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PDBsum entry 6r8x
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Blood clotting
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PDB id
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6r8x
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Contents |
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228 a.a.
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211 a.a.
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219 a.a.
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References listed in PDB file
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Key reference
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Title
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Maa868, A novel fxi antibody with a unique binding mode, Shows durable effects on markers of anticoagulation in humans.
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Authors
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A.W.Koch,
N.Schiering,
S.Melkko,
S.Ewert,
J.Salter,
Y.Zhang,
P.Mccormack,
J.Yu,
X.Huang,
Y.H.Chiu,
Z.Chen,
S.Schleeger,
G.Horny,
K.Dipetrillo,
L.Muller,
A.Hein,
F.Villard,
M.Scharenberg,
P.Ramage,
U.Hassiepen,
S.Côté,
J.Degagne,
C.Krantz,
J.Eder,
B.Stoll,
K.Kulmatycki,
D.L.Feldman,
P.Hoffmann,
C.T.Basson,
R.J.A.Frost,
Y.Khder.
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Ref.
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Blood, 2019,
133,
1507-1516.
[DOI no: ]
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PubMed id
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Abstract
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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.
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