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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:187.)
© 2002 American Heart Association, Inc.

Thrombosis

Pharmacokinetics and Pharmacodynamics of AJW200, a Humanized Monoclonal Antibody to von Willebrand Factor, in Monkeys

Shunsuke Kageyama; Hiroshi Yamamoto; Harumi Nakazawa; Junko Matsushita; Tetsuya Kouyama; Akinori Gonsho; Yasuo Ikeda; Ryota Yoshimoto

From the Developmental Research Laboratories (S.K., H.Y., H.N., J.M., T.K., A.G., R.Y.), Pharmaceutical Research Laboratories, Ajinomoto Co, Inc, Kanagawa, and the Department of Internal Medicine (Y.I.), School of Medicine, Keio University, Tokyo, Japan.

Correspondence to Hiroshi Yamamoto, 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-8681, Japan. E-mail hiroshia_yamamoto{at}ajinomoto.com

The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.

Key Words: von Willebrand factor • platelets • shear stress • bleeding time • AJW200

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