序列内的表位:肽1(SEQ ID No.11)、肽2(SEQ IDNo.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ IDNo.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽10(SEQ IDNo.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ ID No.23)、肽14(SEQ IDNo.24)和重组PAM(SEQ ID No.10)。
本申请的另一个实施方式涉及一种测定受试者的体液样品中PAM和/或其同工型或片段的活性的方法,包括以下步骤:
·使所述样品与特异性结合于活性全长PAM、其同工型和/或其活性片段的捕获结合剂接触,
·分离结合于所述捕获结合剂的PAM
·向所述分离的PAM添加PAM的底物
·通过测量所述PAM的底物的转化来量化PAM活性。
本申请的另一个实施方式涉及一种测定受试者的体液样品中PAM和/或同工型和/或其片段的活性的方法,包括以下步骤:
·在t=0min和t=n+1min使所述样品与PAM的底物(肽-Gly)接触一段时间间隔
·在t=0min和t=n+1min检测所述样品中PAM的反应产物(α-酰胺化肽),以及
·通过计算t=0和t=n+1之间所述反应产物的差异来量化PAM的活性。
本申请的一个具体实施方式涉及一种方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
本申请的另一个实施方式涉及一种抗体用于测定PAM和/或其同工型和/或其片段的水平的用途,其中所述抗体特异性结合于选自以下的序列:重组PAM(SEQ ID No.10)、肽1(SEQ ID No.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQID No.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)和肽14(SEQ ID No.24)。
本申请的另一个优选的实施方式涉及一种用于测定PAM水平的试剂盒,其包含一种或多种结合于选自以下的PAM序列的抗体:重组PAM(SEQ ID No.10)、肽1(SEQ IDNo.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ IDNo.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)和肽14(SEQ ID No.24)。
本发明的目的是提供一种用于测定体液样品中PAM和/或其同工型和/或其片段的水平的方法。本发明的一个目的是提供相应的测定法和试剂盒。
本发明的另一个目的是提供一种通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法。
本发明的另一个重要实施方式是一种用于诊断或预后受试者的疾病和/或预测受试者患上疾病或发生不良事件的风险和/或监测受试者的疾病或不良事件的方法,包括:
·测定所述受试者的体液样品中PAM和/或其同工型和/或其片段的水平,
·将所述测定量与预定阈值进行比较,
·其中如果所述测定量低于或高于所述预定阈值,则所述受试者被诊断为患有疾病,或
·其中如果所述测定量低于或高于所述预定阈值,则预测疾病的结果,或
·其中如果所述测定量低于或高于所述预定阈值,则预测所述患者患上疾病或发生不良事件的风险,或
·其中监测所述受试者的疾病或不良事件。
测定PAM水平的方法是本领域已知的。在根据本发明的用于诊断或预后受试者的疾病和/或预测受试者患上疾病或发生不良事件的风险和/或监测受试者的疾病或不良事件的方法的上下文中,可以使用目前先进技术的方法和测定法,或者可以使用上述用于测定PAM水平的方法和测定法。
通过测量健康对照中的PAM和/或其同工型和/或其片段的水平并计算例如相应的75百分位数、更优选90百分位数、甚至更优选95百分位数来预先确定阈值。如果所述患病受试者或有患上疾病或发生不良事件风险的受试者的水平高于阈值,则75百分位数、更优选90百分位数、甚至更优选95百分位数的上限限定了健康对比患病患者或健康对比有患上疾病的风险的受试者或没有发生不良事件风险的受试者对比有发生不良事件风险的受试者的阈值。通过测量健康对照中的PAM和/或其同工型和/或其片段的水平并计算例如相应的25百分位数、更优选10百分位数、甚至更优选5百分位数来预先确定阈值。如果患病受试者或有患上疾病或发生不良事件风险的受试者的水平低于阈值,则25百分位数、更优选10百分位数、甚至更优选5百分位数的下限限定了健康对比患病患者或健康对比有患上疾病的风险的受试者或没有发生不良事件风险的受试者对比有发生不良事件风险的受试者的阈值。PAM和/或其同工型和/或其片段的水平可以被检测为总PAM浓度和/或PAM活性。关于所述百分位数,使用PAM活性测定法,通过检测血浆中的PAM活性来区分健康与患病患者或健康对比有患上疾病的风险的受试者或没有发生不良事件风险的受试者对比有发生不良事件风险的受试者的下限阈值可以介于15μg/(L*h)和8μg/(L*h)之间或更低,更优选介于13.5μg/(L*h)和8μg/(L*h)之间或更低,甚至更优选介于10.5μg/(L*h)和8μg/(L*h)之间或更低,最优选低于8μg/(L*h);血清中的PAM活性可以介于10μg/(L*h)和5μg/(L*h)之间或更低,更优选介于8μg/(L*h)和5μg/(L*h)之间或更低,最优选低于5μg/(L*h)。关于所述百分位数,使用PAM活性测定法,通过检测血浆中的PAM活性来区分健康与患病患者或健康对比有患上疾病的风险的受试者或没有发生不良事件风险的受试者对比有发生不良事件风险的受试者的上限阈值可以介于20μg/(L*h)和40μg/(L*h)之间或以上,更优选介于25μg/(L*h)和40μg/(L*h)之间或以上,甚至更优选介于30μg/(L*h)和40μg/(L*h)之间或以上,最优选高于40μg/(L*h);血清中的PAM活性可以介于10μg/(L*h)和25μg/(L*h)之间或以上,更优选介于15μg/(L*h)和25μg/(L*h)之间或以上,甚至更优选介于20μg/(L*h)和25μg/(L*h)之间或以上,最优选高于25μg/(L*h)。
取决于某些因素,例如性别、年龄、遗传、习惯、种族等,预定值可以在所选择的特定群体之间变化。
本领域技术人员知道如何从进行的先前研究中确定阈值。本领域技术人员知道,特定阈值可能取决于用于计算预定阈值的群组,所述预定阈值可以稍后在例行程序中使用。本领域技术人员知道特定阈值可能取决于测定法中使用的校准。本领域技术人员知道特定阈值可能取决于专业人员似乎可接受的灵敏度和/或特异度。
诊断测试的灵敏度和特异度不仅取决于测试的分析“质量”,还取决于对什么构成异常结果的定义。在实践中,接受者操作特征曲线(ROC曲线)通常是通过绘制变量值与其在“正常”(即表面上健康)和“疾病”人群(即患有感染的患者)中的相对频率的关系图来计算的。根据要解决的特定诊断问题,参考组不一定是“正常的”,而可能是患有另一种疾病的一组患者,应区分其与所关注的患病组。对于任何特定的标志物,患有疾病和未患疾病的受试者的标志物水平分布可能会重叠。在此类情况下,测试不能以100%的准确度绝对区分正常与疾病,并且重叠区域指示测试无法区分正常与疾病之处。选择一个阈值,高于该阈值(或低于该阈值,取决于标志物如何随疾病发生变化)则测试被认为是异常的,而低于该阈值则测试被认为是正常的。ROC曲线下面积是对感知测量结果将允许正确识别疾病的概率的度量。即使测试结果不一定给出准确的数字,也可以使用ROC曲线。只要可以对结果进行排序,就可以创建ROC曲线。例如,“疾病”样品的测试结果可能会根据程度(例如,1=低、2=正常和3=高)进行排序。此排序可以与“正常”人群中的结果相关联,并创建ROC曲线。这些方法在本领域中是众所周知的(参见例如Hartley等人,1982)。优选地,选择阈值以提供大于约0.5、更优选大于约0.7的ROC曲线面积。上下文中的术语“约”是指给定测量结果的+/-5%。
一旦通过使用先前的研究群组确定阈值并考虑所有上述要点,医学专业人员会预先确定的阈值用于根据本发明的诊断或预测疾病和/或预测受试者患上疾病或发生不良事件的风险和/或监测疾病或不良事件的方法,并会确定所述受试者是否具有高于或低于所述预定阈值的值,以便进行适当的诊断、预后、预测或监测。
上面提到的阈值在其他测定法中可能不同,如果这些阈值的校准与本发明中使用的测定系统不同的话。因此,考虑到校准的差异,上述阈值应相应地适用于此类不同校准的测定法。量化校准差异的一种可能性是通过使用这两种方法测量样品中的相应生物标志物或其活性(例如PAM),对所讨论的测定法(例如PAM测定法)与本发明中使用的相应生物标志物测定法进行方法比较分析(相关性)。鉴于该测试具有足够的分析灵敏度,另一种可能性是用所讨论的测定法来测定代表性的正常人群的中值生物标志物水平,将结果与利用另一种测定法的中值生物标志物水平进行比较,并根据通过这种比较获得的差异重新计算校准。通过本发明中使用的校准,测量了来自正常(健康)受试者的样品:中值血浆PAM活性为18.4μg/(L*h)(四分位距[IQR]13.5–21.9μg/(L*h)),中值血清PAM活性为11.0μg/(L*h)(四分位距[IQR]8.1–13.1μg/(L*h)。
如本文所用,术语“诊断”是指检测疾病或确定疾病的阶段或程度。通常,疾病的诊断基于对指示疾病的一种或多种因子和/或症状的评价。也就是说,可以基于指示疾病或病症的存在或不存在的因子的存在、不存在或量来进行诊断。被认为指示特定疾病的诊断的每个因子或症状不需要完全与特定疾病相关,例如,可能存在可以从诊断因子或症状推断的差异诊断。同样,可能存在指示特定疾病的因子或症状存在于未患有特定疾病的个体中的情况。
如本文所用的术语“预后”是指对临床病状或疾病例如败血症的可能进程和结果的预测。通常通过评价指示疾病的有利或不利进程或结果的疾病因子或症状来做出预后。如本文所用的短语“确定预后”是指本领域技术人员可以预测患者的临床病状或疾病的进程或结果的过程。术语“预后”不是指以100%准确度预测临床病状或疾病的进程或结果的能力。相反,本领域技术人员会理解,术语“预后”是指将发生特定进程或结果的概率增加;也就是说,与没有表现出临床病状或疾病的那些个体相比,表现出给定临床病状或疾病的患者更可能发生进程或结果。
在用于诊断或预后受试者的疾病和/或预测受试者患上疾病或发生不良事件的风险和/或监测受试者的疾病或不良事件的所述方法的一个具体实施方式中,所述疾病选自:
·痴呆,其中所述痴呆选自:轻度认知障碍(MCI)、阿尔茨海默病、血管性痴呆、混合性阿尔茨海默病和血管性痴呆、路易体痴呆、额颞叶痴呆、局灶性痴呆(包括进行性失语)、皮质下痴呆(包括帕金森病)和痴呆综合征的继发原因(包括颅内病变)。
·心血管病症,其中所述心血管病症可以选自:动脉粥样硬化、高血压、心力衰竭(包括急性和急性失代偿性心力衰竭)、心房颤动、心血管缺血、脑缺血性损伤、心源性休克、中风(包括缺血性和出血性中风和短暂性脑缺血发作)和心肌梗塞,
·肾脏疾病,其中所述肾脏疾病可以选自:肾毒性(药物诱发的肾脏疾病)、急性肾损伤(AKI)、慢性肾脏疾病(CKD)、糖尿病性肾病、终末期肾病(ESRD),
·癌症,其中所述癌症可以选自:前列腺癌、乳腺癌、肺癌、结直肠癌、膀胱癌、卵巢癌、宫颈癌、皮肤癌(包括黑色素瘤)、胃癌、肝癌、胰腺癌、白血病、非霍奇金淋巴瘤、肾癌、食道癌、咽癌,
·由例如细菌、病毒、真菌或寄生虫的传染性生物引起的传染性疾病,所述传染性疾病选自:SIRS、败血症和败血性休克。
·代谢疾病,选自:1型糖尿病、2型糖尿病、代谢综合征。
在本申请的一个实施方式中,所述疾病是痴呆并且所述痴呆选自:轻度认知障碍(MCI)、阿尔茨海默病、血管性痴呆、混合性阿尔茨海默病和血管性痴呆、路易体痴呆、额颞叶痴呆、局灶性痴呆(包括进行性失语)、皮质下痴呆(包括帕金森病)和痴呆综合征的继发原因(包括颅内病变)。
在一个具体实施方式中,所述痴呆是阿尔茨海默病。
在本申请的一个实施方式中,所述疾病是癌症并且所述癌症选自:前列腺癌、乳腺癌、肺癌、结直肠癌、膀胱癌、卵巢癌、宫颈癌、皮肤癌(包括黑色素瘤)、胃癌、肝癌、胰腺癌、白血病、非霍奇金淋巴瘤、肾癌、食道癌和咽癌。
在一个具体实施方式中,所述癌症是结直肠癌和胰腺癌。
在本申请的一个实施方式中,所述疾病是心血管病症,其中所述心血管病症选自:动脉粥样硬化、高血压、心力衰竭(包括急性和急性失代偿性心力衰竭)、心房颤动、心血管缺血、脑缺血性损伤、心源性休克、中风(包括缺血性和出血性中风和短暂性脑缺血发作)和心肌梗塞。
在一个具体实施方式中,所述心血管病症是心力衰竭(包括急性和急性失代偿性心力衰竭)。
在另一个具体实施方式中,所述心血管病症是中风(包括缺血性和出血性中风和短暂性脑缺血发作)和心肌梗塞。
在另一个具体实施方式中,所述心血管病症是心房颤动(AF)。
在本申请的另一个具体实施方式中,所述疾病是SIRS、败血症或败血性休克。
在本申请的另一个具体实施方式中,所述疾病是1型糖尿病、2型糖尿病、代谢综合征。
本发明方法的上下文中的体液可以选自血液、血清、血浆、脑脊液(CSF)、尿液、唾液、痰和胸腔积液。在所述方法的一个具体实施方式中,所述样品选自全血、血清和血浆。
术语监测是指控制疾病的发展(检测任何变化)或患者的病理生理状态,例如,患上疾病或发生不良事件的风险、疾病的严重程度或对治疗的反应。
本发明的主题是一种方法,其中进行所述监测以评价患上疾病或发生不良事件的风险变化、疾病严重程度的变化或者患者或受试者对治疗的反应。
本发明的一个具体主题是一种方法,其中进行所述监测以评价所述受试者对所采取的预防和/或治疗措施的反应。
本发明的主题是根据本发明的方法,其中所述方法用于将所述受试者分层为风险组。
如本文所用,术语“风险”是指遭受不希望的事件或影响(例如,疾病或不良事件)的概率。
术语“增强的水平”是指高于某个阈值水平的水平。
术语“降低的水平”是指低于某个阈值水平的水平。
“不良事件”被定义为危害个体健康的事件。所述不良事件不限于但可以选自:心脏事件、心血管事件、脑血管事件、癌症、糖尿病和全因死亡。不良事件包括感染、严重感染和败血症样全身感染和败血症。不良事件不是由急性外源性不良事件和/或外源性创伤引起的事件。外源性创伤包括可能由事故(例如车祸)诱发的创伤,因此被排除在不良事件组之外。
在本发明的一个具体实施方式中,所述不良事件是选自以下的心血管事件:心肌梗塞、急性失代偿性心力衰竭、中风和与心肌梗塞、中风或急性心力衰竭相关的死亡率。
患上疾病或发生不良事件的风险是指在一定时间段内患上所述疾病或事件的风险。在一个具体实施方式中,所述时间段是在10年内,或在8年内,或在5年内或在2.5年内,或在1年内,或在6个月内,或在3个月内,或在30天内,或在28天内。
在本发明的一个具体实施方式中,“PAM和/或其同工型和/或其片段的水平”是从受试者获取的样品中PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度(优选地表示为重量/体积;w/v)或者PAM和/或其同工型和/或其片段的活性,其包含序列SEQID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQ ID No.6、SEQ IDNo.7、SEQ ID No.8和SEQ ID No.10。
在本公开中,术语“PAM”是指如SEQ ID No.1至6中所示的PAM同工型1至6的氨基酸序列。在一些方面,本文公开的PAM与SEQ ID No.1至6的氨基酸序列具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%的序列同一性。
在一些方面,所述PAM是功能片段(即PHM(SEQ ID No.7)或PAL(SEQ ID No.8),PAM保留相应全长PAM的PAM活性的至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少70%、至少约80%或至少约90%)。在一些方面,所述PAM是本文公开的PAM的变体或衍生物。
氨基酸或核酸序列的同一性百分比或术语“序列同一性%”在本文中定义为在比对两个序列并在必要时引入空位以达到最大同一性百分比后,候选氨基酸或核酸序列中与参考序列中的残基相同的残基百分比。在一个优选的实施方式中,所述至少百分比的序列同一性的计算是在不引入空位的情况下进行的。用于比对的方法和计算机程序在本领域中是众所周知的,例如“Align 2”或国家生物技术信息中心(NCBI)的BLAST服务。
在本发明的一个具体实施方式中,使用测定法来测定PAM和/或其同工型和/或其片段的水平,其中这种测定法是夹心测定法,优选全自动测定法。
在本发明的一个实施方式中,它可以是所谓的POC测试(护理点),它是一种测试技术,其允许在患者附近不到1小时内执行测试,而无需全自动测定系统。该技术的一个实例是免疫色谱测试技术。
在本发明的一个实施方式中,这样的测定法是使用任何种类的检测技术的夹心免疫测定法,包括但不限于酶标记、化学发光标记、电化学发光标记,优选全自动测定法。在本发明的一个实施方式中,这样的测定法是酶标记夹心测定法。自动或全自动测定法的实例包括可以用于以下系统之一的测定法:RocheAbbottSiemensBrahmsBiomerieuxAlereOrtho ClinicalDiagnostics
在本发明的一个具体实施方式中,所述两种结合剂中的至少一种被标记以便被检测。
优选的检测方法包括各种形式的免疫测定法,例如放射免疫测定法(RIA)、均相酶倍增免疫测定法(EMIT)、化学发光和荧光免疫测定法、酶联免疫测定法(ELISA)、基于Luminex的珠阵列、蛋白质微阵列测定法和快速测试形式例如免疫色谱条测试。
在一个优选的实施方式中,所述标记选自:化学发光标记、酶标记、荧光标记、放射性碘标记。
所述测定法可以是同质或异质测定法、竞争性和非竞争性测定法。在一个实施方式中,所述测定法是夹心测定法的形式,其是非竞争性免疫测定法,其中待检测和/或量化的分子与第一抗体和第二抗体结合。所述第一抗体可以与固相例如珠、孔或其他容器的表面、芯片或条带结合,并且所述第二抗体是例如用染料、放射性同位素或反应性或催化活性部分标记的抗体。然后通过适当的方法测量与分析物结合的标记抗体的量。涉及“夹心测定法”的一般组成和程序是充分确立的并且为本领域技术人员所知(The ImmunoassayHandbook,David Wild编,Elsevier LTD,Oxford;第3版(2005年5月);Hultschig等人,2006.Curr Opin Chem Biol.10(1):4-10)。
在另一个实施方式中,所述测定法包含两种捕获分子,优选抗体,它们都作为分散体存在于液体反应混合物中,其中第一标记组分连接到第一捕获分子,其中所述第一标记组分是基于荧光或化学发光淬灭或扩增的标记系统的一部分,并且所述标记系统的第二标记组分连接到第二捕获分子,使得在两种捕获分子与分析物结合时产生可测量的信号,其允许检测包含样品的溶液中所形成的夹心复合物。
