Multimodal preclinical imaging of Aspergillus fumigatus invasion and treatment

• Applicants: Dr. Nicolas Bézière; Professor Dr. Matthias Gunzer
• Subject Area: Radiology ; Clinical Infectiology and Tropical Medicine ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Pneumology, Thoracic Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512332979

Invasive Aspergillosis (IA) is a life threatening opportunistic disease that affects patients with a compromised immune system and is characterized by a very high mortality rate of over 40% and high societal costs. With non-specific symptoms, this fungal infection is difficult to diagnose in weakened patients as non-invasive imaging methods (MRI, X-ray CT) do not identify specific features. This forces practitioners to rely on invasive procedures (broncho-alveolar lavage or biopsies) with high patient burden to establish a definitive diagnosis. As a result, the administration of treatment is often dangerously delayed. A faster and more specific diagnostic procedure for the identification of IA is desperately needed. To address this clinical need we developed a novel imaging method for the non-invasive diagnosis of IA in a research effort with several European research institutions. This new diagnostic method is based on a radiolabeled antibody specific to the growing fungus and the combination of PET and MR, a so-called “immuno-PET/MR” approach. In parallel to its high specificity and sensitivity in preclinical studies, this antibody-based approach also showed promising results in patients. However, these studies also revealed clear limitations of the approach due to high background noise caused by long circulation times of the antibody, rendering widespread clinical use unlikely baring suitable modifications of the antibody. While early diagnosis of IA enabled by immuno-PET/MR will allow for better therapeutic choices and earlier treatment, the correlation between treatment, changes in fungal burden and radiotracer accumulation remains unclear, making therapy monitoring impossible. Given the swift progression of IA in weakened patients, it is of prime importance to assess the efficiency of treatment rapidly at all infection sites, in particular given the emerging resistant fungal strains and pronounced side effects of present day antifungals. To optimize the radiotracer for these analyses, it is necessary to shorten the circulation times of the antibody vector to increase the signal-to-noise ratio of the approach. In this project, we will therefore modify the existing anti JF5 antibody at its Fc part to greatly reduce the circulation time in vivo. The modified antibody will then be radiolabelled and its ability to detect more rapidly and with clearer signal the presence of the fungus in a mouse model in vivo will be investigated (Aim 1). Furthermore, the expression of the JF5 antigen during antimycotic therapy will be investigated. At several therapeutically relevant measurement points, a correlation of the measurement signal to the actual fungal load in the test animals will be established (Aim 2). In the final step, we will investigate how this method can reliably detect cerebral aspergillosis in a mouse model (objective 3).

• DFG Programme: Research Grants