Antibody vectors for imaging.
Antibody vectors for imaging.
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DOI：
10.1053/j.semnuclmed.2009.12.005
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发表时间：
2010-05
影响因子：
4.9
通讯作者：
Wu AM
中科院分区：
文献类型：
--
作者：
Olafsen T;Wu AM
非侵入性分子成像方法包括核成像、光学成像、MRI成像、CT成像、超声成像和光声成像，这些方法需要在目标部位积累探针传递的信号。单克隆抗体（mAb）是可用于向细胞表面分子特异性、高信号递送的高亲和力分子。然而，它们在血液中的长循环时间使它们不适合作为成像探针。已经通过蛋白质工程进行了在不损害亲和力和特异性的情况下改善抗体药代动力学的努力。已经产生了抗原结合位点和大小不同的抗体变体，并将其作为目标组织的成像探针进行评价。具有一个抗原结合位点（单价）的快速清除片段（如单链Fv（scFv; 25 kDa））在肿瘤中的蓄积较低，这是由于对靶标的暴露时间较短。使用scFv作为结构单元以产生更大的二价片段，例如scFv二聚体（双抗体，50 kDa）和scFv融合蛋白（80 kDa微抗体和105 kDa scFv-Fc），由于它们在血液中的停留时间更长，导致更高的肿瘤积累。放射性标记后这些碎片的成像研究已经证明了在伽马相机和PET扫描仪中的出色的高对比度图像。几项研究还研究了与荧光（近红外染料）、生物发光（荧光素酶）和用于光学成像的量子点以及用于MRI的氧化铁纳米颗粒缀合的抗体片段。然而，这些研究表明，有几个因素影响成功的靶向和成像。这些因素包括抗体片段的稳定性、标记化学（直接或间接）、关键残基是否被修饰、细胞上表达的抗原数量以及靶标是否具有快速再循环速率或在结合后内化。临床前数据是令人信服的，很明显，基于抗体的分子成像示踪剂将在癌症和其他疾病的诊断和管理中发挥重要的未来作用。
Non-invasive molecular imaging approaches include nuclear, optical, MRI, CT, ultrasound and photoacoustic imaging, which require accumulation of a signal delivered by a probe at the target site. Monoclonal antibodies (mAbs) are high affinity molecules that can be used for specific, high signal delivery to cell surface molecules. However, their long circulation time in blood makes them unsuitable as imaging probes. Efforts to improve antibodies pharmacokinetics without compromising affinity and specificity have been made through protein engineering. Antibody variants that differ in antigen binding sites and size have been generated and evaluated as imaging probes to target tissues of interest. Fast clearing fragments such as single-chain Fv (scFv; 25 kDa) with one antigen binding site (monovalent) demonstrated low accumulation in tumors due the low exposure time to the target. Using scFv as building block to produce larger, bivalent fragments such as scFv dimers (diabodies, 50 kDa) and scFv-fusion proteins (80 kDa minibodies and 105 kDa scFv-Fc) resulted in higher tumor accumulation due to their longer residence time in blood. Imaging studies with these fragments following radiolabeling have demonstrated excellent, high contrast images in gamma cameras and PET scanners. Several studies have also investigated antibody fragments conjugated to fluorescence (near infrared dyes), bioluminescence (luciferases) and quantum dots for optical imaging and iron oxides nanoparticles for MRI. However, these studies indicate that there are several factors that influence successful targeting and imaging. These include stability of the antibody fragment, the labeling chemistry (direct or indirect), whether critical residues are modified, the number of antigen expressed on the cell, and whether the target has a rapid recycling rate or internalizes upon binding. The preclinical data presented are compelling and it is evident that antibody-based molecular imaging tracers will play an important future role in the diagnosis and management of cancer and other diseases.
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