CN110402393A - 疾病诊断的组合物 - Google Patents
疾病诊断的组合物 Download PDFInfo
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Abstract
本发明涉及用于诊断胰腺疾病的组合物,并且更具体地,涉及可诊断胰腺癌的组合物,包含所述组合物的诊断试剂盒,以及使用所述组合物提供用于诊断的信息的方法。本发明可准确预测或鉴别胰腺癌的风险,并且另外可通过有效区分胰腺癌与不同类型的癌症来诊断胰腺癌。另外,在本发明中,可能通过非侵入性方法使用从得自个体的血液、血清或血浆获得的单核细胞简单并快速地诊断胰腺癌。
Description
【技术领域】
本发明涉及用于诊断例如胰腺癌的多种疾病的组合物、含有所述组合物的用于诊断的试剂盒,以及使用所述组合物提供诊断信息的方法。
【背景技术】
对癌症(现代人的一种严重疾病)的治疗和诊断方法的研究正在积极进行中,并且集中于具有高发病率的肺癌、肝癌和胃癌。然而,对具有较低发病率的食管癌、结直肠癌、胰腺癌等癌症的研究相对不足。特定地,胰腺癌在初始阶段几乎不展现任何症状,但通常在全身性转移后展现例如疼痛和体重减轻的症状。因此,胰腺癌具有较低治愈率,因此针对所述病的定期诊断非常重要。大多数临床症状发展缓慢,并且食欲减退、疲劳和体重减轻是最常见的症状。胰腺癌是致死性人类癌症,其具有最差预后,5年存活率为1至4%,并且中位存活率为5个月。另外,在诊断时发现,80%至90%的胰腺癌患者处于如下状况中:其中使得能从胰腺癌完全恢复的根治性切除是不可能的。因此,胰腺癌患者的预后较差,并且其治疗主要依赖于化学疗法。因此,首先,对研发胰腺癌早期诊断方法的需求越来越急迫,强于任何其他种类的人类癌症。
目前已知有效抵抗胰腺癌的若干种抗癌药物(包括5-氟尿嘧啶、吉西他滨和Tarceva)的治疗功效极差,并且对化学疗法的应答率较低,即约15%。这表明,迫切地需要更有效的早期诊断和治疗方法以改良胰腺癌患者的预后。
对胰腺癌的诊断迄今是通过胃和十二指肠的x射线摄影术、经皮肤和肝的胆管造影术、内镜逆行胆管造影或类似方法来进行,但最近,超声检查和计算机体层摄影已成为最常用方法。在使用这些方法中的任一种检测疾病的病灶时,更准确的检查结果可通过进行更精确的活检来获得。然而,由于其低准确度或与其相关的明显不适(例如患者的疼痛),患者不愿参与所述诊断方法。因此,需要发展能简单快捷地诊断胰腺癌的检查方法。
就此而言,韩国专利第10-0819122号披露使用母系蛋白、转甲状腺素蛋白和分层蛋白作为胰腺癌标志物的技术,并且韩国专利公开案第2012-0082372号披露使用各种胰腺癌标志物的技术。另外,韩国专利公开案第2009-0003308号披露通过检测来自受试者的血样中表达的REG4蛋白的量诊断胰腺癌的方法;韩国专利公开案第2012-0009781号披露测定方法,包括测量从受试者分离的癌组织中表达的XIST RNA的量以提供诊断胰腺癌所需的信息;韩国专利公开案第2007-0119250号披露新颖基因LBFL313家族,其与正常人类的胰腺组织相比,在人类胰腺癌组织中差异性表达;并且美国专利公开案第2011/0294136号披露使用生物标志物(例如角蛋白8蛋白)诊断胰腺癌的方法。然而,需要鉴别具有更佳效果的标志物,因为标志物的诊断效率和准确度之间差异极大。
【发明内容】
【技术问题】
本发明的目标是提供能简单准确地诊断疾病的组合物,所述疾病例如胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病或干癣,优选地是胰腺癌,所述组合物通过测量以下各项来诊断:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)的蛋白质表达水平,或编码所述蛋白质的基因的mRNA的表达水平。
本发明的另一目标是提供能简单准确的诊断疾病的试剂盒,所述疾病例如胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病或干癣,优选地是胰腺癌,所述试剂盒通过测量以下各项来诊断:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)的蛋白质或编码所述蛋白质的基因的mRNA的表达水平。
本发明的另一目标是提供诊断疾病的信息的方法,所述疾病例如胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病或干癣,优选地是胰腺癌,所述方法通过测量以下各项来进行:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)的蛋白质或编码所述蛋白质的基因的mRNA的表达水平。
【技术方案】
胰腺癌在初始阶段几乎不展现任何症状,但通常在全身性转移后展现例如疼痛和体重减轻的症状。因此,胰腺癌具有较低治愈率,因此针对所述病的定期诊断非常重要。大多数临床症状发展缓慢,并且食欲减退、疲劳和体重减轻是最常见的症状。胰腺癌是致死性人类癌症,其具有最差预后,5年存活率为1至4%,并且中位存活率为5个月。另外,在诊断时发现,80%至90%的胰腺癌患者处于如下状况中:其中使得能从胰腺癌完全恢复的根治性切除是不可能的。因此,胰腺癌患者的预后较差,并且其治疗主要依赖于化学疗法。因此,首先,对研发胰腺癌早期诊断方法的需求越来越急迫,强于任何其他种类的人类癌症。
因此,由于充分且广泛的研发可用于胰腺癌早期诊断的标志物的努力,本发明者已发现,白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)的表达尤其在从胰腺癌患者分离的血液源单核细胞中增加。基于此发现,完成本发明。
根据本发明的一个方面,提供诊断疾病的组合物,其包含用于测量以下各项的试剂:至少一种选自以下的蛋白质的表达水平:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)和干扰素λ受体1同种型1(IFNLR1同种型1),或编码所述蛋白质的基因的mRNA的表达水平。
可适用于使用本发明诊断组合物来预测其发作或发作可能性的疾病的例子包括但不限于胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病、干癣等。
特定地,本发明使得可能使用诊断组合物诊断作为胰腺疾病的胰腺癌或胰腺炎,优选地胰腺癌。具体地,本发明诊断组合物能检测或诊断与正常组不同的胰腺癌患者组。另外,本发明诊断组合物能选择性检测或诊断与其他类型的癌症(例如肺癌或结直肠癌)不同的胰腺癌。
如本文所用,术语“胰腺癌”是指源自胰腺细胞的癌症。存在多个种类的胰腺癌,包括胰管的胰管腺癌,其占胰腺癌病例的约90%。因此,“胰腺癌”通常意指胰管腺癌。另外,存在囊腺癌、内分泌肿瘤等。约5%至10%的胰腺癌患者具有对所述病的遗传倾向性。具有胰腺癌家族史的胰腺癌患者的比例为约7.8%,高于正常人中发作的胰腺癌的比例(0.6%)。胰腺癌具有极差预后,5年存活率小于5%。其原因在于,大多数病例是在癌症进展后才检测到,因此在检测时只在少于20%的病例中可能进行手术切除,并且即使通过目测检查确定已完全切除所述癌症,存活率的增加也因微转移而较低,并且对化学疗法和放射疗法的应答性较低。因此,最重要的提高存活率的方法是在症状不存在或非特异性时的早期检测和手术。
如本文所用,术语“胰腺炎”是指由胰腺炎症引起的疾病,并且包括急性胰腺炎和慢性胰腺炎。胰液含有消化酶,例如淀粉酶(作用于碳水化合物水解)、胰蛋白酶(作用于蛋白质水解)和脂肪酶(作用于脂质水解)。胰腺炎源自多种病因,例如代谢紊乱、药物和腹部损伤,以及由于可归因于酒精滥用、胆结石等的胰液缺陷性流动所致的酶诱导的胰腺自身降解。胰腺炎是胰腺的炎症性疾病,其诱导胰管细胞的损伤、广泛性间质水肿以及嗜中性粒细胞迁移至出血和损伤位点。胰腺炎可大体分为两种类型:轻型胰腺炎,其中检测到间质水肿和胰周脂肪坏死,以及重型胰腺炎,其中检测到广泛性胰周和胰内脂肪坏死以及胰腺实质坏死,伴随出血(Bank PA.,Am.J.gastroenterol.,89,第151-152页,1994.;BradleyEL.,Arch.Surg.,128,第586-590页,1993.;Kim Chang Duk,Korean Journal ofGastroenterology,46,第321-332页,2005)。
