Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1368-76. doi: 10.1007/s00259-009-1370-z. Epub 2010 Feb 13.
Cetuximab is a recombinant, human/mouse chimeric IgG(1) monoclonal antibody that binds to the epidermal growth factor receptor (EGFR/HER1). Cetuximab is approved for the treatment of patients with HER1-expressing metastatic colorectal cancer. Limitations in currently reported radiolabeled cetuximab for PET applications prompted the development of (86)Y-CHX-A''-DTPA-cetuximab as an alternative for imaging HER1-expressing cancer. (86)Y-CHX-A''-DTPA-cetuximab can also serve as a surrogate marker for (90)Y therapy.
Bifunctional chelate, CHX-A''-DTPA was conjugated to cetuximab and radiolabeled with (86)Y. In vitro immunoreactivity was assessed in HER1-expressing A431 cells. In vivo biodistribution, PET imaging and noncompartmental pharmacokinetics were performed in mice bearing HER1-expressing human colorectal (LS-174T and HT29), prostate (PC-3 and DU145), ovarian (SKOV3) and pancreatic (SHAW) tumor xenografts. Receptor blockage was demonstrated by coinjection of either 0.1 or 0.2 mg cetuximab.
(86)Y-CHX-A''-DTPA-cetuximab was routinely prepared with a specific activity of 1.5-2 GBq/mg and in vitro cell-binding in the range 65-75%. Biodistribution and PET imaging studies demonstrated high HER1-specific tumor uptake of the radiotracer and clearance from nonspecific organs. In LS-174T tumor-bearing mice injected with (86)Y-CHX-A''-DTPA-cetuximab alone, (86)Y-CHX-A''-DTPA-cetuximab plus 0.1 mg cetuximab or 0.2 mg cetuximab, the tumor uptake values at 3 days were 29.3 +/- 4.2, 10.4 +/- 0.5 and 6.4 +/- 0.3%ID/g, respectively, demonstrating dose-dependent blockage of the target. Tumors were clearly visualized 1 day after injecting 3.8-4.0 MBq (86)Y-CHX-A''-DTPA-cetuximab. Quantitative PET revealed the highest tumor uptake in LS-174T (29.55 +/- 2.67%ID/cm(3)) and the lowest tumor uptake in PC-3 (15.92 +/- 1.55%ID/cm(3)) xenografts at 3 days after injection. Tumor uptake values quantified by PET were closely correlated (r (2) = 0.9, n = 18) with values determined by biodistribution studies.
This study demonstrated the feasibility of preparation of high specific activity (86)Y-CHX-A''-DTPA-cetuximab and its application for quantitative noninvasive PET imaging of HER1-expressing tumors. (86)Y-CHX-A''-DTPA-cetuximab offers an attractive alternative to previously labeled cetuximab for PET and further investigation for clinical translation is warranted.
西妥昔单抗是一种重组的人/鼠嵌合 IgG(1) 单克隆抗体，可与表皮生长因子受体 (EGFR/HER1) 结合。西妥昔单抗被批准用于治疗 HER1 表达的转移性结直肠癌患者。目前报道的用于 PET 应用的放射性标记西妥昔单抗存在局限性，促使开发了 (86)Y-CHX-A''-DTPA-西妥昔单抗作为成像 HER1 表达癌症的替代方法。(86)Y-CHX-A''-DTPA-西妥昔单抗也可用作 (90)Y 治疗的替代标志物。
双功能螯合剂 CHX-A''-DTPA 与西妥昔单抗偶联，并与 (86)Y 标记。在表达 HER1 的 A431 细胞中评估体外免疫反应性。在携带表达 HER1 的人结直肠 (LS-174T 和 HT29)、前列腺 (PC-3 和 DU145)、卵巢 (SKOV3) 和胰腺 (SHAW) 肿瘤异种移植的小鼠中进行体内生物分布、PET 成像和非隔室药代动力学研究。通过注射 0.1 或 0.2 mg 西妥昔单抗证明了受体阻断。
(86)Y-CHX-A''-DTPA-西妥昔单抗的常规制备方法是特异性活度为 1.5-2 GBq/mg，体外细胞结合率为 65-75%。生物分布和 PET 成像研究表明，放射性示踪剂对肿瘤具有高度的 HER1 特异性摄取，并从非特异性器官中清除。在单独注射 (86)Y-CHX-A''-DTPA-西妥昔单抗、(86)Y-CHX-A''-DTPA-西妥昔单抗加 0.1 mg 西妥昔单抗或 0.2 mg 西妥昔单抗的 LS-174T 荷瘤小鼠中，第 3 天肿瘤摄取值分别为 29.3 +/- 4.2、10.4 +/- 0.5 和 6.4 +/- 0.3%ID/g，表明靶标存在剂量依赖性阻断。在注射 3.8-4.0 MBq (86)Y-CHX-A''-DTPA-西妥昔单抗后 1 天即可清晰观察到肿瘤。定量 PET 显示，在注射后第 3 天，LS-174T 中的肿瘤摄取最高（29.55 +/- 2.67%ID/cm(3)），PC-3 中的肿瘤摄取最低（15.92 +/- 1.55%ID/cm(3)）。通过 PET 定量的肿瘤摄取值与通过生物分布研究确定的值密切相关 (r (2) = 0.9，n = 18)。
本研究证明了高比活度 (86)Y-CHX-A''-DTPA-西妥昔单抗的制备可行性及其在 HER1 表达肿瘤的定量非侵入性 PET 成像中的应用。(86)Y-CHX-A''-DTPA-西妥昔单抗为之前标记的西妥昔单抗提供了一种有吸引力的替代方法，进一步的临床转化研究是必要的。
