RT Journal Article
SR Electronic
T1 Imaging of Epidermal Growth Factor Receptor Expression in Head and Neck Cancer with SPECT/CT and <sup>111</sup>In-Labeled Cetuximab-F(ab′)<sub>2</sub>
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 2118
OP 2124
DO 10.2967/jnumed.113.123612
VO 54
IS 12
A1 van Dijk, Laura K.
A1 Hoeben, Bianca A.W.
A1 Kaanders, Johannes H.A.M.
A1 Franssen, Gerben M.
A1 Boerman, Otto C.
A1 Bussink, Johan
YR 2013
UL http://jnm.snmjournals.org/content/54/12/2118.abstract
AB 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 111In-cetuximab-F(ab′)2 tracer to image EGFR targeting in vivo. Methods: The affinity and internalization kinetics of 111In-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 111In-cetuximab-F(ab′)2 or 111In-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 111In-cetuximab-F(ab′)2 was internalized into FaDu cells within 24 h. The half maximal inhibitory concentration (IC50) of 111In-cetuximab-F(ab′)2 and 111In-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 111In-cetuximab-F(ab′)2 in tumors was obtained at doses of 10 μg/mouse or less (13.5 ± 5.2 percentage injected dose per gram [%ID/g]). Tumor uptake of 111In-cetuximab was significantly higher (26.9 ± 3.3 %ID/g, P &lt; 0.01). However, because of rapid blood clearance, tumor-to-blood ratios at 24 h after injection were significantly higher for 111In-cetuximab-F(ab′)2 (31.4 ± 3.8 vs. 1.7 ± 0.2, respectively; P &lt; 0.001). The intratumoral distribution of 111In-cetuximab-F(ab′)2 correlated well with the immunohistochemical distribution of EGFR (r = 0.64 ± 0.06, P &lt; 0.0001). micro-SPECT images of 111In-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 111In-cetuximab (107.0 ± 17.0 vs. 69.7 ± 3.9, respectively; P &lt; 0.05). Conclusion: 111In-cetuximab-F(ab′)2 displays higher tumor-to-blood ratios early after injection than 111In-cetuximab in an HNSCC model, making it more suitable for EGFR visualization and potentially for selecting patients for treatment with EGFR inhibitors.