另外,如本文所用,术语“自身免疫疾病”是指针对受试者自身组织生成和特化的非恶性疾病或障碍。所有正常受试者的一个最重要的性质是,其对构成自身的抗原性物质无负面反应,但其可识别非自身抗原,对其应答并移除所述抗原。生物体对自身抗原的无反应性被称为“免疫无应答性”或“耐受性”。然而,在自身耐受性的诱导或维持出现异常时,发生对自身抗原的免疫应答,并且因此发生攻击自身组织的现象。由前述过程引起的疾病被称为“自身免疫疾病”。自身免疫疾病是炎症性疾病,其中产生针对患者自身器官组织或成分的抗体,并且通常可称为在多个组织和器官中引起慢性全身性炎症的疾病。
具体地,根据本发明的自身免疫疾病包括但不限于类风湿性关节炎(SLE)、系统性红斑狼疮、克罗恩氏病、溃疡性结肠炎、多发性硬化、葡萄膜炎、自身免疫性脑膜炎、舍格伦综合征、硬皮病、韦格纳肉芽肿病、结节病、脓毒性休克、泪腺炎、中风、动脉硬化、血管再狭窄、I型糖尿病、II型糖尿病、荨麻疹、结膜炎、干癣、系统性炎症综合征、多发性肌炎、皮肌炎、结节性多发性关节炎、混合性结缔组织病、痛风、帕金森病、肌萎缩侧索硬化、糖尿病视网膜病变、慢性甲状腺炎、乳糜泻、重症肌无力、膀胱天疱疮、病毒性疾病、细菌性疾病、动脉硬化、血管瘤、血管纤维瘤、再灌注损伤、心脏肥大等。
如本文所用,术语“过敏症”可与“特应性障碍”互换使用,并且可指由生物化学现象引起的疾病,所述生物化学现象显示对外来物质(即,过敏原)的特异性和经修饰的应答。
在本发明中,过敏症可包括特应性皮炎、接触性皮炎、湿疹、哮喘、超敏反应、过敏性鼻炎、过敏性结膜炎、过敏性皮炎、荨麻疹、昆虫过敏、食物过敏、药物过敏等,但不限于此。
在本发明中,术语“诊断”意图包括确定受试者对特定疾病或障碍的易感性,确定受试者目前是否患有特定疾病或障碍,确定患有特定疾病或障碍的受试者的预后(例如,鉴别转移前或转移癌性条件,确定癌症阶段或确定癌症对治疗的应答),或治疗测定(例如,监测受试者状态以提供关于治疗效果的信息)。关于本发明的目标,诊断是要确定疾病的发作或发作可能性(风险)。
本发明诊断组合物可优选地含有用于测量白介素10受体(IL-1OR)或编码白介素10受体的基因的mRNA的表达水平的试剂。
如本文所用,术语“白介素10受体(IL-10R)”是指II型细胞因子受体,其对应于由两个α(阿耳法)亚单元和两个β(贝塔)亚单元组成的四聚体。α亚单元在造血细胞(例如T细胞、B细胞、NK细胞、肥大细胞和树突细胞)中表达,并且β亚单元以多种方式表达。在本发明中,白介素10受体优选为由SEQ ID NO:1表示的白介素10受体的β亚单元(IL-10RB)。
另外,本发明诊断组合物进一步含有用于测量白介素22受体(IL-22R)或编码白介素22受体的基因的mRNA的表达水平的试剂,由此提高疾病诊断的准确度。
如本文所用,术语“白介素22受体(IL-22R)”是指II型细胞因子受体,其对应于α1亚单元和β2亚单元的异二聚体并结合至白介素22。在本发明中,白介素22受体可为由SEQID NO:2表示的白介素22受体α1亚单元(IL-22RA1)。
另外,本发明诊断组合物进一步含有用于测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平的试剂:白介素22(IL-22)、白介素29(IL-29)和干扰素λ受体1同种型1(IFNLR1同种型1),由此提高疾病诊断的准确度。
如本文所用,术语“白介素22(IL-22)”是指属于称为“IL-10家族”或“IL-10超家族”(IL-19、IL-20、IL-24和IL-26)的细胞因子组的细胞因子,其介导细胞免疫应答。白介素22结合至由IL-10R2和IL-22R1的亚单元组成的异二聚细胞表面受体。在本发明中,白介素22可由SEQ ID NO:3的氨基酸序列表示。
如本文所用,术语“白介素29(IL-29)”,其还被称为“干扰素λ-1”,是指由位于染色体19上的白介素29基因编码的蛋白质,属于螺旋细胞因子家族,并且对应于III型干扰素。白介素29在抵抗微生物的宿主防御中具有关键作用,并且其表达水平在病毒感染的细胞中显著增加。在本发明中,白介素29可由SEQ ID NO:4的氨基酸序列表示。
如本文所用,术语“干扰素λ受体1(IFNLR1)”是指由属于II型细胞因子受体家族的基因编码的蛋白质,并且结合至白介素10受体β亚单元以形成受体复合物。受体复合物可与白介素28A、白介素28B和白介素29相互作用。在本发明中,干扰素λ受体1可为干扰素λ受体1同种型1(IFNLR1同种型1),由SEQ ID NO:5的氨基酸序列表示。
在本发明中,白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的蛋白质或编码所述蛋白质的基因的mRNA可存在于活检样本中,所述样本优选地为从目标受试者分离的血液、血清或血浆,并且更优选地为从所述血液、血清或血浆分离的单核细胞或外排体。
在测量用于诊断各种疾病、特别是胰腺疾病的生物标志物的表达水平的常规方法中,从胰腺组织分离细胞,并测量所述细胞中生物标志物的表达水平。所述方法的缺点在于与为了诊断胰腺疾病优选地胰腺癌而从胰腺组织分离细胞相关的不便,以及由于在胰腺癌的初始阶段不存在可观察的症状,几乎不可能早期诊断胰腺癌。
然而,本发明使得可能快速并简单地,而且非常准确地诊断包括胰腺癌在内的多种疾病的发作和其发作可能性,其是通过测量白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1或其基因的mRNA在从目标受试者分离的血液、血清或血浆中所含单核细胞或外排体中的表达水平来实现。
具体地,当在如上所述从目标受试者分离的单核细胞或外排体中测量根据本发明的标志物的表达水平时,可快速并简单地诊断疾病的发作或其发作可能性,因为不需要侵入性程序,例如包括对患者进行剖腹术和从组织(例如,胰腺组织)分离组织细胞,并且耗时约5分钟或更短来获得包括单核细胞或外排体的活检样本以及约2小时或更短来测量来自所述单核细胞或外排体的根据本发明的各种疾病生物标志物的表达水平。
在本发明中,用于测量白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的表达水平的试剂并无特别限制,但优选地包括选自以下的至少一种:特异性结合至白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的相应蛋白质的抗体、寡肽、配体、PNA(肽核酸)和适体。
如本文所用,术语“蛋白质的表达水平的测量”是指本发明的检测生物样品中白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的蛋白质(其是用于诊断胰腺疾病的标志物)的存在以及其表达水平,以诊断包括胰腺癌在内的疾病的过程。用于测量受体的表达水平或其竞争性分析的方法包括但不限于蛋白质芯片分析、免疫测定、配体结合测定、MALDI-TOF(基质辅助激光解吸/电离飞行时间质谱)分析、SELDI-TOF(表面增强的激光解吸/电离飞行时间质谱)分析、放射免疫测定、放射免疫扩散、奥氏(ouchterlony)免疫扩散、火箭免疫电泳、组织免疫染色、补体结合分析、2D电泳分析、液相色谱-质谱(LC-MS)、液相色谱-质谱/质谱(LC-MS/MS)、蛋白质印迹法、酶联免疫吸附测定(ELISA)等。
如本文所用,术语“抗体”是指特异性结合至抗原以诱导抗原-抗体反应的物质。关于本发明的目标,抗体意指特异性结合至白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的抗体。本发明抗体同时包括多克隆抗体、单克隆抗体和重组抗体。抗体可使用本领域中熟知的技术容易地产生。例如,多克隆抗体可通过本领域熟知的方法来制备,包括将白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的抗原注射至动物中并从所述动物收集血液以获得含有抗体的血清。多克隆抗体可从任何动物产生,例如山羊、兔子、绵羊、猴子、马、猪、牛和狗。另外,单克隆抗体可使用本领域熟知的杂交瘤方法(参见Kohler和Milstein(1976)European Journal of Immunology 6:511-519)或噬菌体抗体文库技术(参见Clackson等人,Nature,352:624-628,1991;Marks等人,J.Mol.Biol.,222:58,1-597,1991)来产生。通过所述方法制备的抗体可通过例如以下的方法来分离并纯化:凝胶电泳、透析、盐沉淀、离子交换色谱或亲和色谱。另外,本发明抗体不仅包括具有两个全长轻链和两个全长重链的完整抗体,还包括抗体分子的功能片段。抗体分子的功能片段意指具有至少抗原结合功能的片段,并且包括Fab、F(ab')、F(ab')2、Fv等。
