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DOI: 10.1055/s-0039-1683488
Translational immunoPET/MR imaging of invasive pulmonary aspergillosis
Publikationsverlauf
Publikationsdatum:
27. März 2019 (online)
Ziel/Aim:
The ubiquitous fungus Aspergillus fumigatus (AF) can cause life-threatening invasive pulmonary aspergillosis (IPA) in immunocompromised patients. Current non-invasive diagnostics lack specificity and sensitivity, while invasive biopsy or bronchoalveolar lavage and subsequent culture of the fungus is slow and carries risks for the patient. Through radiolabeling of an AF specific humanized antibody (JF5), we propose a specific non-invasive method to diagnose IPA in vivo.
Methodik/Methods:
JF5 was generated from the variable regions of murine JF5 [1] and human IgG1 framework, conjugated to NODAGA and radiolabeled using [64Cu]CuCl2. Neutropenic C57BL/6 mice were infected intra-tracheally using 4 × 106 AF spores and subsequently injected with 13 MBq of the radiotracer. Simultaneous in vivo PET/MR was performed 3, 24 and 48h after infection using a small animal PET/MRI. In vivo results were validated using ex vivo biodistribution by gamma counting, autoradiography and fluorescence microscopy. For human application the chelator conjugation and radiolabeling were upscaled within a GMP setting and toxicity testing was performed in rodents.
Ergebnisse/Results:
Radiolabeled hJF5 revealed high uptake in vivo to AF infection sites and negligible accumulation in control animals. Specific uptake was not observed with [64Cu]CuCl2 nor radiolabeled isotype antibody. [64Cu]NODAGA-hJF5 was found to provide the best uptake ratio 48h after injection in the diseased lungs (17.1 ± 2.5%ID/cc) compared to PBS treated lungs (9.4 ± 1.1%ID/cc) [2]. Toxicity testing showed no adverse effects of repeated dosing. Conjugation procedure and radiolabeling were successfully validated and we expect to obtain first human data within the next weeks.
Schlussfolgerungen/Conclusions:
[64Cu]NODAGA-hJF5 proved to be a highly specific and sensitive tracer for IPA, showing very promising results in preclinical models. After recently establishing the GMP compliant synthesis of this tracer and successful systemic toxicity evaluations, first-in-human trials are currently starting.
Literatur/References:
[1] Rolle et al. PNAS 2016; 113(8); 1026 – 1033.
[2] Davies et al., Theranostics. 2017; 7(14): 3398 – 3414.
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