Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging
Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging
复制标题
DOI：
10.2967/jnumed.108.060392
复制
发表时间：
2009-06-01
影响因子：
9.3
通讯作者：
Lub-de Hooge, Marjolijn N.
中科院分区：
文献类型：
--
作者：
Dijkers, Eli C. F.;Kosterink, Jos G. W.;Lub-de Hooge, Marjolijn N.
抗人表皮生长因子受体2（HER 2/neu）抗体曲妥珠单抗用于HER 2/neu过表达乳腺癌患者。全身非侵入性HER 2/neu乳腺成像可以帮助评估和量化所有病变的HER 2/neu表达，包括不可及的转移瘤。本研究的目的是开发用于临床HER 2/neu免疫PET显像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，并支持早期抗体开发。将PET放射性药物Zr-89-曲妥珠单抗与SPECT示踪剂In-111-曲妥珠单抗进行了比较，我们已经在临床上进行了测试。方法：曲妥珠单抗分别用Zr-89和In-111标记。使用携带人HER 2/neu阳性或阴性肿瘤异种移植物的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。结果：曲妥珠单抗被有效地用Zr-89以高放射化学纯度和比活性放射标记。抗原结合能力得到保留，放射性药物被证明在溶剂和人血清中稳定长达7天。在测试的蛋白剂量中，最小剂量的曲妥珠单抗（100 μ g）被证明是成像的最佳剂量。比较生物分布研究显示，与HER 2/neu阴性肿瘤相比，HER 2/neu阳性肿瘤中Zr-89-曲妥珠单抗的水平更高，尤其是在第6天（33.4 +/- 7.6 [平均值+/- SEM] vs. 7.1 +/- 0.7注射剂量百分比/g组织）。小动物PET图像和生物分布数据之间以及肿瘤中Zr-89-曲妥珠单抗和In-111-曲妥珠单抗摄取之间存在良好的相关性（R-2 = 0.972）。结论：临床级Zr-89-曲妥珠单抗在良好分辨率下显示出高的HER 2/neu特异性肿瘤摄取。
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 Zr-89-trastuzumab was compared with the SPECT tracer In-111-trastuzumab, which we have tested in the clinic already. Methods: Trastuzumab was labeled with Zr-89 and (for comparison) with In-111. 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. Results: Trastuzumab was efficiently radiolabeled with Zr-89 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 mu g) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of Zr-89-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 Zr-89-trastuzumab and In-111-trastuzumab uptake in tumors (R-2 = 0.972). Conclusion: Clinical-grade Zr-89-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.