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PDBsum entry 6o9c
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Immune system
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PDB id
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6o9c
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References listed in PDB file
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Key reference
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Title
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An engineered antibody fragment targeting mutant β-Catenin via major histocompatibility complex i neoantigen presentation.
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Authors
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M.S.Miller,
J.Douglass,
M.S.Hwang,
A.D.Skora,
M.Murphy,
N.Papadopoulos,
K.W.Kinzler,
B.Vogelstein,
S.Zhou,
S.B.Gabelli.
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Ref.
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J Biol Chem, 2019,
294,
19322-19334.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in CTNNB1, the gene encoding β-catenin, are common in colon
and liver cancers, the most frequent mutation affecting Ser-45 in β-catenin.
Peptides derived from WT β-catenin have previously been shown to be presented
on the cell surface as part of major histocompatibility complex (MHC) class I,
suggesting an opportunity for targeting this common driver gene mutation with
antibody-based therapies. Here, crystal structures of both the WT and S45F
mutant peptide bound to HLA-A*03:01 at 2.20 and 2.45 Å resolutions,
respectively, confirmed the accessibility of the phenylalanine residue for
antibody recognition. Phage display was then used to identify single-chain
variable fragment clones that selectively bind the S45F mutant peptide presented
in HLA-A*03:01 and have minimal WT or other off-target binding. Following the
initial characterization of five clones, we selected a single clone, E10, for
further investigation. We developed a computational model of the binding of E10
to the mutant peptide-bound HLA-A3, incorporating data from affinity maturation
as initial validation. In the future, our model may be used to design clones
with maintained specificity and higher affinity. Such derivatives could be
adapted into either cell-based (CAR-T) or protein-based (bispecific T-cell
engagers) therapies to target cancer cells harboring the S45F mutation in
CTNNB1.
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