CN115372618A - 一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的诊断产品中的应用 - Google Patents
一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的诊断产品中的应用 Download PDFInfo
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Abstract
本发明公开了一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的诊断产品中的应用，涉及肿瘤治疗检测技术领域。PPIB蛋白可以用于肿瘤治疗效果的监测及预后复发。与现有的蛋白标志物相比，PPIB蛋白对患者治疗监测和预后的灵敏度和特异性较高，通过对患者PPIB蛋白的水平进行检测或监测，可以实现无创的肿瘤诊断，对于肿瘤的治疗监测和复发预后对提高治疗决策的有效性，延长患者生存时间具有非常重要的意义。
Description
技术领域
本发明涉及肿瘤治疗检测技术领域，具体而言，涉及一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的诊断产品中的应用。
背景技术
肺癌是严重危害人类健康的重大疾病。在所有恶性肿瘤中，肺癌的死亡率位居首位。大多数患者确诊时往往已经是晚期，错过了手术治疗的最佳时期。在肿瘤的内科治疗中，除了存在有靶向药物针对的靶点突变，能够进行靶向治疗；或者符合免疫治疗指征，能够进行免疫治疗之外，大多数患者只能接受化疗。此外，一、二线靶向和免疫治疗失败的患者，在后续治疗时也要进行化疗。而对肿瘤的治疗监测和复发预后对提高治疗决策的有效性、延长患者生存时间具有非常重要的意义。
血清标志物检测，是一种无创的肿瘤诊断手段，具有很高的应用前景。目前临床上广泛使用的血清标志物主要针对肿瘤早期诊断，对患者治疗监测和预后的灵敏度和特异性都不高。
鉴于此，特提出本发明。
发明内容
本发明的目的在于提供一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的诊断产品中的应用，从而有效监测肿瘤治疗中的进展和预后复发。
本发明是这样实现的：
本发明提供了一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的检测产品或诊断产品中的应用，蛋白标志物为PPIB。
亲环素B(Cyclophillin B，PPIB，又称为CypB)属于亲环素家族，为免疫抑制剂环孢素A(CsA)的细胞内受体，通过肽基脯氨酰顺反异构酶(PPIase)的活性和分子伴侣在细胞内发挥重要的作用。
发明人发现了PPIB蛋白，可作为肿瘤治疗效果评估的蛋白标志物，可以用于肿瘤治疗效果的监测及预后复发。
在本发明应用较佳的实施方式中，上述肿瘤选自恶性肿瘤。
在本发明应用较佳的实施方式中，上述肿瘤选自结直肠癌、肺癌、乳头状瘤、胃癌、子宫癌、卵巢癌、宫颈癌、腺癌、乳腺癌、腺瘤、骨髓瘤、胶质瘤或鳞癌。
在一种可选的实施方式中，腺癌包括不限于肺腺癌、甲状腺癌、涎腺癌或胰腺癌。
在一种可选的实施方式中，腺瘤包括不限于囊腺瘤、纤维腺瘤、多形性腺瘤或息肉状腺瘤。
在一种可选的实施方式中，乳腺癌包括不限于乳腺导管癌、乳腺上皮癌或乳腺小叶癌。乳腺癌，优选II期至IV期和/或不良分化的侵袭性导管癌、粉刺癌以及髓样癌(优选2级)。
卵巢癌，浆液性和粘液性癌(优选地Ic期至IIIb期)、颗粒细胞肿瘤、表面上皮-间质肿瘤(腺癌)、囊腺癌以及子宫内膜样肿瘤。
子宫癌，优选地包括子宫内膜样腺癌(优选地I期至IIIc期)。
膀胱癌，优选地包括移行细胞癌(优选地II期至IV期)。
肺癌，优选地包括小细胞肺癌(优选地I期至IIIb期)、非小细胞肺癌(优选地不良至中度分化的鳞状和腺癌)以及大细胞肺癌。
鳞癌为口腔鳞癌、咽鳞癌、喉癌、食道鳞癌(例如食管鳞癌)、唇的鳞状细胞癌、子宫鳞癌、阴道鳞癌和皮肤鳞癌中的一种或多种。
口腔鳞状上皮细胞癌(oral squamous cell carcinoma，OSCC)又称口腔鳞癌。口腔鳞癌例如包括不限于舌鳞癌。
在其他实施方式中，上述鳞癌也可以是支气管、膀胱、肾盂等部位通过鳞状上皮化生而形成的鳞状细胞癌。
在其他实施方式中，上述肿瘤包括不限于PPIB蛋白过表达诱导的疾病。
PPIB蛋白标志物，尤其是针对肺癌的治疗效果监测和预后复发评估具有较高的灵敏度和特异性。
在本发明应用较佳的实施方式中，上述肿瘤治疗为化疗、免疫治疗、外科手术、放射治疗、抗炎症治疗、靶向治疗和它们的组合。
免疫治疗例如靶向免疫检查点抗原，免疫检查点抗原优选包括PD-1、PD-L1、Tim3、LAG3、CD47，靶向治疗的靶点优选包括肿瘤细胞表面的生长因子受体(EGFR)、细胞内信号传导和抗肿瘤血管生成；靶向治疗的靶点例如选自SIRPα。
