FXI antibody with a unique binding mode — shows durable effects on markers of anticoagulation in humans Short Title : Novel Factor XI antibody with unique binding mode

A large unmet medical need exists for safer anti-thrombotic drugs since all currently approved anticoagulants interfere with hemostasis leading to an increased risk of bleeding. Genetic and pharmacological evidence in humans and animals suggest that reducing Factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with minimal risk of bleeding. We generated a fully human antibody—MAA868—that binds the catalytic domain of both FXI (zymogen) and the activated FXI (FXIa). Our structural studies show that MAA868 traps FXI and FXIa in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process revealing a particularly attractive anticoagulant profile of the antibody. MAA868 showed favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a FeCl3-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by aPTT without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects demonstrating that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in doseand time-dependent robust and sustained aPTT prolongation and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as potential once monthly subcutaneous anticoagulant therapy. For personal use only. on January 30, 2019. by guest www.bloodjournal.org From