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The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Topic:

New vitamin K-dependent proteins

DOI: https://doi.org/10.1160/TH08-02-0073
Issue: 2008: 100/4 (Oct) pp. 517-726
Pages: 670-677

The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons

Alexandre Fontayne 1, Muriel Meiring 2, Seb Lamprecht 2, Jan Roodt 2, Eddy Demarsin 3, Philippe Barbeaux 3, Hans Deckmyn1
1 Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Belgium; 2 Department of Hematology and Cell Biology, Faculty of Health Sciences, University of the Free State, South Africa; 3 Thrombogenics, Leuven, Belgium

Keywords

thrombosis, platelet adhesion, Antithrombotic, glycoprotein Ib, humanized antibody

Summary

The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibα and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding or thrombocytopenia. Recently, we developed a fully recombinant and humanized version of 6B4-Fab-fragment, h6B4-Fab, which maintains its inhibitory capacities in vitro and ex vivo after injection in baboons. We here investigated the antithrombotic properties, the effect on bleeding time and blood loss and initial pharmacokinetics of h6B4-Fab in baboons. The antithrombotic effect of h6B4-Fab on acute platelet-mediated thrombosis was studied in baboons where thrombus formation is induced at an injured and stenosed site of the femoral artery, allowing for cyclic flow reductions (CFRs) which are measured on an extracorporeal femoral arteriovenous shunt. Injection of 0.5 mg/kg h6B4-Fab significantly reduced the CFRs by 80%, whereas two extra injections, resulting in cumulative doses of 1.5 and 2.5 mg/kg, completely inhibited the CFRs. Platelet receptor occupancy, plasma concentrations and effects ex vivo were consistent with what was previously observed. Finally, minimal effects on bleeding time and blood loss, no spontaneous bleeding and no thrombocytopenia were observed. We therefore conclude that h6B4-Fab maintains the antithrombotic capacities of the murine 6B4-Fab, without causing side effects and therefore can be used for further development.

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