在另一个实施方式中,所述标记系统包含稀土穴状化合物或稀土螯合物与荧光染料或化学发光染料、特别是花青型染料的组合。在本发明的上下文中,基于荧光的测定法包括使用染料,其可以例如选自:FAM(5-或6-羧基荧光素)、VIC、NED、荧光素、异硫氰酸荧光素(FITC)、IRD-700/800,花青染料,例如CY3、CY5、CY3.5、CY5.5、Cy7、呫吨(xanthen)、6-羧基-2',4',7',4,7-六氯荧光素(HEX)、TET、6-羧基-4',5'-二氯-2',7'-二甲氧基荧光素(JOE)、N,N,N',N'-四甲基-6-羧基罗丹明(TAMRA)、6-羧基-X-罗丹明(ROX)、5-羧基罗丹明-6G(R6G5)、6-羧基罗丹明-6G(RG6)、罗丹明、罗丹明绿、罗丹明红、罗丹明110,BODIPY染料,例如BODIPY TMR、俄勒冈绿,香豆素如伞形酮,苯甲酰亚胺如Hoechst 33258;菲啶,例如德州红(Texas Red)、亚基马黄(Yakima Yellow)、Alexa Fluor、PET、溴化乙锭、吖啶鎓染料、咔唑染料、吩噁嗪染料、卟啉染料、聚甲炔染料等。
在本发明的上下文中,基于化学发光的测定法包括基于(Kirk-Othmer, Encyclopedia of chemical technology,第4版,1993.John Wiley&Sons,第15卷:518- 562,通过引用并入本文,包括第551-562页上的引用)中的化学发光材料所描述的物理原理使用染料。优选的化学发光染料是吖啶酯。
如本文所述,“测定法”或“诊断测定法”可以是在诊断领域应用的任何类型。这样的测定法可以基于待检测的分析物与具有一定亲和力的一种或多种捕获探针的结合。可以用于测定PAM和/或其同工型和/或其片段的水平的结合剂对PAM和/或其同工型和/或其片段表现出至少107M-1、优选108M-1的亲和常数,优选的亲和常数大于109M-1,最优选大于1010M-1。本领域技术人员知道,可以考虑通过应用较高剂量的化合物来补偿较低的亲和力,并且该措施不会导致超出本发明的范围。
在本发明的上下文中,“结合剂分子”是可以用于结合来自样品的一个或多个所关注分子,即分析物(即在本发明上下文中PAM和其同工型及其片段)的分子。因此,结合剂分子必须在空间上和表面特征(例如表面电荷、疏水性、亲水性、路易斯供体和/或受体的存在或不存在)方面充分成形,以特异性结合所关注的一种或多种目标分子。因此,结合可以例如由离子、范德华、π-π、σ-π、疏水或氢键相互作用或捕获分子与所关注的一种或多种目标分子之间的上述相互作用中的两种或更多种的组合来介导。在本发明的上下文中,结合剂分子可以例如选自:核酸分子、碳水化合物分子、PNA分子、蛋白质、抗体、肽或糖蛋白。优选地,所述结合剂分子是抗体,包括其对所关注的目标或分子具有足够亲和力的片段,并且包括重组抗体或重组抗体片段,以及所述抗体或衍生自变体链的片段的化学和/或生化修饰衍生物。
在一个具体实施方式中,所述结合剂可以选自抗体、抗体片段或非IgG支架。
化学发光标记可以是吖啶酯标记、涉及异鲁米诺标记的类固醇标记等。
酶标记可以是乳酸脱氢酶(LDH)、肌酸激酶(CPK)、碱性磷酸酶、天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、酸性磷酸酶、葡萄糖-6-磷酸脱氢酶等。
在本发明的一个实施方式中,所述两种结合剂中的至少一者结合于例如磁性颗粒和聚苯乙烯表面的固相。
本发明的主题是一种使用测定法来测定体液样品中PAM和/或同工型和/或其片段的水平的方法,其中所述测定法包含结合于PAM的两个不同表位的两种结合剂,其中所述两种结合剂针对长度为至少5个氨基酸、优选至少4个氨基酸的表位。
表位,也称为抗原决定簇,是抗原(例如肽或蛋白质)中被免疫系统、具体而言被抗体识别的部分。例如,表位是抗体结合的抗原的特定片段。与表位结合的抗体部分被称为互补位。蛋白质抗原的表位根据其结构和与互补位的相互作用分为两个类别:构象表位和线性表位。
线性或连续表位是抗体通过其氨基酸的线性序列或一级结构识别并由连续氨基酸残基相互作用采用的3-D构象形成的表位。构象和线性表位基于表位采用的3-D构象与互补位相互作用,这由所涉及表位残基的表面特征和抗原其他区段的形状或三级结构决定。构象表位由不连续氨基酸残基相互作用所采用的3-D构象形成。
在本发明的一个实施方式中,线性表位与以下PAM免疫肽序列有关:肽1(SEQ IDNo.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ IDNo.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)、肽14(SEQ ID No.24)。
在本发明的一个实施方式中,线性和/或构象表位与以下PAM序列有关:SEQ IDNo.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQ ID No.6、SEQ ID No.7、SEQ ID No.8、SEQ ID No.10。
所述表位可以包含至少6个氨基酸,优选至少5个氨基酸,最优选至少4个氨基酸。
在本发明的一个实施方式中,所述第一和第二结合剂结合于包含在以下PAM序列中的表位:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5和SEQ IDNo.6。
在本发明的一个实施方式中,所述第一和第二结合剂结合于包含在PAM的PAL亚基(SEQ ID No.8)中的表位。
在本发明的一个实施方式中,所述第一和第二结合剂结合于包含在PAM的PHM亚基(SEQ ID No.7)中的表位。
在本发明的一个具体实施方式中,所述第一结合剂结合于包含在PAM的PAL亚基(SEQ ID No.8)中的表位,并且所述第二结合剂结合于包含在PAM的PHM亚基(SEQ ID No.7)中的表位。
在本发明的一个具体实施方式中,所述第一和第二结合剂结合于包含在以下PAM序列中的表位:肽1(SEQ ID No.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ IDNo.14)、肽5(SEQ ID No.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ IDNo.18)、肽9(SEQ ID No.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ IDNo.22)、肽13(SEQ ID No.23)、肽14(SEQ ID No.24)和重组PAM(SEQ ID No.10)。
至少两种结合剂用于测定PAM和/或其同工型和/或其片段的水平的用途,其中所述至少一种结合剂针对包含在以下PAM序列中的表位:肽1(SEQ ID No.11)、肽2(SEQ IDNo.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ IDNo.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽10(SEQ IDNo.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ ID No.23)、肽14(SEQ IDNo.24)和重组PAM(SEQ ID No.10)。
本发明的主题是一种用于测定受试者的体液样品中PAM和/或同工型和/或其片段的活性的方法,包括以下步骤
·使所述样品与特异性结合于活性全长PAM、其同工型和/或其活性片段的捕获结合剂接触,
·分离结合于所述捕获结合剂的PAM
·向所述分离的PAM添加PAM的底物
·通过测量所述PAM的底物的转化来量化PAM活性。
在本发明的一个具体实施方式中,所述方法是酶捕获测定法(ECA,参见例如US5612186A、US5601986A)。
在用于测定受试者的体液样品中PAM活性的所述方法的一个具体实施方式中,所述分离步骤是洗涤步骤,其从捕获的PAM和/或其同工型和/或其片段中去除样品中未与所述捕获结合剂结合的成分。该分离步骤可以是将结合于所述捕获结合剂的PAM与所述体液样品的成分分离的任何其他步骤。
本发明的一个实施方式涉及PAM的化学测定法。所述测定法使用与PAM和/或其同工型和/或其片段反应的肽底物以形成可检测的反应产物。或者,可以监测底物的反应速率以测定测试样品中PAM和/或其同工型和/或其片段的水平。
实施此类试剂和反应的测定法可以在任何合适的反应容器,例如试管或微量滴定板的孔中进行。或者,可以以一次性形式开发测定装置,例如本领域技术人员熟知的并且易于制造和使用的量杆或试纸装置形式。这样的一次性测定装置可以包装成含有所有必要材料、试剂和使用说明的试剂盒形式。
在一个替代的测定实施方式中,可以检测反应发生的速率作为测试样品中存在的PAM和/或其同工型和/或其片段的水平的指示。例如,底物反应的速率可以用于指示测试样品中存在的PAM和/或其同工型和/或其片段的水平。或者,反应产物形成的速率可以用于指示测试样品中存在的PAM和/或其同工型和/或其片段的水平。
在又一个实施方式中,可以进行捕获或结合测定法以测定PAM和/或其同工型和/或其片段的活性。例如,可以将与PAM蛋白反应但不干扰其酶活性的抗体固定在固相上。使测试样品通过固定抗体,并且PAM和/或其同工型和/或其片段(如果存在)结合于抗体并且自身被固定以用于检测。然后可以添加底物,并且可以检测反应产物以指示测试样品中PAM和/或其同工型和/或其片段的水平。为了本说明书的目的,术语“固相”可以用于包括可在其中或在其上进行测定的任何材料或容器,并且包括但不限于多孔材料、无孔材料、试管、孔、载玻片等。
在通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平用于诊断或预后所述受试者中的疾病和/或预测所述受试者中患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的所述方法的一个具体实施方式中,所述捕获结合剂固定在表面上。对于PAM活性的测定,与PAM和/或其同工型和/或其片段反应但不干扰酶活性超过50%、优选低于40%、优选低于30%的结合剂可以固定在固相上。为了防止PAM的抑制,捕获结合剂不应在活性中心和底物结合区域周围的区域中结合PAM。
在用于测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平的所述方法的一个具体实施方式中,所述结合剂可以选自抗体、抗体片段、非Ig支架或适体。
本发明的另一个主题是一种用于测定受试者的体液样品中PAM和/或同工型和/或其片段的活性的方法,包括以下步骤
·在t=0min和t=n+1min使所述样品与PAM的底物(肽-Gly)接触一段时间间隔
·在t=0min和t=n+1min检测所述样品中PAM的反应产物(α-酰胺化肽),以及
·通过计算t=0和t=n+1之间所述反应产物的差异来量化PAM的活性。
本发明的另一个主题是一种用于测定受试者的体液样品中的PAM活性的方法,包括以下步骤
·在t=0min和t=n+1min使所述样品与PAM的底物ADM-Gly接触一段时间间隔
·使用免疫测定法在t=0min和t=n+1min检测所述样品中PAM的反应产物ADM-NH2,以及
·通过计算t=0min和t=n+1min之间所述反应产物ADM-NH2的差异来量化PAM的活性。
术语“t=n+1min”是时间间隔,其中n定义为≥0min。
本申请的一个实施方式涉及一种用于执行诊断或预后受试者的疾病和/或预测受试者中患上疾病或发生不良事件的风险和/或监测受试者的疾病或不良事件的方法的试剂盒,其中所述试剂盒包含至少两种结合剂,其针对重组PAM(SEQ ID No.10)、肽1(SEQ IDNo.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ IDNo.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)和肽14(SEQ ID No.24)。
本申请的一个具体实施方式涉及一种用于检测PAM水平的试剂盒,其包含一种或多种与选自以下的PAM序列结合的结合剂:重组PAM(SEQ ID No.10)、肽1(SEQ ID No.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽10(SEQID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ ID No.23)和肽14(SEQID No.24)。
本申请的另一个实施方式涉及一种用于执行测定受试者的体液样品中PAM和/或同工型和/或其片段的活性的方法的试剂盒,其中所述试剂盒包含肽-Gly作为PAM底物,其中所述肽-Gly是ADM-Gly。
PAM的活性可以通过检测来自其甘氨酸化前体肽底物(肽-Gly)的α-酰胺化肽(肽-酰胺)来测量。近一半的生物活性肽以C末端α-酰胺封端(Vishvanatha等人,2014.J Biol Chem 289(18):12404-20)。
所述甘氨酸化前体肽底物可以选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素、加压素。
在一个优选的实施方式中,所述肽-Gly是肾上腺髓质素-Gly(ADM-Gly)并且所述肽-酰胺是肾上腺髓质素-酰胺(ADM-NH2)。
其他非肽特性的底物可以包括N-脂肪酰基-甘氨酸,它们被PAM转化为初级脂肪酸酰胺(PFAM)如油酰胺。
根据上述上下文,以下连续编号的实施方式提供了本发明的进一步的具体方面:
1.一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,
其中所述受试者中的所述疾病选自:痴呆、心血管病症、肾脏疾病、癌症、炎性或感染性疾病和/或代谢疾病,
其中所述不良事件选自:心脏事件、心血管事件、脑血管事件、癌症、糖尿病、感染、严重感染、败血症样全身感染、败血症和全因死亡。
2.一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,所述方法包括以下步骤:
·测定所述受试者的体液样品中PAM和/或其同工型和/或其片段的水平,
·将所述测定量与预定阈值进行比较,
·其中如果所述测定量低于或高于所述预定阈值,则所述受试者被诊断为患有疾病,或
·其中如果所述测定量低于或高于所述预定阈值,则预示疾病的结果,或
·其中如果所述测定量低于或高于所述预定阈值,则预测所述患者患上疾病或发生不良事件的风险,或
·其中监测所述受试者的疾病或不良事件。
3.根据实施方式1和2所述的方法,其中PAM和/或其同工型和/或其片段的所述水平是所述受试者的体液样品中PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度或者PAM和/或其同工型和/或其片段的活性。
4.根据实施方式1-3所述的方法,其中PAM和/或其同工型和/或其片段的所述活性选自以下序列:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQID No.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
5.根据实施方式1-3所述的方法,其中用免疫测定法检测PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度。
6.根据实施方式3-4所述的方法,其中使用肽-Gly作为底物检测PAM和/或其同工型和/或其片段的活性。
7.根据实施方式6所述的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
8.根据实施方式1-7所述的通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中所述PAM和/或其同工型和/或其片段选自:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ IDNo.5、SEQ ID No.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
9.根据实施方式1-8所述的通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中确定受试者患上疾病的风险,其中所述受试者是健康受试者。
10.根据实施方式9所述的方法,其中所述疾病选自阿尔茨海默病、结直肠癌和胰腺癌。
11.一种使用测定法来测定体液样品中PAM和/或同工型和/或其片段的水平的方法,其中所述测定法包含结合PAM的两个不同区域的两种结合剂,其中所述两种结合剂针对长度为至少5个氨基酸、优选地至少4个氨基酸的表位,其中所述两种结合剂针对包含在以下PAM序列中的表位:肽1(SEQ ID No.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQID No.18)、肽9(SEQ ID No.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ IDNo.22)、肽13(SEQ ID No.23)、肽14(SEQ ID No.24)和重组PAM(SEQ ID No.10)。
12.一种测定受试者的体液样品中PAM和/或其同工型或片段的活性的方法,所述方法包括以下步骤
·使所述样品与特异性结合于活性全长PAM、其同工型和/或其活性片段的捕获结合剂接触,
·分离结合于所述捕获结合剂的PAM,
·向所述分离的PAM添加PAM的底物,以及
·通过测量PAM的底物的转化来量化PAM活性。
13.一种测定受试者的体液样品中PAM和/或同工型和/或其片段的活性的方法,所述方法包括以下步骤
·在t=0min和t=n+1min使所述样品与PAM的底物(肽-Gly)接触一段时间间隔
·在t=0min和t=n+1min检测所述样品中PAM的反应产物(α-酰胺化肽),以及
·通过计算t=0和t=n+1之间所述反应产物的差异来量化PAM的活性。
14.根据实施方式13所述的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
15.一种抗体用于测定PAM和/或其同工型和/或其片段的水平的用途,其中所述抗体特异性结合于选自以下的序列:重组PAM(SEQ ID No.10)、肽1(SEQ ID No.11)、肽2(SEQID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ IDNo.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽10(SEQ IDNo.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ ID No.23)和肽14(SEQ IDNo.24)。
16.一种用于测定PAM和/或其同工型和/或其片段的水平的试剂盒,所述试剂盒包含一种或多种结合于选自以下的PAM序列的抗体:重组PAM(SEQ ID No.10)、肽1(SEQ IDNo.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ IDNo.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)和肽14(SEQ ID No.24)。
附图说明
