Pretargeted Immuno-PET of Pancreatic Cancer: Overcoming Circulating Antigen and Internalized Antibody to Reduce Radiation Doses.
Pretargeted Immuno-PET of Pancreatic Cancer: Overcoming Circulating Antigen and Internalized Antibody to Reduce Radiation Doses.
复制标题
DOI：
10.2967/jnumed.115.163824
复制
发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Lewis JS
中科院分区：
文献类型：
--
作者：
Houghton JL;Zeglis BM;Abdel-Atti D;Sawada R;Scholz WW;Lewis JS
5 B1是一种完全人源的单克隆抗体，已显示出用于表达碳水化合物抗原19.9（CA19.9）的癌症的PET成像的前景，CA19.9是一种在具有异常糖基化的细胞中普遍存在的碳水化合物，并且是转移的既定效应物。抗体的长生理半衰期和来自循环CA 19.9的干扰可能增加生成高质量图像所需的时间以及在重复PET成像期间对健康组织的辐射暴露风险。预靶向方法是快速获取PET图像的有效方法，但在这种情况下，预靶向方法因表达CA19.9的细胞内化5 B1而变得复杂。我们试图适应和优化的预靶向策略，利用反式环辛烯（TCO）和四嗪（Tz）之间的生物正交反应，以克服这些并发症。用TCO修饰5 B1，并合成新型NOTA-PEG 7-Tz放射性配体，目的是改进先前报道的类似物。使用荧光测定法评价BxPC 3和Capan-2细胞内化抗CA 19.9抗体的能力，并将相同细胞系的异种移植物用于体内研究。优化了预靶向方法，并在胰腺癌小鼠模型中使用生物分布和PET成像比较了2种放射性配体。BxPC 3和Capan-2细胞显示出快速内化抗CA 19.9单克隆抗体，包括5 B1。相对于使用5 B1-TCO作为靶向载体的64 Cu-NOTA-Tz，64 Cu-NOTA-PEG 7-Tz显示出改善的体内药代动力学。PET成像和生物分布研究表明，在给予5 B1-TCO后72小时注射放射性配体导致最佳摄取（注射后20小时每克注射剂量的8.2 ± 1.7%）和肿瘤与背景活性浓度比。剂量学计算显示，相对于89 Zr-去铁胺-5B1，预靶向系统产生了大于25倍的全身辐射暴露减少。PET/CT成像在原位Capan-2异种移植模型-分泌大量的CA19.9和更迅速地内化抗CA19.9抗体-表明，这种方法是可行的，即使在困难的情况下提出的循环抗原和内化的靶向载体。在这些研究中评价的5 B1-TCO和64 Cu-NOTA-PEG 7-Tz系统可以描绘胰腺癌的鼠模型中的CA19.9阳性异种移植物，尽管存在循环抗原和5 B1-TCO内化的组合所带来的挑战。
5B1 is a fully human, monoclonal antibody that has shown promise for the PET imaging of cancers expressing carbohydrate antigen 19.9 (CA19.9)—a carbohydrate prevalent in cells with aberrant glycosylation and an established effector of metastasis. The long physiologic half-life of the antibody and interference from circulating CA19.9 may increase the time required to generate quality images as well as the risk of radiation exposure to healthy tissues during repeated PET imaging. Pretargeting methodologies are an effective approach to expeditiously acquire PET images, but in this case, the pretargeting approach is complicated by the internalization of 5B1 by CA19.9-expressing cells. We sought to adapt and optimize a pretargeting strategy that exploits the bioorthogonal reaction between transcyclooctene (TCO) and tetrazine (Tz) to overcome these complications. 5B1 was modified with TCO, and a novel NOTA-PEG7-Tz radioligand was synthesized with the goal of improving on a previously reported analog. BxPC3 and Capan-2 cells were evaluated for their ability to internalize anti-CA19.9 antibodies using a fluorometric assay, and xenografts of the same lines were used for in vivo studies. The pretargeting approach was optimized, and the 2 radioligands were compared using biodistribution and PET imaging in murine models of pancreatic cancer. BxPC3 and Capan-2 cells were shown to rapidly internalize anti-CA19.9 monoclonal antibodies, including 5B1. 64Cu-NOTA-PEG7-Tz showed improved in vivo pharmacokinetics relative to 64Cu-NOTA-Tz using 5B1-TCO as the targeting vector. PET imaging and biodistribution studies showed that injecting the radioligand 72 h after the administration of 5B1-TCO resulted in the best uptake (8.2 ± 1.7 percentage injected dose per gram at 20 h after injection) and tumor-to-background activity concentration ratios. Dosimetry calculations revealed that the pretargeting system produced a greater than 25-fold reduction in total body radiation exposure relative to 89Zr-desferrioxamine-5B1. PET/CT imaging in an orthotopic Capan-2 xenograft model—which secretes large amounts of CA19.9 and more rapidly internalizes anti-CA19.9 antibodies—showed that this approach is viable even in the difficult circumstances presented by a circulating antigen and internalized targeting vector. The 5B1-TCO and 64Cu-NOTA-PEG7-Tz system evaluated in these studies can delineate CA19.9-positive xenografts in murine models of pancreatic cancer despite the challenges posed by the combination of circulating antigen and internalization of the 5B1-TCO.