抗炎症治疗包括向对象施用环加氧酶抑制剂，任选地为环加氧酶-2特异的抑制剂。
在本发明应用较佳的实施方式中，上述产品选自试剂、试剂盒或芯片。
芯片例如选自液相芯片。本发明提供的应用，在检测时，也可采用流式细胞仪的方法进行检测。
在本发明应用较佳的实施方式中，上述产品为试剂盒时，试剂盒包括微孔板，检测蛋白标志物水平的试剂包括PPIB蛋白标准品、抗PPIB蛋白的抗体和酶标二抗。
在其他实施方式中，试剂盒的检测方法包括不限于：双抗夹心ELISA方法或其他任意的免疫杂交方法。
在本发明应用较佳的实施方式中，上述评估肿瘤治疗效果包括：若肿瘤治疗后的PPIB水平低于肿瘤治疗前的PPIB水平，则评估肿瘤治疗有效；具体的也表现为肿瘤缩小。
若肿瘤治疗后的PPIB水平高于肿瘤治疗前的PPIB水平，则评估肿瘤治疗效果差。
在本发明应用较佳的实施方式中，上述评估肿瘤治疗效果包括：若在多个肿瘤治疗周期内，存在治疗后期的PPIB水平高于肿瘤治疗前期的PPIB水平，则评估肿瘤可能产生耐药，需要调整治疗方案。
在本发明应用较佳的实施方式中，上述评估肿瘤治疗效果中，待测样本为体液或外泌体。外泌体例如是经过尺寸排阻色谱、密度梯度离心、差速离心、超滤、亲和捕获、亲和纯化、微流体分离或它们的组合处理之后的外泌体。
在本发明应用较佳的实施方式中，上述体液选自尿液、血清、血浆、外周血和脐带血。
本发明具有以下有益效果：
本发明提供了PPIB蛋白作为肿瘤治疗效果评估的蛋白标志物的新的用途，可以用于肿瘤治疗效果的监测及预后复发。与现有的蛋白标志物相比，PPIB蛋白对患者治疗监测和预后的灵敏度和特异性较高，通过对患者PPIB蛋白的水平进行检测或监测，可以实现无创的肿瘤诊断，对于肿瘤的治疗监测和复发预后对提高治疗决策的有效性，延长患者生存时间具有非常重要的意义。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为13例患者的血清CypB水平差值统计结果图；
图2为评价PD和PR的ROC曲线图；
图3为41例ELISA结果；
图4为TCGA公共数据分析统计结果图。
具体实施方式
现将详细地提供本发明实施方式的参考，其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上，对本领域技术人员而言，显而易见的是，可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如，作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中，来产生更进一步的实施方式。
除非另外指明，否则实践本发明将采用细胞生物学、分子生物学(包含重组技术)、微生物学、生物化学和免疫学的常规技术，所述常规技术在本领域技术人员的能力范围内。文献中充分解释了这种技术，如《分子克隆：实验室手册(Molecular Cloning:ALaboratory Manual)》，第二版(Sambrook等人，1989)；《寡核苷酸合成(OligonucleotideSynthesis)》(M.J.Gait编，1984)；《动物细胞培养(Animal Cell Culture)》(R.I.Freshney编，1987)；《酶学方法(Methods in Enzymology)》(学术出版社有限公司(Academic Press，Inc.)；《实验免疫学手册(Handbook of Experimental Immunology)》(D.M.Weir和C.C.Blackwell编)；《哺乳动物细胞用基因转移载体(Gene Transfer Vectors forMammalian Cells)》(J.M.Miller和M.P.Calos编，1987)；《当代分子生物学方法(CurrentProtocols in Molecular Biology)》(F.M.Ausubel等人编，1987)；《PCR:聚合酶链反应(PCR:The Polymerase Chain Reaction)》(Mullis等人编，1994)；以及《当代免疫学方法(Current Protocols in Immunology)》(J.E.Coligan等人编，1991)，所述文献中的每个文献均通过引用明确并入本文中。
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例针对13例肺癌患者进行疾病的评估。
在患者进行化疗前，或者下一周期化疗开始前收集患者外周血，分离血清。在患者本周期化疗周期结束后收集患者外周血，分离血清。
采用ELISA法检测血清CypB表达水平：
