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Evaluation préclinique et clinique de cAbVCAM1-5, nouveau radiotraceur des plaques d'athérome

Abstract : Cardiovascular diseases (CVD) are the leading causes of death worldwide, and Coronary Artery Disease (CAD) is responsible for the majority of CVD deaths. Myocardial infarction and stroke are mainly caused by the rupture of vulnerable atherosclerotic plaques. Despite recent advances in treatment and detection of CAD, no non-invasive tool is currently available for the diagnosis of vulnerable plaques. The laboratory UMR_S1039 Radiopharmaceutiques Biocliniques has recently developed a new radiotracer (99mTc-cAbVCAM1-5) targeted to the inflammatory marker Vascular Cell Adhesion Molecule 1 (VCAM-1) expressed in vulnerable plaques. 99mTc-cAbVCAM1-5 belongs to a new class of radiotracers derived from single domain antibodies (sdAb), or nanobodies, that are composed of the single variable domain of the heavy chain antibodies of camelidae. Aortic plaques have been successfully visualized noninvasively by SPECT in an Apolipoprotein E (ApoE) deficient mouse model of atherosclerosis. The objectives of my thesis were to complete the preclinical characterization of cAbVCAM1-5 and to transfer this innovative tool to the clinic. The sensitivity of 99mTc-cAbVCAM1-5 imaging has been successfully demonstrated using gold standard therapies (statin, ezetimibe). Those good results allowed us to employ this imaging agent for the evaluation of new therapeutics and to initiate the clinical translation of cAbVCAM1-5. The productions of cAbVCAM1-5 and of the tricarbonyl employed for its radiolabeling have been performed according to good manufacturing practices (GMP). Both products have been evaluated and validated. Furthermore, the radiolabeling method has been optimized to facilitate its clinical transfer. Single dose toxicity study is currently ongoing. At the end of this PhD fellowship, the U1039 Laboratory therefore possesses all required products and knowledge for the onset of a first in human clinical trial.
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Laurent Dumas. Evaluation préclinique et clinique de cAbVCAM1-5, nouveau radiotraceur des plaques d'athérome. Médecine humaine et pathologie. Université Grenoble Alpes, 2018. Français. ⟨NNT : 2018GREAS024⟩. ⟨tel-02384990⟩

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