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

Abstract

Thrombosis is a major cause of morbidity and mortality. Current antithrombotic drugs are not ideal in that they must balance prevention of thrombosis against bleeding risk. Inhibition of coagulation factor XI (FXI) may offer an improvement over existing antithrombotic strategies by preventing some forms of thrombosis with lower bleeding risk. To permit exploration of this hypothesis in humans, we generated and characterized 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 IgGs, C24 and DEF, inhibited clotting in whole human blood and prevented FeCl3-induced carotid artery occlusion in FXI-deficient mice reconstituted with human FXI and in thread-induced venous thrombosis in rabbits at clinically relevant doses. At doses substantially higher than those required for inhibition of intravascular thrombus formation in these models, DEF did not increase cuticle bleeding in rabbits or cause spontaneous bleeding in macaques over a 2-week study. Anticipating the desirability of a reversal agent, we also generated a human IgG that rapidly reversed DEF activity ex vivo in human plasma and in vivo in rabbits. Thus, an active site-directed FXIa-specific antibody can block thrombosis in animal models and, together with the reversal agent, may facilitate exploration of the roles of FXIa in human disease.

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

“…Thus, perturbation of TF through the AHR-STUB1 axis represents an effective therapeutic strategy in CKD patients, because none of the current antithrombotics or the investigational agents such as factor XII and XI inhibitors target CKD-specific thrombosis (14, 15). Their suboptimum efficacy is likely to be exacerbated by poor thrombus control from a persistent nidus of exposed vSMCs secondary to compromised reendothelialization of the vascular wound in the uremic milieu (43).…”

“…This risk is further exacerbated by current anti-thrombotics (13), which target the hemostatic defenses in the blood. Even newer antithrombotics that are deemed safer, although not tested specifically in the uremic milieu, may function suboptimally in CKD, because none target CKD-specific risk factors (14) and may paradoxically enhance thrombosis due to altered baseline platelet reactivity in CKD (15). Targeting CKD-associated thrombotic factors is likely to lower the thrombosis risk to non-CKD range and may create a milieu more conducive to current antithrombotics/antiplatelet agents.…”

Plasma contact factors as therapeutic targets

“…David et al described humanized IgGs from a phage display library with high affinity for FXIa but not zymogen FXI [142]. C24 prevented FeCl 3 -induced carotid artery occlusion in FXI-deficient mice reconstituted with human FXI.…”

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

“…Strategies to inhibit FXI are illustrated in Table 2 and include (1) ASOs that reduce hepatic synthesis of the clotting protein 27,33,44 ; (2) monoclonal antibodies that block FXI activation, FXIa activity, or both 25,45,46 ; (3) aptamers that block FXI activation or activity 47,48 ; and (4) small molecules that block the active site of FXIa [49][50][51] or induce allosteric modulation.…”