Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York.
J Nucl Med. 2013 Nov;54(11):1876-82. doi: 10.2967/jnumed.113.119867. Epub 2013 Sep 12.
Despite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncology is a high frequency of false-positive indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker production from benign disorders in unrelated host tissues, we hypothesized that probing the sites of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels.
In preparation to address this hypothesis clinically, we developed (89)Zr-5B1, a fully human, antibody-based radiotracer targeting tumor-associated CA19.9 in the preclinical setting.
(89)Zr-5B1 localized to multiple tumor models representing diseases with undetectable and supraphysiologic serum CA19.9 levels. Among these, (89)Zr-5B1 detected orthotopic models of pancreatic ductal adenocarcinoma, an elusive cancer for which the serum assay is measured in humans but with limited specificity in part because of the frequency of CA19.9 secretion from benign hepatic pathologies.
In this report, a general strategy to supplement some of the shortcomings of otherwise highly useful circulating biomarkers with immunoPET is described. To expedite the clinical validation of this model, a human monoclonal antibody to CA19.9 (a highly visible but partially flawed serum biomarker for several cancers) was radiolabeled and evaluated, and the compelling preclinical evidence suggests that the radiotracer may enhance the fidelity of diagnosis and staging of pancreatic ductal adenocarcinoma, a notoriously occult cancer.
尽管有许多优势，但许多循环生物标志物存在着有据可查的局限性。在肿瘤学中，一个突出的缺点是在初步诊断中恶性疾病的假阳性指示的频率很高。由于假阳性的一个常见原因是来自无关宿主组织的良性疾病的生物标志物产生，我们假设用成像工具探测生物标志物分泌的部位可能是一种广泛有用的策略，可以分解令人担忧但不确定的循环生物标志物水平的含义。
为了在临床上解决这个假设，我们在临床前环境中开发了（89）Zr-5B1，一种针对肿瘤相关 CA19.9 的完全人源、基于抗体的放射性示踪剂。
（89）Zr-5B1 定位于多个肿瘤模型，这些模型代表了血清 CA19.9 水平无法检测和超生理的疾病。在这些模型中，（89）Zr-5B1 检测到胰腺导管腺癌的原位模型，这是一种难以捉摸的癌症，在人类中测量血清检测，但由于良性肝病理中 CA19.9 分泌的频率，特异性有限。
在本报告中，描述了一种用免疫 PET 补充一些 otherwise 非常有用的循环生物标志物的缺点的一般策略。为了加快该模型的临床验证，对 CA19.9 的人源单克隆抗体（几种癌症的高度可见但部分有缺陷的血清生物标志物）进行了放射性标记和评估，令人信服的临床前证据表明，该示踪剂可能增强对胰腺导管腺癌的诊断和分期的准确性，这是一种众所周知的隐匿性癌症。
