Factor XIa-specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis

Area of Science:

• Hematology
• Pharmacology
• Immunology

Background:

• Thrombosis poses significant health risks, with current treatments balancing efficacy against bleeding complications.
• Coagulation factor XI (FXI) inhibition is a potential strategy to mitigate thrombosis while minimizing bleeding.
• Developing targeted FXI inhibitors requires careful characterization to ensure specificity and safety.

Purpose of the Study:

• To develop and evaluate human antibodies that specifically inhibit the active site of coagulation factor XIa (FXIa).
• To assess the antithrombotic efficacy and safety profile of these FXIa inhibitors in preclinical models.
• To create a reversal agent for the FXIa inhibitor to manage potential bleeding events.

Main Methods:

• Generation and characterization of human IgG antibodies targeting FXIa active site.
• In vitro clotting assays in human blood.
• In vivo thrombosis models (FeCl3-induced carotid artery occlusion, thread-induced venous thrombosis) in relevant animal species.
• Bleeding assessment in rabbits and macaques.
• Development and testing of an FXIa inhibitor reversal agent.

Main Results:

• Developed potent FXIa-specific IgG antibodies (C24, DEF) that inhibit FXIa activity without affecting FXI zymogen.
• DEF demonstrated effective antithrombotic activity in multiple animal models at clinically relevant doses.
• DEF showed no increased bleeding risk in rabbits or macaques, even at supra-therapeutic doses.
• A reversal agent was successfully developed, demonstrating rapid reversal of DEF activity both ex vivo and in vivo.

Conclusions:

• Active site-directed, FXIa-specific antibodies can effectively inhibit thrombosis in preclinical models.
• These antibodies, along with a developed reversal agent, offer a potential new therapeutic strategy for thrombosis with an improved safety profile.
• Further exploration of FXIa inhibition in human diseases is warranted based on these findings.