Imaging of Epidermal Growth Factor Receptor Expression in Head and Neck Cancer with SPECT/CT and 111In-Labeled Cetuximab-F(ab′)2
Imaging of Epidermal Growth Factor Receptor Expression in Head and Neck Cancer with SPECT/CT and 111In-Labeled Cetuximab-F(ab′)2
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DOI：
10.2967/jnumed.113.123612
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发表时间：
2013-12-01
影响因子：
9.3
通讯作者：
Bussink, Johan
中科院分区：
文献类型：
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作者：
van Dijk, Laura K.;Hoeben, Bianca A. W.;Bussink, Johan
晚期头颈部鳞状细胞癌（HNSCC）联合放疗和表皮生长因子受体（EGFR）抑制剂西妥昔单抗治疗与单独放疗相比可改善临床结局，但仅在少数病例中有效。为了选择那些最有可能受益于EGFR抑制的患者，在治疗之前和可能在治疗期间量化肿瘤EGFR状态可能是有利的。本研究的目的是开发和表征In-111-西妥昔单抗-F（ab '）（2）示踪剂，以体内成像EGFR靶向。方法：体外测定In-111-西妥昔单抗-F（ab '）（2）的亲和力和内化动力学。在具有皮下头颈癌模型（FaDu）的裸鼠中确定用于成像的最佳蛋白片段剂量。在注射后4、24、48和168小时，使用In-111-西妥昔单抗-F（ab '）（2）或In-111-西妥昔单抗IgG对FaDu肿瘤小鼠进行超高分辨率SPECT成像。在肿瘤切片的微型SPECT和放射自显影图像上确定肿瘤示踪剂摄取。免疫组化染色分析EGFR在肿瘤中的表达。结果：在体外，超过50%的（111）Incetuximab-F（ab '）（2）在24小时内内化到FaDu细胞中。In-111-西妥昔单抗-F（ab '）（2）和In-111-西妥昔单抗的半数最大抑制浓度（IC 50）相似：分别为0.42 +/- 0.16 nM和0.28 +/- 0.14 nM。蛋白质剂量递增研究表明，In-111-西妥昔单抗-F（ab '）（2）在肿瘤中的最高摄取是在10 μ g/小鼠或更低剂量下获得的（13.5 +/-5.2%注射剂量/克[%ID/g]）。In-111-西妥昔单抗的肿瘤摄取显著更高（26.9 +/-3.3%ID/g，P < 0.01）。然而，由于快速血液清除，注射后24小时In-111-西妥昔单抗-F（ab '）（2）的肿瘤-血液比显著更高（分别为31.4 +/- 3.8对1.7 +/- 0.2; P < 0.001）。In-111-cetuximab-F（ab '）（2）的瘤内分布与EGFR的免疫组化分布相关（r = 0.64 ± 0.06，P < 0.0001）。In-111-西妥昔单抗-F（ab '）（2）的微型SPECT图像清楚地显示从4小时开始在肿瘤中优先摄取，与In-111-西妥昔单抗相比，在24小时具有上级肿瘤-背景对比度（分别为107.0 +/-17.0 vs. 69. 7 +/-3.9; P < 0.05）。结论：在HNSCC模型中，In-111-西妥昔单抗-F（ab '）（2）在注射后早期显示出比In-111-西妥昔单抗更高的肿瘤-血液比，使其更适合EGFR可视化，并可能用于选择EGFR抑制剂治疗的患者。
Combined treatment of advanced head and neck squamous cell carcinomas (HNSCC) with radiotherapy and the epidermal growth factor receptor (EGFR) inhibitor cetuximab improves clinical outcome in comparison to radiotherapy alone but is effective only in a few cases. To select those patients most likely to benefit from EGFR inhibition, it can be advantageous to quantify the tumor EGFR status before and possibly during therapy. The aim of this study was to develop and characterize the In-111-cetuximab-F(ab')(2) tracer to image EGFR targeting in vivo. Methods: The affinity and internalization kinetics of In-111-cetuximab-F(ab')(2) were determined in vitro. The optimal protein-fragment dose for imaging was determined in nude mice with a subcutaneous head and neck carcinoma model (FaDu). Mice with FaDu tumors were imaged using ultra-high-resolution SPECT with In-111-cetuximab-F(ab')(2) or In-111-cetuximab IgG at 4, 24, 48, and 168 h after injection. Tumor tracer uptake was determined on micro-SPECT and autoradiography images of tumor sections. Immunohistochemical staining was used to analyze EGFR expression in the tumor. Results: In vitro, more than 50% of (111)Incetuximab-F(ab')(2) was internalized into FaDu cells within 24 h. The half maximal inhibitory concentration (IC50) of In-111-cetuximab-F (ab')(2) and In-111-cetuximab was similar: 0.42 +/- 0.16 nM versus 0.28 +/- 0.14 nM, respectively. The protein dose-escalation study showed that the highest uptake of In-111-cetuximab-F(ab')(2) in tumors was obtained at doses of 10 mu g/mouse or less (13.5 +/- 5.2 percentage injected dose per gram [%ID/g]). Tumor uptake of In-111-cetuximab was significantly higher (26.9 +/- 3.3 %ID/g, P < 0.01). However, because of rapid blood clearance, tumor-to-blood ratios at 24 h after injection were significantly higher for In-111-cetuximab-F(ab')(2) (31.4 +/- 3.8 vs. 1.7 +/- 0.2, respectively; P < 0.001). The intratumoral distribution of In-111-cetuximab-F(ab')(2) correlated well with the immunohistochemical distribution of EGFR (r = 0.64 0.06, P < 0.0001). micro-SPECT images of In-111-cetuximab-F(ab')(2) clearly showed preferential uptake in the tumor from 4 h onward, with superior tumor-to-background contrast at 24 h, compared with In-111-cetuximab (107.0 +/- 17.0 vs. 69.7 +/- 3.9, respectively; P < 0.05). Conclusion: In-111-cetuximab-F(ab')(2) displays higher tumor-to-blood ratios early after injection than In-111-cetuximab in an HNSCC model, making it more suitable for EGFR visualization and potentially for selecting patients for treatment with EGFR inhibitors.