图1:PAM同工型1的示意图。黑色粗箭头指示双碱性氨基酸处的切割位点。
图2:PAM催化的酶促反应
图3:重组PAM的代表性校准曲线(ADM成熟活性[AMA]。
图4:自我报告的健康个体(n=120)中AMA的频率分布(直方图)
图5:来自自我报告的健康个体(n=20)的基质对(肝素锂和血清)中AMA的相关性
图6A-L:PAM夹心免疫测定法的典型校准曲线。A-J以重组PAM作为校准材料。(A)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对肽9(SEQ ID No.19)的抗体;(B)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对肽10(SEQ ID No.20)的抗体;(C)固相:针对肽9(SEQ ID No.19)的抗体,示踪剂:针对肽10(SEQ ID No.20)的抗体;(D)固相:针对重组PAM(SEQ ID No.10)的抗体,示踪剂:针对重组PAM(SEQ ID No.10)的抗体;(E)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对重组PAM(SEQ ID No.10)的抗体;(F)固相:针对肽13(SEQ ID No.23)的抗体,示踪剂:针对肽10(SEQ ID No.20)的抗体;(G)固相:针对肽14(SEQID No.24)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体;(H)固相:针对重组PAM(SEQID No.10)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体;(I)固相:针对肽13(SEQ IDNo.23)的抗体,示踪剂:针对肽9(SEQ ID No.19)的抗体;(J)固相:针对肽10(SEQ IDNo.20)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体。K和L以天然PAM(EDTA-血浆)作为校准材料:(K)固相:针对肽14(SEQ ID No.24)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体;(L)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体。
图6M-O:酶捕获测定法(ECA)-(M)针对肽10(SEQ ID No.20)的固相抗体;(N)针对全长PAM(SEQ ID No.10)的固相抗体;(O)针对肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽13(SEQ ID No.23)和肽14(SEQ ID No.24)的固相抗体,重组PAM/肝素血浆用作样品。
图6P:来自健康志愿者的肝素样品中PAM活性与PAM浓度之间的相关性(n=26;Spearman r=0.49,p=0.0109)。
图7:典型的ADM-Gly剂量/信号曲线
图8:MPP研究中的ADM成熟活性(PAM活性)(阿尔茨海默病的预测)
图9:Kaplan-Meier曲线图(MPP研究中阿尔茨海默病[AD]的预测)
图10:MPP研究中的ADM成熟活性(PAM活性)(结直肠癌[CRC]的预测)
图11:MPP研究中的MR-proADM(结直肠癌[CRC]的预测)
图12:Kaplan-Meier曲线图(MPP研究中结直肠癌[CRC]的预测)
图13:MPP研究中胰腺癌的诊断
图14:用于诊断胰腺癌的ADM成熟活性(PAM活性)的接受者操作曲线(ROC曲线图)(MPP研究)
图15:Kaplan-Meier曲线图(MPP研究中全因死亡率的预测)
图16:Kaplan-Meier曲线图(MPP研究中心血管死亡率的预测)
图17:Kaplan-Meier曲线图(MPP研究中心力衰竭的预测)
图18:Kaplan-Meier曲线图(MPP研究中心房颤动的预测)
图19:用于诊断流行性阿尔茨海默病(AD)的ADM成熟活性(PAM活性)
图20:用于AdrenOSS-1研究中败血症/败血性休克结果预后的ADM成熟活性(PAM活性)(n=145名幸存者;n=52名非幸存者)
图21:28天死亡率的ADM成熟活性(PAM活性)的Kaplan-Meier曲线图(AdrenOSS-1研究)
图22:健康受试者(n=5)的唾液中的ADM成熟活性(PAM活性)
实施例
实施例1-重组PAM的生产
PAM cDNA是根据Uniprot登录号P19021合成的,其编码包括对于在哺乳动物细胞中表达密码子优化的PAM蛋白的氨基酸21-834。PAM的信号序列被人血清白蛋白信号序列(MKWVTFISLLFLFSSAYSFR[SEQ ID No.9])替换。在PAM的C末端添加了六组氨酸标签,经由GS接头连接到PAM。重组PAM的序列(没有信号序列和六组氨酸标签的PAM的氨基酸21-834)显示在SEQ ID No.10中。使用5'-NotI和3'HindIII限制位点将cDNA克隆到表达载体(质粒DNA)中。将带有用于PAM表达的cDNA的表达载体在大肠杆菌(E.coli)中复制并从大肠杆菌制备,作为低内毒素制剂。
在无血清悬浮培养中,使用INVect转染试剂用表达载体转染HEK-INV细胞。经由与含有GFP-(绿色荧光蛋白)的表达载体共转染来控制转染率。在丙戊酸和青霉素-链霉素存在下在37℃和5%CO2下进行细胞培养。当活力达到<60%(>2000g,30-45min,2-8℃)时经由离心收获细胞。细胞培养上清液(CCS)用100mM Tris/HCl pH 8.0经由切向流过滤(TFF,30kDa截止)洗涤5次。
重组PAM的纯化包括在Q-琼脂糖快速流动树脂(GE Healthcare)上应用缓冲液交换的CCS并利用NaCl梯度(高达2M)洗脱。将含有酰胺化活性的级分合并并应用到具有100mMTris/HCl、200mM NaCl、pH8.0洗脱缓冲液的Superdex 200pg(GE Healthcare)尺寸排阻色谱柱上。将含有酰胺化活性的级分合并,针对100mM Tris HCl、200mM NaCl、pH 8.0透析,无菌过滤(0.2μm)。内毒素载量由Charles River PTS Endosafe系统测定并且低于5EU/mL。
实施例2-抗体的生产
根据本发明的抗PAM抗体可以如下合成:
合成了用于免疫接种的PAM肽,参见表1,(Peptides&Elephants,Hennigsdorf,Germany),带有一个额外的C末端半胱氨酸(如果所选PAM序列中不存在半胱氨酸)残基,用于将肽与牛血清白蛋白(BSA)缀合。通过使用Sulfolink偶联凝胶(Perbio-science,Bonn,Germany)将肽共价连接到BSA。根据Perbio的手册进行偶联程序。重组PAM由Hennigsdorf的InVivo Biotech Services生产,如实施例1中所述。
表1:PAM免疫肽
*根据SEQ ID No.1;氨基酸(aa)
Balb/c小鼠在第0天腹膜内(i.p.)注射100μg重组PAM或100μgPAM-肽-BSA-缀合物(在TiterMax Gold Adjuvant中乳化),在第14天分别注射100μg和100μg(在完全弗氏佐剂中乳化)以及在第21天和第28天分别注射50μg和50μg(在不完全弗氏佐剂中)。所述动物在第40天接受静脉内(i.v.)注射50μg重组PAM,或在第45天接受溶解在盐水中的50μg PAM-肽-BSA-缀合物。三天后处死小鼠并进行免疫细胞融合。
将经免疫接种小鼠的脾细胞和骨髓瘤细胞系SP2/0的细胞与1ml50%聚乙二醇在37℃下融合30s。洗涤后,将细胞接种在96孔细胞培养板中。通过在HAT培养基(补充有20%胎牛血清和HAT补充剂的RPMI 1640培养基)中生长来选择杂交克隆。一周后,将HAT培养基更换为HT培养基,传代三次,接着恢复为正常细胞培养基。
在融合两周后,主要筛选细胞培养上清液中的重组PAM结合IgG抗体。因此,将重组PAM(SEQ ID No.10)固定在96孔板(100ng/孔)中,并与每孔50μl细胞培养上清液在室温下温育2小时。洗涤板后,加入50μl/孔POD-兔抗小鼠IgG并在室温下温育1h。
在接下来的洗涤步骤之后,将50μl色原溶液(柠檬酸盐/磷酸氢盐缓冲液中的3.7mM邻苯二胺,0.012%H2O2)加入每个孔中,在室温下温育15分钟,并且通过加入50μl 4N硫酸来终止显色反应。在490mm处检测吸光度。
将阳性测试的微培养物转移到24孔板中进行增殖。在重新测试后,使用限制稀释技术克隆和重新克隆选定的培养物,并确定同种型。
针对重组人PAM或PAM肽产生的抗体经由标准抗体生产方法(Marx等人,1997)生产并经由蛋白A纯化。根据SDS凝胶电泳分析,抗体纯度≥90%。
实施例3-PAM活性测定法
来自自我报告的健康志愿者的人血清或肝素锂血浆被用作人天然PAM的来源。每个样品(20μl)在100mM Tris-HCl中稀释两倍,一式两份。通过加入160μl PAM反应缓冲液(100mM Tris-HCl pH 7.5、6.25μM CuSO4、2.5mM L-抗坏血酸盐、125μg/mL过氧化氢酶、62.5μM阿玛他汀(amastatin)、250μM亮抑酶肽(leupeptin)、36ng/mL合成ADM-Gly和375μg/mL NT-ADM抗体)来起始酰胺化反应。之后,将100μl重复样品的每个单独反应物组合并转移到20μl的200mM EDTA中以终止酰胺化反应并产生t=0分钟反应时间点,接着在37℃下温育40分钟。之后用10μl 200mM EDTA停止未终止的反应。为了测定PAM活性,使用bio-ADM免疫测定法(Weber等人,2017)在每个样品中对作为反应产物的bio-ADM进行量化。使用已知活性的人重组PAM生成的6点校准曲线来校准酰胺化测定法。以相同方式处理样品和校准物。经由bio-ADM免疫测定法测定的每个样品的相对光单位(RLUt40min-t0min)针对校准物的RLU(t40min-t0min)进行拟合,以测定样品中的PAM活性。PAM活性被描述为以每小时和每L样品中形成的μg bio-ADM计的“肾上腺髓质素成熟活性”(AMA)。
典型的PAM校准曲线示于图3中。来自n=120名自我报告的健康志愿者的肝素锂样品中AMA的分布示于图4中。肝素锂AMA的中值[IQR]为18.4μg/(L*h)[13.5-21.9]。第10个和第90个百分位数分别为10.5和24.2μg/(L*h)。第2.5个、第97.5个和第99个百分位数分别为8.1、31.6和40.8μg/(L*h)。此外,测量了来自n=20名受试者的匹配血清样品,并揭示出高度显著的相关性(r=0.89;p<0.0001)(图5),尽管与肝素锂相比,血清中的AMA值低约40%。
实施例4–PAM免疫测定法
如实施例1所述产生针对重组PAM(SEQ ID No.10)和PAM肽(SEQ ID No.11至24)的抗体。
所使用的技术是基于吖啶酯标记的夹心发光免疫测定法。
4.1.标记化合物(示踪剂)
纯化的抗体(0.2g/L)通过在10%标记缓冲液(500mmol/L磷酸钠,pH 8.0)中与1:5mol/L比率的MACN-吖啶-NHS-酯(1g/L,InVent GmbH)一起在22℃下温育20min进行标记。加入5%1mol/L Tris-HCl pH 8.0持续10min后,经由CentriPure P10柱(emp BiotechGmbH)将相应抗体与游离标记分离。将纯化的标记抗体稀释在300mmol/l磷酸钾、100mmol/lNaCl、10mmol/l Na-EDTA、5g/l牛血清白蛋白(pH 7.0)中。最终浓度为每150μL约20ng标记抗体。
4.2.固相
白色聚苯乙烯微量滴定板(Greiner Bio-One International AG)用相应的抗体(每孔2μg/0.2mL,50mmol/L Tris-HCl,100mmol/L NaCl,pH 7.8)包被(20℃下18h)。用30g/L Karion、5g/L BSA(不含蛋白酶)、6.5mmol/L磷酸二氢钾、3.5mmol/L磷酸二氢钠(pH 6.5)封闭后,将板真空干燥。
4.3校准
使用如实施例1中所述的重组PAM稀释液对测定法进行校准。典型浓度范围在5–5,000ng/mL范围内。
4.4.PAM免疫测定法:
4.4.1.PAM-LIA
一步版本:将50μL样品/校准物移液到预包被微量滴定板中。在缓冲液(300mmol/L磷酸钾、100mmol/L NaCl、10mmol/L Na-EDTA、50μmol/L阿玛他汀、100μmol/L亮抑酶肽、0.1%牛IgG、0.02%小鼠IgG、0.5%BSA,pH 7.0)中加入200μL标记抗体后,将微量滴定板在2-8℃下在600rpm搅拌下温育20h。通过用洗涤溶液(20mmol/L PBS、1g/L Triton X-100,pH7.4)洗涤5次(每孔每次350μL)去除未结合的示踪剂。通过使用Centro LB 960微量滴定板发光读数器(Berthold Technologies)测量孔结合化学发光,每孔1s。
两步版本:将50μL样品/校准物移液到预包被微量滴定板中。添加200μL缓冲液(如一步版本中所述)后,将微量滴定板在600rpm搅拌下在2-8℃下温育15-20h。通过用洗涤溶液洗涤4次(每孔每次350μL)除去未结合的样品,随后加入200μl示踪剂材料并在室温下温育微量滴定板2h。通过用洗涤溶液洗涤4次(每孔每次350μL)去除未结合的示踪剂。通过使用Centro LB 960微量滴定板发光读数器(Berthold Technologies)测量孔结合化学发光,每孔1s。
结果:用重组PAM以及血液样品测试结合于固相的抗体以及针对不同PAM免疫肽以及全长(重组)PAM的标记抗体(参见实施例2)。不同抗体组合的示例性标准曲线示于图6(A-L)中。图6(A-J)以重组PAM作为校准材料:(A)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对肽9(SEQ ID No.19)的抗体;(B)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对肽10(SEQ ID No.20)的抗体;(C)固相:针对肽9(SEQ ID No.19)的抗体,示踪剂:针对肽10(SEQ ID No.20)的抗体;(D)固相:针对重组PAM(SEQ ID No.10)的抗体,示踪剂:针对重组PAM(SEQ ID No.10)的抗体;(E)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对重组PAM(SEQ ID No.10)的抗体;(F)固相:针对肽13(SEQ ID No.23)的抗体,示踪剂:针对肽10(SEQ ID No.20)的抗体;(G)固相:针对肽14(SEQ ID No.24)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体;(H)固相:针对重组PAM(SEQ ID No.10)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体;(I)固相:针对肽13(SEQ ID No.23)的抗体,示踪剂:针对肽9(SEQID No.19)的抗体;(J)固相:针对肽10(SEQ ID No.20)的抗体,示踪剂:针对肽13(SEQ IDNo.23)的抗体。图6(K和L)以天然PAM(EDTA-血浆)作为校准材料:(K)固相:针对肽14(SEQID No.24)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体;(L)固相:针对肽10(SEQ IDNo.20)的抗体,示踪剂:针对肽13(SEQ ID No.23)的抗体。对于所有抗体组合,在人血浆和血清样品中也可检测到PAM。
4.4.2.用于检测PAM活性的酶捕获测定法(ECA)
建立酶捕获测定法以检测PAM的活性。将50μL样品/校准物移液到预包被微量滴定板中(如4.2.中所述)。加入200μL缓冲液(300mmol/L磷酸钾、100mmol/L NaCl、50μmol/L阿玛他汀、100μmol/L亮抑酶肽、0.1%牛IgG、0.02%小鼠IgG、0.5%BSA,pH 7.0)后,在600rpm搅拌下将微量滴定板在室温下温育1h。通过用洗涤溶液洗涤4次(每孔每次350μL)除去未结合的样品,随后每孔加入200μl反应缓冲液并在37℃下温育。除了使用100μg/mL NT-ADM-抗体和288ng/mL ADM-Gly之外,包括所有组分和最终浓度的反应缓冲液如实施例3中所述。通过将10μl的每个单独反应物转移到190μl含有EDTA的缓冲液(300mmol/L磷酸钾、100mmol/LNaCl、10mmol/L Na-EDTA、50μmol/L阿玛他汀、100μmol/L亮抑酶肽、0.1%牛IgG、0.02%小鼠IgG、0.5%BSA,pH 7.0)中,在若干时间点终止反应。将终止的反应应用于bio-ADM免疫测定法,以量化所产生的bio-ADM。使用针对PAM免疫肽10(SEQ ID No.20)的抗体作为固相的典型标准曲线示于图6M中。图6N示出了使用针对全长重组PAM(SEQ IDNo.10)的抗体的典型标准曲线。其他针对肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽13(SEQ ID No.23)和肽14(SEQ ID No.24)的抗体被用作酶捕获测定法的固相,并测量重组PAM或肝素血浆样品(250μl)的PAM活性(图6O)。这些结果表明,抗体可以用于使用ECA技术检测人体样品中的PAM活性。在血浆和血清样品中也可检测到PAM。
在另一个步骤中,使用PAM-LIA(针对全长PAM的固相抗体,针对肽13[SEQ IDNo.23]的示踪抗体)测定来自健康志愿者(n=26)的肝素样品中的PAM活性(如实施例3中所述)和PAM浓度。PAM活性和PAM浓度显著相关,如图6P中所示(Spearman r=0.49,p=0.0109)。
实施例5–ADM-Gly免疫测定法
基于用于生物活性ADM的Weber等人(Weber等人,2017.JALM 2(2):222-233)利用以下修改对ADM-Gly进行量化:用MACN-吖啶鎓-NHS标记的用于ADM-Gly检测的示踪抗体针对ADM-Gly的C末端甘氨酸。所述测定法用合成的ADM-Gly校准。ADM-Gly的检测限(LOD)为10pg/mL。针对ADM的C末端甘氨酸的抗体与bio-ADM的交叉反应性以浓度依赖性方式介于6%和50%之间的范围内。所有测定的ADM-Gly浓度都针对交叉反应性进行如下校正:对于每个ADM-Gly定量,使用bio-ADM免疫测定法对相应样品中的bio-ADM进行额外的定量。相应的bio-ADM值用于测定在bio-ADM校准曲线上用针对ADM的C末端甘氨酸的抗体产生的信号(RLU)。所测定的信号(RLU)用于使用ADM-Gly校准曲线计算假阳性ADM-Gly浓度(pg/mL)。从最初测定的ADM-Gly浓度中减去该浓度。典型的标准曲线示于图7中。
实施例6-健康受试者中的疾病预测
6.1.研究群组
