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PDBsum entry 6pxr
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Immune system
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PDB id
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6pxr
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References listed in PDB file
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Key reference
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Title
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Characterization of tau binding by gosuranemab.
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Authors
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R.Sopko,
O.Golonzhka,
J.Arndt,
C.Quan,
J.Czerkowicz,
A.Cameron,
B.Smith,
Y.Murugesan,
G.Gibbons,
S.J.Kim,
J.Q.Trojanowski,
V.M.Y.Lee,
K.R.Brunden,
D.L.Graham,
P.H.Weinreb,
H.Hering.
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Ref.
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Neurobiol Dis, 2020,
146,
105120.
[DOI no: ]
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PubMed id
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Abstract
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Deposition of tau aggregates in the brain is a pathological hallmark of several
neurodegenerative diseases, termed tauopathies, such as Alzheimer's disease
(AD), corticobasal degeneration, and progressive supranuclear palsy (PSP). As
transcellular spread of pathological tau aggregates has been implicated in
disease progression, immunotherapy is being considered as a treatment for
tauopathies. Here we report a detailed biochemical and biophysical
characterization of the tau-binding properties of gosuranemab, a humanized
monoclonal antibody directed against N-terminal tau that is currently being
investigated as a treatment for AD. Binding experiments showed that gosuranemab
exhibited high affinity for tau monomer, tau fibrils, and insoluble tau from
different tauopathies. Epitope mapping studies conducted using X-ray
crystallography and mutagenesis showed that gosuranemab bound to human tau
residues 15-22. Immunodepletion of pathological human brain homogenates and
transgenic mouse interstitial fluid (ISF) with gosuranemab resulted in reduced
tau aggregation in tau biosensor cells. Preincubation of seed-competent AD-tau
with gosuranemab significantly inhibited tau aggregation in mouse primary
cortical neurons. Gosuranemab also significantly reduced unbound N-terminal tau
in cerebrospinal fluid (CSF) from individuals with PSP and AD, and in ISF and
CSF of treated transgenic mice. These results are consistent with the >90%
target engagement observed in the CSF of some clinical trial dosing cohorts and
support the evaluation of gosuranemab as a potential treatment for AD.
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