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

Koch, Alexander and Schiering, Nikolaus and Melkko, Samu and Ewert, Stefan and Salter, Janeen and Zhang, Yiming and McCormack, Peter and Yu, Jianying and Huang, Xueming and Chiu, Yu-Hsin and Chen, Zhiping and Schleeger, Simone and Horny, Geraldine and DiPetrillo, Keith and Muller, Lionel and Hein, Andreas and Villard, Frederic and Scharenberg, Meike and Ramage, Paul and Hassiepen, Ulrich and Cote, Serge and De Gagne, Julie and Krantz, Carsten and Eder, Joerg and Stoll, Brian and Kulmatycki, Kenneth and Feldman, David and Hofmann, Peter and Basson, Craig and Frost, Robert and Khder, Yasser (2019) MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans. Blood, 133 (13). pp. 1507-1516. ISSN 15280020

Abstract

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.

Item Type: Article
Date Deposited: 14 May 2019 00:45
Last Modified: 14 May 2019 00:45
URI: https://oak.novartis.com/id/eprint/38638

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