Tumor Imaging using a picomolar affinity HER2 binding affibody molecule
Tumor Imaging using a picomolar affinity HER2 binding affibody molecule
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DOI：
10.1158/0008-5472.can-05-3521
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Nilsson, FY
中科院分区：
文献类型：
--
作者：
Orlova, A;Magnusson, M;Nilsson, FY
检测由于恶性肿瘤中异常基因表达而产生的细胞结合蛋白可以提供影响患者管理的重要诊断信息。如果能够提供足够的结合亲和力和特异性，使用小型放射性标记靶向蛋白将能够对表达此类抗原的癌症进行高对比度放射性核素成像。在这里，我们描述了一种具有 22 pmol/L 亲和力的 HER2 特异性 6 kDa Affibody 分子（以下称为 Affibody 分子），可用于使用伽马相机对体内肿瘤中 HER2 表达进行可视化。通过对第一代纳摩尔亲和力 (50 nmol/L) 变体进行比对后确定的相关位置进行重新随机化，构建了亲和力成熟库。一种选定的 Affibody 分子 Z(HER2:342) 通过单文库亲和力成熟步骤实现了 2,200 倍以上的亲和力增加。当放射性碘标记时，亲和力成熟的 Affibody 分子早在注射后 6 小时就在小鼠体内表达 HER2 的异种移植物中显示出清晰、高对比度的可视化。注射后 4 小时，肿瘤摄取量提高了 4 倍（由于亲和力增加），肿瘤中每克组织的注射剂量为 9%。 Affibody 分子代表了一类新型亲和分子，可以提供小尺寸、高亲和力的癌症特异性配体，可能非常适合肿瘤成像。
The detection of cell-bound proteins that are produced due to aberrant gene expression in malignant tumors can provide important diagnostic information influencing patient management. The use of small radiolabeled targeting proteins would enable high-contrast radionuclide imaging of cancers expressing such antigens if adequate binding affinity and specificity could he provided. Here, we describe a HER2-specific 6 kDa Affibody molecule (hereinafter denoted Affibody molecule) with 22 pmol/L affinity that can be used for the visualization of HER2 expression in tumors in vivo using gamma camera. A library for affinity maturation was constructed by re-randomization of relevant positions identified after the alignment of first-generation variants of nanomolar affinity (50 nmol/L). One selected Affibody molecule, Z(HER2:342) showed a > 2,200-fold increase in affinity achieved through a single-library affinity maturation step. When radioiodinated, the affinity-matured Affibody molecule showed clear, high-contrast visualization of HER2-expressing xenografts in mice as early as 6 hours post-injection. The tumor uptake at 4 hours post-injection was improved 4-fold (due to increased affinity) with 9% of the injected dose per gram of tissue in the tumor. Affibody molecules represent a new class of affinity molecules that can provide small sized, high affinity cancer-specific ligands, which may be well suited for tumor imaging.