马尔默预防项目(Preventive Project,MPP)在20世纪70年代中期获得资助,旨在探索普通人群的CV风险因素,并招收了居住在马尔默的33,346名个体(Fedorowski等人,2010.Eur Heart J31:85–91)。在2002年至2006年期间,共有18,240名原始参与者响应了邀请(参与率,70.5%),并进行了包括全面体格检查和血液样品采集在内的筛查(Fava等人,2013.Hypertension 2013;61:319–26)。MPP的复查在本研究中被视为基线。基线时有既往CVD的受试者被排除在外。所有参与者都获得了知情同意,并且瑞典隆德的隆德大学伦理委员会(Ethical Committee of Lund University,Lund,Sweden)批准了研究方案。
商业全自动均相时间分辨荧光免疫测定法用于测量血浆中的MR-proADM(BRAHMSMR-proADM KRYPTOR;BRAHMS GmbH,Hennigsdorf,Germany)(Caruhel等人,2009.Clin Biochem.42(7-8):725-8)。
如Weber等人,2017(Weber等人,2017.JAMA 2(2):222-233)所述测量Bio-ADM。如实施例3中所述在来自MPP的4942个血清样品中测定AMA。每个样品一式两份地测量。以相同方式处理样品、对照和校准物。分层至四分位数后AMA的基线临床特征示于表2中。
表2:根据所分析受试者在基线时的AMA四分位数(Q)的基线临床特征
N/A:不适用
统计分析:数值表示为平均值和标准差、中值和四分位距(IQR),或适当时的计数和百分比。使用Kruskal-Wallis检验进行连续变量的组比较。对生物标志物数据进行对数转换。Cox比例风险回归用于在单变量和多变量分析中分析风险因素对生存的影响。对所有变量的比例风险假设进行了测试。对于连续变量,风险比(HR)被标准化以描述一个IQR的生物标志物变化的HR。给出了风险因素的95%置信区间(CI)和卡方(Wald检验)的显著性水平。通过模型似然比卡方统计量评估每个模型的预测值。一致性指数(C指数)作为效果度量给出。它等效于二元结果采用的AUC概念。对于多变量模型,给出了C指数的引导校正版本。通过Kaplan-Meier方法绘制的生存曲线用于说明目的。为了检验PAM与临床变量的独立性,我们对嵌套模型使用似然比卡方检验。所有统计检验都是2尾的并且两侧p值为0.05被认为是显著性的。
6.2.阿尔茨海默病的预测
选择了3954份关于血液透析CKD患者中痴呆诊断补充效率信息的样品(n=174有偶发性AD)。关于痴呆诊断的信息来自瑞典国家患者登记处(SNPR)。根据国际疾病分类(ICD)代码290、293(ICD-8)、290、331(ICD-9)或F00、F01、F03、G30(ICD-10)的不同修订收集登记册中的诊断。自1987年以来,SNPR包括瑞典的所有住院护理,并且此外,还包含2000年之后记录的私人和公共护理人员的门诊就诊数据,包括日间手术和精神科护理。全因痴呆症是根据精神病症诊断和统计手册(DSM)-III修订版的标准进行诊断的,而DSM-IV标准适用于阿尔茨海默病和血管性痴呆的诊断。通过对医疗记录以及可用的神经影像学数据进行全面审查来验证诊断结果。研究医师为每名患者指定了最终诊断,并在未解决的病例中咨询了专门研究认知障碍的老年病学家。PAM活性(AMA)的测定如实施例3中所述。MPP群组中的AMA示于图8中:与非AD组相比,随着时间的推移发展为AD的患者(偶发性AD,n=174)的AMA显著降低(p=0.01)。
血清AMA降低强烈预测阿尔茨海默病,针对年龄调整时的风险比(HR)为0.74(CI0.6–0.88;p<0.001)并且HR为0.72(CI 0.6–0.85)(表3)。图9示出了使用AMA预测阿尔茨海默病的Kaplan-Meier曲线图(分析中排除了流行性AD病例)。最低的三分位数与患上AD的风险最高相关。
此外,AMA作为AD的预测因子独立于bio-ADM浓度。这两个标志物都有助于AD预测。虽然仅AMA的C指数为0.571(CI 0.525–0.616;Chi2 10.97),但两种组合标志物(即AMA和bio-ADM)的C指数为0.595(Chi2 18.96;p<0.0001)。此外,AMA结合bio-ADM和MR-proADM浓度进一步提高了对偶发性阿尔茨海默病的预测。虽然单独的MR-proADM对AD没有预测价值,但AMA、bio-ADM和MR-proADM的组合显示C指数为0.622(Chi2 26.73;p=0.00001)。
表3:阿尔茨海默病的预测
6.3.结直肠癌(CRC)的预测
具有和不具有偶发性CRC的受试者的AMA示于图10中。与非CRC组相比,随着时间的推移发展为CRC的患者(n=93)的AMA显著降低(p=0.0008;Kruskal-Wallis)。相反,如图11所示,与非CRC组相比,随着时间的推移发展为CRC的患者的MR-proADM浓度更高(p=0.023)。
单个标志物和标志物组合的结果示于表3中。血清AMA降低(年龄调整)强烈预测CRC的发展,风险比(HR)为0.68(p<0.0001)。图12示出了用AMA预测CRC的Kaplan-Meier曲线图(分析中排除了流行性病例)。最低的三分位数与CRC发展的最高风险相关(p<0.005)。
增加的MR-proADM浓度预测CRC的发展,HR为1.36p<0.05)。最高四分位数与CRC发展的最高风险相关(p=0.051)。
虽然bio-ADM浓度不能预测CRC的发展,但bio-ADM和AMA的组合显示了改进的CRC预测(参见表4)。此外,AMA和MR-proADM的组合进一步提高了对CRC发展的预测。
总之,降低的AMA值预测CRC的发展。增加的MR-proADM浓度也预测CRC的发展。AMA与bio-ADM或MR-proADM的组合增强了CRC的预测价值。
表4:结直肠癌的预测
生物标志物 | 风险比(HR) | p值 | C指数(CI) | Chi<sup>2</sup> |
AMA | 0.68(0.6-0.85) | p<0.00001 | 0.588(0.535-0.641) | 8.51 |
AMA、bio-ADM | p<0.002 | 0.598 | 12.48 | |
MR-proADM | 1.36(1.08-1.72) | p<0.05 | 0.587(0.532-0.642) | 6.27 |
AMA、MR-proADM | p<0.0005 | 0.612 | 16.51 |
6.4.胰腺癌的预测
此外,与没有胰腺癌的受试者相比,偶发性胰腺癌的AMA增加(p<0.005)(图13)。AMA强烈预测胰腺癌,优势比(OR)为0.44(CI 0.33–0.58)。AMA各自的接受者操作曲线(ROC曲线图)示于图14中,并且揭示AUC为0.71。
6.5.全因死亡率和心血管死亡率的预测
对来自MPP群组的4942个具有关于死亡和心血管事件的信息的样品进行了死亡率分析。关于心血管事件和诊断的信息来自瑞典国家患者登记处(SNPR)。登记册中的诊断是根据国际疾病分类(ICD)代码的不同修订收集的。自1987年以来,SNPR包括瑞典的所有住院护理,并且此外,还包含2000年之后记录的私人和公共护理人员的门诊就诊数据,包括日间手术和精神科护理。PAM活性(AMA)的测定如实施例3中所述。在来自MPP研究群组的一批总 共4942份血清样品中,在12.8年的随访期间,1361名受试者死亡(全因死亡率)。在1361起死 亡事件的总数中,有480起事件被归为心血管死亡率。
血清AMA升高强烈预测全因死亡率,风险比(HR)为1.354(CI1.197–1.531;p<0.0001)(表5)。AMA的预测价值独立于常见的心血管风险因素(年龄、性别、血压、体重指数、抗高血压药物、低密度和高密度脂蛋白以及糖尿病史)。图15示出了使用AMA预测全因死亡率的Kaplan-Meier曲线图。高AMA与死亡率风险增加相关。
血清AMA升高强烈预测心血管死亡率,危险比(HR)为1.6(CI 1.3–1.969;p<0.0001)(表5)。AMA的预测价值独立于常见的心血管风险因素(年龄、性别、血压、体重指数、抗高血压药物、低密度和高密度脂蛋白以及糖尿病史)。图16示出了使用AMA预测心血管死亡率的Kaplan-Meier曲线图。高AMA与心血管死亡率风险增加相关。
表5:通过PAM活性预测全因和心血管死亡率
6.6.心血管病症的预测
对来自MPP群组的具有关于死亡和心血管事件的信息的4942个样品进行了心血管病症分析。关于心血管事件和诊断的信息来自瑞典国家患者登记处(SNPR)。登记册中的诊断是根据国际疾病分类(ICD)代码的不同修订收集的。自1987年以来,SNPR包括瑞典的所有住院护理,并且此外,还包含2000年之后记录的私人和公共护理人员的门诊就诊数据,包括日间手术和精神科护理。PAM活性(AMA)的测定如实施例3中所述。在来自MPP研究群组的一 批总共4942份血清样品中,在12.8年的随访期间,278名受试者发生了心力衰竭(偶发性心 力衰竭)并且633名受试者发生了心房颤动(偶发性心房颤动)。
血清AMA升高强烈预测偶发性心力衰竭(分析中排除了83例流行性HF病例),风险比(HR)为1.537(CI 1.169–2.021;p<0.0007)(表6)。图17示出了使用AMA预测全因死亡率的Kaplan-Meier曲线图。高AMA与患上心力衰竭的风险增加相关。
血清AMA升高强烈预测偶发性心房颤动(分析中排除了267例流行性AF病例),风险比(HR)为1.459(CI 1.214–1.752;p<0.0001)(表6)。图18示出了使用AMA预测全因死亡率的Kaplan-Meier曲线图。高AMA与患上心力衰竭的风险增加相关。
表6:心血管病症的预测
实施例7–疾病的诊断
7.1.阿尔茨海默病的诊断
27名确诊阿尔茨海默病的个体的血清样品获自InVent Diagnostica GmbH。AD诊断基于认知测试(CERAD、DemTec、MMST和画时钟测试)以及MRI(磁共振成像)和CT扫描。作为对照,使用了来自自我报告的健康志愿者的67份血清样品。如实施例3中所述检测AMA。
如图19中所示,与对照群组相比,AD群组的患者显示显著降低的血清AMA(n=67;p<0.0001)。
7.2.心血管和代谢病症的诊断
在来自MPP研究群组的一批总共4942份血清样品中,存在267例流行性心房颤动、83例流行性慢性心力衰竭和533例流行性糖尿病。与没有流行性心房颤动的个体(平均AMA:12.8个AMA单位,n=4675)相比,在流行性心房颤动(平均AMA:13.92个AMA单位,n=267)中观察到血清AMA显著升高(p<0.0001)。
与没有流行性心力衰竭的个体(平均AMA:12.84个AMA单位,n=4859)相比,在流动性慢性心力衰竭(平均AMA:14.31个AMA单位,n=83)中观察到血清AMA显著升高(p=0.0019)。
与没有流行性糖尿病的个体(平均AMA:12.89个AMA单位,n=4409)相比,在流行性糖尿病(平均AMA:12.69个AMA单位,n=533)中观察到血清AMA显著降低(p=0.0035)。
实施例8–预后和监测
8.1.研究群组AdrenOSS-1
AdrenOSS-1是一项欧洲前瞻性观察研究。五个国家(法国、比利时、荷兰、意大利和德国)的24个中心为583名招收患者(从2015年6月至2016年5月招募)的试验成就做出了贡献。研究方案经当地伦理委员会批准并按照赫尔辛基宣言(Declaration of Helsinki)进行。所述研究招收了18岁及以上的患者,所述患者(1)因败血症或败血性休克入住ICU或(2)在入院后不到24小时内从另一个ICU转入败血症和败血性休克状态。根据2001年以来对败血症和器官衰竭的定义(Levy等人,2003.2001 SCCM/ESICM/ACCP/ATS/SIS国际败血症定义 会议(2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference).Crit Care Med.31(4):1250–6)将纳入的患者按严重败血症和败血性休克分层。术语“败血症”是指败血症-3的更新定义(Singer等人,2016败血症和败血性休克的第三 次国际共识定义(败血症-3)(The Third International Consensus Definitions for Sepsis and Septic Shock(Sepsis-3)).JAMA.315(8):801–10)。根据当地实践对患者进行治疗,并对治疗以及程序进行登记。主要终点是28天死亡率。次要终点涉及器官衰竭(由顺序器官衰竭评估[SOFA]评分定义)和器官支持、血管加压药/正性肌力药的使用、体液平衡和肾脏替代疗法(RRT)的使用。
入院时,记录人口统计学(年龄、性别)、体重指数、败血性休克的存在、入住ICU的类型、器官功能障碍评分(SOFA、急性生理学评估和慢性健康评价II[APACHE II])、败血症的起源、预先存在的合并症(即在过去一年内接受过治疗)、既往病史、实验室值和器官支持情况,并抽取血液用于测量bio-ADM和其他标志物。患者招收后,第一周期间每天收集以下数据:SOFA评分、抗微生物疗法、体液平衡、通气状态、格拉斯哥昏迷量表(Glasgow ComaScale)评分、中心静脉压、RRT需求、败血症控制的侵入性手术和血管加压药/正性肌力药治疗。此外,在ICU入院后第28天记录出院状态和死亡率。
中心实验室的血液在ICU入院后24h内采样并且在第一次采样后的第2天(平均47h,SD 9h)采样。随后对样品进行处理并在-80℃下储存。在n=197个血浆样品中如实施例3中所述测量PAM活性(AMA),所述血浆样品从AdrenOSS-I群组中随机选择。
8.2.败血症的结果预后
如图20中所示,AdrenOSS-I群组中的AMA揭示,与存活组相比,非存活组的AMA显著更高(p<0.05)。高血浆AMA强烈预测28天死亡率,HR为1.41(p<0.05)。图21示出了用于预测败血症和败血性休克患者的28天死亡率的Kaplan-Meier曲线图。
此外,AdrenOSS-I群组中的ADM-Gly浓度也揭示出与幸存者相比,非幸存者中显著更高的浓度(p<0.0001)。高ADM-Gly浓度强烈预测28天死亡率,HR为2.29(p<0.005)。
单一生物标志物AMA和ADM-Gly的28天死亡率结果示于表7中。分别选择AMA和ADM-Gly浓度的截止值以产生80.4%的相等灵敏度,而AMA和ADM-Gly的特异度分别为21.7%和38.5%。当两种标志物按比率组合时,28天存活率的特异度提高到43.4%。此外,PAM和ADMGly的优势比(OR)分别为1.13和2.56,而两种标志物的组合导致OR增加了3.14。
表7:用于评价28天死亡率结果的交叉表。
[μg/(L*h)] | 28天死亡率 | 28天存活率 | |
AMA>17.1 | 41 | 112 | PPV:26.8% |
AMA<17.1 | 10 | 31 | NPV:75.6% |
发病率:26.3% | 灵敏度:80.4% | 特异度:21.7% | OR:1.13 |
[pg/mL] | 28天死亡率 | 28天存活率 | 15 |
ADM-Gly>140 | 41 | 88 | PPV:31.8% |
ADM-Gly<140 | 10 | 55 | NPV:84.6% |
发病率:26.3% | 灵敏度:80.4% | 特异度:38.5% | OR:2.56 |
AMA/ADM-Gly比率 | 28天死亡率 | 28天存活率 | |
AMA/ADM-Gly<132 | 41 | 81 | PPV:33.6% |
AMA/A DM-Gly>132 | 10 | 62 | NPV:86.1% |
发病率:26.3% | 灵敏度:80.4% | 特异度:43.4% | OR:3.14 |
9.人类唾液中PAM活性的测定
唾液从5名自我报告的健康受试者中收集在单独的无菌试管中。如实施例3所述测试人类唾液样品中的PAM活性。可以在唾液样品中测量PAM活性(范围为约700至2000ng/(L*h)(图22),并且与血浆样品相比大约低10倍。
序列
SEQ ID NO:1-Prepro-PAM同工型1AS 1-973
SEQ ID NO:2-Prepro-PAM同工型2AS 1-868
SEQ ID No.:3-Prepro-PAM同工型3AS(SEQ ID No.1的氨基酸829-896缺失)
SEQ ID No.4-Prepro-PAM同工型4(SEQ ID No.1的氨基酸829-914缺失)
SEQ ID No.5-Prepro-PAM同工型5(在位置896中具有另一个aa的同工型1)
SEQ ID No.6-Prepro-PAM同工型6(SEQ ID No.1的氨基酸897-914缺失)
SEQ ID No.7-PAM的PHM亚基
SEQ ID No.8-PAM的PAL亚基
SEQ ID No.9–人血清白蛋白信号序列
SEQ ID No.10-重组人PAM的序列
SEQ ID No.11-肽1(PAM SEQ ID No.1的aa 42-56)
SEQ ID No.12-肽2(PAM SEQ ID No.1的aa 109-128)
SEQ ID No.13-肽3(PAM SEQ ID No.1的aa 168-180)
SEQ ID No.14-肽4(PAM SEQ ID No.1的aa 204-216)
SEQ ID No.15-肽5(PAM SEQ ID No.1的aa 329-342)
SEQ ID No.16-肽6(PAM SEQ ID No.1的aa 291-310)
SEQ ID No.17-肽7(PAM SEQ ID No.1的aa 234-244)
SEQ ID No.18-肽8(PAM SEQ ID No.1的aa 261-276)
SEQ ID No.19-肽9(PAM SEQ ID No.1的aa 530-557)
SEQ ID No.20-肽10(PAM SEQ ID No.1的aa 611-631)
SEQ ID No.21-肽11(PAM SEQ ID No.1的aa 562-579)
SEQ ID No.22-肽12(PAM SEQ ID No.1的aa 745-758)
SEQ ID No.23-肽13(PAM SEQ ID No.1的aa 669-687)
SEQ ID No.24-肽14(PAM SEQ ID No.1的aa 710-725)
序列表
<110> PAM治疗诊断有限公司(PAM Theragnostics GmbH)
<120> 测定肽酰甘氨酸α-酰胺化单加氧酶(PAM)的方法及其用于诊断目的的用途
<130> P75340WO
<150> 20159645.9
<151> 2020-02-26
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Leu Glu His Arg Ser Val Lys Lys Ala Gly Ile Glu Val Gln Glu Ile
705 710 715 720
Lys Glu Ala Glu Ala Val Val Glu Thr Lys Met Glu Asn Lys Pro Thr
725 730 735
