This project will develop monoclonal antibodies of therapeutic utility to interrupt severe life-threatening thrombotic and related diseases in which the activation of the coagulation protease pathways play a significant pathogenetic role. The monoclonal antibodies are predicted to be of therapeutic efficacy based on specific binding and functional neutralization of the cell surface bimolecular complex of Tissue Factor and Factor VIIa (TF:VIIa), the major initiator of the coagulation protease cascades. Based on the fundamental changes in function when factor VIIa is bound to Tissue Factor, i. e. the ability to associate with substrates and to mediate proteolytic cleavage, the induction of one or more discrete conformational epitopes is predicted. Such epitopes represent neoantigens specific for the active initiation complex and will permit neutralization in vivo. In Phase I monoclonal antibodies that neutralize the bimolecular complex of (TF:VIIa) will be developed and their molecular specificity will be established including whether they are specific for the predicted neoantigen. Monoclonal antibodies to factor VIIa that neutralize as well as to (TF:VIIa) neo will be characterized in vitro. In Phase II selected neutralizing monoclonal antibodies to factor VIIa and to (TF:VIIa) neo will be evaluated for efficacy in vitro with cellular systems to mimic in vivo. Subsequently, the therapeutic efficacy will be evaluated in vivo for the ability to both prevent and to interrupt forms of disseminated intravascular coagulation, septic shock and thrombosis.