如本文所用,术语“PNA(肽核酸)”是指人工合成的DNA样或RNA样聚合物,其是由哥本哈根大学(丹麦)的教授Nielsen、Egholm、Berg和Buchardt于1991年首次介绍。DNA具有磷酸-核糖主链,但PNA具有通过肽键连接的重复的N-(2-氨基乙基)-甘氨酸主链,并且由此提供显著增强的对DNA或RNA的结合能力以及稳定性,并且由此用于分子生物学、诊断测定和反义疗法中。PNA详细披露于文献中[Nielsen PE,Egholm M,Berg RH,Buchardt O(1991年12月).“Sequence-selective recognition of DNA by strand displacement with athymine-substituted polyamide”.Science 254(5037):1497-1500]。
如本文所用,术语“适体”是指寡核苷酸或肽分子,并且适体的一般内容详细披露于文献中[Bock LC等人,Nature 355(6360):5646(1992);Hoppe-Seyler F,Butz K“Peptide aptamers:powerful new tools for molecular medicine”.J Mol Med.78(8):42630(2000);Cohen BA,Colas P,Brent R.“An artificial cell-cycle inhibitorisolated from a combinatorial library”.Proc.Natl.Acad.Sci.USA.95(24):14272-7(1998)]。
在根据本发明的诊断组合物中,用于测量编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中每一者的基因的mRNA的表达水平的试剂可包括选自以下的至少一种:特异性结合至编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中每一者的基因的mRNA的引物、探针和反义核苷酸。由于根据本发明的白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1的信息是已知的,本领域技术人员可基于所述信息容易地设计特异性结合至编码所述蛋白质的基因的mRNA的引物、探针或反义核苷酸。
如本文所用,术语“mRNA的表达水平的测量”是指本发明的检测生物样品中编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的基因的mRNA的存在和其表达水平,以诊断包括胰腺癌在内的疾病的过程,并且意指对mRNA的量的测量。用于测量mRNA的表达水平的分析方法包括但不限于逆转录聚合酶链式反应(RT-PCR)、竞争性逆转录聚合酶链式反应(竞争性RT-PCR)、实时RT-PCR、RNA酶保护测定(RPA)、RNA印迹法、DNA芯片等。
如本文所用,术语“引物”是指识别靶基因序列的片段,并且包括正向和反向的引物对,但优选地是提供特异性且灵敏的分析结果的引物对。可赋予其中其核酸是与存于样品中的非靶序列不一致的序列的引物高特异性,使得仅扩增含有互补引物结合位点的靶基因序列,并且不诱导非特异性扩增。
如本文所用,术语“探针”是指能特异性结合至要在样品中检测的靶物质的物质,并且是指能通过所述结合而特异性检测样品中靶物质的存在的物质。探针的类型并无特别限制,只要其在本领域中常用即可,并且优选地为PNA(肽核酸)、LNA(锁核酸)、肽、多肽、蛋白质、RNA或DNA,并且最优选地为PNA。更具体地,探针是源自生物体的生物分子或其类似物,或是在体外产生,并且包括例如酶、蛋白质、抗体、微生物、动物和/或植物细胞和器官、DNA和RNA,DNA可包括cDNA、基因组DNA和寡核苷酸,RNA可包括基因组RNA、mRNA和寡核苷酸,并且蛋白质的例子可包括抗体、抗原、酶、肽等。
如本文所用,术语“LNA(锁核酸)”意指包括2'-O、4'-C亚甲基桥的核酸类似物[JWeiler,J Hunziker和J Hall Gene Therapy(2006)13,496.502]。LNA核苷包括DNA和RNA的常见核苷酸碱,并且可根据Watson-Crick碱基配对规则形成碱基对。然而,由于可归因于亚甲基桥的分子“锁定”,LNA未能在Watson-Crick键中形成理想形状。在将LNA并入DNA或RNA寡核苷酸中时,其可更快地与互补核苷酸链配对,以增强双链的稳定性。如本文所用,术语“反义”意指具有核苷酸碱基序列和亚单元之间的主链的寡聚物,其中反义寡聚物依照Watson-Crick碱基配对与RNA中的靶序列杂交,以容许形成靶序列中的mRNA和RNA:寡聚物异二聚体。寡聚物可具有与靶序列互补的准确或近似序列。
根据本发明的另一方面,提供诊断疾病的试剂盒,其含有根据本发明的诊断组合物。
适用于使用本发明的诊断试剂盒预测其发作或发作可能性的疾病的例子包括但不限于胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病、干癣等。
特定地,本发明使得可能使用诊断试剂盒来诊断作为胰腺疾病的胰腺癌或胰腺炎,优选地胰腺癌。具体地,本发明试剂盒能检测或诊断与正常组不同的胰腺癌患者组。另外,本发明试剂盒能选择性检测或诊断与其他类型的癌症(例如肺癌或结直肠癌)不同的胰腺癌。
在本发明中,试剂盒可为RT-PCR试剂盒、DNA芯片试剂盒、ELISA试剂盒、蛋白质芯片试剂盒、快速试剂盒或多反应监测(MRM)试剂盒,但不限于此。
本发明用于诊断疾病的试剂盒可进一步包括适于分析方法的一种或多种类型的其他组分组合物、溶液或装置。
例如,诊断试剂盒可进一步包括进行逆转录聚合酶链式反应所需的必要元件。RT-PCR试剂盒包括对编码标志物蛋白质的基因具有特异性的引物对。引物是具有对基因的核酸序列具有特异性的序列的核苷酸,并且可具有约7bp至50bp、更优选地约10bp至30bp的长度。引物还可包括对控制基因的核酸序列具有特异性的引物。另外,RT-PCR试剂盒可包括试管或其他适当容器、反应缓冲液(具有不同pH和镁浓度)、脱氧核苷酸(dNTP)、酶(例如Taq聚合酶和逆转录酶)、DNA酶和/或RNA酶抑制剂、DEPC水、无菌水等。
另外,本发明的诊断试剂盒可包括操作DNA芯片所需的必要元件。DNA芯片试剂盒可包括对应于基因或其片段的cDNA或寡核苷酸所附接的基底,以及用于产生荧光标记探针的试剂、药剂、酶等。基底还可包括对应于控制基因或其片段的cDNA或寡核苷酸。
另外,本发明的诊断试剂盒可包括进行ELISA所需的必要元件。ELISA试剂盒包括对蛋白质具有特异性的抗体。所述抗体具有对标志物蛋白质的高特异性和亲和性,并且对其他蛋白质几乎没有交叉反应性,并且是单克隆抗体、多克隆抗体或重组抗体。ELISA试剂盒还可包括对对照蛋白具有特异性的抗体。此外,ELISA试剂盒可包括能检测所结合抗体(例如经标记二次抗体)的试剂、生色团、酶(例如,缀合至抗体)和其底物,可结合至抗体或诸如此类的另一物质。
根据本发明的另一方面,提供用于诊断疾病的信息的方法,其包括在从目标受试者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)。
可适用于在根据本发明的提供信息的方法中预测其发作或发作可能性的疾病的例子包括但不限于胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病、干癣等。
特定地,本发明使得可能更准确诊断和预测前述疾病(特定地胰腺疾病,具体地,胰腺癌或胰腺炎,更优选地胰腺癌)的发作或发作可能性。
具体地,根据本发明的提供信息的方法能检测或诊断与正常组不同的胰腺癌患者组,并且能选择性检测或诊断与其他类型的癌症(例如肺癌或结直肠癌)不同的胰腺癌。
在本发明中,自身免疫疾病和过敏症的具体类型与本发明诊断组合物中所述的那些类型重叠,并且下文将省略其说明。
如本文所用,术语“目标受试者”是指受试者,对于所述受试者不确定是否发展上述疾病,并且其非常可能发展所述疾病。
如本文所用,术语“活检样本”是指用于组织病理检查应用的组织,其是通过将中空针等插入生物体的器官中,而不是切割具有发展疾病的高可能性的患者的皮肤来收集,并且活检样本可包括患者的组织、细胞、血液、血清、血浆、唾液或痰,优选地患者的血液、血清或血浆,并且更优选地从血液、血清或血浆分离的单核细胞或外排体。
