Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody
Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody
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DOI：
10.1007/s00259-006-0361-6
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发表时间：
2007-06-01
影响因子：
9.1
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Cai, Weibo;Chen, Kai;Chen, Xiaoyuan
西妥昔单抗（Cetuximab）是一种靶向癌细胞表面表皮生长因子受体（EGFR）的嵌合单克隆抗体，已获FDA批准用于治疗转移性结直肠癌。它目前也处于治疗其他几种实体瘤的晚期开发阶段。在这里，我们首次报道了使用cu -64标记的西妥昔单抗对异种移植小鼠EGFR表达的定量正电子发射断层扫描（PET）成像。方法将西妥昔单抗与大环螯合剂1,4,7,10-四氮十二烷-N，N‘，N’，N' -四乙酸（DOTA）偶联，用Cu-64标记，并在7种异种移植肿瘤模型中检测所制得的Cu-64-DOTA-西妥昔单抗。PET示踪剂摄取与western blotting测定的EGFR表达相关。基于PET数据计算了Sprague-Dawley大鼠的人体剂量学估计。结果pet显像显示，随着时间的推移，cu -64- dota -西妥昔单抗在egfr阳性肿瘤中的肿瘤活性积累增加，但在egfr阴性肿瘤中的吸收相对较低（< 5%ID/g）。示踪剂摄取（PET测定）与EGFR表达水平（western blotting测定）具有良好的相关性（R-2=0.80）。人体剂量学估计表明，示踪剂可以安全地用于肿瘤诊断的人类患者，剂量限制器官是肝脏。结论利用cu -64- dota -西妥昔单抗成功进行egfr阳性肿瘤显像，可应用于临床，用于表征药代动力学，选择合适的患者群体进行egfr靶向治疗，监测抗egfr治疗的疗效，优化西妥昔单抗单用或联合其他治疗药物的剂量。
Purpose Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, was approved by the FDA to treat patients with metastatic colorectal cancer. It is currently also in advanced-stage development for the treatment of several other solid tumors. Here we report for the first time the quantitative positron emission tomography (PET) imaging of EGFR expression in xenograft-bearing mice using Cu-64-labeled cetuximab.Methods We conjugated cetuximab with macrocyclic chelating agent 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA), labeled with Cu-64, and tested the resulting Cu-64-DOTA-cetuximab in seven xenograft tumor models. The tracer uptake measured by PET was correlated with the EGFR expression quantified by western blotting. The estimated human dosimetry based on the PET data in Sprague-Dawley rats was also calculated.Results MicroPET imaging showed that Cu-64-DOTA-cetuximab had increasing tumor activity accumulation over time in EGFR-positive tumors but relatively low uptake in EGFR-negative tumors at all times examined (< 5%ID/g). There was a good correlation (R-2=0.80) between the tracer uptake (measured by PET) and the EGFR expression level (measured by western blotting). Human dosimetry estimation indicated that the tracer may be safely administered to human patients for tumor diagnosis, with the dose-limiting organ being the liver.Conclusion The success of EGFR-positive tumor imaging using Cu-64-DOTA-cetuximab can be translated into the clinic to characterize the pharmacokinetics, to select the right population of patients for EGFR-targeted therapy, to monitor the therapeutic efficacy of anti-EGFR treatment, and to optimize the dosage of either cetuximab alone or cetuximab in combination with other therapeutic agents.