dianas 7(1) > Ruiz-López etal

dianas | Vol 7 Num 1 | marzo 2018 | e201803p04

Virtual Biopsy: development of non-invasive immunotargeted imaging agents for the diagnosis of glioblastoma.

Eduardo Ruiz-López^a, Ruth González-Gómez, Beatriz Torres-Herrero, Sara Naya-Forcano, Natalia Magro, Héctor Tejero, Fátima Al-Shahrour, Luis Oriol, Miguel Ángel Morcillo, Alberto Jiménez Schuhmacher

Instituto de Investigación Sanitaria de Aragón (IIS Aragón).

a. educalata21@gmail.com

III Congreso de Señalización Celular, SECUAH 2017.
20-22 de marzo, 2018. Universidad de Alcalá. Alcalá de Henares, Madrid. España.
Sesión

Resumen

Glioblastoma (GBM) is the most common and aggressive brain tumor. Patient survival has improved marginally during the past 3 decades, averaging 14.6 months with only 3-5% of patients surviving more than 3 years. Current diagnosis by Magnetic Resonance Imaging (MRI) provides morphological information, which is sometimes inaccurate, and the final diagnosis of GBM often requires a brain biopsy. These biopsies may not depict the high intratumoral heterogeneity present in GBM and may favor its recurrence. These disadvantages highlight the importance of looking for other molecular imaging based technologies that allow efficient and safe diagnosis. Positron Emission Tomography (PET) is an alternative but unfortunately, the most widely used tracer 18F-Fluorodeoxyglucose (18F-FDG) is ineffective in GBM due to the high consumption of glucose by the brain. Other radiotracers for GBM, mostly interrogating the metabolism, are under evaluation. An innovative option is termed immunotargeted imaging. This approach combines the target selectivity and specificity of antibodies and engineered fragments against a given tumor cell surface marker with the main characteristics (high spatial resolution, sensitivity, quantitative capabilities) of imaging techniques. ImmunoPET could be considered a virtual biopsy, comparable to conduct an in vivo, integrated, quantifiable, 3D, full body immunohistochemistry allowing the diagnosis and monitoring of patients over time in a non-invasive manner. Applying bioinformatics on patient datasets, we have identified ATP Binding Cassette Subfamily C Member 3 (ABCC3) as a molecular target for the development of an immunoPET agent for GBM, due to the high levels of ABCC3 protein expression in GBM and negligable levels in normal brain. Importantly, ABCC3 is located in the plasma membrane and the increase of its expression is associated with tumor grade, poor survival and impaired response to the most currently used chemotherapy. We propose to develope a novel immunoPET agent against ABCC3. First, we will validate ABCC3 as a suitable target for immunoimaging using a murine monoclonal antibody labeled with 89Zirconium in xenograft mice and avatar/tumorgraft models. For further clinical development, we will need to reduce the radioactivity exposure and optimize the blood brain barrier permeability of the tracer. To this end, we will generate different antibody fragments with faster clearance and pharmacokinetics. As matching of the physical half-life of the positron-emitting radionuclide with the biological half-life of the antibody or fragment is crucial for immunoPET, these smaller derivatives will be labeled with PET isotopes of shorter half-lives, such as 68Galium, which advantageously can be produced in a generator rather than a cyclotron. Finally, we will use click chemistry by biorthogonal reactions in vivo in order to match other antibodies/fragments with tracers and thereby diminishing the exposure to radioactivity and ensuring a better signal-to-noise ratio. Click chemistry also allows to label multiple imaging tracers (MRI-tracers such as (Gd)-complexes or SPIO nanoparticles) to the same pretargeted molecule as well as multi-modal, multifunctional imaging and teragnostics. The successful development of these tracers has the potential to improve diagnoses, and may have a major impact on the survival of patients with GBM.