Platelets

Activation-specific platelet inhibitors

Platelet adhesion to arterial vascular lesions and plaques plays a key role in the complications of atherosclerosis leading to acute coronary syndromes (such as myocardial infarctions) as well as to ischemic cerebral strokes.

Dimeric glycoprotein (GP) VI-Fc (Revacept) is a human Fc fusion protein, which prevents the local activation of platelets at sites of vascular injury, acting like a “vascular coating”. This agent was originally conceived in a cooperation with the group of Meinrad Gawaz (Medical Clinic III of the University of Tübingen). Efficacy studies showed that Revacept resulted in significantly reduced thrombus formation at these sites. However, systemic hemostasis is not affected.

In a first in man study, all doses were well tolerated, no drug-related adverse events occurred, bleeding time was not prolonged. No bleeding complications nor platelet depletion (thrombopenia) were observed. This drug is now being investigated in larger patient trials.

A clinical phase II study investigated the incidence of brain infarctions/strokes in patients with symptomatic carotid artery stenosis (Eudra-CT 2011-001006-10). The anticipated patient recruitment has been fully achieved – no relevant adverse effects have been observed. A first analysis of study data showed beneficial effects for the patients.

(project of advancecor)

Additionally, marker-labelled GPVI-Fc is being used to detect instable plaques in patients with vascular disease in an innovative imaging method (PET-NMR) which is investigated in a clinical study at the University of Tübingen.

Moreover, the Munich Heart Alliance of the German Centre for Cardiovascular Research (DZHK) performs the investigator-initiated ISAR-PLASTER trial on Revacept in coronary heart disease (NCT 03312855; EudraCT 2015-000686-32). The study protocol has recently been published (Schüpke et al., 2019). The teams of Prof. Adnan Kastrati, German Heart Center, Munich and of Prof. Steffen Massberg, Großhadern Clinic of the Ludwig-Maximilian University, and further large clinical entities, who cooperate within the DZHK  have already recruited almost all anticipated patients. Due to the blinded study design, the analysis of efficacy will be done at the end of the trial.

References

Platelet-inhibiting antibodies

Platelet adhesion to arterial vascular lesions and plaques can also be inhibited by using antibodies which specifically block glycoprotein VI -dependent signal pathways.

Such monoclonal antibodies were designed in a cooperation with the group of  Meinrad Gawaz (now: Medical Clinic III of the University of Tübingen) and Dr. Kremmer at Helmholtz Centre Munich, Germany. Efficacy studies showed that also these antibodies resulted in significantly reduced thrombus formation at these sites, but systemic hemostasis was not affected.

Also these antibodies including fully human variants have already been tested in preclinical studies for safety. The group of Prof. Siess at the institute for cardiovascular research at Munich investigated their efficacy by using human carotid surgery-derived plaques which were superfused with human blood, as published in the Journal of the American College of Cardiology.

The pros and cons of using such anti-glycoprotein VI antibodies versus glycoprotein VI fusion proteins are discussed in the recent editorial of Kleiman und Kolandaivelu „Expanding the Roster : Developing New Inhibitors of Intravascular Thrombosis“ in the Journal of the American College of Cardiology 2015;  65 (22): 2416 – 2419.

Fusion proteins with GPVI-Fc

The platelet inhibitory potential of GPVI-Fc was further increased by fusing it to the ecto-nucleotidase CD39 which inhibits local adenosine diphosphate (ADP) accumulation at vascular plaques, and hence to create a lesion-directed dual antiplatelet therapy. GPVI-CD39 effectively stimulated local ADP degradation, and led to a significantly increased inhibition of plaque-induced platelet thrombus formation under arterial flow conditions.