Molecular imaging of platelet-derived growth factor receptor-alpha (PDGFRα) in papillary thyroid cancer using immuno-PET

• Published in: Nuclear medicine and biology Vol. 58; pp. 51 - 58
• Main Authors: Wagner, Michael, Wuest, Melinda, Hamann, Ingrit, Lopez-Campistrous, Ana, McMullen, Todd P.W., Wuest, Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2018; Elsevier BV
• Subjects: Blood platelets; Bone marrow; Cancer; Chromatography; Copper; Copper-64; Health risks; Imaging; Immuno-PET; Lymphocytes B; Medical personnel; Metastases; Molecular machines; Monoclonal antibodies; Papillary thyroid cancer; Physicians; Platelet-derived growth factor; Platelet-derived growth factor receptor; Positron emission; Protein-tyrosine kinase receptors; Radiochemistry; Spleen; Thyroid; Thyroid cancer; Titration; Tomography; Tumors; Tyrosine; Immuno-PET; Papillary thyroid cancer; Copper-64; Platelet-derived growth factor receptor
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2017.12.005

Receptor tyrosine kinase (RTK) platelet-derived growth factor receptor-alpha (PDGFRα) was recently identified as a molecular switch for dedifferentiation in thyroid cancer that predicts resistance to therapy as well as recurrence of disease in papillary thyroid cancer. Here we describe the radiolabeling and functional characterization of an imaging probe based on a PDGFRα-specific monoclonal antibody (mAb) for immuno-PET imaging of PDGFRα in papillary thyroid cancer. Antibody D13C6 (Cell Signaling) was decorated with chelator NOTA using bioconjugation reaction with 2-(p-NCS-Bz)-NOTA. Radiolabeling was carried out using 40 μg of antibody-NOTA conjugate with 143–223 MBq of [64Cu]CuCl2 in 0.25 M NaOAc (pH 5.5) at 30 °C for 1 h. The reaction mixture was purified with size-exclusion chromatography (PD-10 column). PDGFRα and mock transfected B-CPAP thyroid cancer cells lines for validation of 64Cu-labeled immuno-conjugates were generated using LVX-Tet-On technology. PET imaging was performed in NSG mice bearing bilaterally-induced PDGFRα (+/−) B-CPAP tumors. Bioconjugation of NOTA chelator to monoclonal antibody D13C6 resulted in 2.8 ± 1.3 chelator molecules per antibody as determined by radiometric titration with 64Cu. [64Cu]Cu-NOTA-D13C6 was isolated in high radiochemical purity (>98%) and good radiochemical yields (19–61%). The specific activity was 0.9–5.1 MBq/μg. Cellular uptake studies revealed a specific radiotracer uptake in PDGFRα expressing cells compared to control cells. PET imaging resulted in SUVmean values of ~5.5 for PDGFRα (+) and ~2 for PDGFRα (−) tumors, after 48 h p.i.. After 1 h, radiotracer uptake was also observed in the bone marrow (SUVmean ~5) and spleen (SUVmean ~8.5). Radiolabeled antibody [64Cu]Cu-NOTA-D13C6 represents a novel and promising radiotracer for immuno-PET imaging of PDGFRα in metastatic papillary thyroid cancer. The presented work has the potential to allow physicians to identify papillary thyroid cancer patients at risk of metastases by using the novel immuno-PET imaging assay based on PDGFRα-targeting antibody [64Cu]Cu-NOTA-D13C6.