Anti-human VWF monoclonal antibody SZ-123 prevents arterial thrombus formation by inhibiting VWF-collagen and VWF-platelet interactions in Rhesus monkeys.

Abstract

The interactions between collagen, von Willebrand factor (VWF), and glycoprotein Ib (GPIb) are crucial for hemostasis and thrombosis. This axis represents a promising target for the development of new antithrombotic agents. In this study, we investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123 and its potential underlying mechanisms. Cyclic flow reductions (CFRs), an indicator of arterial thrombosis, were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of SZ-123. Ex vivo VWF binding to collagen, platelet agglutination, platelet count, and template bleeding time were used as measurements of antithrombotic activity. In addition, plasma VWF and SZ-123 levels, and VWF occupancy were measured by ELISA. Administration of 0.1, 0.3, and 0.6 mg/kg SZ-123 resulted in 45.3%, 78.2%, and 100% reductions in CFRs, respectively. When 0.3 and 0.6 mg/kg SZ-123 were administered, 100% of VWF was occupied by the antibody. Moreover, 100% ex vivo inhibition of VWF-collagen binding and 60-95% inhibition of platelet agglutination were observed from 15 min to 1 h. None of the doses resulted in significant prolongation of bleeding time. In vitro experiments revealed that SZ-123 not only blocks the collagen-VWF A3 interaction but also indirectly inhibits VWF A1 binding to GPIbα induced by ristocetin. Thus, we demonstrate that SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3-collagen and VWF A1-platelet interactions and does not significantly prolong bleeding time.

• Authors: Yi-ming Zhao, Miao Jiang, Shun-dong Ji, Yang He, Fei Shen, Xue-mei Li, Chang-geng Ruan
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 85 Issue 7 Pg. 945-53 (Apr 01 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23295157 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Collagen Type III
• Fibrinolytic Agents
• Membrane Glycoproteins
• Platelet Glycoprotein GPIb-IX Complex
• adhesion receptor
• von Willebrand Factor

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, pharmacology, therapeutic use)
• Bleeding Time
• Blood Coagulation (drug effects)
• Blood Platelets (drug effects, pathology)
• Collagen Type III (metabolism)
• Cross Reactions
• Female
• Femoral Artery (drug effects, physiopathology)
• Fibrinolytic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Macaca mulatta
• Male
• Membrane Glycoproteins (metabolism)
• Platelet Aggregation (drug effects)
• Platelet Count
• Platelet Glycoprotein GPIb-IX Complex
• Protein Binding
• Regional Blood Flow
• Thrombosis (physiopathology, prevention & control)
• von Willebrand Factor (immunology, metabolism)