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

Jin-an Jiao; Andrew B. Kelly; Ulla M. Marzec; Esperanza Nieves; Jorge Acevedo; Martin Burkhardt; Ana Edwards; Xiao-yun Zhu; Pierre-Andre Chavaillaz; Alice Wong; Jeffrey L. Wong; Jack O. Egan; Dean Taylor; Peter R. Rhode; Hing C. Wong

doi:10.1160/TH09-06-0400

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(01): 224-233
DOI: 10.1160/TH09-06-0400

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

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

Authors

Jin-an Jiao

¹Sunol Molecular Corporation, Miramar, Florida, USA
Andrew B. Kelly

²Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, USA
Ulla M. Marzec

²Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, USA
Esperanza Nieves

¹Sunol Molecular Corporation, Miramar, Florida, USA
Jorge Acevedo

¹Sunol Molecular Corporation, Miramar, Florida, USA
Martin Burkhardt

¹Sunol Molecular Corporation, Miramar, Florida, USA
Ana Edwards

¹Sunol Molecular Corporation, Miramar, Florida, USA
Xiao-yun Zhu

¹Sunol Molecular Corporation, Miramar, Florida, USA

³Altor BioScience Corporation, Miramar, Florida, USA
Pierre-Andre Chavaillaz

¹Sunol Molecular Corporation, Miramar, Florida, USA

³Altor BioScience Corporation, Miramar, Florida, USA
Alice Wong

¹Sunol Molecular Corporation, Miramar, Florida, USA
Jeffrey L. Wong

¹Sunol Molecular Corporation, Miramar, Florida, USA
Jack O. Egan

¹Sunol Molecular Corporation, Miramar, Florida, USA

³Altor BioScience Corporation, Miramar, Florida, USA
Dean Taylor

¹Sunol Molecular Corporation, Miramar, Florida, USA

³Altor BioScience Corporation, Miramar, Florida, USA
Peter R. Rhode

¹Sunol Molecular Corporation, Miramar, Florida, USA

³Altor BioScience Corporation, Miramar, Florida, USA
Hing C. Wong

³Altor BioScience Corporation, Miramar, Florida, USA

Abstract

Summary

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 ¹¹¹In-Oxine and post-surgical gamma camera imaging of ¹¹¹In-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.

Keywords

Tissue factor / factor VII - animal models - arterial thrombosis - coagulation inhibitors

Full Text

References

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