在测量用于胰腺疾病诊断的生物标志物的表达水平的常规方法中,从其中预测将发展疾病的组织(例如,胰腺组织)分离细胞,并且测量所述细胞中生物标志物的表达水平。然而,本发明使得可能快速并简单地,而且非常准确地诊断包括胰腺癌在内的多种疾病的发作和其发作可能性,其是通过测量根据本发明的疾病生物标志物在从目标受试者分离的血液、血清或血浆中所含单核细胞或外排体中的表达水平来实现。
具体地,当在如上所述从目标受试者分离的单核细胞或外排体中测量根据本发明的标志物的表达水平时,可非常快速并简单地诊断疾病的发作或其发作可能性,因为不需要侵入性程序,例如包括对患者进行剖腹术和从组织(例如,胰腺组织)分离组织细胞,并且耗时约5分钟或更短来获得包括单核细胞的活检样本以及约2小时或更短来测量来自所述单核细胞的根据本发明的生物标志物的表达水平。
根据本发明的提供信息的方法优选地能从经分离活检样本测量作为生物标志物的白介素10受体或编码白介素10受体的基因的mRNA的表达水平。
另外,根据本发明的提供信息的方法进一步包括从活检样本测量作为根据本发明用于诊断疾病(包括胰腺癌)的另一生物标志物的白介素22受体或编码白介素22受体的基因的mRNA的表达水平,由此提高疾病诊断的准确度。
另外,根据本发明的提供信息的方法进一步包括从活检样本测量作为根据本发明用于诊断疾病(包括胰腺癌)的另一生物标志物的选自白介素22、白介素29和干扰素λ受体1同种型1的至少一种蛋白质或编码所述蛋白质的基因的mRNA的表达水平,由此提高疾病诊断的准确度。
用于测量白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的表达水平的试剂并无特别限制,但优选地包括选自以下的至少一种:特异性结合至白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中的每一者的抗体、寡肽、配体、PNA(肽核酸)和适体。
优选地,在本发明中,可使用特异性结合至白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的抗体测量并比较白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的表达水平。这可使用检测抗原-抗体复合物的方法来实施,所述复合物是由抗体与生物样品中的相应蛋白质形成。如本文所用,术语“抗原-抗体复合物”是指用于检测生物样品中相应基因的存在或不存在的蛋白质抗原与识别所述蛋白质抗原的抗体的组合。对抗原-抗体复合物的检测可使用本领域熟知的任何方法来实施,例如,光谱、光化学、生物化学、免疫化学、电学、吸收光谱测定、化学和其他方法。
同时,在本发明中,测量蛋白质的表达水平或其竞争性分析的方法包括但不限于蛋白质芯片分析、免疫测定、配体结合测定、MALDI-TOF(基质辅助激光解吸/电离飞行时间质谱)分析、放射免疫测定、放射免疫扩散、SELDI-TOF(表面增强的激光解吸/电离飞行时间质谱)分析、放射免疫测定、放射免疫扩散、奥氏免疫扩散、火箭免疫电泳、组织免疫染色、补体结合分析、2D电泳分析、液相色谱-质谱(LC-MS)、液相色谱-质谱/质谱(LC-MS/MS)、蛋白质印迹法、酶联免疫吸附测定(ELISA)等。
另外,在本发明中,用于测量编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中的每一者的基因的mRNA的表达水平的试剂可包括选自以下的至少一种:特异性结合至编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中的每一者的蛋白质的基因的mRNA的引物、探针和反义核苷酸。由于根据本发明的白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1的信息是已知的,本领域技术人员可基于所述信息容易地设计特异性结合至编码所述蛋白质的基因的mRNA的引物、探针或反义核苷酸。
在本发明中,编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的基因的mRNA的表达水平的测量和比较可使用包括但不限于以下各项的方法来实施:逆转录聚合酶链式反应(RT-PCR)、竞争性逆转录聚合酶链式反应(竞争性RT-PCR)、实时RT-PCR、RNA酶保护测定(RPA)、RNA印迹法、DNA芯片等。正常对照组中mRNA的表达水平和需要关于疾病发作的诊断的受试者的mRNA的表达水平可通过这些测量方法来确定,并且例如胰腺癌的疾病的发作可能性可通过这些表达水平之间的比较来诊断或预测。
在从目标受试者分离的活检样本中测量的白介素10受体或编码白介素10受体的基因的mRNA的表达水平高于正常对照组时,确定疾病(特定地胰腺疾病)的发作可能性高。更优选地,在从目标受试者分离的活检样本中测量的表达水平为正常对照组中表达水平的至少2倍、至少3倍、至少4倍、至少5倍、至少6倍、至少7倍、至少8倍或至少9倍时,确定胰腺疾病的发作可能性高。
在本发明中,在从目标受试者分离的活检样本中测量的白介素10受体的表达水平(例如,表达白介素10受体的细胞数的比率)为正常对照组的3至20倍、4至18倍、5至13倍、7至11倍或8至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。优选地,在从目标受试者分离的活检样本中测量的白介素10受体的表达水平大于正常对照组中表达水平的8至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的编码白介素10受体的基因的mRNA的表达水平为正常对照组的表达水平的2至20倍、2至15倍、2.5至15倍、2至10倍或2.5至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。优选地,在从目标受试者分离的活检样本中测量的编码白介素10受体的基因的mRNA的表达水平大于正常对照组中表达水平的2.5至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的白介素22受体或编码白介素22受体的基因的mRNA的表达水平高于正常对照组的表达水平时,确定疾病(特定地胰腺疾病)的发作可能性高。更优选地,在从目标受试者分离的活检样本中测量的表达水平为正常对照组中表达水平的至少1.5倍、至少2倍、至少3倍、至少4倍、至少5倍或至少6倍时,确定胰腺疾病的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的白介素22受体的表达水平(例如,表达白介素22受体的细胞数的比率)为正常对照组的2至10倍、3至9倍、4至8倍、5至7倍或6至7倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。另外,在本发明中,在从目标受试者分离的活检样本中测量的编码白介素22受体的基因的mRNA的表达水平大于正常对照组中表达水平的1.5至10倍、1.5至9倍、1.5至8倍或2至7倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
在本发明中,在从目标受试者分离的活检样本中测量的白介素22或编码白介素22的基因的mRNA的表达水平高于正常对照组的表达水平时,确定疾病(特定地胰腺疾病)的发作可能性高。更优选地,在从目标受试者分离的活检样本中测量的表达水平为正常对照组中表达水平的至少2倍、至少3倍、至少4倍、至少5倍或至少6倍时,确定胰腺疾病的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的白介素22的表达水平(例如,表达白介素22的细胞数的比率)为正常对照组的3至16倍、4至15倍、4至13倍、5至10倍、5至8倍、5至7倍或6至7倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的编码白介素22的基因的mRNA的表达水平为正常对照组的2至15倍、2.5至15倍、3至13倍、3.5至13倍、4至13倍或4至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
