Molecular Imaging of coronary lesions in clinical practice – MC2

In the European Union and the United States of America, cardiovascular diseases are responsible for 40% of the total mortality, the vast majority of those deaths being caused by coronary artery disease and its direct clinical consequence, the rupture of a vulnerable atherosclerotic plaque (VP). However, there is no clinical tool available for the diagnosis of such lesions. The size of the patient population that would be interested by a methodology allowing the non-invasive detection of VP is estimated at 40 million when considering the US only. Among the medical imaging modalities that are potentially useful for the noninvasive detection of vulnerable plaques on large patient populations, Nuclear Imaging seems particularly well suited. This technique relies on the administration of a radiolabelled tracer which specifically binds to a molecular target.

The UMR_S U1039 laboratory (partner 1) focus on developing new radiopharmaceuticals dedicated to nuclear imaging. This laboratory initiated an international consortium aimed at evaluating nanobody-based radiotracers dedicated to nuclear cardiology. For the purpose of vulnerable plaque imaging, nanobody-based tracers directed against the inflammatory marker Vascular Cell Adhesion Molecule 1 (VCAM-1) have been produced and evaluated. The final goal being the clinical application of the most potent candidates, preclinical studies were specifically designed to produce cross reactive tracers. Evaluations were performed in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in ApoE-deficient mice. The lead compound cAbVCAM1-5 demonstrated exquisite properties for the non-invasive molecular imaging of atherosclerotic lesions. Therefore, these results, published in Circulation Research in 2012, led to a patent application (PCT/EP2012/066348), filed by the partner 1 and collaborators under the supervision of Floralis, Grenoble University technology transfer subsidiary.

In order to bring this new radiotracer to the clinic, the UMR_S 1039 initiated a collaboration with two departments of Grenoble University Hospital (partner 2): the Nuclear Medicine department, and the Cardiology department. Catherine Ghezzi, head of UMR_S 1039, will coordinate the project. The UMR_S 1039 will be in charge of the GMP grade production and preclinical validation of radiolabeled cAbVCAM1-5. The nuclear imaging and cardiology departments will be in charge of the toxicology and clinical phase I/IIA studies.

More specifically, the objectives will be:
1. To produce and fully characterized a GMP grade cAbVCAM1-5
2. To control and transfer to the clinic the radiolabeling procedures, including quality controls.
3. To perform preclinical studies in order to confirm the in vitro and in vivo properties of GMP grade cAbVCAM1-5, previously validated using the non-GMP version.
4. To perform toxicology studies.
5. To perform a phase I/IIA clinical trial in order to assess biodistribution and safety in humans of this new radiopharmaceutical.

In order to fulfil these objectives, this project will be subdivided into 6 tasks, including a translational intellectual property and communication task.

Within the framework of above mentioned consortium, the partners will benefit of the knowledge acquired during the previous clinical translation of a nanobody-based radiotracer. In addition, all protocols dedicated to the preclinical evaluation of cAbVCAM1-5 have been fully validated by partner 1. Moreover, the partners involved in this proposal have a strong experience in preclinical developments of new radiopharmaceuticals (partner 1), as well as in their transfer into clinical trials (partner 2).

Therefore, the completion of this project will allow translating into clinical trials a new radiopharmaceutical for the nuclear imaging of atherosclerotic lesions.