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

Alexander W. Koch, Nikolaus Schiering, Samu Melkko, Stefan Ewert, Janeen Salter, Yiming Zhang, Peter McCormack, Jianying Yu, Xueming Huang, Yu-Hsin Chiu, Zhiping Chen, Simone Schleeger, Geraldine Horny, Keith DiPetrillo, Lionel Muller, Andreas Hein, Frederic Villard, Meike Scharenberg, Paul Ramage, Ulrich Hassiepen, Serge Côté, Julie DeGagne, Carsten Krantz, Jörg Eder, Brian Stoll, Kenneth Kulmatycki, David L. Feldman, Peter Hoffmann, Craig T. Basson, Robert J. A. Frost and Yasser Khder

Key points

  • 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.

Abstract

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 dose and 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.

  • Submitted October 23, 2018.
  • Accepted January 12, 2019.