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DARTRIX Report Summary

Project ID: 278580
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 3 - DARTRIX (DARPin Targeted Magnetic Hyperthermic Therapy for Glioblastoma)

Project Context and Objectives:
DARPin Targeted Rx (therapy) (DARTRIX) is a multidisciplinary collaboration to develop therapeutic, biocompatible, targeted superparamagnetic iron-oxide nanoparticles (SPIONs) for localised hyperthermia treatment of glioblastoma. In current clinical practice, SPIONs are used as contrast agents in magnetic resonance imaging (MRI). When subjected to
an alternating field, SPIONs can be activated to generate heat, a process termed magnetic alternating current hyperthermia (MACH). The field itself is harmless and, placed intra-tumourally, SPIONs can readily heat to temperatures above 42°C, causing localised hyperthermia. This is toxic to cancer cells and may also provide a danger signal that will stimulate the immune system. Because SPIONs are not tumour specific, the goal is to target them to cell surface proteins such as epidermal growth factor receptor (EGFR), a widely recognized tumour target that is overexpressed in glioblastoma. The targeting agents of choice are Designed Ankyrin Repeat Proteins (DARPins), which as small non-immunoglobulin human protein scaffolds that can be engineered to bind specific targets which high affinity. The DARTRIX project aims to develop a new safe and efficient approach to targeted hyperthermia treatment by creating and applying a cancer-targeted SPION or ‘DARTRIX particle’, in parallel with a custom-made MACH device to deliver the alternating magnetic field.

Project Results:

In the 37-54 M period, the DARTRIX consortium has continued to make significant progress towards their ambitious objectives. In the previous period, UZH developed a modular system to generate new DARPins with potential to resist uptake by the reticulo-endothelial system (RES); a major challenge for targeted SPION delivery to cancer cells. An efficient purification strategy has now been developed for these RES-resistant DARPins, which will now be conjugated to DARTRIX particles and tested for EGFR specificity. Furthermore, UZH have successfully obtained and characterised an anti-cMet DARPin, and have also made significant progress in isolating an anti-EGFRvIII DARPin; two targets of interest in glioblastoma.
A new range of ferric oxide particles, generated by Micromod Partikeltechnologie GmbH has now been developed with surface chemistries tailored for the DARTRIX project. These new particles are produced in a clean-room facility for GMP compliance and show favourable and consistent heating properties. Furthermore, the particles remain stable during storage and have been successfully conjugated to the E69 anti-EGFR DARPin. DARTRIX particles conjugated to the anti-EGFR monoclonal antibody (mAb) cetuximab have demonstrated specific binding to EGFR expressing cells and this conjugation strategy and testing platform will be adapted for DARPin conjugations. The immunocompetent GL261 pre-clinical model of glioblastoma has been established as orthotopic (in the brain) and subcutaneous (under the skin) tumours at UCL. Both of these models have been tested using the new DARTRIX particles, and preliminary results have established the feasibility of magnetic hyperthermia and suggest a survival benefit from magnetic hyperthermia therapy. Quantitative methods to assess the histological responses to magnetic hyperthermia in the GL261 model have been developed to evaluate the efficacy of treatment. In parallel to these pre-clinical studies, siting toxicity testing has been conducted by TOPASS, identifying a lead DARTRIX particle to be taken forward into GLP toxicity testing.

Validation and calibration of the GMP equipment for production of the E69 DARPin (UCL) has been completed along with the GMP compliant production documentation. These procedures have been used to manufacture E69 for toxicity and stability testing, which have shown promising results. Further improvements have been made by RCL on the machine to induce Magnetic Alternating Current Hyperthermia (MACH) in the clinic. The MACH system is now operating at clinical relevant field strengths and is currently undergoing testing to achieve CE marking. Preparation for the clinical trial continues to progress. A draft clinical trial protocol has been produced and the UCL comprehensive clinical trials unit (CCTU) has approved the proposal for development.

Potential Impact:

The 60-month collaborative DARTRIX project addresses the objectives of the HEALTH priority of the FP7 Cooperation programme, specifically the ‘Development and production of new, high affinity protein scaffolds for therapeutic use’. These scaffold proteins are DARPins and the project aim is to conjugate DARPins to SPIONs and use the resulting ‘DARTRIX particle’ to generate therapeutic heating within tumours expressing the target of interest.
The first DARTRIX particle, modified by surface chemistry, has been generated and is undergoing GMP compliant stability testing at UCL. This will be the first particle to reach the clinic and will establish the feasibility of the DARTRIX concept. In this clinical trial, the particles will be delivered to the tumour site by direct surgical injection and intratumoural distribution will be monitored using MRI. Once injected into the tumour, the DARTRIX particles will be activated to generate heat using a magnetic-field generating device designed and manufactured specifically for this project. In our pre-clinical models, we will test whether magnetic hyperthermia can be used to ‘prime’ the immune system to recognise the tumour and whether this immune response can be augmented using system immune checkpoint inhibitors.
Now that stable DARTRIX particles with reliable heating properties have been generated, and conjugation strategies have been developed, the new DARPins from UZH will be conjugated to create the next wave of targeted DARTRIX particles for personalised therapies in glioblastoma. The multidisciplinary DARTRIX consortium brings together experts from biology, bioprocessing, chemistry, physics, imaging, ethics and oncology to cover all fields required for the success of this ambitious project. The DARTRIX project has already successfully developed a system to provide a shield for resisting the uptake of DARTRIX particles by macrophages in a pre-clinical setting. This system will be further investigated to establish whether it can be translated into the clinic, and used to facilitate the targeting ability of systemically administered DARTRIX particles.
Glioblastoma is a highly infiltrative and rapidly progressive disease. It is invariably fatal with most patients dying within 12 months of diagnosis. Despite decades of research, there is no standard treatment for patients with recurrent/relapsed disease. A successful outcome of the DARTRIX project would form a foundation for development of new treatments for glioblastoma and eventually other diseases.

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Michael Browne, (LEAR and Head of European R&I)
Tel.: +44 20 3108 9376
Fax: +44 20 3108 9376


Life Sciences
Record Number: 192746 / Last updated on: 2016-12-16
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