Ex vivo evaluation of anti-GPVI antibody in Cynomolgus monkeys: Dissociation between anti-platelet aggregatory effect and bleeding time

Yutaka Matsumoto; Hisao Takizawa; Kazuhiro Nakama; Xiaoqi Gong; Yoshihisa Yamada; Narendra N. Tandon; Junichi Kambayashi

doi:10.1160/TH06-05-0266

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(02): 167-175
DOI: 10.1160/TH06-05-0266

Platelets and Blood Cells

Schattauer GmbH

Ex vivo evaluation of anti-GPVI antibody in Cynomolgus monkeys: Dissociation between anti-platelet aggregatory effect and bleeding time

Yutaka Matsumoto

¹Otsuka Maryland Medicinal Laboratories, Rockville, Maryland, USA

,

Hisao Takizawa

¹Otsuka Maryland Medicinal Laboratories, Rockville, Maryland, USA

,

Kazuhiro Nakama

²Shin Nippon Biomedical Laboratories, Kagoshima, Japan

,

Xiaoqi Gong

¹Otsuka Maryland Medicinal Laboratories, Rockville, Maryland, USA

,

Yoshihisa Yamada

³First Institute of New Drug Discovery, Otsuka Pharmaceutical Co. , Ltd. , Tokushima, Japan

,

Narendra N. Tandon

¹Otsuka Maryland Medicinal Laboratories, Rockville, Maryland, USA

,

Junichi Kambayashi

¹Otsuka Maryland Medicinal Laboratories, Rockville, Maryland, USA

› Author Affiliations

Abstract

Summary

Recent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibitory effect on platelet aggregation and bleeding by GPVI blockade, we examined the effects of Fab fragment of OM2, an anti-human GPVI monoclonal antibody on ex vivo collagen-induced platelet aggregation and skin bleeding time after intravenous injection in cynomolgus monkeys. In a dose-escalation study, OM2 potently (>80%) inhibited collagen-induced platelet aggregation at the cumulative dose of 0. 2 mg/kg with a slight prolongation of bleeding time (1. 3 times baseline value). Furthermore, at 18. 8 mg/kg, the highest dose tested, prolongation of bleeding time was still mild (1. 9 times). In contrast, abciximab, Fab fragment of anti-GPIIb/IIIa antibody prolonged bleeding time by 5. 0 times at 0. 35 mg/kg, the lowest effective dose on platelet aggregation. Ina pharmacodynamic study,a bolus injection of OM2 at 0. 4 mg/kg produced potent inhibition of collagen-induced aggregation up to six hours after injection, showing longer half-life than that of abciximab. The injection of OM2 Fab did not induce thrombocytopenia and GPVI depletion in monkeys. These results suggest that blockade of GPVI by antibody can exerta potent inhibitory effect on collagen-induced platelet aggregation with a milder prolongation of bleeding time than blockade of GPIIb/IIIa. This study indicates that OM2 has the potential to be developed as a new class of therapeutic tool.

Keywords

GPVI - antibody - platelet

Full Text

References

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