Ser Ser Glu Leu Gln Lys Met Gln Glu Lys Gln Lys Leu Ile Lys Glu
740 745 750
Pro Gly Ser Gly Val Pro Val Val Leu Ile Thr Thr Leu Leu Val Ile
755 760 765
Pro Val Val Val Leu Leu Ala Ile Ala Ile Phe Ile Arg Trp Lys Lys
770 775 780
Ser Arg Ala Phe Gly Asp Ser Glu His Lys Leu Glu Thr Ser Ser Gly
785 790 795 800
Arg Val Leu Gly Arg Phe Arg Gly Lys Gly Ser Gly Gly Leu Asn Leu
805 810 815
Gly Asn Phe Phe Ala Ser Arg Lys Gly Tyr Ser Arg Lys Gly Phe Asp
820 825 830
Arg Leu Ser Thr Glu Gly Ser Asp Gln Glu Lys Glu Asp Asp Gly Ser
835 840 845
Glu Ser Glu Glu Glu Tyr Ser Ala Pro Leu Pro Ala Leu Ala Pro Ser
850 855 860
Ser Ser
865
<210> 3
<211> 905
<212> PRT
<213> 智人
<400> 3
Met Ala Gly Arg Val Pro Ser Leu Leu Val Leu Leu Val Phe Pro Ser
1 5 10 15
Ser Cys Leu Ala Phe Arg Ser Pro Leu Ser Val Phe Lys Arg Phe Lys
20 25 30
Glu Thr Thr Arg Pro Phe Ser Asn Glu Cys Leu Gly Thr Thr Arg Pro
35 40 45
Val Val Pro Ile Asp Ser Ser Asp Phe Ala Leu Asp Ile Arg Met Pro
50 55 60
Gly Val Thr Pro Lys Gln Ser Asp Thr Tyr Phe Cys Met Ser Met Arg
65 70 75 80
Ile Pro Val Asp Glu Glu Ala Phe Val Ile Asp Phe Lys Pro Arg Ala
85 90 95
Ser Met Asp Thr Val His His Met Leu Leu Phe Gly Cys Asn Met Pro
100 105 110
Ser Ser Thr Gly Ser Tyr Trp Phe Cys Asp Glu Gly Thr Cys Thr Asp
115 120 125
Lys Ala Asn Ile Leu Tyr Ala Trp Ala Arg Asn Ala Pro Pro Thr Arg
130 135 140
Leu Pro Lys Gly Val Gly Phe Arg Val Gly Gly Glu Thr Gly Ser Lys
145 150 155 160
Tyr Phe Val Leu Gln Val His Tyr Gly Asp Ile Ser Ala Phe Arg Asp
165 170 175
Asn Asn Lys Asp Cys Ser Gly Val Ser Leu His Leu Thr Arg Leu Pro
180 185 190
Gln Pro Leu Ile Ala Gly Met Tyr Leu Met Met Ser Val Asp Thr Val
195 200 205
Ile Pro Ala Gly Glu Lys Val Val Asn Ser Asp Ile Ser Cys His Tyr
210 215 220
Lys Asn Tyr Pro Met His Val Phe Ala Tyr Arg Val His Thr His His
225 230 235 240
Leu Gly Lys Val Val Ser Gly Tyr Arg Val Arg Asn Gly Gln Trp Thr
245 250 255
Leu Ile Gly Arg Gln Ser Pro Gln Leu Pro Gln Ala Phe Tyr Pro Val
260 265 270
Gly His Pro Val Asp Val Ser Phe Gly Asp Leu Leu Ala Ala Arg Cys
275 280 285
Val Phe Thr Gly Glu Gly Arg Thr Glu Ala Thr His Ile Gly Gly Thr
290 295 300
Ser Ser Asp Glu Met Cys Asn Leu Tyr Ile Met Tyr Tyr Met Glu Ala
305 310 315 320
Lys His Ala Val Ser Phe Met Thr Cys Thr Gln Asn Val Ala Pro Asp
325 330 335
Met Phe Arg Thr Ile Pro Pro Glu Ala Asn Ile Pro Ile Pro Val Lys
340 345 350
Ser Asp Met Val Met Met His Glu His His Lys Glu Thr Glu Tyr Lys
355 360 365
Asp Lys Ile Pro Leu Leu Gln Gln Pro Lys Arg Glu Glu Glu Glu Val
370 375 380
Leu Asp Gln Gly Asp Phe Tyr Ser Leu Leu Ser Lys Leu Leu Gly Glu
385 390 395 400
Arg Glu Asp Val Val His Val His Lys Tyr Asn Pro Thr Glu Lys Ala
405 410 415
Glu Ser Glu Ser Asp Leu Val Ala Glu Ile Ala Asn Val Val Gln Lys
420 425 430
Lys Asp Leu Gly Arg Ser Asp Ala Arg Glu Gly Ala Glu His Glu Arg
435 440 445
Gly Asn Ala Ile Leu Val Arg Asp Arg Ile His Lys Phe His Arg Leu
450 455 460
Val Ser Thr Leu Arg Pro Pro Glu Ser Arg Val Phe Ser Leu Gln Gln
465 470 475 480
Pro Pro Pro Gly Glu Gly Thr Trp Glu Pro Glu His Thr Gly Asp Phe
485 490 495
His Met Glu Glu Ala Leu Asp Trp Pro Gly Val Tyr Leu Leu Pro Gly
500 505 510
Gln Val Ser Gly Val Ala Leu Asp Pro Lys Asn Asn Leu Val Ile Phe
515 520 525
His Arg Gly Asp His Val Trp Asp Gly Asn Ser Phe Asp Ser Lys Phe
530 535 540
Val Tyr Gln Gln Ile Gly Leu Gly Pro Ile Glu Glu Asp Thr Ile Leu
545 550 555 560
Val Ile Asp Pro Asn Asn Ala Ala Val Leu Gln Ser Ser Gly Lys Asn
565 570 575
Leu Phe Tyr Leu Pro His Gly Leu Ser Ile Asp Lys Asp Gly Asn Tyr
580 585 590
Trp Val Thr Asp Val Ala Leu His Gln Val Phe Lys Leu Asp Pro Asn
595 600 605
Asn Lys Glu Gly Pro Val Leu Ile Leu Gly Arg Ser Met Gln Pro Gly
610 615 620
Ser Asp Gln Asn His Phe Cys Gln Pro Thr Asp Val Ala Val Asp Pro
625 630 635 640
Gly Thr Gly Ala Ile Tyr Val Ser Asp Gly Tyr Cys Asn Ser Arg Ile
645 650 655
Val Gln Phe Ser Pro Ser Gly Lys Phe Ile Thr Gln Trp Gly Glu Glu
660 665 670
Ser Ser Gly Ser Ser Pro Leu Pro Gly Gln Phe Thr Val Pro His Ser
675 680 685
Leu Ala Leu Val Pro Leu Leu Gly Gln Leu Cys Val Ala Asp Arg Glu
690 695 700
Asn Gly Arg Ile Gln Cys Phe Lys Thr Asp Thr Lys Glu Phe Val Arg
705 710 715 720
Glu Ile Lys His Ser Ser Phe Gly Arg Asn Val Phe Ala Ile Ser Tyr
725 730 735
Ile Pro Gly Leu Leu Phe Ala Val Asn Gly Lys Pro His Phe Gly Asp
740 745 750
Gln Glu Pro Val Gln Gly Phe Val Met Asn Phe Ser Asn Gly Glu Ile
755 760 765
Ile Asp Ile Phe Lys Pro Val Arg Lys His Phe Asp Met Pro His Asp
770 775 780
Ile Val Ala Ser Glu Asp Gly Thr Val Tyr Ile Gly Asp Ala His Thr
785 790 795 800
Asn Thr Val Trp Lys Phe Thr Leu Thr Glu Lys Leu Glu His Arg Ser
805 810 815
Val Lys Lys Ala Gly Ile Glu Val Gln Glu Ile Lys Asp Ser Glu His
820 825 830
Lys Leu Glu Thr Ser Ser Gly Arg Val Leu Gly Arg Phe Arg Gly Lys
835 840 845
Gly Ser Gly Gly Leu Asn Leu Gly Asn Phe Phe Ala Ser Arg Lys Gly
850 855 860
Tyr Ser Arg Lys Gly Phe Asp Arg Leu Ser Thr Glu Gly Ser Asp Gln
865 870 875 880
Glu Lys Glu Asp Asp Gly Ser Glu Ser Glu Glu Glu Tyr Ser Ala Pro
885 890 895
Leu Pro Ala Leu Ala Pro Ser Ser Ser
900 905
<210> 4
<211> 887
<212> PRT
<213> 智人
<400> 4
Met Ala Gly Arg Val Pro Ser Leu Leu Val Leu Leu Val Phe Pro Ser
1 5 10 15
Ser Cys Leu Ala Phe Arg Ser Pro Leu Ser Val Phe Lys Arg Phe Lys
20 25 30
Glu Thr Thr Arg Pro Phe Ser Asn Glu Cys Leu Gly Thr Thr Arg Pro
35 40 45
Val Val Pro Ile Asp Ser Ser Asp Phe Ala Leu Asp Ile Arg Met Pro
50 55 60
Gly Val Thr Pro Lys Gln Ser Asp Thr Tyr Phe Cys Met Ser Met Arg
65 70 75 80
Ile Pro Val Asp Glu Glu Ala Phe Val Ile Asp Phe Lys Pro Arg Ala
85 90 95
Ser Met Asp Thr Val His His Met Leu Leu Phe Gly Cys Asn Met Pro
100 105 110
Ser Ser Thr Gly Ser Tyr Trp Phe Cys Asp Glu Gly Thr Cys Thr Asp
115 120 125
Lys Ala Asn Ile Leu Tyr Ala Trp Ala Arg Asn Ala Pro Pro Thr Arg
130 135 140
Leu Pro Lys Gly Val Gly Phe Arg Val Gly Gly Glu Thr Gly Ser Lys
145 150 155 160
Tyr Phe Val Leu Gln Val His Tyr Gly Asp Ile Ser Ala Phe Arg Asp
165 170 175
Asn Asn Lys Asp Cys Ser Gly Val Ser Leu His Leu Thr Arg Leu Pro
180 185 190
Gln Pro Leu Ile Ala Gly Met Tyr Leu Met Met Ser Val Asp Thr Val
195 200 205
Ile Pro Ala Gly Glu Lys Val Val Asn Ser Asp Ile Ser Cys His Tyr
210 215 220
Lys Asn Tyr Pro Met His Val Phe Ala Tyr Arg Val His Thr His His
225 230 235 240
Leu Gly Lys Val Val Ser Gly Tyr Arg Val Arg Asn Gly Gln Trp Thr
245 250 255
Leu Ile Gly Arg Gln Ser Pro Gln Leu Pro Gln Ala Phe Tyr Pro Val
260 265 270
Gly His Pro Val Asp Val Ser Phe Gly Asp Leu Leu Ala Ala Arg Cys
275 280 285
Val Phe Thr Gly Glu Gly Arg Thr Glu Ala Thr His Ile Gly Gly Thr
290 295 300
Ser Ser Asp Glu Met Cys Asn Leu Tyr Ile Met Tyr Tyr Met Glu Ala
305 310 315 320
Lys His Ala Val Ser Phe Met Thr Cys Thr Gln Asn Val Ala Pro Asp
325 330 335
Met Phe Arg Thr Ile Pro Pro Glu Ala Asn Ile Pro Ile Pro Val Lys
340 345 350
Ser Asp Met Val Met Met His Glu His His Lys Glu Thr Glu Tyr Lys
355 360 365
Asp Lys Ile Pro Leu Leu Gln Gln Pro Lys Arg Glu Glu Glu Glu Val
370 375 380
Leu Asp Gln Gly Asp Phe Tyr Ser Leu Leu Ser Lys Leu Leu Gly Glu
385 390 395 400
Arg Glu Asp Val Val His Val His Lys Tyr Asn Pro Thr Glu Lys Ala
405 410 415
Glu Ser Glu Ser Asp Leu Val Ala Glu Ile Ala Asn Val Val Gln Lys
420 425 430
Lys Asp Leu Gly Arg Ser Asp Ala Arg Glu Gly Ala Glu His Glu Arg
435 440 445
Gly Asn Ala Ile Leu Val Arg Asp Arg Ile His Lys Phe His Arg Leu
450 455 460
Val Ser Thr Leu Arg Pro Pro Glu Ser Arg Val Phe Ser Leu Gln Gln
465 470 475 480
Pro Pro Pro Gly Glu Gly Thr Trp Glu Pro Glu His Thr Gly Asp Phe
485 490 495
His Met Glu Glu Ala Leu Asp Trp Pro Gly Val Tyr Leu Leu Pro Gly
500 505 510
Gln Val Ser Gly Val Ala Leu Asp Pro Lys Asn Asn Leu Val Ile Phe
515 520 525
His Arg Gly Asp His Val Trp Asp Gly Asn Ser Phe Asp Ser Lys Phe
530 535 540
Val Tyr Gln Gln Ile Gly Leu Gly Pro Ile Glu Glu Asp Thr Ile Leu
545 550 555 560
Val Ile Asp Pro Asn Asn Ala Ala Val Leu Gln Ser Ser Gly Lys Asn
565 570 575
Leu Phe Tyr Leu Pro His Gly Leu Ser Ile Asp Lys Asp Gly Asn Tyr
580 585 590
Trp Val Thr Asp Val Ala Leu His Gln Val Phe Lys Leu Asp Pro Asn
595 600 605
Asn Lys Glu Gly Pro Val Leu Ile Leu Gly Arg Ser Met Gln Pro Gly
610 615 620
Ser Asp Gln Asn His Phe Cys Gln Pro Thr Asp Val Ala Val Asp Pro
625 630 635 640
Gly Thr Gly Ala Ile Tyr Val Ser Asp Gly Tyr Cys Asn Ser Arg Ile
645 650 655
Val Gln Phe Ser Pro Ser Gly Lys Phe Ile Thr Gln Trp Gly Glu Glu
660 665 670
Ser Ser Gly Ser Ser Pro Leu Pro Gly Gln Phe Thr Val Pro His Ser
675 680 685
Leu Ala Leu Val Pro Leu Leu Gly Gln Leu Cys Val Ala Asp Arg Glu
690 695 700
Asn Gly Arg Ile Gln Cys Phe Lys Thr Asp Thr Lys Glu Phe Val Arg
705 710 715 720
Glu Ile Lys His Ser Ser Phe Gly Arg Asn Val Phe Ala Ile Ser Tyr
725 730 735
Ile Pro Gly Leu Leu Phe Ala Val Asn Gly Lys Pro His Phe Gly Asp
740 745 750
Gln Glu Pro Val Gln Gly Phe Val Met Asn Phe Ser Asn Gly Glu Ile
755 760 765
Ile Asp Ile Phe Lys Pro Val Arg Lys His Phe Asp Met Pro His Asp
770 775 780
Ile Val Ala Ser Glu Asp Gly Thr Val Tyr Ile Gly Asp Ala His Thr
785 790 795 800
Asn Thr Val Trp Lys Phe Thr Leu Thr Glu Lys Leu Glu His Arg Ser
805 810 815
Val Lys Lys Ala Gly Ile Glu Val Gln Glu Ile Lys Gly Lys Gly Ser
820 825 830
Gly Gly Leu Asn Leu Gly Asn Phe Phe Ala Ser Arg Lys Gly Tyr Ser
835 840 845
Arg Lys Gly Phe Asp Arg Leu Ser Thr Glu Gly Ser Asp Gln Glu Lys
850 855 860
Glu Asp Asp Gly Ser Glu Ser Glu Glu Glu Tyr Ser Ala Pro Leu Pro
865 870 875 880
Ala Leu Ala Pro Ser Ser Ser
885
<210> 5
<211> 974
<212> PRT
<213> 智人
<400> 5
Met Ala Gly Arg Val Pro Ser Leu Leu Val Leu Leu Val Phe Pro Ser
1 5 10 15
Ser Cys Leu Ala Phe Arg Ser Pro Leu Ser Val Phe Lys Arg Phe Lys
20 25 30
Glu Thr Thr Arg Pro Phe Ser Asn Glu Cys Leu Gly Thr Thr Arg Pro
35 40 45
Val Val Pro Ile Asp Ser Ser Asp Phe Ala Leu Asp Ile Arg Met Pro
50 55 60
Gly Val Thr Pro Lys Gln Ser Asp Thr Tyr Phe Cys Met Ser Met Arg
65 70 75 80
Ile Pro Val Asp Glu Glu Ala Phe Val Ile Asp Phe Lys Pro Arg Ala
85 90 95
Ser Met Asp Thr Val His His Met Leu Leu Phe Gly Cys Asn Met Pro
100 105 110
Ser Ser Thr Gly Ser Tyr Trp Phe Cys Asp Glu Gly Thr Cys Thr Asp
115 120 125
Lys Ala Asn Ile Leu Tyr Ala Trp Ala Arg Asn Ala Pro Pro Thr Arg
130 135 140
Leu Pro Lys Gly Val Gly Phe Arg Val Gly Gly Glu Thr Gly Ser Lys
145 150 155 160
Tyr Phe Val Leu Gln Val His Tyr Gly Asp Ile Ser Ala Phe Arg Asp
165 170 175
Asn Asn Lys Asp Cys Ser Gly Val Ser Leu His Leu Thr Arg Leu Pro
180 185 190
Gln Pro Leu Ile Ala Gly Met Tyr Leu Met Met Ser Val Asp Thr Val
195 200 205
Ile Pro Ala Gly Glu Lys Val Val Asn Ser Asp Ile Ser Cys His Tyr
210 215 220
Lys Asn Tyr Pro Met His Val Phe Ala Tyr Arg Val His Thr His His
225 230 235 240
Leu Gly Lys Val Val Ser Gly Tyr Arg Val Arg Asn Gly Gln Trp Thr
245 250 255
Leu Ile Gly Arg Gln Ser Pro Gln Leu Pro Gln Ala Phe Tyr Pro Val
260 265 270
Gly His Pro Val Asp Val Ser Phe Gly Asp Leu Leu Ala Ala Arg Cys
275 280 285
Val Phe Thr Gly Glu Gly Arg Thr Glu Ala Thr His Ile Gly Gly Thr
290 295 300
Ser Ser Asp Glu Met Cys Asn Leu Tyr Ile Met Tyr Tyr Met Glu Ala
305 310 315 320
Lys His Ala Val Ser Phe Met Thr Cys Thr Gln Asn Val Ala Pro Asp
325 330 335
Met Phe Arg Thr Ile Pro Pro Glu Ala Asn Ile Pro Ile Pro Val Lys
340 345 350
Ser Asp Met Val Met Met His Glu His His Lys Glu Thr Glu Tyr Lys
355 360 365
Asp Lys Ile Pro Leu Leu Gln Gln Pro Lys Arg Glu Glu Glu Glu Val
370 375 380
Leu Asp Gln Gly Asp Phe Tyr Ser Leu Leu Ser Lys Leu Leu Gly Glu
385 390 395 400
Arg Glu Asp Val Val His Val His Lys Tyr Asn Pro Thr Glu Lys Ala
405 410 415
Glu Ser Glu Ser Asp Leu Val Ala Glu Ile Ala Asn Val Val Gln Lys
420 425 430
Lys Asp Leu Gly Arg Ser Asp Ala Arg Glu Gly Ala Glu His Glu Arg
435 440 445
Gly Asn Ala Ile Leu Val Arg Asp Arg Ile His Lys Phe His Arg Leu
450 455 460
Val Ser Thr Leu Arg Pro Pro Glu Ser Arg Val Phe Ser Leu Gln Gln
465 470 475 480
Pro Pro Pro Gly Glu Gly Thr Trp Glu Pro Glu His Thr Gly Asp Phe
485 490 495
His Met Glu Glu Ala Leu Asp Trp Pro Gly Val Tyr Leu Leu Pro Gly
500 505 510
Gln Val Ser Gly Val Ala Leu Asp Pro Lys Asn Asn Leu Val Ile Phe
515 520 525
His Arg Gly Asp His Val Trp Asp Gly Asn Ser Phe Asp Ser Lys Phe
530 535 540
Val Tyr Gln Gln Ile Gly Leu Gly Pro Ile Glu Glu Asp Thr Ile Leu
545 550 555 560
Val Ile Asp Pro Asn Asn Ala Ala Val Leu Gln Ser Ser Gly Lys Asn
565 570 575
Leu Phe Tyr Leu Pro His Gly Leu Ser Ile Asp Lys Asp Gly Asn Tyr
580 585 590
Trp Val Thr Asp Val Ala Leu His Gln Val Phe Lys Leu Asp Pro Asn
595 600 605
Asn Lys Glu Gly Pro Val Leu Ile Leu Gly Arg Ser Met Gln Pro Gly
610 615 620
Ser Asp Gln Asn His Phe Cys Gln Pro Thr Asp Val Ala Val Asp Pro
625 630 635 640
Gly Thr Gly Ala Ile Tyr Val Ser Asp Gly Tyr Cys Asn Ser Arg Ile
645 650 655
Val Gln Phe Ser Pro Ser Gly Lys Phe Ile Thr Gln Trp Gly Glu Glu
660 665 670
Ser Ser Gly Ser Ser Pro Leu Pro Gly Gln Phe Thr Val Pro His Ser
675 680 685
Leu Ala Leu Val Pro Leu Leu Gly Gln Leu Cys Val Ala Asp Arg Glu
690 695 700
Asn Gly Arg Ile Gln Cys Phe Lys Thr Asp Thr Lys Glu Phe Val Arg
705 710 715 720
Glu Ile Lys His Ser Ser Phe Gly Arg Asn Val Phe Ala Ile Ser Tyr
725 730 735
Ile Pro Gly Leu Leu Phe Ala Val Asn Gly Lys Pro His Phe Gly Asp
740 745 750
Gln Glu Pro Val Gln Gly Phe Val Met Asn Phe Ser Asn Gly Glu Ile
755 760 765
Ile Asp Ile Phe Lys Pro Val Arg Lys His Phe Asp Met Pro His Asp
770 775 780
Ile Val Ala Ser Glu Asp Gly Thr Val Tyr Ile Gly Asp Ala His Thr
785 790 795 800
Asn Thr Val Trp Lys Phe Thr Leu Thr Glu Lys Leu Glu His Arg Ser
805 810 815
Val Lys Lys Ala Gly Ile Glu Val Gln Glu Ile Lys Glu Ala Glu Ala
820 825 830
Val Val Glu Thr Lys Met Glu Asn Lys Pro Thr Ser Ser Glu Leu Gln
835 840 845
Lys Met Gln Glu Lys Gln Lys Leu Ile Lys Glu Pro Gly Ser Gly Val
850 855 860
Pro Val Val Leu Ile Thr Thr Leu Leu Val Ile Pro Val Val Val Leu
865 870 875 880
Leu Ala Ile Ala Ile Phe Ile Arg Trp Lys Lys Ser Arg Ala Phe Gly
885 890 895
Ala Asp Ser Glu His Lys Leu Glu Thr Ser Ser Gly Arg Val Leu Gly
900 905 910
Arg Phe Arg Gly Lys Gly Ser Gly Gly Leu Asn Leu Gly Asn Phe Phe
915 920 925
Ala Ser Arg Lys Gly Tyr Ser Arg Lys Gly Phe Asp Arg Leu Ser Thr
930 935 940
Glu Gly Ser Asp Gln Glu Lys Glu Asp Asp Gly Ser Glu Ser Glu Glu
945 950 955 960
Glu Tyr Ser Ala Pro Leu Pro Ala Leu Ala Pro Ser Ser Ser
965 970
<210> 6
<211> 955
<212> PRT
<213> 智人
<400> 6
Met Ala Gly Arg Val Pro Ser Leu Leu Val Leu Leu Val Phe Pro Ser
1 5 10 15
Ser Cys Leu Ala Phe Arg Ser Pro Leu Ser Val Phe Lys Arg Phe Lys
20 25 30
Glu Thr Thr Arg Pro Phe Ser Asn Glu Cys Leu Gly Thr Thr Arg Pro
35 40 45
Val Val Pro Ile Asp Ser Ser Asp Phe Ala Leu Asp Ile Arg Met Pro
50 55 60
Gly Val Thr Pro Lys Gln Ser Asp Thr Tyr Phe Cys Met Ser Met Arg
65 70 75 80
Ile Pro Val Asp Glu Glu Ala Phe Val Ile Asp Phe Lys Pro Arg Ala
85 90 95
Ser Met Asp Thr Val His His Met Leu Leu Phe Gly Cys Asn Met Pro
100 105 110
Ser Ser Thr Gly Ser Tyr Trp Phe Cys Asp Glu Gly Thr Cys Thr Asp
115 120 125
Lys Ala Asn Ile Leu Tyr Ala Trp Ala Arg Asn Ala Pro Pro Thr Arg
130 135 140
Leu Pro Lys Gly Val Gly Phe Arg Val Gly Gly Glu Thr Gly Ser Lys
145 150 155 160
Tyr Phe Val Leu Gln Val His Tyr Gly Asp Ile Ser Ala Phe Arg Asp
165 170 175
Asn Asn Lys Asp Cys Ser Gly Val Ser Leu His Leu Thr Arg Leu Pro
180 185 190
Gln Pro Leu Ile Ala Gly Met Tyr Leu Met Met Ser Val Asp Thr Val
195 200 205
Ile Pro Ala Gly Glu Lys Val Val Asn Ser Asp Ile Ser Cys His Tyr
210 215 220
Lys Asn Tyr Pro Met His Val Phe Ala Tyr Arg Val His Thr His His
225 230 235 240
Leu Gly Lys Val Val Ser Gly Tyr Arg Val Arg Asn Gly Gln Trp Thr
245 250 255
Leu Ile Gly Arg Gln Ser Pro Gln Leu Pro Gln Ala Phe Tyr Pro Val
260 265 270
Gly His Pro Val Asp Val Ser Phe Gly Asp Leu Leu Ala Ala Arg Cys
275 280 285
Val Phe Thr Gly Glu Gly Arg Thr Glu Ala Thr His Ile Gly Gly Thr
290 295 300
Ser Ser Asp Glu Met Cys Asn Leu Tyr Ile Met Tyr Tyr Met Glu Ala
305 310 315 320
Lys His Ala Val Ser Phe Met Thr Cys Thr Gln Asn Val Ala Pro Asp
325 330 335
Met Phe Arg Thr Ile Pro Pro Glu Ala Asn Ile Pro Ile Pro Val Lys
340 345 350
Ser Asp Met Val Met Met His Glu His His Lys Glu Thr Glu Tyr Lys
355 360 365
Asp Lys Ile Pro Leu Leu Gln Gln Pro Lys Arg Glu Glu Glu Glu Val
370 375 380
Leu Asp Gln Gly Asp Phe Tyr Ser Leu Leu Ser Lys Leu Leu Gly Glu
385 390 395 400
Arg Glu Asp Val Val His Val His Lys Tyr Asn Pro Thr Glu Lys Ala
405 410 415
Glu Ser Glu Ser Asp Leu Val Ala Glu Ile Ala Asn Val Val Gln Lys
420 425 430
Lys Asp Leu Gly Arg Ser Asp Ala Arg Glu Gly Ala Glu His Glu Arg
435 440 445
Gly Asn Ala Ile Leu Val Arg Asp Arg Ile His Lys Phe His Arg Leu
450 455 460
Val Ser Thr Leu Arg Pro Pro Glu Ser Arg Val Phe Ser Leu Gln Gln
465 470 475 480
Pro Pro Pro Gly Glu Gly Thr Trp Glu Pro Glu His Thr Gly Asp Phe
485 490 495
His Met Glu Glu Ala Leu Asp Trp Pro Gly Val Tyr Leu Leu Pro Gly
500 505 510
Gln Val Ser Gly Val Ala Leu Asp Pro Lys Asn Asn Leu Val Ile Phe
515 520 525
His Arg Gly Asp His Val Trp Asp Gly Asn Ser Phe Asp Ser Lys Phe
530 535 540
Val Tyr Gln Gln Ile Gly Leu Gly Pro Ile Glu Glu Asp Thr Ile Leu
545 550 555 560
