Anti-human vWF monoclonal antibody, AJvW-2 Fab, inhibits repetitive coronary artery thrombosis without bleeding time prolongation in dogs.
The antithrombotic and antihaemostatic effects of the monoclonal antibody against human vWF (AJvW-2 Fab) were investigated in comparison with those of the monoclonal antibody against platelet GPIIb/IIIa (abciximab) in dogs. The ex vivo platelet aggregation and template bleeding time were measured before, 5, 90, 210 min and 24 h after injection of either AJvW-2 Fab or abciximab in anesthetized beagle dogs. Plasma concentration, vWF occupancy and plasma vWF antigen level were also measured by ELISA. In addition, the antithrombotic effect was evaluated in a canine model of repetitive coronary thrombosis (Folts model). AJvW-2 Fab significantly inhibited the ex vivo botrocetin-induced platelet aggregation at 0.18 mg/kg (53% plasma vWF occupancy) and also inhibited cyclic flow reductions (CFRs) at 0.06 mg/kg (31% occupancy). A significant prolongation of the bleeding time was observed at 1.8 mg/kg (95% occupancy), which was 30 times as high as the antithrombotic effective dose. Whereas, abciximab significantly inhibited both the ex vivo ADP-induced platelet aggregation and CFRs at 0.8 mg/kg, which was the minimally effective dose, also resulting in a significant prolongation of the bleeding time. These results suggest that blockade of the GPIb-vWF axis with AJvW-2 Fab leads to the inhibition of thrombus formation in the stenosed coronary arteries without less bleeding time prolongation than the GPIIb/IIIa blockade with abciximab.
Kageyama
S
S
Pharmaceutical Research Laboratories, Developmental Research Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan.
Yamamoto
H
H
Nakazawa
H
H
Yoshimoto
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001760:Bleeding Time; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control*; D004285:Dogs; D005343:Fibrinolytic Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D007700:Kinetics; D010974:Platelet Aggregation / Q000187:drug effects; D012008:Recurrence; D014841:von Willebrand Factor / Q000032:analysis / Q000276:immunology*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D007140:Immunoglobulin Fab Fragments; D014841:von Willebrand Factor