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19.03.2017 | Original Article | Ausgabe 8/2017 Open Access

European Journal of Nuclear Medicine and Molecular Imaging 8/2017

89Zr-Onartuzumab PET imaging of c-MET receptor dynamics

Zeitschrift:
European Journal of Nuclear Medicine and Molecular Imaging > Ausgabe 8/2017
Autoren:
Martin Pool, Anton G. T. Terwisscha van Scheltinga, Arjan Kol, Danique Giesen, Elisabeth G. E. de Vries, Marjolijn N. Lub-de Hooge
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00259-017-3672-x) contains supplementary material, which is available to authorized users.

Abstract

Purpose

c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of 89Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts.

Methods

In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent 89Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent 89Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results.

Results

In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213 ± 44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69 ± 9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, 89Zr-onartuzumab uptake was 26% higher (P < 0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P < 0.001) following NVP-AUY-922 treatment.

Conclusion

The results show that 89Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.

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Zusatzmaterial
Supplementary Fig. 1 a Efficiency of conjugation of Df to onartuzumab at various molar reaction ratios. b Radiochemical purity for 89Zr labelling at various Df to onartuzumab molar conjugation ratios, with specific activities between 50 and 1,000 MBq/mg conjugate. c Retained affinity of 89Zr-onartuzumab at various Df to onartuzumab molar conjugation ratios compared with that of naked onartuzumab in a competition assay. d Stability of 89Zr-onartuzumab in 0.9% NaCl at 4 °C, human serum at 37 °C and HEPES, pH 7.2 at 37° °C up to 7 days (PDF 38 kb)
259_2017_3672_MOESM1_ESM.pdf
Supplementary Fig. 2 a Ex vivo organ uptake in HCC827 xenograft-bearing mice of 89Zr-onartuzumab 6 days after injection at protein doses of 10, 25 and 100 μg (six, five and four mice, respectively) and uptake of 89Zr-OA-NBC 6 days after injection at a protein dose of 10 μg. b Corresponding ex vivo organ uptake in HCC827 xenograft-bearing mice of 111In-OA-NBC 6 days after injection. Data are expressed as %ID/g ± SD (PDF 48 kb)
259_2017_3672_MOESM2_ESM.pdf
Supplementary Fig. 3 Ex vivo organ uptake of 89Zr-onartuzumab and 111In-OA-NBC both 6 days after injection at a dose of 10 μg in ten HCC827 and HCC827ErlRes tumour-bearing mice. Data are expressed as %ID/g ± SD (PDF 35 kb)
259_2017_3672_MOESM3_ESM.pdf
Supplementary Fig. 4 a Ex vivo organ uptake of 89Zr-onartuzumab 6 days after injection in six vehicle-treated and seven NVP-AUY-922-treated (at a dose of 100 mg/kg) HCC827 xenograft-bearing mice. b Corresponding ex vivo organ uptake of 111In-OA-NBC 6 days after injection in HCC827 xenograft-bearing mice. Data are expressed as %ID/g ± SD (PDF 42 kb)
259_2017_3672_MOESM4_ESM.pdf
Supplementary Fig. 5 Histological grading of necrosis (H&E staining) of (a) HCC827 and HCC827ErlRes tumours and (b) vehicle-treated and NVP-AUY-922-treated HCC827 tumours, where score 0+ represents 0–5% necrosis, 1+ 5–15% necrosis, 2+ 15–25% necrosis, 3+ 25–35% necrosis and 4+ >35% necrosis. (PDF 25 kb)
259_2017_3672_MOESM5_ESM.pdf
Supplementary Fig. 6 Correlation between ex vivo 89Zr-onartuzumab/89Zr-OACD8 tumour uptake (%ID/g) and in vivo PET tumour uptake (SUVmean). (PDF 31 kb)
259_2017_3672_MOESM6_ESM.pdf
Literatur
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