OC 22.5 - Development of an innovative approach based on targeted anticoagulation for the treatment of venous thromboembolism.

Background: Venous thromboembolism (VTE) is the third leading cause of death worldwide. It is a common thrombotic disorder encompassing deep vein thrombosis and pulmonary embolism. Anticoagulant drugs reduce the burden of VTE, but foster an increased risk of bleeding.

Aims: We developed an innovative anticoagulation approach, based on an antibody-drug-conjugate (ADC) combining a highly specific anti-fibrin antibody to the direct thrombin inhibitor, hirudin. As this agent concentrates within a fibrin-rich thrombus, a very low systemic concentration is required to achieve efficient anticoagulation at site of thrombosis. This also implies a low bleeding risk.

Methods: We generated five ADCs molecules. Their anticoagulant potential and enzymatic activity were tested using aPTT and a fluorogenic assay. The antithrombotic effect of one ADC was compared to hirudin in experimental models of arterial thrombosis and thromboembolism. Its pharmacokinetic was studied in mice using aPTT. The impact on hemostasis was determined in a tail-bleeding assay.

Results: Amongst the five ADCs, we selected ADC-hir10 based on its efficient anticoagulant effect in the aPTT assay. Its anticoagulant potential reached 65% of an equivalent dose of hirudin. Its ability to bind immobilized fibrin or fibrin-rich clots was evidenced both in a microfluidic assay, and after localized FeCl3-induced injury of a mouse carotid. Concerning its pharmacokinetic, a dose of 0.1 mg/kg of ADC-hir10 injected IV, entailed an anticoagulant effect for up to 30 hours, while 10 mg/kg of hirudin was active for only 1 hour (Fig 1A). The ADC-hir10 showed superiority over equivalent dose of hirudin after the FeCl3-injury model. It also protected mice from a tissue factor-induced thromboembolism (TE) (Fig 1B-C). Finally, the ADC-hir10 did not prolong the tail-bleeding time at doses it provided protection in the TE model.

Conclusion(s): We developed a promising targeted strategy that efficiently prevents experimental thrombosis with no impact on hemostasis.