Val Ile Asp Pro Asn Asn Ala Ala Val Leu Gln Ser Ser Gly Lys Asn
565 570 575
Leu Phe Tyr Leu Pro His Gly Leu Ser Ile Asp Lys Asp Gly Asn Tyr
580 585 590
Trp Val Thr Asp Val Ala Leu His Gln Val Phe Lys Leu Asp Pro Asn
595 600 605
Asn Lys Glu Gly Pro Val Leu Ile Leu Gly Arg Ser Met Gln Pro Gly
610 615 620
Ser Asp Gln Asn His Phe Cys Gln Pro Thr Asp Val Ala Val Asp Pro
625 630 635 640
Gly Thr Gly Ala Ile Tyr Val Ser Asp Gly Tyr Cys Asn Ser Arg Ile
645 650 655
Val Gln Phe Ser Pro Ser Gly Lys Phe Ile Thr Gln Trp Gly Glu Glu
660 665 670
Ser Ser Gly Ser Ser Pro Leu Pro Gly Gln Phe Thr Val Pro His Ser
675 680 685
Leu Ala Leu Val Pro Leu Leu Gly Gln Leu Cys Val Ala Asp Arg Glu
690 695 700
Asn Gly Arg Ile Gln Cys Phe Lys Thr Asp Thr Lys Glu Phe Val Arg
705 710 715 720
Glu Ile Lys His Ser Ser Phe Gly Arg Asn Val Phe Ala Ile Ser Tyr
725 730 735
Ile Pro Gly Leu Leu Phe Ala Val Asn Gly Lys Pro His Phe Gly Asp
740 745 750
Gln Glu Pro Val Gln Gly Phe Val Met Asn Phe Ser Asn Gly Glu Ile
755 760 765
Ile Asp Ile Phe Lys Pro Val Arg Lys His Phe Asp Met Pro His Asp
770 775 780
Ile Val Ala Ser Glu Asp Gly Thr Val Tyr Ile Gly Asp Ala His Thr
785 790 795 800
Asn Thr Val Trp Lys Phe Thr Leu Thr Glu Lys Leu Glu His Arg Ser
805 810 815
Val Lys Lys Ala Gly Ile Glu Val Gln Glu Ile Lys Glu Ala Glu Ala
820 825 830
Val Val Glu Thr Lys Met Glu Asn Lys Pro Thr Ser Ser Glu Leu Gln
835 840 845
Lys Met Gln Glu Lys Gln Lys Leu Ile Lys Glu Pro Gly Ser Gly Val
850 855 860
Pro Val Val Leu Ile Thr Thr Leu Leu Val Ile Pro Val Val Val Leu
865 870 875 880
Leu Ala Ile Ala Ile Phe Ile Arg Trp Lys Lys Ser Arg Ala Phe Gly
885 890 895
Gly Lys Gly Ser Gly Gly Leu Asn Leu Gly Asn Phe Phe Ala Ser Arg
900 905 910
Lys Gly Tyr Ser Arg Lys Gly Phe Asp Arg Leu Ser Thr Glu Gly Ser
915 920 925
Asp Gln Glu Lys Glu Asp Asp Gly Ser Glu Ser Glu Glu Glu Tyr Ser
930 935 940
Ala Pro Leu Pro Ala Leu Ala Pro Ser Ser Ser
945 950 955
<210> 7
<211> 464
<212> PRT
<213> 智人
<400> 7
Phe Lys Glu Thr Thr Arg Pro Phe Ser Asn Glu Cys Leu Gly Thr Thr
1 5 10 15
Arg Pro Val Val Pro Ile Asp Ser Ser Asp Phe Ala Leu Asp Ile Arg
20 25 30
Met Pro Gly Val Thr Pro Lys Gln Ser Asp Thr Tyr Phe Cys Met Ser
35 40 45
Met Arg Ile Pro Val Asp Glu Glu Ala Phe Val Ile Asp Phe Lys Pro
50 55 60
Arg Ala Ser Met Asp Thr Val His His Met Leu Leu Phe Gly Cys Asn
65 70 75 80
Met Pro Ser Ser Thr Gly Ser Tyr Trp Phe Cys Asp Glu Gly Thr Cys
85 90 95
Thr Asp Lys Ala Asn Ile Leu Tyr Ala Trp Ala Arg Asn Ala Pro Pro
100 105 110
Thr Arg Leu Pro Lys Gly Val Gly Phe Arg Val Gly Gly Glu Thr Gly
115 120 125
Ser Lys Tyr Phe Val Leu Gln Val His Tyr Gly Asp Ile Ser Ala Phe
130 135 140
Arg Asp Asn Asn Lys Asp Cys Ser Gly Val Ser Leu His Leu Thr Arg
145 150 155 160
Leu Pro Gln Pro Leu Ile Ala Gly Met Tyr Leu Met Met Ser Val Asp
165 170 175
Thr Val Ile Pro Ala Gly Glu Lys Val Val Asn Ser Asp Ile Ser Cys
180 185 190
His Tyr Lys Asn Tyr Pro Met His Val Phe Ala Tyr Arg Val His Thr
195 200 205
His His Leu Gly Lys Val Val Ser Gly Tyr Arg Val Arg Asn Gly Gln
210 215 220
Trp Thr Leu Ile Gly Arg Gln Ser Pro Gln Leu Pro Gln Ala Phe Tyr
225 230 235 240
Pro Val Gly His Pro Val Asp Val Ser Phe Gly Asp Leu Leu Ala Ala
245 250 255
Arg Cys Val Phe Thr Gly Glu Gly Arg Thr Glu Ala Thr His Ile Gly
260 265 270
Gly Thr Ser Ser Asp Glu Met Cys Asn Leu Tyr Ile Met Tyr Tyr Met
275 280 285
Glu Ala Lys His Ala Val Ser Phe Met Thr Cys Thr Gln Asn Val Ala
290 295 300
Pro Asp Met Phe Arg Thr Ile Pro Pro Glu Ala Asn Ile Pro Ile Pro
305 310 315 320
Val Lys Ser Asp Met Val Met Met His Glu His His Lys Glu Thr Glu
325 330 335
Tyr Lys Asp Lys Ile Pro Leu Leu Gln Gln Pro Lys Arg Glu Glu Glu
340 345 350
Glu Val Leu Asp Gln Gly Asp Phe Tyr Ser Leu Leu Ser Lys Leu Leu
355 360 365
Gly Glu Arg Glu Asp Val Val His Val His Lys Tyr Asn Pro Thr Glu
370 375 380
Lys Ala Glu Ser Glu Ser Asp Leu Val Ala Glu Ile Ala Asn Val Val
385 390 395 400
Gln Lys Lys Asp Leu Gly Arg Ser Asp Ala Arg Glu Gly Ala Glu His
405 410 415
Glu Arg Gly Asn Ala Ile Leu Val Arg Asp Arg Ile His Lys Phe His
420 425 430
Arg Leu Val Ser Thr Leu Arg Pro Pro Glu Ser Arg Val Phe Ser Leu
435 440 445
Gln Gln Pro Pro Pro Gly Glu Gly Thr Trp Glu Pro Glu His Thr Gly
450 455 460
<210> 8
<211> 323
<212> PRT
<213> 智人
<400> 8
Asp Phe His Met Glu Glu Ala Leu Asp Trp Pro Gly Val Tyr Leu Leu
1 5 10 15
Pro Gly Gln Val Ser Gly Val Ala Leu Asp Pro Lys Asn Asn Leu Val
20 25 30
Ile Phe His Arg Gly Asp His Val Trp Asp Gly Asn Ser Phe Asp Ser
35 40 45
Lys Phe Val Tyr Gln Gln Ile Gly Leu Gly Pro Ile Glu Glu Asp Thr
50 55 60
Ile Leu Val Ile Asp Pro Asn Asn Ala Ala Val Leu Gln Ser Ser Gly
65 70 75 80
Lys Asn Leu Phe Tyr Leu Pro His Gly Leu Ser Ile Asp Lys Asp Gly
85 90 95
Asn Tyr Trp Val Thr Asp Val Ala Leu His Gln Val Phe Lys Leu Asp
100 105 110
Pro Asn Asn Lys Glu Gly Pro Val Leu Ile Leu Gly Arg Ser Met Gln
115 120 125
Pro Gly Ser Asp Gln Asn His Phe Cys Gln Pro Thr Asp Val Ala Val
130 135 140
Asp Pro Gly Thr Gly Ala Ile Tyr Val Ser Asp Gly Tyr Cys Asn Ser
145 150 155 160
Arg Ile Val Gln Phe Ser Pro Ser Gly Lys Phe Ile Thr Gln Trp Gly
165 170 175
Glu Glu Ser Ser Gly Ser Ser Pro Leu Pro Gly Gln Phe Thr Val Pro
180 185 190
His Ser Leu Ala Leu Val Pro Leu Leu Gly Gln Leu Cys Val Ala Asp
195 200 205
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Val Arg Glu Ile Lys His Ser Ser Phe Gly Arg Asn Val Phe Ala Ile
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Ser Tyr Ile Pro Gly Leu Leu Phe Ala Val Asn Gly Lys Pro His Phe
245 250 255
Gly Asp Gln Glu Pro Val Gln Gly Phe Val Met Asn Phe Ser Asn Gly
260 265 270
Glu Ile Ile Asp Ile Phe Lys Pro Val Arg Lys His Phe Asp Met Pro
275 280 285
His Asp Ile Val Ala Ser Glu Asp Gly Thr Val Tyr Ile Gly Asp Ala
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His Thr Asn Thr Val Trp Lys Phe Thr Leu Thr Glu Lys Leu Glu His
305 310 315 320
Arg Ser Val
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Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Phe Arg
20
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<213> 智人
<400> 10
Ser Pro Leu Ser Val Phe Lys Arg Phe Lys Glu Thr Thr Arg Pro Phe
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Ser Asn Glu Cys Leu Gly Thr Thr Arg Pro Val Val Pro Ile Asp Ser
20 25 30
Ser Asp Phe Ala Leu Asp Ile Arg Met Pro Gly Val Thr Pro Lys Gln
35 40 45
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Ala Phe Val Ile Asp Phe Lys Pro Arg Ala Ser Met Asp Thr Val His
65 70 75 80
His Met Leu Leu Phe Gly Cys Asn Met Pro Ser Ser Thr Gly Ser Tyr
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Trp Phe Cys Asp Glu Gly Thr Cys Thr Asp Lys Ala Asn Ile Leu Tyr
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Ala Trp Ala Arg Asn Ala Pro Pro Thr Arg Leu Pro Lys Gly Val Gly
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His Tyr Gly Asp Ile Ser Ala Phe Arg Asp Asn Asn Lys Asp Cys Ser
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Gly Val Ser Leu His Leu Thr Arg Leu Pro Gln Pro Leu Ile Ala Gly
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Met Tyr Leu Met Met Ser Val Asp Thr Val Ile Pro Ala Gly Glu Lys
180 185 190
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Val Phe Ala Tyr Arg Val His Thr His His Leu Gly Lys Val Val Ser
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Gly Tyr Arg Val Arg Asn Gly Gln Trp Thr Leu Ile Gly Arg Gln Ser
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Pro Gln Leu Pro Gln Ala Phe Tyr Pro Val Gly His Pro Val Asp Val
245 250 255
Ser Phe Gly Asp Leu Leu Ala Ala Arg Cys Val Phe Thr Gly Glu Gly
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Arg Thr Glu Ala Thr His Ile Gly Gly Thr Ser Ser Asp Glu Met Cys
275 280 285
Asn Leu Tyr Ile Met Tyr Tyr Met Glu Ala Lys His Ala Val Ser Phe
290 295 300
Met Thr Cys Thr Gln Asn Val Ala Pro Asp Met Phe Arg Thr Ile Pro
305 310 315 320
Pro Glu Ala Asn Ile Pro Ile Pro Val Lys Ser Asp Met Val Met Met
325 330 335
His Glu His His Lys Glu Thr Glu Tyr Lys Asp Lys Ile Pro Leu Leu
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Leu Ile Leu Gly Arg Ser Met Gln Pro Gly Ser Asp Gln Asn His Phe
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690 695 700
Phe Gly Arg Asn Val Phe Ala Ile Ser Tyr Ile Pro Gly Leu Leu Phe
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Ala Val Asn Gly Lys Pro His Phe Gly Asp Gln Glu Pro Val Gln Gly
725 730 735
Phe Val Met Asn Phe Ser Asn Gly Glu Ile Ile Asp Ile Phe Lys Pro
