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PDBsum entry 4pub
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Immune system
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PDB id
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4pub
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References listed in PDB file
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Key reference
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Title
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Inhibition of plasma kallikrein by a highly specific active site blocking antibody.
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Authors
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J.A.Kenniston,
R.R.Faucette,
D.Martik,
S.R.Comeau,
A.P.Lindberg,
K.J.Kopacz,
G.P.Conley,
J.Chen,
M.Viswanathan,
N.Kastrapeli,
J.Cosic,
S.Mason,
M.Dileo,
J.Abendroth,
P.Kuzmic,
R.C.Ladner,
T.E.Edwards,
C.Tenhoor,
B.A.Adelman,
A.E.Nixon,
D.J.Sexton.
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Ref.
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J Biol Chem, 2014,
289,
23596-23608.
[DOI no: ]
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PubMed id
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Abstract
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Plasma kallikrein (pKal) proteolytically cleaves high molecular weight kininogen
to generate the potent vasodilator and the pro-inflammatory peptide, bradykinin.
pKal activity is tightly regulated in healthy individuals by the serpin
C1-inhibitor, but individuals with hereditary angioedema (HAE) are deficient in
C1-inhibitor and consequently exhibit excessive bradykinin generation that in
turn causes debilitating and potentially fatal swelling attacks. To develop a
potential therapeutic agent for HAE and other pKal-mediated disorders, we used
phage display to discover a fully human IgG1 monoclonal antibody (DX-2930)
against pKal. In vitro experiments demonstrated that DX-2930 potently inhibits
active pKal (Ki = 0.120 ± 0.005 nm) but does not target either the zymogen
(prekallikrein) or any other serine protease tested. These findings are
supported by a 2.1-Å resolution crystal structure of pKal complexed to a
DX-2930 Fab construct, which establishes that the pKal active site is fully
occluded by the antibody. DX-2930 injected subcutaneously into cynomolgus
monkeys exhibited a long half-life (t½ ∼12.5 days) and blocked high molecular
weight kininogen proteolysis in activated plasma in a dose- and time-dependent
manner. Furthermore, subcutaneous DX-2930 reduced carrageenan-induced paw edema
in rats. A potent and long acting inhibitor of pKal activity could be an
effective treatment option for pKal-mediated diseases, such as HAE.
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