Anti-thrombotic effects and bleeding risk of AJvW-2, a monoclonal antibody against human von Willebrand factor |
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Authors: | Shunsuke Kageyama Hiroshi Yamamoto Mitsuyo Nagano Harumi Arisaka Takashi Kayahara Ryota Yoshimoto |
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Institution: | Central Research Laboratories, Ajinomoto Co., Inc., Yokohoma, Japan |
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Abstract: | - A murine anti-human vWF monoclonal antibody, AJvW-2, was developed that inhibited the interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (vWF) during the ristocetin- (IC50=0.7±0.1 μg ml−1) and botrocetin- (IC50=1.8±0.3 μg ml−1) induced aggregation of human platelets.
- AJvW-2 inhibited the high shear stress (10.8 N m−2) induced aggregation of human platelets dose-dependently with an IC50=2.4±0.3 μg ml−1, but had no effect on low shear stress induced platelet aggregation (1.2 N m−2) up to 100 μg ml−1.
- AJvW-2 also inhibited the high shear stress (5.0 N m−2) induced adhesion of human platelets to collagen I with the same efficacy (IC50=2.4±0.3 μg ml−1), but had no effect at low shear conditions (1.5 N m−2).
- AJvW-2 inhibited the botrocetin-induced aggregation of platelets from guinea-pig, rat, rabbit, dog and pig at the same concentration range as human platelets; it likewise also inhibited the high shear stress induced aggregation and adhesion to collagen I of guinea-pig platelets.
- AJvW-2 prevented arterial thrombus formation in guinea-pigs at a dose of 100 μg kg−1 without prolonging the template bleeding time, whereas the GPIIb/IIIa antagonist lamifiban mediated inhibition of thrombosis at 1000 μg kg−1 was accompanied by a significant prolongation of the bleeding time.
- These results suggest that AJvW-2 is a potent inhibitor of the GPIb-vWF interaction and a potential novel antithrombotic agent with lower bleeding risk than GPIIb/IIIa antagonists.
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Keywords: | AJvW-2 von Willebrand factor GPIb GPIIb/IIIa shear stress thrombosis bleeding risk |
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