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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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PDB id:
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| Name: |
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Blood clotting
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Title:
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Coagulation factor xi catalytic domain in complex with fab-portion of maa868
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Structure:
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Coagulation factor xi. Chain: a. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Anti-factor-xi fab fragment light chain maa868. Chain: b. Engineered: yes. Anti-factor-xi fab fragment heavy chain maa868. Chain: c.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Unidentified. Organism_taxid: 32644.
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Resolution:
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2.04Å
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R-factor:
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0.220
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R-free:
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0.282
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Authors:
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N.Schiering,A.Koch
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Key ref:
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A.W.Koch
et al.
(2019).
MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.
Blood,
133,
1507-1516.
PubMed id:
DOI:
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Date:
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02-Apr-19
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Release date:
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10-Apr-19
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PROCHECK
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Headers
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References
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P03951
(FA11_HUMAN) -
Coagulation factor XI from Homo sapiens
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Seq:
Struc:
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625 a.a.
228 a.a.*
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Enzyme class:
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Chain A:
E.C.3.4.21.27
- coagulation factor XIa.
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Reaction:
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Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.
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DOI no:
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Blood
133:1507-1516
(2019)
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PubMed id:
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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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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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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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Links
