Imaging of Epidermal Growth Factor Receptor Expression in Head and Neck Cancer with SPECT/CT and 111In-Labeled Cetuximab-F(ab')2
SourceThe Journal of Nuclear Medicine (1978), 54, 12, (2013), pp. 2118-24
Article / Letter to editor
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The Journal of Nuclear Medicine (1978)
SubjectONCOL 3: Translational research; ONCOL 3: Translational research NCMLS 2: Immune Regulation
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 (111)In-cetuximab-F(ab')2 tracer to image EGFR targeting in vivo. METHODS: The affinity and internalization kinetics of (111)In-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 (111)In-cetuximab-F(ab')2 or (111)In-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)In-cetuximab-F(ab')2 was internalized into FaDu cells within 24 h. The half maximal inhibitory concentration (IC50) of (111)In-cetuximab-F(ab')2 and (111)In-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 (111)In-cetuximab-F(ab')2 in tumors was obtained at doses of 10 mug/mouse or less (13.5 +/- 5.2 percentage injected dose per gram [%ID/g]). Tumor uptake of (111)In-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 (111)In-cetuximab-F(ab')2 (31.4 +/- 3.8 vs. 1.7 +/- 0.2, respectively; P < 0.001). The intratumoral distribution of (111)In-cetuximab-F(ab')2 correlated well with the immunohistochemical distribution of EGFR (r = 0.64 +/- 0.06, P < 0.0001). micro-SPECT images of (111)In-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 (111)In-cetuximab (107.0 +/- 17.0 vs. 69.7 +/- 3.9, respectively; P < 0.05). CONCLUSION: (111)In-cetuximab-F(ab')2 displays higher tumor-to-blood ratios early after injection than (111)In-cetuximab in an HNSCC model, making it more suitable for EGFR visualization and potentially for selecting patients for treatment with EGFR inhibitors.
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