The GPVI-Fc fusion protein Revacept reduces thrombus formation and improves vascular dysfunction in atherosclerosis without any impact on bleeding times.
OBJECTIVE
Glycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced platelet activation and consecutive atherothrombosis, but GPVI is also involved in platelet-mediated atheroprogression. Therefore, interference in GPVI-mediated platelet activation has the potential to combine short-term and long-term beneficial effects, specificity and safety especially regarding bleeding complications.


RESULTS
We investigated the effects of the soluble dimeric GPVI receptor fusion protein, Revacept, an antagonist of collagen-mediated platelet activation, in an animal model of atherosclerosis: twenty week old rabbits, which had been fed on a cholesterol-rich diet for 8 weeks, received Revacept (8 mg/kg) or control twice weekly for 4 weeks. Pharmacokinetics indicated a slight accumulation of the drug in the serum after repeated dosing of Revacept for 3 weeks. A significant improvement of endothelial dysfunction after 0.06 and 0.6 µg/min acetylcholine and a significant decrease of vessel wall thickening were found after Revacept treatment. Accordingly, aortic vessel weight was reduced, and plaque sizes, macrophage and T-cell invasion tended to be reduced in histological evaluations. Bleeding time was determined after tail clipping in mice. Revacept alone or in combination with widely used anti-platelet drugs revealed a high safety margin with no prolongation of bleeding times.


CONCLUSIONS
Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time.
advanceCOR GmbH, Martinsried, Germany.
Martin
M
Ungerer
Zhongmin
Z
Li
Christine
C
Baumgartner
Silvia
S
Goebel
Jasmin
J
Vogelmann
Hans-Peter
HP
Holthoff
Meinrad
M
Gawaz
Götz
G
Münch
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000150:complications* / Q000503:physiopathology*; D001760:Bleeding Time; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006023:Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D008214:Lymphocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000473:pathology; D011817:Rabbits; D013927:Thrombosis / Q000209:etiology*
D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; C559357:Revacept; D002784:Cholesterol; D000109:Acetylcholine