Theranostics 2017; 7(14):3398-3414. doi:10.7150/thno.20919

Research Paper

Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo

Genna Davies1*, Anna-Maria Rolle2*, Andreas Maurer2, Philipp R. Spycher3, Claudia Schillinger2, Djamschid Solouk-Saran4, Mike Hasenberg4, Juliane Weski4, Jesper Fonslet5, 6, Adrien Dubois7, Frederic Boschetti7, Franck Denat8, Matthias Gunzer4, Martin Eichner9, Lauren S Ryder1, Mikael Jensen5, 6, Roger Schibli3, Bernd J. Pichler2, Stefan Wiehr2, Christopher R. Thornton1✉

1. ISCA Diagnostics Ltd. and Biosciences, College of Life & Environmental Sciences, University of Exeter, Exeter, United Kingdom;
2. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Germany;
3. Paul Scherrer Institute, Research Department Biology and Chemistry, Center for Radiopharmaceutical Sciences (CRS), Switzerland;
4. Institute for Experimental Immunology and Imaging, University Hospital, University of Duisburg-Essen, Essen, Germany;
5. The Hevesy Laboratory, DTU Nutech, Technical University of Denmark;
6. Center for Nanomedicine and Theranostics, Technical University of Denmark;
7. CheMatech, Faculté des Sciences Mirande, Dijon, France;
8. Institut de Chimie Moléculaire, Université de Bourgogne, Dijon, France;
9. Institute for Clinical Epidemiology and Applied Biometry, Eberhard Karls University Tübingen, Germany.
* GD and AMR contributed equally to this work.

Abstract

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or 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 β1,5-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.

Keywords: Infectious Diseases, Aspergillus, Aspergillosis, Monoclonal Antibody, JF5, ImmunoPET/MRI.

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How to cite this article:
Davies G, Rolle AM, Maurer A, Spycher PR, Schillinger C, Solouk-Saran D, Hasenberg M, Weski J, Fonslet J, Dubois A, Boschetti F, Denat F, Gunzer M, Eichner M, Ryder LS, Jensen M, Schibli R, Pichler BJ, Wiehr S, Thornton CR. Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo. Theranostics 2017; 7(14):3398-3414. doi:10.7150/thno.20919. Available from http://www.thno.org/v07p3398.htm