In collaboration with a Brussels University team under the leadership of Nick Devoogdt and a French team from INSERM, Serge Muyldermans and his team, associated with VIB and Vrije Universiteit Brussel, have succeeded in developing the first patient-friendly, non-invasive method for differentiating dangerous strictures in blood vessels, so-called vulnerable atherosclerotic plaques, from less dangerous ones. These strictures or atherosclerotic plaques are caused by lipid accumulation on the lining of the arterial wall – a process that is accelerated by high cholesterol levels. The dangerous variants of so-called vulnerable atherosclerotic plaques increase the risk of heart attacks and sudden death.
With thanks to the dromedary
Vulnerable atherosclerotic plaques are a hive of activity. They are host to an inflammation process that involves white blood cells and a whole array of molecules. One of the molecules that play a major role is VCAM1 (vascular cell adhesion molecule), a receptor that appears at the surface of arterial wall cells. VCAM 1 receptors ensure that white blood cells stick to arterial wall lesions. The presence of VCAM1 is therefore an indicator of vulnerable atherosclerotic plaque. Reliable visualization of VCAM 1 receptors in arterial strictures would allow us to distinguish between harmful vulnerable plaques and innocent lesions.
Researchers at VIB, Brussels University and INSERM succeeded in doing just that. They produced blocking anti-VCAM1 antibodies with the help of dromedaries. Dromedaries produce antibodies that are much smaller and more stable than conventional antibodies. When these animals are administered recombinant VCAM1 molecules, they develop anti-VCAM1 antibodies. Of each antibody, only the tiny fragment that binds to the receptor is kept. Such fragments are called nanobodies. The VCAM1 nanobodies are then given a radioactive marker and administered to mice with vulnerable plaques. Due to their minute size and good stability, they bind very specifically to VCAM1 in the strictures. With a so-called 3-D SPECT scan it is then possible to reliably identify vulnerable plaques by visualizing VCAM1. Since the tested nanobodies bind to both murine and human VCAM1, their application in the diagnosis of vulnerable strictures in patients could be developed fairly quickly.
What is its importance?
Cardiovascular disease remains the biggest cause of death worldwide in spite of the progress made in treatment and our knowledge about primary prevention. Cardiac arrest and sudden death often result when one of the coronary arteries, the blood vessels that supply the heart with oxygen, becomes completely blocked. Many victims never even experienced any symptoms such as chest pain. Most blocked coronary arteries are caused by atherosclerosis. The aging process causes everyone to eventually develop atherosclerosis and stenosis. Sophisticated cardiology technologies, such as coronarography, can provide good images but no information about the nature of the stricture. However, it is not the seriousness but the type of atherosclerotic lesion that increases the risk of cardiac arrest and sudden death. So-called vulnerable atherosclerotic plaques can tear and form clots, causing a sudden obstruction of the artery.
VCAM1 nanobodies provide a safe and effective method for visualizing atherosclerotic lesions. By giving them a radioactive marker, the exact location of the lesions can be located with SPECT, a 3-D imaging technology that requires radioactively marked substances. The nanobodies open the way for a new class of non-invasive markers in cardiology.