在本发明中,在从目标受试者分离的活检样本中测量的白介素29或编码白介素29的基因的mRNA的表达水平高于正常对照组时,确定疾病(特定地胰腺疾病)的发作可能性高。更优选地,在从目标受试者分离的活检样本中测量的表达水平为正常对照组中表达水平的至少2倍、至少3倍、至少4倍、至少5倍或至少6倍时,确定胰腺疾病的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的白介素29的表达水平(例如,表达白介素29的细胞数的比率)为正常对照组的3至16倍、4至15倍、4至13倍、5至10倍、5至8倍、5至7倍或6至7倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的编码白介素29的基因的mRNA的表达水平为正常对照组的2至15倍、2.5至15倍、3至13倍、3.5至13倍、4至13倍或4至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
在本发明中,在从目标受试者分离的活检样本中测量的干扰素λ受体1同种型1或编码干扰素λ受体1同种型1的基因的mRNA的表达水平高于正常对照组的表达水平时,确定疾病(特定地胰腺疾病)的发作可能性高。更优选地,在从目标受试者分离的活检样本中测量的表达水平为正常对照组中表达水平的至少1.5倍、至少2倍、至少3倍、至少4倍、至少5倍或至少6倍时,确定胰腺疾病的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的干扰素λ受体1同种型1的表达水平(例如,表达干扰素λ受体1同种型1的细胞数的比率)为正常对照组的3至16倍、4至15倍、4至13倍、5至10倍、5至8倍、5至7倍或6至7倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
另外,在本发明中,在从目标受试者分离的活检样本中测量的编码干扰素λ受体1同种型1的基因的mRNA的表达水平为正常对照组的1.5至15倍、2至15倍、2.5至15倍、3至13倍、3.5至13倍、4至13倍或4至10倍时,确定胰腺疾病(特定地胰腺癌)的发作可能性高。
在本发明中,如上所述,胰腺癌的发作可能性可通过测量以下各项的表达水平以高准确度来诊断:白介素10受体的标志物,优选地白介素10受体和白介素22受体的标志物,更优选地,除了白介素10受体和白介素22受体以外,还有白介素22、白介素29和干扰素λ受体1同种型1的至少一种标志物。
此外,所述方法可进一步包括在通过在从目标患者分离的活检样本中测量至少一种选自白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1的蛋白质或编码所述蛋白质的基因的mRNA的表达水平预测或诊断疾病(特定地胰腺疾病,优选地胰腺癌)的发作可能性高时,使目标受试者经历适当治疗,例如给予用于疾病的药物(例如用于胰腺癌的抗癌药)、放射疗法或免疫疗法。
根据本发明的另一方面,提供筛选疾病的治疗药物的方法,其包括:
(a)在从患有所述疾病的患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1;
(b)向所述患者给予候选药物;以及
(c)在给予所述候选药物后,在从所述患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1。
可适用于在根据本发明的筛选药物的方法中预测药物的效用或易感性的疾病的例子包括但不限于胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、自身免疫性淋巴增生综合征(ALPS)、重症肌无力、川崎病、干癣等。
特定地,本发明使得可能更准确地预测用于前述疾病(特定地,胰腺疾病,具体地,胰腺癌或胰腺炎,更优选地,胰腺癌)的治疗药物的效用或易感性。
在本发明中,自身免疫疾病和过敏症的具体类型与本发明诊断组合物中所述的那些类型重叠,并且下文将省略其说明。
如本文所用,术语“活检样本”是指用于组织病理检查应用的组织,其是通过将中空针等插入生物体的器官中,而不是切割具有发展疾病的高可能性的患者的皮肤来收集,并且活检样本可包括患者的组织、细胞、血液、血清、血浆、唾液或痰,优选地患者的血液、血清或血浆,并且更优选地从血液、血清或血浆分离的单核细胞或外排体。
根据本发明的筛选药物的方法优选地能从在步骤(a)和(c)中患者分离的活检样本中测量作为生物标志物的白介素10受体或编码白介素10受体的基因的mRNA的表达水平。
另外,根据本发明的筛选药物的方法进一步包括除了白介素10受体或编码白介素10受体的基因的mRNA的表达水平以外,从在步骤(a)和(c)中从患者分离的活检样本中测量白介素22受体或编码白介素22的基因的mRNA受体的表达水平,由此进一步提高预测治疗药物的易感性的准确度。
另外,根据本发明的筛选药物的方法进一步包括除了白介素10受体、白介素22受体或编码这些受体的基因的mRNA的表达水平以外,从在步骤(a)和(c)中从患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素22、白介素29和干扰素λ受体1同种型1,由此进一步提高预测治疗药物对疾病的易感性的准确度。
用于测量白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的表达水平的试剂并无特别限制,但优选地包括选自以下的至少一种:特异性结合至白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中的每一者的抗体、寡肽、配体、PNA(肽核酸)和适体。
优选地,在本发明中,可使用特异性结合至白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的抗体测量并比较白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的表达水平。这可使用检测抗原-抗体复合物的方法来实施,所述复合物是由抗体与生物样品中的相应蛋白质形成。如本文所用,术语“抗原-抗体复合物”是指用于检测生物样品中相应基因的存在或不存在的蛋白质抗原与识别所述蛋白质抗原的抗体的组合。对抗原-抗体复合物的检测可使用本领域熟知的任何方法来实施,例如,光谱、光化学、生物化学、免疫化学、电学、吸收光谱测定、化学和其他方法。
同时,在本发明中,测量蛋白质的表达水平或其竞争性分析的方法包括但不限于蛋白质芯片分析、免疫测定、配体结合测定、MALDI-TOF(基质辅助激光解吸/电离飞行时间质谱)分析、放射免疫测定、放射免疫扩散、SELDI-TOF(表面增强的激光解吸/电离飞行时间质谱)分析、放射免疫测定、放射免疫扩散、奥氏免疫扩散、火箭免疫电泳、组织免疫染色、补体结合分析、2D电泳分析、液相色谱-质谱(LC-MS)、液相色谱-质谱/质谱(LC-MS/MS)、蛋白质印迹法、酶联免疫吸附测定(ELISA)等。
另外,在本发明中,用于测量编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中的每一者的基因的mRNA的表达水平的试剂可包括选自以下的至少一种:特异性结合至编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1中的每一者的蛋白质的基因的mRNA的引物、探针和反义核苷酸。由于根据本发明的白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1的信息是已知的,本领域技术人员可基于所述信息容易地设计特异性结合至编码所述蛋白质的基因的mRNA的引物、探针或反义核苷酸。
在本发明中,编码白介素10受体、白介素22受体、白介素22、白介素29或干扰素λ受体1同种型1的基因的mRNA的表达水平的测量和比较可使用包括但不限于以下各项的方法来实施:逆转录聚合酶链式反应(RT-PCR)、竞争性逆转录聚合酶链式反应(竞争性RT-PCR)、实时RT-PCR、RNA酶保护测定(RPA)、RNA印迹法、DNA芯片等。正常对照组中mRNA的表达水平和需要关于疾病发作的诊断的受试者的mRNA的表达水平可通过这些测量方法来确定,并且例如胰腺癌的疾病的发作可能性可通过这些表达水平之间的比较来诊断或预测。
根据本发明的方法可进一步包括当在步骤(c)中测量的至少一种选自由白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1的蛋白质或编码所述蛋白质的基因的mRNA的表达水平与在步骤(a)中测量的相同生物标志物的表达水平相比有所降低时,选择候选药物作为适于治疗疾病的治疗药物。
【有利效应】
本发明使得可能通过测量白介素10受体、白介素22受体、白介素22、白介素29和/或干扰素λ受体1同种型1的蛋白质的表达水平,准确预测和诊断多种疾病,例如胰腺疾病、自身免疫疾病、过敏症、格雷夫斯病、桥本甲状腺炎、干癣、川崎病和自身免疫性淋巴增生综合征(ALPS),特定地胰腺癌。
