Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma
Julia Schmitt, Johannes Schwenck, Andreas Maurer, Mirko Przybille, Dominik Sonanini, Gerald Reischl, Jöri E. Wehrmüller, Leticia Quintanilla-Martı́nez, Stephen D. Gillies, Marcel A. Krueger, Juergen F. Schaefer, Christian la Fougère, Rupert Handgretinger, Bernd J. Pichler
Abstract
Background: Antibodies targeting surface expressed disialoganglioside GD2 are increasingly used in neuroblastoma immunotherapy and might also have potential for use in radioimmunotherapy. As such targeted treatments might benefit from a dedicated theranostic approach, we studied the influence of radiolabeling on the binding characteristics of ch14.18 antibodies produced by Chinese hamster ovary (CHO) cells and evaluated the benefit of GD2-ImmunoPET as a potential tool for therapy planning. Methods: 64 Cu was used to reduce radiation burden, which is of high importance especially in a pediatric patient population. 64 Cu-labeling was accomplished using the chelators NOTA-or DOTAGA-NCS. Radiolabeled antibodies were characterized in vitro. [ 64 Cu]Cu-DOTAGA-ch14.18/CHO was studied in a neuroblastoma mouse model (subcutaneous CHP-134 xenografts). In vivo PET and MR images were acquired at 3 h, 24 h, and 48 h p.i. The specificity of binding was verified using GD2-negative tumors (HEK-293 xenografts), a control antibody and in vivo blocking. A first translational application was performed by PET/MRI in a patient with metastasized neuroblastoma. Results: Radiolabeling at an antibody-to-chelator ratio 1:10 yielded a product with a radiochemical purity of 90% and a specific activity of 0.2-1.0 MBq/g. Radiochelation was stable over 48 h in PBS, mouse serum or EDTA, and 50.8 3.5% and 50.8 2.0% of the radiolabeled conjugates, prepared at antibody-to-chelator ratios of 1:10 or 1:15, were immunoreactive. In vivo, highly specific accumulation (31.6 5.8% ID/g) in neuroblastoma was shown preclinically. Clinical PET/MR scans using [ 64 Cu]Cu-NOTA-ch14.18/CHO (NOTA used for safety reasons) could visualize neuroblastoma metastases. Conclusions: In vivo, 64 Cu-labeled ch14.18/CHO is suitable for specific identification of neuroblastoma in PET. A first patient PET indicated the feasibility of the method for clinical translation and the potential utility in image-guided therapy.