An anti-tissue factor monoclonal antibody which inhibits TF.VIIa complex is a potent anticoagulant in plasma.
Tissue factor (TF) functions as the receptor and cofactor for factor VIIa (VIIa) to form a proteolytically active TF.VIIa complex on cell surfaces. We here demonstrate that most MAbs against human TF were poor inhibitors of TF function in plasma and that they inhibited preformed TF.VIIa complex at a slow rate which was dependent on dissociation of VIIa from the cell surface TF. An exception was defined by one MAb (TF8-5G9) which was an effective immediate anticoagulant in plasma. Binding of TF8-5G9 to TF.VIIa inhibited catalytic function prior to dissociation of the TF.VIIa complex. This analysis thus establishes two distinct mechanisms by which MAbs interfere with TF function. The MAb TF8-5G9 introduces a therapeutic principle for rapid arrest of inappropriate triggering of coagulation by TF as well as the TF.VIIa complex in vivo.
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Department of Immunology, Research Institute of Scripps Clinic, La Jolla, CA.
Edgington
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D000911:Antibodies, Monoclonal / Q000276:immunology*; D000925:Anticoagulants / Q000276:immunology*; D002460:Cell Line; D005164:Factor IX / Q000302:isolation & purification / Q000502:physiology; D005167:Factor VII / Q000302:isolation & purification / Q000502:physiology; D015942:Factor VIIa / Q000276:immunology / Q000502:physiology*; D005170:Factor X / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D001749:Urinary Bladder Neoplasms
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D005167:Factor VII; D005164:Factor IX; D005170:Factor X; D013925:Thromboplastin; D015942:Factor VIIa