另外,本发明使得可能通过测量来自存在于从目标受试者分离的血液、血清或血浆中的单核细胞或外排体的生物标志物的表达水平预测或诊断疾病的发作,由此与常规情形相比更快速简单,而且更准确地以非侵入性方式诊断疾病(例如胰腺癌)。
【附图说明】
现在将详细参考本发明的优选实施方案,其实施例在附图中阐明。只要有可能,在整个附图中将使用相同的附图标记来指代相同或相似的部分。
图1显示在实施例1中使用FACS分析从正常对照组、胰腺癌患者、胰腺炎患者、肺癌患者和结直肠癌患者收集的血液中,表达IL-22的单核细胞的数目相对于单核细胞的总数的比例(%)。
图2显示在实施例1中使用FACS分析从正常对照组、胰腺癌患者、胰腺炎患者、肺癌患者和结直肠癌患者收集的血液中,表达IL-22R的单核细胞的数目相对于单核细胞的总数的比例(%)。
图3显示在实施例1中使用FACS分析从正常对照组、胰腺癌患者、胰腺炎患者、肺癌患者和结直肠癌患者收集的血液中,表达IL-10R的单核细胞的数目相对于单核细胞的总数的比例(%)。
图4是显示在实施例2中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的血液中,单核细胞中IL-10RB的mRNA表达水平的比较的图表。
图5是显示在实施例2中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的血液中,单核细胞中IL-10RA的mRNA表达水平的比较的图表。
图6是显示在实施例3中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的血液中,单核细胞中IL-22的mRNA表达水平的比较的图表。
图7是显示在实施例3中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的血液中,单核细胞中IL-29的mRNA表达水平的比较的图表。
图8是显示在实施例4中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的血液中,单核细胞中IFNLR1同种型1的mRNA表达水平的比较的图表。
图9是显示在实施例4中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的血液中,单核细胞中IFNLR1同种型3的mRNA表达水平的比较的图表。
图10显示在实施例5中在手术之前和之后从胰腺癌患者收集的血液中,表达IL-22的单核细胞的数目相对于单核细胞的总数的比例(%)。
图11显示在实施例5中在手术之前和之后从胰腺癌患者收集的血液中,表达IL-22R的单核细胞的数目相对于单核细胞的总数的比例(%)。
图12显示在实施例5中在手术之前和之后从胰腺癌患者收集的血液中,表达IL-10R的单核细胞的数目相对于单核细胞的总数的比例(%)。
图13是显示在实施例6中在手术之前和手术之后3个月从胰腺癌患者收集的血液测量表达IL-10R的单核细胞的数目相对于单核细胞的总数的比例后,通过配对T测试分析的结果的图表。
图14是显示在实施例7中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的外排体中,IL-10RB的mRNA表达水平的比较的图表。
图15是显示在实施例7中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的外排体中,IL-22RA的mRNA表达水平的比较的图表。
图16是显示在实施例7中从正常对照组、胰腺癌患者、胆管癌患者和胆囊癌患者收集的外排体中,IFNLR1同种型1的mRNA表达水平的比较的图表。
【具体实施方式】
根据本发明的实施方案,本发明涉及用于诊断疾病的组合物,其含有用于测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平的试剂:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)和干扰素λ受体1同种型1(IFNLR1同种型1)。
根据本发明的另一实施方案,本发明涉及用于诊断疾病的试剂盒,其含有根据本发明的诊断组合物。
根据本发明的又一实施方案,本发明涉及提供用于诊断的信息的方法,其包括在从目标受试者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)。
根据本发明的又一实施方案,本发明涉及筛选用于疾病的治疗药物的方法,其包括(a)在从患有所述疾病的患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1,(b)向患者给予候选药物,和(c)在给予所述候选药物后,在从所述患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1。
【实施例】
在下文中,将参考以下实施例更详细地描述本发明。然而,以下实施例仅用于说明本发明,并且不应视为限制本发明的范围。
[制备实施例1]
Histopaq 1077购自Sigma-Aldrich Corporation,并且布雷非德菌素A购自BioLegend Inc。作为抗体,Alexa 647抗IL-22和PE抗小鼠IL-10R购自BioLegend Inc.,并且PerCP小鼠IL-22R购自R&D。使用含有0.5%牛血清白蛋白(BSA)的PBS(磷酸盐缓冲溶液)作为FACS缓冲液。细胞固定缓冲液和渗透化/洗涤缓冲液也购自BioLegend Inc。
[实施例1]
1.外周血单核细胞(PBMC)的分离
从3名胰腺癌患者、3名胰腺炎患者、3名正常对照组受试者、3名肺癌患者和3名结直肠癌患者收集血样并储存于室温下。由于在血液粘度高时难以分离单核细胞,通过在1XPBS中1:1稀释来制备血样。以与血液相同的体积在15ml锥形管中制备蔗聚糖(Ficoll,Histopaque 1077,Sigma)。将血样添加至蔗聚糖上,使得血样不混合。将所得血样以400g用最小加速度和减速度离心30分钟。在此过程期间,单独收集白细胞(单核细胞)层,并向其添加PBS以在400g下离心3分钟情况下实施洗涤。收集经洗涤细胞,将其再悬浮于50μl FACS缓冲液中,并且随后与PE抗小鼠IL-10R抗体和PerCP小鼠IL-22R抗体一起在冰上培养1小时。然后将细胞用FACS缓冲液洗涤两次,并且再悬浮于500μl FACS缓冲液中。
2.用布雷非德菌素A处理
计数所收集的细胞,以1×106个细胞/ml密封于含有2%青霉素和链霉素的RPMI1640培养基中,用1X布雷非德菌素A处理并培养6小时。
3.固定、渗透化和染色
收集所培养的细胞,用FACS缓冲液(0.5%BSA,于PBS中)洗涤两次,并用500μl固定缓冲液在冰上固定30分钟。然后,将细胞用FACS缓冲液洗涤两次,再悬浮于1ml渗透化缓冲液中,并随后两次离心20分钟。然后,再次收集细胞,再悬浮于50μl渗透化缓冲液中,并且随后与Alexa 647抗IL-22抗体一起在冰上培养1小时。将细胞用FACS洗涤两次,并且再悬浮于500μl FACS缓冲液中。
4.FACS分析
使用FACSCalibur(BD Biosciences,San Jose,CA)将表达IL-10R、IL-22R或IL-22的细胞相对于单核细胞总数的数目以%表述。结果显示于下表1和图1至3中。在下表1中,数据表述为平均值±SD,并且使用Kruskal-Wallis测试使用Dunn事后分析进行统计学分析。
[表1]
如表1和图1至3中所示,IL-22在胰腺炎患者和胰腺癌患者中的表达水平分别对应于相对于IL-22在正常对照组中的表达水平的约1.7倍和0.9倍,但IL-22所结合的IL-10R的表达水平在胰腺炎患者中比在正常对照组中增加至约14.8倍,并且在胰腺癌患者中比在正常对照组中增加至约9.0倍。然而,IL-10R的表达水平在肺癌患者中比在正常对照组中增加至约2.75倍,并且IL-10R的表达水平在结直肠癌患者比在正常对照组中降低至约0.78倍。
另外,发现,关于IL-22R的表达水平,胰腺炎患者与正常对照组相比增加至约18.66倍,并且胰腺癌患者与正常对照组相比增加至约6.57倍。然而,肺癌患者与正常对照组相比降低至约0.28倍,并且结直肠癌患者与正常对照组相比显著降低至约0.17倍。
