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Nanoparticle-aided glycovariant assays to bridge biomarker performance and ctDNA results.
Molecular Aspects of Medicine ( IF 10.6 ) Pub Date : 2019-11-29 , DOI: 10.1016/j.mam.2019.11.001
Kamlesh Gidwani 1 , Henna Kekki 1 , Joonas Terävä 1 , Tero Soukka 1 , Karin Sundfeldt 2 , Kim Pettersson 1
Affiliation  

Numerous immunoassay based cancer biomarkers established in the 1970 and 1980′ies are widely used in clinical routine. Initial expectations of biomarkers such as CEA, CA125, CA19-9, AFP to provide decisive help in the diagnosis of early stage, pre-symptomatic cancers have not been realized. Thus, they are primarily used for monitoring disease progression and occasionally being useful as prognostic indicators. This limitation is due to the marker also being measurable in healthy individuals and frequently at elevated concentrations in common benign conditions. Most conventional tumor markers are glycosylated and interestingly specific alterations of the glycostructure part can often be seen early in the cancerous process. Conventional double monoclonal immunoassays are however blind to such changes as they are based on peptide epitope recognition. Wide selections of carbohydrate recognizing macromolecules, lectins, but also glycan structure recognizing antibodies are potentially useful for detecting such changes. Despite numerous attempts generating proof-of-principle evidence for this, such assays have generally not been successfully introduced into clinical routine. The affinity constants of lectin and glycan specific antibodies for their corresponding carbohydrate structures may be up to several orders too low to provide the detection limits and robustness expected from routine tumor markers. In this review, we describe an approach based on the use of highly fluorescent Eu3+--chelate dyed nanoparticles onto which lectins or glycan specific antibodies are coated to provide the necessary binding strength and signal amplification to provide low detection limits, while maintaining the original glycan-structure specificity. This concept applied to three markers, PSA, CA125 and CA15-3 provide glycoform assays of greatly enhanced cancer specificity using sample volumes similar or lower than corresponding traditional ELISAs. For ovarian cancer, we show that this new approach when applied to ovarian cyst fluid samples provide results similar to the performance obtained with ctDNA determinations of a set of 17 driver mutations and greatly superior compared to corresponding conventional immunoassays. Based on our results, we predict that the nanoparticle-lectin concept will enable a new generation of simple, low-cost biomarker assays of highly improved cancer specificity. Such tools should ideally be evaluated together with determination of ctDNA to establish early detection schemes for cancers e.g. ovarian, pancreas, lung where the detection rate of early stage disease is presently unacceptably low.



中文翻译:

纳米粒子辅助糖变异分析法可桥接生物标记物性能和ctDNA结果。

在1970和1980年代建立的许多基于免疫测定的癌症生物标记物被广泛用于临床常规中。尚未实现对CEA,CA125,CA19-9,AFP等生物标志物的初步期望,它们可为早期症状性癌症的诊断提供决定性的帮助。因此,它们主要用于监测疾病的进展,偶尔可用作预后指标。该限制是由于标记物在健康个体中也是可测量的,并且在常见的良性条件下经常以升高的浓度测量。大多数常规的肿瘤标志物都是糖基化的,有趣的是,在癌变过程的早期常常可以看到糖结构部分的特异性改变。然而,常规的双重单克隆免疫测定法基于肽表位识别,因此对这种改变是盲目的。碳水化合物识别大分子,凝集素以及聚糖结构识别抗体的多种选择可能对检测此类变化有用。尽管为此进行了许多尝试来产生原理证明的尝试,但是这种测定通常没有成功地引入临床常规中。凝集素和聚糖特异性抗体对其相应的碳水化合物结构的亲和常数可能高达几个数量级,以至于无法提供常规肿瘤标记物预期的检测限和稳健性。在这篇综述中,我们描述了一种基于使用高荧光Eu的方法 尽管为此进行了许多尝试来产生原理证明的尝试,但是这种测定通常没有成功地引入临床常规中。凝集素和聚糖特异性抗体对其相应的碳水化合物结构的亲和常数可能高达几个数量级,以至于无法提供常规肿瘤标记物预期的检测限和稳健性。在这篇综述中,我们描述了一种基于使用高荧光Eu的方法 尽管为此进行了许多尝试来产生原理证明的尝试,但是这种测定通常没有成功地引入临床常规中。凝集素和聚糖特异性抗体对其相应的碳水化合物结构的亲和常数可能高达几个数量级,以至于无法提供常规肿瘤标记物预期的检测限和稳健性。在这篇综述中,我们描述了一种基于使用高荧光Eu的方法3 +--螯合物染色的纳米颗粒,其上包被有凝集素或聚糖特异性抗体,以提供必要的结合强度和信号放大,以提供低检测限,同时保持原始的聚糖结构特异性。该概念适用于PSA,CA125和CA15-3三种标记物,可使用与相应传统ELISA相似或更低的样品量大大提高了癌症特异性的糖型测定。对于卵巢癌,我们证明了这种新方法在应用于卵巢囊肿液样品时可提供与ctDNA测定一组17种驱动基因突变所获得的性能相似的结果,并且与相应的常规免疫分析方法相比,其优越性更高。根据我们的结果,我们预测纳米粒子凝集素概念将使新一代的简单,高度提高癌症特异性的低成本生物标志物检测方法。理想情况下,应评估此类工具并确定ctDNA,以建立针对癌症(如卵巢癌,胰腺癌,肺癌)的早期检测方案,其中早期疾病的检测率目前低得令人无法接受。

更新日期:2019-11-29
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