Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site

• Published in: Thrombosis and haemostasis Vol. 103; no. 1; p. 224
• Main Authors: Jiao, Jin-an, Kelly, Andrew B, Marzec, Ulla M, Nieves, Esperanza, Acevedo, Jorge, Burkhardt, Martin, Edwards, Ana, Zhu, Xiao-yun, Chavaillaz, Pierre-Andre, Wong, Alice, Wong, Jeffrey L, Egan, Jack O, Taylor, Dean, Rhode, Peter R, Wong, Hing C
• Format: Journal Article
• Language: English
• Published: Germany 01.01.2010
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Antibody Specificity; Binding Sites; Blood Coagulation - drug effects; Blood Loss, Surgical - prevention & control; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Endarterectomy; Factor IX - metabolism; Factor VIIa - metabolism; Factor X - metabolism; Female; Femoral Artery - surgery; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - pharmacology; Hemorrhage - chemically induced; Humans; Injections, Intravenous; Mice; Mice, Inbred BALB C; Pan troglodytes; Radionuclide Imaging; Recombinant Fusion Proteins - pharmacology; Thromboplastin - antagonists & inhibitors; Thromboplastin - immunology; Thromboplastin - metabolism; Thrombosis - blood; Thrombosis - diagnostic imaging; Thrombosis - etiology; Thrombosis - prevention & control
• DOI: 10.1160/TH09-06-0400

Tissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing haemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees. A bolus (1 mg/kg) of ALT-836 was injected intravenously immediately preceding the restoration of flow in the endarterectomised femoral artery. Pre-surgical labelling of autologous platelets using (111)In-Oxine and post-surgical gamma camera imaging of (111)In-platelet deposition at endarterectomy sites was performed. The manipulated arterial segments were harvested for patency analysis 30 days following surgery. The results indicate that ALT-836 was highly effective at reducing acute vascular thrombosis, with no significant variations in surgical blood loss and template-bleeding time in the treated group compared to the control animals. These data suggest that ALT-836 is an effective and safe antithrombotic agent in preventing TF-initiated vascular thrombogenesis without compromising haemostasis.