另外,关于IL-22R相对于IL-22的表达水平,在胰腺炎患者中IL-22R的表达水平相对于IL-22的表达水平为约9.93倍,并且在胰腺癌中IL-22R的表达水平相对于IL-22的表达水平为约6.31倍。这表明,虽然IL-22结合至IL-22R,但IL-22R的表达水平与IL-22相比显著增加。然而,在肺癌患者中IL-22R的表达水平相对于IL-22的表达水平为约1.18倍,并且在结直肠癌患者中IL-22R的表达水平相对于IL-22的表达水平为约1.76倍。这表明,IL-22的表达水平与IL-22R的表达水平类似。
这些结果证实,在胰腺炎或胰腺癌患者中IL-10R的表达水平与正常对照组或其他疾病的患者明显不同,并且胰腺炎和胰腺癌还具有不同的表达行为。
因此,通过根据本发明的方法,可以高准确度检测并诊断胰腺炎和胰腺癌,并且在实施所述诊断的同时可区分胰腺炎与胰腺癌。
[实施例2]
从4名正常对照组受试者、4名胰腺癌患者、2名胆管癌患者和2名胆囊癌患者收集血样,并以与实施例1相同的方式从血样分离外周血单核细胞(PBMC),并且测量IL-10Rβ亚单元(IL-10RB)和IL-22Rα亚单元(IL-22RA)在PBMC中的mRNA表达水平与正常对照组相比的比率,并且结果显示于图4和5中。
如图4和5中所示,与正常对照组相比,在从胰腺癌患者分离的PBMC中,分别地,IL-10RB mRNA表达水平增加至约3倍,并且IL-22RA mRNA表达水平增加至约6倍,但在胆管癌和胆囊癌患者中,IL-10RB mRNA的表达水平增加至约1至2倍,并且在胆管癌患者中,IL-22RAmRNA的表达水平降低。
这些结果表明,与其他类型的癌症相比,在PBMC中检测的IL-10RB和IL-22RA的mRNA表达水平在胰腺癌中显著增加。
[实施例3]
从4名正常对照组受试者、4名胰腺癌患者、2名胆管癌患者和2名胆囊癌患者收集血样,并以与实施例1相同的方式从血样分离外周血单核细胞(PBMC),并测量IL-22和IL-29在PBMC中的mRNA表达水平与正常对照组相比的比率,并且结果显示于图6和7中。
如图6和7中所示,与正常对照组相比,在从胰腺癌患者分离的PBMC中,IL-22 mRNA和IL-29 mRNA的表达水平增加至约4倍或更多,但这两种标志物在胆管癌患者中的表达水平降低,并且其在胆囊癌患者中的表达水平仅增加至约2至3倍。
这些结果表明,与其他类型的癌症相比,在PBMC中检测的IL-22和IL-29的mRNA表达水平在胰腺癌中显著增加。
[实施例4]
从4名正常对照组受试者、4名胰腺癌患者、2名胆管癌患者和2名胆囊癌患者收集血样,然后以与实施例1相同的方式从血样分离外周血单核细胞(PBMC),并测量结合至IL-29的干扰素受体1同种型1(IFNLR1同种型1)和干扰素受体1同种型3(IFNLR1同种型3)在PBMC中的mRNA表达水平与正常对照组相比的比率,并且结果显示于图8和9中。
如图8和9中所示,与正常对照组相比,在从胰腺癌患者分离的PBMC中,结合至IL-29的干扰素受体1同种型1的mRNA表达水平增加至约3倍或更多,但在胆管癌和胆囊癌患者中增加至约1至2倍。
这些结果表明,与其他类型的癌症相比,在PBMC中检测的干扰素受体1同种型1的mRNA表达水平在胰腺癌中显著增加。
[实施例5]
在手术之前和之后,从经历胰腺癌切除(胰腺切开术)的胰腺癌患者收集血样,然后以与实施例1相同的方式从血样分离PBMC,并且使用FACSCalibur(BD Biosciences,SanJose,CA)将表达IL-10R、IL-22R或IL-22的细胞相对于单核细胞总数的数目以%表述。结果显示于下表2和图10至12中。
[表2]
如从表2和图10至12可见,在胰腺癌组织的总质量由于胰腺癌患者的胰腺切开术而下降时,IL-10R、IL-22和IL-22R在单核细胞中的表达水平显著下降,并且特定地,IL-10R的表达水平显著下降。
[实施例6]
在手术之前和手术之后3个月从经历胰腺癌切除(胰腺切开术)的胰腺癌患者收集血样,然后以与实施例1相同的方式从血样分离PBMC,并使用FACSCalibur(BDBiosciences,San Jose,CA)测量表达IL-10R(标志物C)的细胞相对于单核细胞的总数的数目,并且随后使用配对T测试分析。结果显示于图13中。
如图13中所示,与手术之前相比,表达IL-10R的单核细胞的比例在使用胰腺切开术从胰腺癌患者移除癌症组织后显著降低。
[实施例7]
从4名正常对照组受试者、4名胰腺癌患者、2名胆管癌患者和2名胆囊癌患者收集血样,从血样分离在血浆中循环的外排体,并测量IL-10Rβ亚单元(IL-10RB)、IL-22Rα1(IL-22RA)和干扰素受体1同种型1(IFNLR1同种型1)在外排体中的mRNA表达水平与正常对照组相比的比率,并且结果显示于图14至16中。
如从图14至16可见,在从胰腺癌患者分离的外排体中,IL-10RB mRNA、IL-22RAmRNA和干扰素受体1同种型1 mRNA的表达水平分别比正常对照组中增加至约4倍、约1.5倍和约2.5倍。然而,在从胆管癌患者分离的外排体中,IL-10RB mRNA的表达水平比正常对照组增加至约1.5倍,并且干扰素受体1同种型1 mRNA的表达水平仅比正常对照组增加至约1.5倍,特定地,IL-22RA mRNA的表达水平与正常对照组相比降低。在胆囊癌患者的情形中,在从其分离的外排体中,IL-10RB mRNA的表达水平与正常对照组相当,并且IL-22RA和干扰素受体1同种型1的mRNA表达水平与正常对照组相比至多为约1.5倍高。
结果显示,在从胰腺癌患者的血浆分离的外排体中表达的IL-10RB、IL-22RA和干扰素受体1同种型1 mRNA的表达水平与正常对照组和其他癌症患者相比显著增加。【工业实用性】
本发明涉及用于诊断例如胰腺癌的多种疾病的组合物、含有所述组合物的用于诊断的试剂盒,以及使用所述组合物提供诊断信息的方法。
【序列表自由文本】
SEQ ID NO:1(IL-10RB):mawslgswlggcllvsalgmvpppenvrmnsvnfknilqwespafakgnltftaqylsyrifqdkcmnttltecdfsslskygdhtlrvraefadehsdwvnitfcpvddtiigppgmqvevladslhmrflapkieneyetwtmknvynswtynvqywkngtdekfqitpqydfevlrnlepwttycvqvrgflpdrnkagewsepvceqtthdetvpswmvavilmasvfmvclallgcfallwcvykktkyafsprnslpqhlkeflghphhntllffsfplsdendvfdklsviaedsesgkqnpgdscslgtppgqgpqs
SEQ ID NO:2(IL-22RA):mrtlltiltvgslaahapedpsdllqhvkfqssnfeniltwdsgpegtpdtvysieyktygerdwvakkgcqritrkscnltvetgnltelyyarvtavsaggrsatkmtdrfsslqhttlkppdvtciskvrsiqmivhptptpiragdghrltledifhdlfyhlelqvnrtyqmhlggkqreyeffgltpdteflgtimicvptwakesapymcrvktlpdrtwtysfsgaflfsmgflvavlcylsyryvtkppappnslnvqrvltfqplrfiqehvlipvfdlsgpsslaqpvqysqirvsgprepagapqrhslseitylgqpdisilqpsnvpppqilsplsyapnaapevgppsyapqvtpeaqfpfyapqaiskvqpssyapqatpdswppsygvcmegsgkdsptgtlsspkhlrpkgqlqkeppagscmlgglslqevtslameesqeakslhqplgictdrtsdpnvlhsgeegtpqylkgqlpllssvqieghpmslplqppsrpcspsdqgpspwglleslvcpkdeakspapetsdleqpteldslfrglaltvqwes
SEQ ID NO:3(IL-22):maalqksvssflmgtlatscllllallvqggaaapisshcrldksnfqqpyitnrtfmlakeasladnntdvrligeklfhgvsmsercylmkqvlnftleevlfpqsdrfqpymqevvpflarlsnrlstchiegddlhiqrnvqklkdtvkklgesgeikaigeldllfmslrnaci
SEQ ID NO:4(IL-29):maaawtvvlvtlvlglavagpvptskptttgkgchigrfkslspqelasfkkardaleeslklknwscsspvfpgndlrllqvrerpvaleaelaltlkvleaaagpaledvldqplhtlhhilsqlqaciqpqptagprprgrlhhwlhrlqeapkke sagcleasvt fnlfrlltrdlkyvadgnlclrtsthpest
