Florian Peter, Wonerow Peter, Harder Sebastian, Kuczka Karina, Dubar Michel, Graff Jochen
Sanofi-Aventis Deutschland GmbH, R&D, Industriepark Hoechst, Frankfurt am Main, Germany.
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany.
Eur J Clin Pharmacol. 2017 Aug;73(8):949-956. doi: 10.1007/s00228-017-2264-9. Epub 2017 May 18.
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 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.
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/cm, [p < 0.01] and fibrin 0.095 ± 0.014 compared to 0.032 ± 0.008 μg/cm, [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.
糖蛋白VI（GPVI）是胶原蛋白介导的血小板黏附和激活的主要血小板受体。SAR264565是一种抗GPVI-Fab，与GPVI具有高亲和力结合，并在体外阻断人血小板中的GPVI功能。
使用Sakariassen的体外血栓形成灌注室模型，在模拟动脉血流的条件下，在胶原蛋白包被的表面上研究了SAR26456对21名健康男性受试者血液中血小板反应性的影响。在给研究对象服用阿司匹林或氯吡格雷之前（基线）、单独服用阿司匹林（2×300mg）后以及联合服用阿司匹林（2×300mg）/氯吡格雷（600mg）后，研究了SAR264565（10和100μg/mL）的体外作用。还进行了额外的体外和体外血小板试验。
向灌注室中添加SAR264565剂量依赖性地减少了血小板和纤维蛋白沉积，在100μg/mL时达到统计学显著性（与137±36个血小板/cm相比，为415±67个，[p<0.01]；与0.032±0.008μg/cm相比，纤维蛋白为0.095±0.014，[p<0.001]）。服用阿司匹林导致SAR264565诱导的血小板和纤维蛋白沉积呈累加性和剂量依赖性减少。联合服用阿司匹林/氯吡格雷并未导致SAR264565诱导的血小板或纤维蛋白沉积的额外抑制。
抗GPVI-Fab片段SAR264565对GPVI的拮抗作用在动脉剪切力下剂量依赖性地抑制胶原蛋白表面的血小板黏附和纤维蛋白形成。在预先服用阿司匹林后观察到累加性抑制，在阿司匹林与氯吡格雷联合使用的基础上没有进一步增强。体外抗血小板试验证实了SAR264565对胶原蛋白诱导的血小板激活具有选择性抑制作用。
