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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1199.)
© 2007 American Heart Association, Inc.

Thrombosis

The Fab Fragment of a Novel Anti-GPVI Monoclonal Antibody, OM4, Reduces In Vivo Thrombosis Without Bleeding Risk in Rats

Haiquan Li; Simon Lockyer; Alice Concepcion; Xiaoqi Gong; Hisao Takizawa; Moe Guertin; Yutaka Matsumoto; Junichi Kambayashi; Narendra N. Tandon; Yongge Liu

From the Department of Cardiology and Thrombosis, Otsuka Maryland Medicinal Laboratories Inc, Rockville, Md.

Correspondence to Yongge Liu, PhD, FAHA, Otsuka Maryland Medicinal Laboratories Inc, 9900 Medical Center Drive, Rockville, MD 20850. E-mail yonggel{at}otsuka.com

Background— Inhibition of GPVI has been proposed as a useful antithrombotic strategy; however, in vivo proof-of-concept animal studies targeting GPVI are lacking. We evaluated a novel anti-human GPVI monoclonal antibody OM4 Fab in rats.

Methods and Results— OM4 Fab specifically inhibited collagen-induced aggregation of rat platelets in vitro with an IC₅₀ of 20 to 30 µg/mL but not ADP and AA-induced platelet aggregation. After intravenous administration of OM4 Fab, a rapid inhibition of ex vivo platelet aggregation was observed with a gradual recovery within 60 to 90 minutes which corresponded to the decline in OM4 Fab plasma concentration and time-dependent decrease in platelet-bound OM4 Fab. In contrast to previous reports in mice, intravenous OM4 Fab did not deplete platelet GPVI. Injection of OM4 IgG caused acute thrombocytopenia. In a modified Folts model of cyclic flow reduction in rat carotid artery, the number of complete occlusions was significantly reduced by intravenous administration of OM4 Fab (20 mg/kg) before or after mechanical injury to the vessel, without prolongation of bleeding time.

Conclusion— Fab fragment of the monoclonal antibody OM4 effectively inhibits collagen induced platelet aggregation in vitro and ex vivo, and in vivo thrombosis in rats without prolonging bleeding time. Antibodies against GPVI may have therapeutic potential, inhibiting thrombosis without prolonging bleeding time.

The Fab fragment of a novel anti-human GPVI monoclonal antibody, OM4, inhibited ex vivo collagen-induced aggregation of rat platelets and thrombosis in vivo without the prolongation of bleeding time or GPVI-depletion. The inhibition was short-lived (30 to 45 minutes) with full recovery in 90 minutes. Inhibition of GPVI may be a viable antithrombotic strategy.

Key Words: glycoprotein VI • platelet • aggregation • thrombosis • bleeding time

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