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

INTRODUCTION: 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.
METHODS: 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 μg/mL) were investigated before administration of aspirin or clopidogrel to study subjects (baseline), after aspirin (2× 300 mg) administration alone, and after combined aspirin (2× 300 mg)/clopidogrel (600 mg) administration. Additional ex vivo and in vitro platelet tests were also performed.
RESULTS: Addition of SAR264565 to the perfusion chamber dose-dependently reduced platelet and fibrin deposition, reaching statistical significance at 100 μg/mL (415 ± 67 compared to 137 ± 36 platelets/cm2, [p < 0.01] and fibrin 0.095 ± 0.014 compared to 0.032 ± 0.008 μg/cm2, [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.
CONCLUSION: 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.