Dijkers Eli C F, Kosterink Jos G W, Rademaker Anna P, Perk Lars R, van Dongen Guus A M S, Bart Joost, de Jong Johan R, de Vries Elisabeth G E, Lub-de Hooge Marjolijn N
Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Nucl Med. 2009 Jun;50(6):974-81. doi: 10.2967/jnumed.108.060392. Epub 2009 May 14.
The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In-trastuzumab, which we have tested in the clinic already.
Trastuzumab was labeled with (89)Zr and (for comparison) with (111)In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice.
Trastuzumab was efficiently radiolabeled with (89)Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 microg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of (89)Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 +/- 7.6 [mean +/- SEM] vs. 7.1 +/- 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between (89)Zr-trastuzumab and (111)In-trastuzumab uptake in tumors (R(2) = 0.972).
Clinical-grade (89)Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.
抗人表皮生长因子受体2（HER2/neu）抗体曲妥珠单抗用于HER2/neu过表达的乳腺癌患者。全身无创性HER2/neu闪烁扫描有助于评估和量化所有病灶（包括难以触及的转移灶）的HER2/neu表达。本研究的目的是开发用于临床HER2/neu免疫正电子发射断层扫描（immunoPET）的临床级放射性标记曲妥珠单抗，以改善诊断成像、指导基于抗体的治疗并支持抗体的早期开发。将正电子发射断层扫描（PET）放射性药物89Zr标记的曲妥珠单抗与我们已在临床中测试过的单光子发射计算机断层扫描（SPECT）示踪剂111In标记的曲妥珠单抗进行比较。
用89Zr标记曲妥珠单抗（并与111In标记的曲妥珠单抗作比较）。用人HER2/neu阳性或阴性肿瘤异种移植小鼠确定最佳小动物PET成像和生物分布所需的曲妥珠单抗最小剂量。
曲妥珠单抗能高效地用89Zr进行放射性标记，放射化学纯度和比活度高。抗原结合能力得以保留，放射性药物在溶剂和人血清中证明长达7天稳定。在所测试的蛋白剂量中，曲妥珠单抗最小剂量（100微克）被证明是成像的最佳剂量。比较生物分布研究显示，HER2/neu阳性肿瘤中89Zr标记的曲妥珠单抗水平高于HER2/neu阴性肿瘤，尤其是在第6天（分别为每克组织33.4±7.6[平均值±标准误]和7.1±0.7注射剂量百分比）。小动物PET图像与生物分布数据之间以及肿瘤中89Zr标记的曲妥珠单抗和111In标记的曲妥珠单抗摄取之间存在良好相关性（R2 = 0.972）。
临床级89Zr标记的曲妥珠单抗在良好分辨率下显示出高且HER2/neu特异性的肿瘤摄取。
