The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons.
The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibalpha 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.
Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, E. Sabbelaan 53, Kortrijk, Belgium.
Alexandre
A
Fontayne
Muriel
M
Meiring
Seb
S
Lamprecht
Jan
J
Roodt
Eddy
E
Demarsin
Philippe
P
Barbeaux
Hans
H
Deckmyn
D000208:Acute Disease; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001760:Bleeding Time; D001792:Blood Platelets / Q000276:immunology*; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D006470:Hemorrhage / Q000139:chemically induced / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000276:immunology; D051379:Mice; D010215:Papio; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000276:immunology; D010976:Platelet Count; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000009:adverse effects / Q000276:immunology*; D012039:Regional Blood Flow; D012310:Ristocetin / Q000494:pharmacology; D013314:Stress, Mechanical; D013921:Thrombocytopenia / Q000139:chemically induced / Q000276:immunology; D013927:Thrombosis / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology
D000900:Anti-Bacterial Agents; D007140:Immunoglobulin Fab Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D012310:Ristocetin