Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - MATHIAS (New Molecular-Functional Imaging Technologies and Therapeutic Strategies for Theranostic of Invasive Aspergillosis)

Project Context and Objectives:
The development of novel technologies to diagnose and clinically treat invasive Aspergillus fumigatus infections is the scope of this research consortium. Invasive pulmonary aspergillosis (IPA) is a frequently fatal lung disease of hematological malignancy and bone marrow transplant patients caused by the ubiquitous air-borne fungus A. fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity and culture of the fungus from lung biopsy, the gold standard for IPA detection, is invasive and often not possible in critically ill patients. The MATHIAS consortium is using the highly specific monoclonal antibody JF5, developed by ISCA, in a non-invasive disease imaging procedure known as ImmunoPET/MRI. It would be of high financial benefit for clinics and has the potential to increase the survival rates of immuno-compromised patients, if a definitive diagnosis of IPA could be obtained early and its response to treatment be monitored. This would allow applying the correct therapy at a dose and duration exactly tailored to the patient’s needs. Equally important is the development of new treatment options which can replace existing systemic antifungal drugs with their known severe side effects. The approach of the consortium is to develop new disease specific tracers based on the monoclonal antibody JF5 along with the combined molecular imaging technology PET/MRI. With this objective, ISCA has developed a humanised version of the antibody (hJF5) that can be used to visualise lung infections in humans. By coupling the hJF5 antibody to the radionuclide 64Cu using novel conjugation chemistries, the antibody tracer has been shown to be highly accurate in detecting A. fumigatus lung infections in neutropenic mice.
The overall goal is the translation of the most suited radiolabelled Ab from bench-to-bedside. Based on the preclinical data the eligible antibody derivative as well as the best evaluated chelator will be produced according to GMP. Additionally, toxicity tests of newly developed radiolabeled tracers will be performed to evaluate these molecules regarding their potential threat for humans. The primary aim of a small scale clinical study is the safety assessment of the radioimmunoconjugate and a proof-of-concept for the diagnostic potential of the Ab in patients at high risk of an established pulmonary aspergillosis using combined PET/MRI.
The WP1 Deliverable D1.1-4 and Tasks 1.1 to 1.4 encompass Tasks 1.5, 1.6 and 1.7 in WP1. ISCA’s activities during the second reporting period were to support the activities of the other project partners in achieving the Milestones and Deliverables for the different Work Packages. In addition, ISCA has carried out further characterisation of the humanised JF5 antibody and its target antigen (antibody functionality and stability, and epitope identification) in support of GMP antibody.
In WP2, task 2.3 proofed the successful radiolabeling with 64Cu and the highly specific binding of NODAGA-hJF5 to A. fumigatus. Furthermore, there are no deleterious effects on mJF5 or hJF5 immuno-reactivities following chelation of the antibodies to DOTAGA or NODAGA. In vitro binding studies support in vivo molecular imaging studies, demonstrating increased affinity of the hJF5 antibody in the Aspergillus-infected mouse lung when compared to mJF5. Task 2.4 supports the use of accurate, non-invasive ImmunoPET/MR imaging for the diagnosis of IPA, which is so far not used for diagnosis.
The aim of Task 3 of WP3 is the safety assessment of the radioimmunoconjugate as well as the identification of the diagnostic potential of the investigational product in patients at high risk of an established pulmonary aspergillosis. In order to prepare a clinical trial the consortium visited the Paul-Ehrlich Institute to make use of its advisory service. Additionally, the leader of WP3 is in close contact with the clinicians of UKEssen and the colleagues from ZKSE to set up an appropriate study protocol.

Project Results:
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), which utilizes a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to A. fumigatus. Considering clinical translation and application of the tracer in patients, we developed a humanized variant t (hJF5) of the mAb, radiolabeled and tested the new immunoPET tracer in preclinical settings. The hJF5 showed increased uptake in A. fumigatus infected lung tissue compared to the radiolabeled murine antibody. Furthermore, we successfully optimized the biodistribution of the radiolabeled immunoconjugate in regards to reducing tracer uptake in the liver by replacing the chelator DOTA with DOTAGA or NODAGA for improved in vivo stability. Those results support continued development of this antibody-based PET tracer as a potential diagnostic tool for the rapid and highly specific detection of IPA in patients.

Potential Impact:
Invasive pulmonary aspergillosis accounts for more than 200,000 human infections each year, with an associated mortality rate of 30-90% and attendant economic burden to healthcare systems. There is an urgent need to develop accurate, non-invasive methods for identifying IPA in the ever-expanding population of immune deficient patients at risk of acquiring the disease, to allow timely treatment with antifungal drugs. The MATHIAS consortium is using a non-invasive state-of-the-art procedure (Immuno-PET/MR) to detect IPA by employing a humanised monoclonal antibody specific to the aspergillosis pathogen. Using this novel diagnostic approach, we are able to identify active infection in the lung and to differentiate Aspergillus from other lung pathogens. The work breaks new ground in infectious disease diagnosis and is a paradigm shift in the way we diagnose this devastating disease in immunocompromised individuals such as haematological malignancy and bone marrow transplant patients.

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