MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans

• Published in: Blood Vol. 133; no. 13; pp. 1507 - 1516
• Main Authors: Koch, Alexander W., Schiering, Nikolaus, Melkko, Samu, Ewert, Stefan, Salter, Janeen, Zhang, Yiming, McCormack, Peter, Yu, Jianying, Huang, Xueming, Chiu, Yu-Hsin, Chen, Zhiping, Schleeger, Simone, Horny, Geraldine, DiPetrillo, Keith, Muller, Lionel, Hein, Andreas, Villard, Frederic, Scharenberg, Meike, Ramage, Paul, Hassiepen, Ulrich, Côté, Serge, DeGagne, Julie, Krantz, Carsten, Eder, Jörg, Stoll, Brian, Kulmatycki, Kenneth, Feldman, David L., Hoffmann, Peter, Basson, Craig T., Frost, Robert J.A., Khder, Yasser
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-03-2019
• Subjects: Adolescent; Adult; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Blood Coagulation - drug effects; Factor XI - antagonists & inhibitors; Female; Humans; Immunoglobulin G - pharmacology; Immunoglobulin G - therapeutic use; Macaca fascicularis; Male; Mice, Inbred C57BL; Middle Aged; Molecular Docking Simulation; Thrombosis - blood; Thrombosis - drug therapy; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-10-880849

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI 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 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride–induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.
•MAA868 is a novel, fully human, potent factor XI antibody that uniquely binds with high affinity both active enzyme and zymogen•MAA868 exhibits strong and long-lasting anticoagulant activity in humans with a promising safety profile
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