Work packages

The MATHIAS project is divided into four work packages (WP), three scientific work packages and one management work package. For each work package a work package leader has been appointed and the specific objectives of each work package have been defined.

Work package 1

Generation of specific tracers

Work package leader: Christopher Thornton (ISCA)

This WP will use antibody engineering technologies to develop single-chain Fv (scFv), Fab, and chimeric and fully humanised antibody variants of Isca's patented Aspergillus-specific monoclonal antibody JF5. This antibody forms the basis of Isca's flagship lateral-flow device for invasive aspergillosis detection. Previous collaborative work between Isca and partner organisations in the MATHIAS consortium has shown the supreme specificity of the intact JF5 antibody molecule in visualising Aspergillus lung infections using radiometal labelling and PET/MR imaging. The smaller size of the antibody fragments generated in WP1 will enable improved pharmacokinetic properties of the antibody tracers, while the chimeric and fully humanised versions will allow the detection of lung infections in immunocompromised patients. The antibody variants produced in WP1 are a critical first-step in the MATHIAS project, providing engineered antibodies for conjugation to radiometals and use in state-of-the art imaging systems by partner organisations. Isca has formed a collaboration with Irish life science company Fusion Antibodies to use their trademarked next-generation in silico CDRx technology to develop the fully humanised JF5 antibody. A fully humanised JF5 antibody is an essential step in the progression of therapeutic drugs to the clinic and the in-house expertise at Fusion Antibodies ensures its success.

Work package 2

Preclinical evaluation of potential tracers

Work package leader: Stefan Wiehr (EKUT)

The task of work package 2 is to test the newly generated A. fumigatus specific biomarkers in vitro and in vivo. These important tests have to be done to evaluate the suitability for diagnosing the infection. In this work package we will test the engineered antibodies and antibody fragments in vitro and in vivo. The biomarkers radiolabelled with various radiometals will act as tracers to highly specific detect an Aspergillus fumigatus infection. The goal of the work package 2 is to identify the most suitable tracers which display the brightest positron emission tomography (PET) signal and show the lowest background signal along with innovative multimodal imaging workflows. These important tests will be performed to evaluate the suitability for diagnosing the infection of the biomarkers.of the biomarkers.

Work package 3

cGMP production and toxicity test, first clinical trial

Work package leader: Matthias Gunzer (UKEssen)

The overall goal of WP3 is the translation of the most suited radiolabelled Ab from bench-to-bedside. Based on the emerging data from WP1 and WP2 the eligible antibody derivative as well as the best evaluated chelator will be produced according to good radiopharmaceutical manufacturing practice (GMP). Additionally, toxicity tests of newly developed non-radiolabeled and radiolabeled tracers (WP1 und WP2) will be performed to deeply evaluate these molecules regarding their potential threat for humans. Using the optimized format of the A. fumigatus-specific antibody we will perform a small scale clinical study to analyze patients from the local hospital at risk of being infected with A. fumigatus by PET/MR.
The trial will be conducted in compliance with the protocol, Declaration of Helsinki, Good Clinical Practice (GCP) and the German drug law. The study schedule will be developed together with the center for clinical trial studies of the University Hospital in Essen (Zentrum für Klinische Studien Essen, ZKSE ) and the Phase I unit of the University Hospital, Essen. At present, the ZKSE acts as a scientific provider for more than 20 clinical trials - still more in planning. The ZKSE will be responsible for the design of the trial, data management, monitoring and data analyses. As full member of the national Network of Coordinating Centres for Clinical Trials (KKS Network), the ZKSE has adapted all harmonized standard operation procedures to the local conditions.
The primary aim of this trial is the safety assessment of the radioimmunoconjugate. Secondary criteria are its pharmacokinetic and pharmacodynamic properties and, finally, to provide proof-of-concept evidence for the diagnostic potential of the Ab in patients at high risk of an established pulmonary aspergillosis using combined PET/MRI.

Work package 4

Project management

Work package leader: Rebecca Rock (EKUT)

Work package 4 comprises the coordination and administrative management of the project. One main objective of this workpackage is to support the coordinator in fulfilling the contractual duties with the European Commission. This includes the monitoring of the finances, the project reports and the project progress. Furthermore WP4 serves as a central communication platform for the consortium, fostering good communication and cooperation between all partners. Further objectives are to support the partners with dissemination through the public scientific and non-scientific channels as well as the management of intellectual property within the project and the exploitation of results.