Anti-thrombotic effects and bleeding risk of AJvW-2, a monoclonal antibody against human von Willebrand factor.
1. A murine anti-human vWF monoclonal antibody, AJvW-2, was developed that inhibited the interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (vWF) during the ristocetin- (IC50 = 0.7 +/- 0.1 microgram ml-1) and botrocetin- (IC50 = 1.8 +/- 0.3 microgram ml-1) induced aggregation of human platelets. 2. AJvW-2 inhibited the high shear stress (10.8 N m-2) induced aggregation of human platelets dose-dependently with an IC50 = 2.4 +/- 0.3 micrograms ml-1, but had no effect on low shear stress induced platelet aggregation (1.2 N m-2) up to 100 micrograms ml-1. 3. AJvW-2 also inhibited the high shear stress (5.0 N m-2) induced adhesion of human platelets to collagen I with the same efficacy (IC50 = 2.4 +/- 0.3 micrograms ml-1), but no effect at low shear conditions (1.5 N m-2). 4. AJvW-2 inhibited the botrocetin-induced aggregation of platelets from guinea-pig, rat, rabbit, dog and pig at the same concentration range as human platelets; it likewise also inhibited the high shear stress induced aggregation and adhesion to collagen I of guinea-pig platelets. 5. AJvW-2 prevented arterial thrombus formation in guinea-pigs at a dose of 100 micrograms kg-1 without prolonging the template bleeding time, whereas the GPIIb/IIIa antagonists lamifiban mediated inhibition of thrombosis at 1000 micrograms kg-1 was accompanied by a significant prolongation of the bleeding time. 6. These results suggest that AJvW-2 is a potent inhibitor of the GPIb-vWF interaction and a potential novel antithrombotic agent with lower bleeding risk than GPIIb/IIIa antagonists.
Kageyama
S
S
Central Research Laboratories, Ajinomoto Co., Inc., Yokohama, Japan.
Yamamoto
H
H
Nagano
M
M
Arisaka
H
H
Kayahara
T
T
Yoshimoto
R
R
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003435:Crotalid Venoms / Q000494:pharmacology; D004285:Dogs; D005343:Fibrinolytic Agents / Q000378:metabolism* / Q000494:pharmacology*; D006168:Guinea Pigs; D006470:Hemorrhage / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012310:Ristocetin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control; D014841:von Willebrand Factor / Q000276:immunology* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D003435:Crotalid Venoms; D005343:Fibrinolytic Agents; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D012310:Ristocetin; C030961:botrocetin; D003094:Collagen