ANR 2019 - PRCI - DualmAb - Dual labeling (PET and fluorescence) of antibodies targeting endothelin 1 receptors

ANR PRC program 2019 a joint cooperation between ICMUB-DIJON (Prof. Franck DENAT), JOLIOT Institut des sciences du vivant FRÉDÉRIC-JOLIOT, INM Institut des Neurosciences de Montpellier, Kaer Labs KAER LABS, and SHFJ Imagerie Moléculaire In Vivo

ANR details

Glioblastoma (GBM), the most aggressive form of glial tumors (overall survival 2-3 years), represent more than 50% of brain cancer. In the standard of care of treatment, the main option is the surgical resection but because of the infiltrating property of GBM and the difficulty to differentiate healthy from malignant tissues using white-light microscopy, a complete resection is achieved only in a minority of patients. To overcome this limitation, we propose in the DualmAb project to develop new antibody-based bimodal imaging agents allowing i) the pre-operative detection and staging of the tumor thanks to Positron Emission Tomography (PET) imaging and ii) the intra-operative delineation of the tumor margins thanks to fluorescence (Fluorescence Guided Surgery). To do so, we will target the endothelin 1 receptors (ET1R) – overexpressed in Glioblastoma cancer stem cells (GSC) – using two new antibodies as targeting vectors. In order to obtain chemically-defined conjugates, we will synthesize MonOmolecular Multimodal Imaging Probes (MOMIP), containing both a fluorescent dye and a chelator for a positron emitter radiometal on a single platform, that will be attached to the antibodies using site-specific bioconjugation techniques. In addition to the probes and bioconjugates preparation, we will gain deeper insight on the distribution pattern of ET1R in a large series of GSC cell lines mainly established by our clinician partner from patient biopsies (different grades of glioblastoma). In vitro evaluation of the radioimmunoconjugates (affinity, aggregation, stability) will allow us to select the most promising agents that will undergo further investigations. Optical and PET imaging studies on mice bearing human GSC subcutaneous xenografts will be performed to assess the in vivo behavior of the conjugates (tumor accumulation and pharmacokinetics). Besides, our industry partner will develop key technologies to deliver a fluorescence imaging device adapted to glioblastoma guided surgery, allowing us to assess the potential of the two best agents in an orthotopic model. This project will generate innovative tools and new insights against a new glioblastoma target. By providing a detailed topographic mapping of gliomas, it will contribute to a better monitoring (prognosis, diagnosis, and recurrence) and care (guided-surgery) for these incurable tumors.

Principal investigator:  Prof. Franck DENAT (ICMUB - UMR 6302)