6R8X

COAGULATION FACTOR XI CATALYTIC DOMAIN IN COMPLEX WITH FAB-PORTION OF MAA868

6R8X の概要

• エントリーDOI: 10.2210/pdb6r8x/pdb
• 分子名称: Coagulation factor XI, anti-Factor-XI Fab fragment light chain MAA868, anti-Factor-XI Fab fragment heavy chain MAA868, ... (4 entities in total)
• 機能のキーワード: coagulation fxi, zymogen, antibody, antagonist, blood clotting
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 74741.64

構造登録者

Schiering, N.,Koch, A. (登録日: 2019-04-02, 公開日: 2019-04-10, 最終更新日: 2024-10-23)

主引用文献

Koch, A.W.,Schiering, N.,Melkko, S.,Ewert, S.,Salter, J.,Zhang, Y.,McCormack, P.,Yu, J.,Huang, X.,Chiu, Y.H.,Chen, Z.,Schleeger, S.,Horny, G.,DiPetrillo, K.,Muller, L.,Hein, A.,Villard, F.,Scharenberg, M.,Ramage, P.,Hassiepen, U.,Cote, S.,DeGagne, J.,Krantz, C.,Eder, J.,Stoll, B.,Kulmatycki, K.,Feldman, D.L.,Hoffmann, P.,Basson, C.T.,Frost, R.J.A.,Khder, Y.
MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.
Blood, 133:1507-1516, 2019

PubMed 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.

PubMed: 30692123
DOI: 10.1182/blood-2018-10-880849

実験手法

X-RAY DIFFRACTION (2.04 Å)