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Scientific result | Positron Emission Tomography | Cancer | Medical imaging
Researchers at BioMaps (SHFJ) and SPI (DMTS) have studied the pharmacokinetics of a novel immuno-radioligand targeting the endothelin A receptor (ETA), overexpressed in many cancers, particularly glioblastoma. The immunoPET imaging approach used in this study in a preclinical model confirms the theranostic potential of this antibody for, as an example, applications to assist surgical procedures during the excision of these particularly complex and aggressive brain tumors.
Glioblastoma (GBM) is the most common primary brain tumor in adults. The average survival of patients is 2 to 3 years, and its incidence in France increased fourfold or more between 1990 (471 new cases) and 2018 (2003 new cases). Clinical symptoms appear late, due to the brain's plasticity, which allows a large tumor mass to develop and tumor cells to infiltrate brain tissue. GBMs contain subpopulations of glioblastoma stem cells (GSCs) that are quiescent, highly tumorigenic and insensitive to current antimitotic therapies. As a result, GSCs are responsible for tumor resurgence after patient management, which mainly consists of tumor removal by surgery, radiotherapy and chemotherapy. This therapeutic scheme has not undergone any major evolution in the last ten years, and the need for new treatments is essential for patients. The endothelin (ET) axis regulates multiple physiological functions, and the two endothelin receptor subtypes (ETA and ETB) are now recognized as relevant therapeutic targets in oncology. Recent work has classified this physiological pathway as a driver of tumor progression in several cancers, including gliomas, and more than 30 clinical trials have already been carried out with small molecule antagonists of ETA and ETB in various cancers, including two in GBM. Despite the absence of any significant increase in patient survival, these trials highlight the relevance of targeting ETA and ETB in a therapeutic approach for GBM. More specifically, ETA overexpression in GSCs is a biomarker of interest for targeting this cell subpopulation.
In this context, the teams of Didier Boquet (SPI/DMTS) and Charles Truillet (BioMaps), in collaboration with researchers from the universities of Dijon and Montpellier, have studied the fate of Rendomab A63 (RA63), a CEA-patented monoclonal antibody specific to the ETA receptor, in a relevant preclinical model (Jean-Philippe Hugnot, IGF, Montpellier). Two formats of RA63 were used, the full-length antibody named xiRA63 and its Fab fragment, ThioFab-xiRA63, on the assumption that the smaller ThioFab could more easily reach the tumor in the mouse brain. Both were labeled with zirconium-89 (89Zr) to assess their ability to detect ETA+ tumors in vivo, using PET imaging. Analyses of tissue biodistribution and pharmacokinetic parameters highlighted the ability of both radioligands to cross the brain tumour barrier and specifically target ETA+ tumours, with, surprisingly, better accumulation for xiRA63. The rapid elimination of Fab from the bloodstream, the alteration of the BBB and the presence of neoangiogenic vessels in the late stages of glioblastoma could explain this result. This immunoPET study provided the pharmacokinetic profiles of two antibody formats directed against the endothelin A receptor in an animal model of glioblastoma, and quantified their biodistribution in target organs, particularly in the tumor zone. It reveals the high potential of zirconium-89-labeled Rendomab A63 to specifically detect ETA+ tumors. These results are promising for clinical applications of this antibody. Contacts : Didier Boquet (RA63 and endothelin receptors) firstname.lastname@example.org & Charles Truillet (ImmunoPET and Pharmacokinetics) email@example.com Figure: Quantitative uptake of [89Zr]Zr-ThioFab-xiRA63 (antibody fragment, left) and [89Zr]Zr-xiRA63 (full antibody, right) in the tumor zone on PET imaging © Hautiere et al., EJNMMI, 2023
Hautiere, M., Vivier, D., Pineau, D., Denis, C., Kereselidze, D., Herbet, A., Costa, N., Goncalves, V., Selingue, E., Larrat, B., Hugnot, J.P., Denat, F., Boquet, D., Truillet, C. ImmunoPET imaging–based pharmacokinetic profiles of an antibody and its Fab targeting endothelin A receptors on glioblastoma stem cells in a preclinical orthotopic model. Eur J Nucl Med Mol Imaging, 2023 https://doi.org/10.1007/s00259-023-06268-3
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.