Suchergebnisse

This is the final published version ; Available from Ivyspring International Publisher via the DOI in this record ; Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy and bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA-hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant 1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting. ; This work was supported by the European Union Seventh Framework Programme FP7/2007-2013 under Grant 602820, the Deutsche Forschungsgemeinschaft (Grant WI3777/1-2 to SW), and the Werner Siemens Foundation. We thank Sven Krappman for use of the A. fumigatustdTomato strain, and acknowledge the Imaging Centre Essen (IMCES) for assistance with optical imaging of lungs.

The β−-particle-emitting erbium-169 is a potential radionuclide toward therapy of metastasized cancer diseases. It can be produced in nuclear research reactors, irradiating isotopically-enriched 168Er2O3. This path, however, is not suitable for receptor-targeted radionuclide therapy, where high specific molar activities are required. In this study, an electromagnetic isotope separation technique was applied after neutron irradiation to boost the specific activity by separating 169Er from 168Er targets. The separation efficiency increased up to 0.5% using resonant laser ionization. A subsequent chemical purification process was developed as well as activity standardization of the radionuclidically pure 169Er. The quality of the 169Er product permitted radiolabeling and pre-clinical studies. A preliminary in vitro experiment was accomplished, using a 169Er-PSMA-617, to show the potential of 169Er to reduce tumor cell viability. © Copyright © 2021 Talip, Borgna, Müller, Ulrich, Duchemin, Ramos, Stora, Köster, Nedjadi, Gadelshin, Fedosseev, Juget, Bailat, Fankhauser, Wilkins, Lambert, Marsh, Fedorov, Chevallay, Fernier, Schibli and van der Meulen. ; The authors thank CERN ISOLDE and RILIS teams for the laser operation (Maxim D. Seliverstov, Katerina Chrysalidis), radiation protection and logistic teams of PSI (Tobias Schneider) and CERN (Alexandre Dorsival, Matthieu Deschamps and Elodie Aubert, Philippe Bertreix, Nicolas Riggaz, Nabil Menaa, Aurore Boscher, Jeremie Comte, Benjamin Juif); the LARISSA workgroup of Mainz University for the laser preparation and erbium laser ionization scheme development (Prof. Dr. Klaus Wendt and Dr. Dominik Studer). The authors are grateful to Fan Sozzi-Guo, Muhamet Djelili, Alexander V?gele and Walter Hirzel (PSI) and Bernard Cr?pieux, Giacomo Lunghi, Francesco Riccardi, Miranda Van Stenis, Thomas Schneider (CERN) for technical support. Funding. ZT and NM received funding from the Swiss National Science Foundation (SNF Grant Number: 200021_188495). CM obtained funding for this project from the Swiss Cancer Research (KFS-4678-02-2019-R). FB received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie Grant Agreement No 701647.