The overall objective of this application 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 state in which they interact with one another to form a thrombus. This event, platelet aggregation, depends upon a change in platelet membrane glycoprotein GPIIIb-IIIa, such that it acquires the capacity to serve as a receptor for adhesive proteins. Occupancy of GPIIb-IIIa by fibrinogen leads to platelet aggregation. Monoclonal antibodies which 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-IIa as an immunogen, will be employed to elicit the monoclonal antibodies. Wjith three independent strategies, with the current knowledge base of the structure function of GPIIb-IIIa, and with the CORVAs expertise on monoclonal antibody 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 prevention of rethrombosis or for delivery of antithrombotic drugs.
