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Anti-GPVI Fab SAR264565 effectively blocks GPVI function in ex vivo human platelets under arterial shear in a perfusion chamber

: Florian, P.; Wonerow, P.; Harder, S.; Kuczka, K.; Dubar, M.; Graff, J.


European journal of clinical pharmacology 73 (2017), No.8, pp.949-956
ISSN: 0031-6970
Journal Article
Fraunhofer IME ()

Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro. The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen's ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow. Ex vivo effects of SAR264565 (10 and 100 mu g/mL) were investigated before administration of aspirin or clopidogrel to study subjects (baseline), after aspirin (2x 300 mg) administration alone, and after combined aspirin (2x 300 mg)/clopidogrel (600 mg) administration. Additional ex vivo and in vitro platelet tests were also performed. Addition of SAR264565 to the perfusion chamber dose-dependently reduced platelet and fibrin deposition, reaching statistical significance at 100 mu g/mL (415 +/- A 67 compared to 137 +/- A 36 platelets/cm(2), [p < 0.01] and fibrin 0.095 +/- A 0.014 compared to 0.032 +/- A 0.008 mu g/cm(2), [p < 0.001]). Aspirin administration caused an additive and dose-dependent reduction of SAR264565-induced platelet and fibrin deposition. Combined aspirin/clopidogrel administration did not lead to additional SAR264565-induced inhibition of platelet or fibrin deposition. GPVI antagonism by the anti-GPVI-Fab fragment SAR264565 dose-dependently inhibits platelet adhesion and fibrin formation on a collagen surface under arterial shear. Additive inhibition is observed after prior aspirin administration with no further amplification on top of a combination of aspirin with clopidogrel. Ex vivo antiplatelet tests confirmed a selective inhibiting effect of SAR264565 on collagen-induced platelet activation.