(1)按照浓度梯度稀释标准品(纯的PPIB蛋白)，按照1:10稀释待测血清，稀释8个梯度。分别是100ng/ml，40ng/ml，16ng/ml，6.4ng/ml，2.560ng/ml，1.024ng/ml，0.410ng/ml，0ng/ml。
(2)将100ul标准品和待测血清依次加入包被好一抗的ELISA微孔板(
ELH-CYPB ELISA试剂盒)。37度孵育2h。
(3)吸走标准品和血清，每孔加入300ul洗涤液，轻微震荡微孔板，再倒掉洗涤液。重复三次上述洗涤过程。
(4)每孔加入100ul稀释好的检测二抗(
ELH-CYPB ELISA试剂盒)，37度孵育2h。
(5)吸走标准品和血清，每孔加入300ul洗涤液，轻微震荡微孔板，再倒掉洗涤液。重复三次上述洗涤过程。
(6)加入稀释好的HRP(辣根过氧化物酶)标记二抗，37度孵育45min。
(7)吸走HRP。
(8)加入100ul显色液，室温显色20min。
(9)加入50ul终止液，酶标仪OD480nm波长检测读数。
(10)根据OD值绘制标准曲线，计算血清中CypB的浓度。
在用于预后治疗评估时，评估值＝CypB治疗后的水平-CypB治疗前的水平，评估值<0,即治疗后CypB水平下降，则判断预测患者治疗有效，肿瘤缩小，疾病得到缓解。若评估值>0，即治疗后CypB水平上升，则预判患者预后差，治疗方案效果差。
在用于疗效监测时：
依次记录患者首次治疗前和每次治疗周期结束时的血清CypB水平，计算每个治疗周期之间的CypB水平差值(后期减去前期)。当该评估值由负转正时，提示肿瘤开始发生分子级别的进展，可能已经开始耐药。应当及时调整治疗方案。
发明人针对13例患者的外周血血清中CypB水平的检测结果参照图1所示，结果显示有4例患者的评估值>0，判断为疾病进展，预判患者预后差，治疗方案效果差。4例患者的评估值<0，判断预测患者治疗有效，肿瘤缩小，疾病得到缓解。5例患者的病情稳定(SD)。缩写PD＝疾病进展，SD＝疾病稳定(即目前肿瘤在影像学上未增大或缩小到原体积的15％)，PR＝疾病缓解。
发明人进一步用上述CypB评估值和疾病状态的关系来评估疾病进展或者缓解的ROC曲线，如图2所示。结果显示，本发明提供的评估方法具有较高的评估准确性和灵敏度。使用缩写PD＝疾病进展，SD＝疾病稳定(即目前肿瘤在影像学上未增大或缩小到原体积的15％)，PR＝疾病缓解。
发明人针对41例非小细胞肺癌患者的外周血血清中CypB水平进行检测，治疗方式包括手术，化疗，靶向治疗。检测结果参照图3所示，患者根据CypB水平分组，发现他们的生存期长短有差异。
由于不同治疗手段对应的患者平均中位生存时间不同，因此我们担心直接将患者的生存时间进行比较可能存在偏移，因此根据该治疗手段的中位生存时间，将患者标记为生存期长(术后DFS大于1年，化疗后PFS大于6个月)和生存期短。
参照图3所示，比较两组患者的血清CypB水平，发现生存期短的患者CypB水平高与生存期长的患者。即CypB仍然能预测患者的治疗预后。
发明人进一步利用肿瘤公共测序数据库的资源，分析了患者CypB表达与化疗后生存预后之间的差异。参照图4所示，发现CypB表达高的患者生存期短，预后差。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种检测蛋白标志物水平的试剂在制备用于评估肿瘤治疗效果的检测产品或诊断产品中的应用，其特征在于，所述蛋白标志物为PPIB。
2.根据权利要求1所述的应用，其特征在于，所述肿瘤选自恶性肿瘤。
3.根据权利要求2所述的应用，其特征在于，所述肿瘤选自肺癌、结直肠癌、腺癌、乳腺癌、腺瘤、骨髓瘤、胶质瘤、乳头状瘤、胃癌、子宫癌、卵巢癌、宫颈癌或鳞癌。
4.根据权利要求3所述的应用，其特征在于，所述肺癌选自非小细胞肺癌和小细胞肺癌。
5.根据权利要求1所述的应用，其特征在于，所述肿瘤治疗为化疗、免疫治疗、外科手术、放射治疗、抗炎症治疗、靶向治疗和它们的组合。
6.根据权利要求1所述的应用，其特征在于，所述产品选自试剂、试剂盒或芯片。
7.根据权利要求1所述的应用，其特征在于，所述评估肿瘤治疗效果包括：若肿瘤治疗后的PPIB水平低于肿瘤治疗前的PPIB水平，则评估肿瘤治疗有效；
若肿瘤治疗后的PPIB水平高于肿瘤治疗前的PPIB水平，则评估肿瘤治疗效果差。
8.根据权利要求1所述的应用，其特征在于，所述评估肿瘤治疗效果包括：若在多个肿瘤治疗周期内，存在治疗后期的PPIB水平高于肿瘤治疗前期的PPIB水平，则评估肿瘤可能产生耐药，需要调整治疗方案。
9.根据权利要求1所述的应用，其特征在于，所述评估肿瘤治疗效果中，待测样本为体液或外泌体。
10.根据权利要求9所述的应用，其特征在于，所述体液选自尿液、血清、血浆、外周血和脐带血。
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