EVALUATION OF THE ANTI VON WILLEBRAND FACTOR (VWF) ANTIBODY

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EVALUATION OF THE ANTI VON WILLEBRAND FACTOR (VWF)
ANTIBODY GBR 600 IN A BABOON MODEL OF ARTERIAL THROMBOSIS
S. Hou1, J. Roodt2, S. Lamprecht2, M. Meiring2, P. Badenhorst2, H. Mottl1
1
  Glenmark Pharmaceuticals S.A., La Chaux-de-Fonds, Switzerland, 2University of the
Free State, Bloemfontein, South Africa

Objectives: To evaluate the therapeutic index (efficacy vs bleeding risk) of the anti
vWF- GP1b-alpha monoclonal antibody GBR 600 in a primate model of arterial
thrombus formation.
Background: Von Willebrand factor plays a key role in primary hemostasis, initiating
adhesion of circulating platelets to the exposed subendothelial surface and aggregation of
platelets under high shear stress. The anti-thrombotic agents that are currently available
are all associated with bleeding complications that limit their clinical utility. A
therapeutic agent that could prevent inappropriate platelet responses without being
associated with bleeding complications would represent a major advance.
Methods: Ability to inhibit arterial thrombus formation was determined using a modified
Folts model with a shunt placed between the femoral vein and artery. Cyclic flow
reductions were recorded after mechanical arterial damage. Bleeding was monitored
through template bleeding time and an incisional bleeding test. Clopidogrel was used as a
control.
Results: GBR 600 inhibited thrombus formation in a dose-dependent manner with an
ED100 of 0.04 mg/kg. Template bleeding time was increased. The maximum blood loss
at doses up to 250 fold ED100 as measured in the incisional bleeding was comparable to
the blood loss which was seen with the clopidogrel control at 2-4 fold the clopidogrel
ED100. Blood loss in the incisional bleeding test was self-limiting and did not increase
linearly with dose.
Conclusion: GBR 600 is a potent inhibitor of the vWF GP1b axis in a primate model of
arterial trombosis. The bleeding tendency of the antibody is low and not dose related.