Orlova Anna, Wållberg Helena, Stone-Elander Sharon, Tolmachev Vladimir
Affibody AB, Bromma, Sweden.
J Nucl Med. 2009 Mar;50(3):417-25. doi: 10.2967/jnumed.108.057919. Epub 2009 Feb 17.
Human epidermal growth factor receptor type 2 (HER2) is a tyrosine kinase, which is often overexpressed in many carcinomas. Imaging HER2 expression in malignant tumors can provide important prognostic and predictive diagnostic information. The use of anti-HER2 tracers labeled with positron-emitting radionuclides may increase the sensitivity of HER2 imaging. The goal of this study was to compare directly 2 approaches for developing anti-HER2 PET tracers: a (124)I-labeled monoclonal antibody and a small (7-kDa) scaffold protein, the Affibody molecule.
The anti-HER2 Affibody Z(HER2:342) and humanized monoclonal antibody trastuzumab were labeled with (124/125)I using p-iodobenzoate (PIB) as a linker. Cellular processing of both tracers by HER2-expressing cells was investigated. The biodistributions of (124)I-PIB-Z(HER2:342) and (125)I-PIB-trastuzumab were compared in BALB/C nu/nu mice bearing HER2-expressing NCI-N87 xenografts using paired labels. Small-animal PET of (124)I-PIB-Z(HER2:342) and (124)I-PIB-trastuzumab in tumor-bearing mice was performed at 6, 24, and 72 h after injection.
Both radioiodinated Z(HER2:342) and trastuzumab bound specifically to HER2-expressing cells in vitro and specifically targeted HER2-expressing xenografts in vivo. Radioiodinated trastuzumab was more rapidly internalized and degraded, which resulted in better retention of radioactivity delivered by Z(HER2:342). Total uptake of trastuzumab in tumors was higher than that of (124)I-PIB-Z(HER2:342). However, tumor-to-organ ratios were appreciably higher for (124)I-PIB-Z(HER2:342) due to the more rapid clearance of radioactivity from blood and normal organs. The ex vivo results were confirmed by small-animal PET.
The use of the small scaffold targeting Affibody provides better contrast in HER2 imaging than does the monoclonal antibody.
人表皮生长因子受体2（HER2）是一种酪氨酸激酶，在许多癌症中常过度表达。对恶性肿瘤中的HER2表达进行成像可提供重要的预后和预测诊断信息。使用正电子发射放射性核素标记的抗HER2示踪剂可能会提高HER2成像的灵敏度。本研究的目的是直接比较开发抗HER2正电子发射断层显像（PET）示踪剂的两种方法：一种是（124）I标记的单克隆抗体，另一种是小的（7千道尔顿）支架蛋白，即亲合体分子。
使用对碘苯甲酸（PIB）作为连接体，用（124/125）I标记抗HER2亲合体Z（HER2:342）和人源化单克隆抗体曲妥珠单抗。研究了HER2表达细胞对两种示踪剂的细胞处理情况。使用配对标记物，比较了（124）I-PIB-Z（HER2:342）和（125）I-PIB-曲妥珠单抗在携带HER2表达的NCI-N87异种移植瘤的BALB/C裸鼠中的生物分布。在注射后6、24和72小时，对荷瘤小鼠进行（124）I-PIB-Z（HER2:342）和（124）I-PIB-曲妥珠单抗的小动物PET检查。
放射性碘化的Z（HER2:342）和曲妥珠单抗在体外均能特异性结合HER2表达细胞，在体内均能特异性靶向HER2表达的异种移植瘤。放射性碘化的曲妥珠单抗内化和降解更快，这导致Z（HER2:342）递送的放射性保留更好。曲妥珠单抗在肿瘤中的总摄取量高于（124）I-PIB-Z（HER2:342）。然而，由于放射性从血液和正常器官中清除更快，（124）I-PIB-Z（HER2:342）的肿瘤与器官比值明显更高。小动物PET证实了体外结果。
与单克隆抗体相比，使用小型支架靶向亲合体在HER2成像中提供了更好的对比度。