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Thr Leu Thr Glu Lys Leu Glu His Arg Ser Val Lys Lys Ala Gly Ile
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Glu Val Gln Glu Ile Lys Glu Ala Glu Ala Val Val Gly Ser
805 810
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<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 11
Cys Leu Gly Thr Thr Arg Pro Val Val Pro Ile Asp Ser Ser Asp
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<213> 人工序列
<220>
<223> 肽
<400> 12
Cys Asn Met Pro Ser Ser Thr Gly Ser Tyr Trp Phe Cys Asp Glu Gly
1 5 10 15
Thr Cys Thr Asp
20
<210> 13
<211> 13
<212> PRT
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<220>
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<400> 13
Tyr Gly Asp Ile Ser Ala Phe Arg Asp Asn Asn Lys Asp
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<213> 人工序列
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<223> 肽
<400> 16
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20
<210> 17
<211> 11
<212> PRT
<213> 人工序列
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<223> 肽
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Tyr Arg Val His Thr His His Leu Gly Lys Val
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<212> PRT
<213> 人工序列
<220>
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Gln Ser Pro Gln Leu Pro Gln Ala Phe Tyr Pro Val Gly His Pro Val
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<211> 28
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<213> 人工序列
<220>
<223> 肽
<400> 19
Arg Gly Asp His Val Trp Asp Gly Asn Ser Phe Asp Ser Lys Phe Val
1 5 10 15
Tyr Gln Gln Ile Gly Leu Gly Pro Ile Glu Glu Asp
20 25
<210> 20
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 20
Glu Gly Pro Val Leu Ile Leu Gly Arg Ser Met Gln Pro Gly Ser Asp
1 5 10 15
Gln Asn His Phe Cys
20
<210> 21
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 21
Ile Asp Pro Asn Asn Ala Ala Val Leu Gln Ser Ser Gly Lys Asn Leu
1 5 10 15
Phe Tyr
<210> 22
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 22
Asn Gly Lys Pro His Phe Gly Asp Gln Glu Pro Val Gln Gly
1 5 10
<210> 23
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 23
Trp Gly Glu Glu Ser Ser Gly Ser Ser Pro Leu Pro Gly Gln Phe Thr
1 5 10 15
Val Pro His
<210> 24
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 24
Cys Phe Lys Thr Asp Thr Lys Glu Phe Val Arg Glu Ile Lys His Ser
1 5 10 15
权利要求书(按照条约第19条的修改)
1.一种通过测定患者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述患者的疾病和/或预测所述患者患上疾病或发生不良事件的风险和/或监测所述患者的疾病或不良事件的方法,
其中所述患者中的所述疾病选自:痴呆、心血管病症、肾脏疾病、癌症、炎性或感染性疾病和/或代谢疾病,
其中所述不良事件选自:心脏事件、心血管事件、脑血管事件、癌症、糖尿病、感染、严重感染、败血症样全身感染、败血症和全因死亡。
2.一种通过测定患者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述患者的疾病和/或预测所述患者患上疾病或发生不良事件的风险和/或监测所述患者的疾病或不良事件的方法,所述方法包括以下步骤:
·测定所述患者的体液样品中PAM和/或其同工型和/或其片段的水平,
·将所述测定量与预定阈值进行比较,
·其中如果所述测定量低于或高于所述预定阈值,则所述患者被诊断为患有疾病,或
·其中如果所述测定量低于或高于所述预定阈值,则预示疾病的结果,或
·其中如果所述测定量低于或高于所述预定阈值,则预测所述患者患上疾病或发生不良事件的风险,或
·其中监测所述患者的疾病或不良事件。
3.根据权利要求1和2所述的方法,其中PAM和/或其同工型和/或其片段的所述水平是所述患者的体液样品中PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度或者PAM和/或其同工型和/或其片段的活性。
4.根据权利要求1-3所述的方法,其中PAM和/或其同工型和/或其片段的所述活性选自以下序列:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQ IDNo.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
5.根据权利要求1-3所述的方法,其中用免疫测定法检测PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度。
6.根据权利要求3-4所述的方法,其中使用肽-Gly作为底物检测PAM和/或其同工型和/或其片段的活性。
7.根据权利要求6所述的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
8.根据权利要求1-7所述的通过测定患者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述患者的疾病和/或预测所述患者患上疾病或发生不良事件的风险和/或监测所述患者的疾病或不良事件的方法,其中所述PAM和/或其同工型和/或其片段选自:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQ ID No.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
9.根据权利要求1-8所述的通过测定患者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述患者的疾病和/或预测所述患者患上疾病或发生不良事件的风险和/或监测所述患者的疾病或不良事件的方法,其中确定患者患上疾病的风险,其中所述患者是健康患者。
10.根据权利要求9所述的方法,其中所述疾病选自阿尔茨海默病、结直肠癌和胰腺癌。
11.一种使用测定法来测定体液样品中PAM和/或同工型和/或其片段的水平的方法,其中所述测定法包含结合PAM的两个不同区域的两种结合剂,其中所述两种结合剂针对长度为至少5个氨基酸、优选地至少4个氨基酸的表位,其中所述两种结合剂针对包含在以下PAM序列中的表位:肽1(SEQ ID No.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ IDNo.14)、肽5(SEQ ID No.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ IDNo.18)、肽9(SEQ ID No.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ IDNo.22)、肽13(SEQ ID No.23)、肽14(SEQ ID No.24)和重组PAM(SEQ ID No.10)。
12.一种测定患者的体液样品中PAM和/或其同工型或片段的活性的方法,所述方法包括以下步骤
·使所述样品与特异性结合于活性全长PAM、其同工型和/或其活性片段的捕获结合剂接触,
·分离结合于所述捕获结合剂的PAM,
·向所述分离的PAM添加PAM的底物,以及
·通过测量PAM的底物的转化来量化PAM活性。
13.一种测定患者的体液样品中PAM和/或同工型和/或其片段的活性的方法,所述方法包括以下步骤
·在t=0min和t=n+1min使所述样品与PAM的底物(肽-Gly)接触一段时间间隔,在t=0min和t=n+1min检测所述样品中PAM的反应产物(α-酰胺化肽),以及
·通过计算t=0和t=n+1之间所述反应产物的差异来量化PAM的活性。
14.根据权利要求13所述的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
15.一种抗体用于测定PAM和/或其同工型和/或其片段的水平的用途,其中所述抗体特异性结合于选自以下的序列:重组PAM(SEQ ID No.10)、肽1(SEQ ID No.11)、肽2(SEQ IDNo.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ IDNo.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽10(SEQ IDNo.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ ID No.23)和肽14(SEQ IDNo.24)。
16.一种用于测定PAM和/或其同工型和/或其片段的水平的试剂盒,所述试剂盒包含一种或多种结合于选自以下的PAM序列的抗体:重组PAM(SEQ ID No.10)、肽1(SEQ IDNo.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ IDNo.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)和肽14(SEQ ID No.24)。
Claims (16)
1.一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,
其中所述受试者中的所述疾病选自:痴呆、心血管病症、肾脏疾病、癌症、炎性或感染性疾病和/或代谢疾病,
其中所述不良事件选自:心脏事件、心血管事件、脑血管事件、癌症、糖尿病、感染、严重感染、败血症样全身感染、败血症和全因死亡。
2.一种通过测定受试者的体液样品中肽酰甘氨酸α-酰胺化单加氧酶(PAM)和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,所述方法包括以下步骤:
·测定所述受试者的体液样品中PAM和/或其同工型和/或其片段的水平,
·将所述测定量与预定阈值进行比较,
·其中如果所述测定量低于或高于所述预定阈值,则所述受试者被诊断为患有疾病,或
·其中如果所述测定量低于或高于所述预定阈值,则预示疾病的结果,或
·其中如果所述测定量低于或高于所述预定阈值,则预测所述患者患上疾病或发生不良事件的风险,或
·其中监测所述受试者的疾病或不良事件。
3.根据权利要求1和2所述的方法,其中PAM和/或其同工型和/或其片段的所述水平是所述受试者的体液样品中PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度或者PAM和/或其同工型和/或其片段的活性。
4.根据权利要求1-3所述的方法,其中PAM和/或其同工型和/或其片段的所述活性选自以下序列:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQ IDNo.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
5.根据权利要求1-3所述的方法,其中用免疫测定法检测PAM和/或其同工型和/或其具有至少12个氨基酸的片段的总浓度。
6.根据权利要求3-4所述的方法,其中使用肽-Gly作为底物检测PAM和/或其同工型和/或其片段的活性。
7.根据权利要求6所述的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
8.根据权利要求1-7所述的通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中所述PAM和/或其同工型和/或其片段选自:SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4、SEQ ID No.5、SEQID No.6、SEQ ID No.7、SEQ ID No.8和SEQ ID No.10。
9.根据权利要求1-8所述的通过测定受试者的体液样品中PAM和/或其同工型和/或其片段的水平来诊断或预后所述受试者的疾病和/或预测所述受试者患上疾病或发生不良事件的风险和/或监测所述受试者的疾病或不良事件的方法,其中确定受试者患上疾病的风险,其中所述受试者是健康受试者。
10.根据权利要求9所述的方法,其中所述疾病选自阿尔茨海默病、结直肠癌和胰腺癌。
11.一种使用测定法来测定体液样品中PAM和/或同工型和/或其片段的水平的方法,其中所述测定法包含结合PAM的两个不同区域的两种结合剂,其中所述两种结合剂针对长度为至少5个氨基酸、优选地至少4个氨基酸的表位,其中所述两种结合剂针对包含在以下PAM序列中的表位:肽1(SEQ ID No.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ IDNo.14)、肽5(SEQ ID No.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ IDNo.18)、肽9(SEQ ID No.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ IDNo.22)、肽13(SEQ ID No.23)、肽14(SEQ ID No.24)和重组PAM(SEQ ID No.10)。
12.一种测定受试者的体液样品中PAM和/或其同工型或片段的活性的方法,所述方法包括以下步骤
·使所述样品与特异性结合于活性全长PAM、其同工型和/或其活性片段的捕获结合剂接触,
·分离结合于所述捕获结合剂的PAM,
·向所述分离的PAM添加PAM的底物,以及
·通过测量PAM的底物的转化来量化PAM活性。
13.一种测定受试者的体液样品中PAM和/或同工型和/或其片段的活性的方法,所述方法包括以下步骤
·在t=0min和t=n+1min使所述样品与PAM的底物(肽-Gly)接触一段时间间隔,在t=0min和t=n+1min检测所述样品中PAM的反应产物(α-酰胺化肽),以及
·通过计算t=0和t=n+1之间所述反应产物的差异来量化PAM的活性。
14.根据权利要求13所述的方法,其中所述肽-Gly底物选自:肾上腺髓质素(ADM)、肾上腺髓质素-2、中叶素-短、肾上腺髓质素原N-20末端肽(PAMP)、胰淀素、胃泌素释放肽、神经调节蛋白C、神经调节蛋白B、神经调节蛋白S、神经调节蛋白U、降钙素、降钙素基因相关肽(CGRP)1和2、胰岛淀粉样蛋白多肽、嗜铬粒蛋白A、胰岛素、胰抑素、催乳素释放肽(PrRP)、胆囊收缩素、大胃泌素、胃泌素、胰高血糖素样肽1(GLP-1)、垂体腺苷酸环化酶激活多肽(PACAP)、促胰液素、生长激素释放素、肽组氨酸蛋氨酸(PHM)、血管活性肠肽(VIP)、促性腺素释放素、亲吻素、MIF-1、转移抑制素、神经肽K、神经肽γ、P物质、神经激肽A、神经激肽B、肽YY、胰腺激素、新皮啡肽I、食欲素A和B、促黑激素α(α-MSH)、促黑激素γ、促甲状腺素释放激素(TRH)、催产素和加压素。
15.一种抗体用于测定PAM和/或其同工型和/或其片段的水平的用途,其中所述抗体特异性结合于选自以下的序列:重组PAM(SEQ ID No.10)、肽1(SEQ ID No.11)、肽2(SEQ IDNo.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ ID No.15)、肽6(SEQ IDNo.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ ID No.19)、肽10(SEQ IDNo.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ ID No.23)和肽14(SEQ IDNo.24)。
16.一种用于测定PAM和/或其同工型和/或其片段的水平的试剂盒,所述试剂盒包含一种或多种结合于选自以下的PAM序列的抗体:重组PAM(SEQ ID No.10)、肽1(SEQ IDNo.11)、肽2(SEQ ID No.12)、肽(SEQ ID No.13)、肽4(SEQ ID No.14)、肽5(SEQ IDNo.15)、肽6(SEQ ID No.16)、肽7(SEQ ID No.17)、肽8(SEQ ID No.18)、肽9(SEQ IDNo.19)、肽10(SEQ ID No.20)、肽11(SEQ ID No.21)、肽12(SEQ ID No.22)、肽13(SEQ IDNo.23)和肽14(SEQ ID No.24)。
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