SEQ ID NO:5(IFNLR1同种型1):magperwgplllcllqaapgrprlappqnvtllsqnfsvyltwlpglgnpqdvtyfvayqssptrrrwreveecagtkellcsmmclkkqdlynkfkgrvrtvspsskspwveseyldylfevepappvlvltqteeilsanatyqlppcmppldlkyevafwkegagnktlfpvtphgqpvqitlqpaasehhclsartiytfsvpkyskfskptcfllevpeanwaflvlpsllilllviaaggviwktlmgnpwfqrakmpraldfsghthpvatfqpsrpesvndlflcpqkeltrgvrptprvrapatqqtrwkkdlaedeeeedeedtedgvsfqpyieppsflgqehqapghseaggvdsgrpraplvpsegssawdssdrswastvdsswdragssgylaekgpgqgpggdghqeslpppefskdsgfleelpednlsswatwgtlppepnlvpggppvslqtltfcwesspeeeeeareseiedsdagswgaestqrtedrgrtlghymar
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<120> 疾病诊断的组合物
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Claims (22)
1.一种用于诊断胰腺疾病的组合物,其包含用于测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平的试剂:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)和干扰素λ受体1同种型1(IFNLR1同种型1)。
2.根据权利要求1的组合物,其中所述组合物用于从目标受试者分离的单核细胞。
3.根据权利要求1的组合物,其中所述组合物包含用于测量所述白介素10受体或编码所述白介素10受体的基因的mRNA的表达水平的试剂。
4.根据权利要求3的组合物,其中所述组合物还包含用于测量所述白介素22受体或编码所述白介素22的基因的mRNA受体的表达水平的试剂。
5.根据权利要求3的组合物,其中所述组合物还包含用于测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平的试剂:白介素22(IL-22)、白介素29(IL-29)和干扰素λ受体1同种型1(IFNLR1同种型1)。
6.根据权利要求1的组合物,其中用于测量所述蛋白质的表达水平的所述试剂包含选自以下的至少一种:特异性结合至所述蛋白质的抗体、寡肽、配体、PNA(肽核酸)和适体。
7.根据权利要求1的组合物,其中用于测量所述mRNA的表达水平的所述试剂包含选自以下的至少一种:特异性结合至所述mRNA的引物、探针和反义核苷酸。
8.根据权利要求1的组合物,其中所述胰腺疾病是胰腺癌。
9.一种用于诊断胰腺疾病的试剂盒,其包含根据权利要求1至8中任一项的诊断组合物。
10.根据权利要求9的试剂盒,其中所述试剂盒是RT-PCR试剂盒、DNA芯片试剂盒、ELISA试剂盒、蛋白质芯片试剂盒、快速试剂盒或多反应监测(MRM)试剂盒。
11.一种提供用于诊断胰腺疾病的信息的方法,其包括在从目标受试者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体(IL-10R)、白介素22受体(IL-22R)、白介素22(IL-22)、白介素29(IL-29)或干扰素λ受体1同种型1(IFNLR1同种型1)。
12.根据权利要求11的方法,其中所述活检样本是选自以下的至少一种:从所述受试者分离的血液、血清和血浆。
13.根据权利要求12的方法,其中所述活检样本包含从所述受试者分离的单核细胞或外排体中的至少一种。
14.根据权利要求11的方法,其包括从所述活检样本测量所述白介素10受体或编码所述白介素10受体的基因的mRNA的表达水平。
15.根据权利要求14的方法,其还包括从所述活检样本测量所述白介素22受体或编码所述白介素22受体的基因的mRNA的表达水平。
16.根据权利要求14的方法,其还包括从所述活检样本测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素22、白介素29和干扰素λ受体1同种型1。
17.根据权利要求11的方法,其中在从所述目标受试者分离的活检样本测量的所述蛋白质或所述mRNA的表达水平高于正常对照组的表达水平时,确定所述胰腺疾病的发作可能性高。
18.根据权利要求14的方法,其中在从所述目标受试者分离的活检样本测量的所述白介素10受体或编码所述白介素10受体的基因的mRNA的表达水平是所述正常对照组的表达水平的2倍或更高时,确定所述胰腺疾病的发作可能性高。
19.根据权利要求15的方法,其中在从所述目标受试者分离的活检样本测量的所述白介素22受体或编码所述白介素22受体的基因的mRNA的表达水平高于正常对照组的表达水平时,确定所述胰腺疾病的发作可能性高。
20.根据权利要求19的方法,其中在从所述目标受试者分离的活检样本测量的所述白介素22受体或编码所述白介素22受体的基因的mRNA的表达水平是所述正常对照组的表达水平的1.5倍或更高时,确定所述胰腺疾病的发作可能性高。
21.根据权利要求11的方法,其中所述胰腺疾病是胰腺癌。
22.一种筛选用于疾病的治疗药物的方法,其包括:
(a)在从患有所述疾病的患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1;
(b)向所述患者给予候选药物;以及
(c)在给予所述候选药物后,在从所述患者分离的活检样本中测量至少一种选自以下的蛋白质或编码所述蛋白质的基因的mRNA的表达水平:白介素10受体、白介素22受体、白介素22、白介素29和干扰素λ受体1同种型1。
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EP3974541A4 (en) * | 2019-05-21 | 2023-10-11 | Acurasysbio Co., Ltd. | COMPOSITION FOR CANCER DIAGNOSIS |
US20220307035A1 (en) * | 2019-06-12 | 2022-09-29 | Acurasysbio Co., Ltd. | Composition for preventing or treating cancer |
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KR20190050951A (ko) | 2019-05-14 |
KR102098294B1 (ko) | 2020-04-07 |
EP4053557A1 (en) | 2022-09-07 |
KR101984286B1 (ko) | 2019-05-31 |
KR20180058650A (ko) | 2018-06-01 |
EP3546943A1 (en) | 2019-10-02 |
KR102054857B1 (ko) | 2019-12-12 |
US20190317098A1 (en) | 2019-10-17 |
KR20190050952A (ko) | 2019-05-14 |
EP3546943A4 (en) | 2020-09-16 |
JP2020513574A (ja) | 2020-05-14 |
KR20190050953A (ko) | 2019-05-14 |
WO2018097646A1 (ko) | 2018-05-31 |
KR101984285B1 (ko) | 2019-05-30 |
JP7145924B2 (ja) | 2022-10-03 |
KR20190050950A (ko) | 2019-05-14 |
KR102068822B1 (ko) | 2020-01-22 |
JP2021043216A (ja) | 2021-03-18 |
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