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

Genna Davies, Anna-Maria Rolle, Andreas Maurer, Philipp R. Spycher, Claudia Schillinger, Djamschid Solouk-Saran, Mike Hasenberg, Juliane Weski, Jesper Fonslet, Adrien Dubois, Frédéric Boschetti, Franck Denat , Matthias Gunzer, Martin Eichner, Lauren S. Ryder, Mikael Jensen, Roger Schibli, Bernd J. Pichler, Stefan Wiehr, Christopher R. Thornton

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    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 beta 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.
    Original languageEnglish
    JournalTheranostics
    Volume7
    Issue number14
    Pages (from-to)3398-3414
    Number of pages17
    ISSN1838-7640
    DOIs
    Publication statusPublished - 2017

    Bibliographical note

    This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license

    Keywords

    • Infectious Diseases
    • Aspergillus
    • Aspergillosis
    • Monoclonal Antibody
    • JF5
    • ImmunoPET/MRI

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