A Novel Antithrombotic Agent Targeting The Human Thromboxane A(2) Receptor

In efforts to define new targets for antithrombotic purposes, there is interest in utilizing antibodies targeting ligand binding domains of platelet receptors. To this end, we have recently shown that an antibody (designated C‐EL2Ab), which targets the C‐terminus of the second extracellular loop (C‐EL2) of the thromboxane A 2 receptor (TPR), selectively blocks TPR‐mediated platelet aggregation. This inhibitory effect was evident under both in vitro and ex vivo experimental conditions. Our current studies employed an in vivo model of thrombosis to determine the potential for the use of C‐EL2Ab as a thromboprotective agent. Thus, a ferric chloride carotid artery injury thrombosis model revealed a significant increase in time for occlusion in mice treated with C‐EL2Ab, when compared to controls such as normal rabbit IgG, or an antibody which targets a region separate from the ligand binding site (i.e., EL1). We next examined the effect of C‐EL2Ab on hemostasis. Bleeding time results showed no increase in tail bleeding times in C‐EL2Ab treated mice, compared to controls. Collectively, these results clearly demonstrate that C‐EL2Ab has anti‐platelet/anti‐thrombotic effects, and is devoid of increased bleeding risk. Moreover, the identification of a functionally active TPR sequence will significantly aid molecular modeling study predictions for organic derivatives which possess in vivo activity.