THERAPEUTIC ANTI-THROMBOTIC MONOCLONAL ANTIBODIES

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 PLAYS 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, 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 THEIREXACT MOLECULAR SPECIFICITY WILL BE ESTABLISHED, INCLUDING WHETHER THEY ARE SPECIFIC FOR THE PREDICTED NEOANTIGEN. MONOCLONAL ANTIBODIES TO FACTOR VIIA THAT NEUTRALIZE AS WELL 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 THEIR ABILITY IN VITRO WITH CELLULAR SYSTEMS TO MIMIC IN VIVO SYSTEMS. SUBSEQUENTLY, THE THERAPEUTIC EFFICACY WILL BE EVALUATED IN VIVO FOR THE ABILITY TO BOTH PREVENT AND INTERRUPT FORMS OF DISSEMINATED INTRAVASCULAR COAGULATION, SEPTIC SHOCK, AND THROMBOSIS.