Antiplatelet and Antithrombotic Effects of YM337, the Fab Fragment of a Humanized Anti-GPIIb/IIIa Monoclonal Antibody in Monkeys

Seiji Kaku; Tomihisa Kawasaki; Nami Hisamichi; Yumiko Sakai; Yuta Taniuchi; Osamu Inagaki; Shinya Yano; Ken-ichi Suzuki; Chinami Terazaki; Yasuhiko Masuho; Noboru Satoh; Toichi Takenaka; Kennichi Yanagi; Norio Ohshima

doi:10.1055/s-0038-1650342

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1996; 75(04): 679-684
DOI: 10.1055/s-0038-1650342

Original Article

Schattauer GmbH Stuttgart

Antiplatelet and Antithrombotic Effects of YM337, the Fab Fragment of a Humanized Anti-GPIIb/IIIa Monoclonal Antibody in Monkeys

Seiji Kaku

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Tomihisa Kawasaki

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Nami Hisamichi

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Yumiko Sakai

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Yuta Taniuchi

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Osamu Inagaki

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Shinya Yano

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Ken-ichi Suzuki

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Chinami Terazaki

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Yasuhiko Masuho

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Noboru Satoh

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Toichi Takenaka

Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan

,

Kennichi Yanagi

¹The Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan

,

Norio Ohshima

¹The Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan

› Institutsangaben

Abstract

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Summary

The antiplatelet and antithrombotic effects of the Fab fragment of the humanized antiplatelet glycoprotein (GP) IIb/IIIa monoclonal antibody C4G1 (YM337) were investigated in monkeys. First, the relationship between the inhibition of platelet aggregation and the prolongation of bleeding time was studied in rhesus monkeys. YM337 dose-dependently inhibited ex vivo platelet aggregation, with complete inhibition at doses higher than 0.25 mg/kg intravenous injection or 1.5 μg/kg/min infusion. At 0.25 mg/kg bolus injection followed by 1.5 μg/kg/min infusion, YM337 immediately and continuously inhibited platelet aggregation during the 6-h infusion period with platelet aggregation rapidly returning to over 50% of baseline within 1 h after the cessation of infusion. Template-bleeding time was significantly prolonged during the period of complete inhibition of platelet aggregation.

Second, the antithrombotic effects of YM337 were investigated in a photochemically-induced thrombosis model in squirrel monkeys. YM337 at a dose of 1 mg/kg intravenous injection followed by 6 μg/kg/min infusion for 60 min prevented occlusive thrombus formation in all 4 monkeys. In contrast, time to occlusive thrombus formation did not change on intravenous bolus injection of aspirin 17 mg/kg (11.3 ± 5.2 min) or sodium ozagrel (9.4 ± 3.0 min) compared with saline (13.3 ± 4.0 min). YM337 but not aspirin or sodium ozagrel significantly inhibited ex vivo ADP-induced platelet aggregation, while all drugs completely inhibited arachidonic acid-induced platelet aggregation. However, while aspirin and sodium ozagrel inhibited the thromboxane B₂ generation accompanying arachidonic acid-induced platelet aggregation, YM337 had no effect on this variable. Platelet counts and bleeding time showed no significant change in any group in this squirrel monkey model.

These results indicate that YM337, with a short half-life, may be a useful therapeutic agent in patients with thrombotic disorders.

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Referenzen

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