The Fab fragment of a novel anti-GPVI monoclonal antibody, OM4, reduces in vivo thrombosis without bleeding risk in rats.
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.


RESULTS
OM4 Fab specifically inhibited collagen-induced aggregation of rat platelets in vitro with an IC50 of 20 to 30 microg/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.


CONCLUSIONS
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.
Li
Haiquan
H
Department of Cardiology and Thrombosis, Otsuka Maryland Medicinal Laboratories Inc, 9900 Medical Center Drive, Rockville, MD 20850, USA.
Lockyer
Simon
S
Concepcion
Alice
A
Gong
Xiaoqi
X
Takizawa
Hisao
H
Guertin
Moe
M
Matsumoto
Yutaka
Y
Kambayashi
Junichi
J
Tandon
Narendra N
NN
Liu
Yongge
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001760:Bleeding Time; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D006470:Hemorrhage / Q000453:epidemiology* / Q000209:etiology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D015994:Incidence; D007275:Injections, Intravenous; D010974:Platelet Aggregation / Q000187:drug effects*; D010976:Platelet Count; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood / Q000276:immunology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI