Photo by Sakurai Midori
Researchers say they have developed an antibody that inhibits factor XIa (FXIa) without increasing the risk of bleeding, as well as an antibody that can reverse the inhibitor’s effects.
The inhibitor—known as DEF—staved off clotting in human blood and animal models.
Even when it was given at extremely high doses, DEF did not induce bleeding in the animals.
Still, the researchers developed an antibody—revC4—that can reverse DEF’s activity.
Tovo David, PhD, of University of California, San Francisco, and his colleagues described this work in Science Translational Medicine.
Initially, the researchers generated a series of human immunoglobulin Gs (IgGs) that blocked FXIa active-site function but did not bind FXI zymogen or other coagulation proteases.
The most potent of these was C24. This IgG inhibited FXIIa-induced thrombin generation and intrinsic pathway–triggered clot formation in human plasma and whole blood. C24 also inhibited FeCl3-induced arterial thrombosis in an FXI-humanized mouse.
Dr David and his colleagues then set out to improve upon C24, rendering it unable to activate complement, engage Fc receptors, or activate platelets and other cells. The resulting molecule was DEF.
The researchers tested DEF in rabbits and cynomolgus macaques. At doses much higher than those required to inhibit thrombus formation, DEF did not increase cuticle bleeding in the rabbits or cause spontaneous bleeding in the monkeys.
Despite this lack of bleeding, Dr David and his colleagues generated a human IgG that can reverse DEF activity because FXI deficiency can be associated with bleeding in humans.
This reversal agent—revC4—proved effective in human plasma (ex vivo) and in rabbits. revC4 reversed the anticoagulant effect of DEF within 30 minutes of dosing.
Based on these results, the researchers concluded that, with further development, their reversible FXIa-specific antibody might provide a new—and potentially safer—type of anticoagulant.
