MONOCLONAL ANTIBODIES SPECIFIC FOR ACTIVATED PLATELETS

THE OVERALL OBJECTIVE OF THIS PROJECT IS TO DEVELOP MONOCLONAL ANTIBODIES SPECIFIC FOR ACTIVATED HUMAN PLATELETS. A CENTRAL EVENT IN THROMBOTIC DISEASES IS THE TRANSITION OF CIRCULATING, NONACTIVATED PLATELETS TO A STATEIN WHICH THEY INTERACT WITH ONE ANOTHER TO FORM A THROMBUS. THIS EVENT, PLATELET AGGREGATION, DEPENDS UPON A CHANGE IN PLATELET MEMBRANE GLYCOPROTEIN GPIIB-IIIA, SUCH THAT IT ACQUIRES THE CAPACITY TO SERVE AS A RECEPTOR FOR ADHESIVE PROTEINS. THE OCCUPANCY OF GPIIB-IIIA BY FIBRINOGEN LEADS TO PLATELET AGGREGATION. MONOCLONAL ANTIBODIES THAT RECOGNIZE FUNCTIONAL GPIIB-IIIA, BUT NOT ITS RESTING CONFORMER, WOULD REACT SELECTIVELY WITH ACTIVATED PLATELETS. THREE STRATEGIES, ONE BASED UPON THE USE OF A PEPTIDE SEQUENCE IN GPIIB-IIIA AS AN IMMUNOGEN, WILL BE EMPLOYED TO ELICIT THE MONOCLONAL ANTIBODIES. WITH THREE INDEPENDENT STRATEGIES, WITH THE CURRENT KNOWLEDGE BASE OF THE STRUCTURE-FUNCTION OFGPIIB-IIIA, AND WITH CORVAS, INC.'S, EXPERTISE IN MONOCLONALANTIBODY PRODUCTION, THE DEVELOPMENT OF REAGENTS WITH THE APPROPRIATE SPECIFICITY IS ANTICIPATED. SUCH ANTIBODIES HAVE ENORMOUS COMMERCIAL POTENTIAL AS IN VITRO DIAGNOSTIC REAGENTS FOR DETECTION OF THROMBOTIC AND PRETHROMBOTIC STATES, AS IN VIVO DIAGNOSTIC REAGENTS FOR THROMBUS IMAGING, AND AS THERAPEUTIC AGENTS FOR THE PREVENTION OF RETHROMBOSIS OR FOR THE DELIVERY OF ANTITHROMBOTIC DRUGS.