Cancers,
Journal Year:
2024,
Volume and Issue:
16(23), P. 3979 - 3979
Published: Nov. 27, 2024
Background/Objectives:
Human
epidermal
growth
factor
receptor
2
(HER2)
is
overexpressed
in
several
malignancies,
such
as
breast,
gastric,
ovarian,
and
lung
cancers,
where
it
promotes
aggressive
tumor
proliferation
unfavorable
prognosis.
Targeting
HER2
has
thus
emerged
a
crucial
therapeutic
strategy,
particularly
for
HER2-positive
malignancies.
The
present
study
focusses
on
the
design
optimization
of
peptide
inhibitors
targeting
HER2,
utilizing
machine
learning
to
identify
enhance
candidates
with
elevated
binding
affinities.
aim
provide
novel
options
malignancies
linked
overexpression.
Methods:
This
started
extraction
structural
examination
protein,
succeeded
by
designing
sequences
derived
from
essential
interaction
residues.
A
technique
(XGBRegressor
model)
was
employed
predict
affinities,
identifying
top
20
possibilities.
underwent
further
screening
via
FreeSASA
methodology
free
energy
calculations,
resulting
selection
four
primary
(pep-17,
pep-7,
pep-2,
pep-15).
Density
functional
theory
(DFT)
calculations
were
utilized
evaluate
molecular
reactivity
characteristics,
while
dynamics
simulations
performed
investigate
inhibitory
mechanisms
selectivity
effects.
Advanced
computational
methods,
QM/MM
simulations,
offered
more
understanding
peptide–protein
interactions.
Results:
Among
principal
peptides,
pep-7
exhibited
most
DFT
values
(−3386.93
kcal/mol)
maximum
dipole
moment
(10,761.58
Debye),
whereas
pep-17
had
lowest
value
(−5788.49
minimal
(2654.25
Debye).
Molecular
indicated
that
steady
−12.88
kcal/mol
consistently
bound
inside
pocket
during
300
ns
simulation.
showed
overall
total
system,
which
combines
both
QM
MM
contributions,
remained
around
−79,000
±
400
kcal/mol,
suggesting
entire
protein–peptide
complex
stable
state,
maintaining
strong,
well-integrated
binding.
Conclusions:
Pep-7
promising
peptide,
displaying
strong
stability,
favorable
energy,
stability
HER2-overexpressing
cancer
models.
These
findings
suggest
viable
candidate
offering
potential
treatment
strategy
against
HER2-driven
Cells,
Journal Year:
2024,
Volume and Issue:
13(22), P. 1833 - 1833
Published: Nov. 6, 2024
Podoplanin
(PDPN)
overexpression
is
associated
with
poor
clinical
outcomes
in
various
tumors.
PDPN
involved
malignant
tumor
progression
by
promoting
invasiveness
and
metastasis.
Therefore,
considered
a
promising
target
of
monoclonal
antibody
(mAb)-based
therapy.
Because
also
plays
an
essential
role
normal
cells
such
as
kidney
podocytes,
cancer
specificity
required
to
reduce
adverse
effects
on
cells.
We
developed
cancer-specific
mAb
(CasMab)
against
PDPN,
PMab-117
(rat
IgM,
kappa),
immunizing
rats
PDPN-overexpressed
glioblastoma
The
recombinant
mouse
IgG
C-C
motif
chemokine
receptor-8
(CCR8)
belongs
to
class
A
of
G
protein-coupled
receptors
(GPCRs).
CCR8
interacts
with
the
specific
ligand
CCL1/I-309
in
humans,
which
is
produced
by
various
cells,
including
tumor-associated
macrophages
and
regulatory
T
cells
(Treg).
highly
expressed
on
Treg
T-helper
2
(TH2)
recruited
inflammation
site
implicated
allergy,
asthma,
cancer
progression.
The
CCR8+Treg
has
been
suggested
be
an
important
regulator
immunosuppressive
tumor
microenvironment
(TME);
therefore,
it
desired
develop
sensitive
monoclonal
antibodies
(mAbs)
for
CCR8.
This
study
developed
a
mAb
human
(hCCR8),
useful
flow
cytometry
employing
Cell-Based
Immunization
Screening
(CBIS)
method.
established
anti-hCCR8
mAb,
C8Mab-21,
(mouse
IgM,
kappa)
reacted
hCCR8-overexpressed
Chinese
hamster
ovary-K1
(CHO/hCCR8)
TALL-1
(acute
lymphoblastic
leukemia),
CCRF-HSB2
(human
T-lymphoblastic
natural
killer
express
endogenous
hCCR8
cytometry.
Furthermore,
C8Mab-21
demonstrated
moderate
binding
affinity
CHO/hCCR8
dissociation
constant
6.5×10-8
M
2.0×10-8
M,
respectively.
was
CBIS
method,
could
tool
analyzing
hCCR8-related
biological
response
using
CD44
is
a
type
I
transmembrane
glycoprotein,
which
associated
with
poor
prognosis
in
various
solid
tumors.
Since
plays
critical
roles
tumor
development
by
regulating
cell
adhesion,
survival,
proliferation,
and
stemness,
it
has
been
considered
target
for
therapy.
Anti-CD44
monoclonal
antibodies
(mAbs)
have
developed
applied
to
antibody-drug
conjugates
chimeric
antigen
receptor-T
We
previously
anti‐pan-CD44
mAbs,
C44Mab-5
C44Mab-46,
can
recognize
both
standard
(CD44s)
variant
isoforms.
In
the
present
study,
defucosylated
mouse
IgG2a
version
of
anti-pan-CD44
mAbs
(5-mG2a-f
C44Mab-46-mG2a-f)
was
generated
evaluate
antitumor
activities
against
CD44-positive
cells.
Both
5-mG2a-f
C44Mab-46-mG2a-f
recognized
CD44s-overexpressed
CHO-K1
(CHO/CD44s)
cells
esophageal
line
(KYSE770)
flow
cytometry.
Furthermore,
could
activate
effector
presence
CHO/CD44s
exhibited
complement‐dependent
cytotoxicity
KYSE770
administration
significantly
suppressed
xenograft
compared
control
IgG2a.
These
results
indicate
that
exert
cancers
be
promising
therapeutic
regimen
CD44
regulates
cell
adhesion,
proliferation,
survival,
and
stemness
has
been
considered
a
tumor
therapy
target.
possesses
the
shortest
standard
(CD44s)
variety
of
variant
(CD44v)
isoforms.
Since
expression
CD44v
is
restricted
in
epithelial
cells
carcinomas
compared
to
CD44s,
promising
target
for
monoclonal
antibody
(mAb)
therapy.
We
previously
developed
an
anti‐CD44v10
mAb,
C44Mab-18
(IgM,
kappa)
recognize
exon
10-encoded
region.
In
present
study,
mouse
IgG2a
version
(C44Mab-18-mG2a)
was
generated
evaluate
antitumor
activities
against
CD44-positive
with
established
anti-pan
C44Mab-46-mG2a.
C44Mab-18-mG2a
exhibited
higher
reactivity
C44Mab-46-mG2a
CD44v3–10-overexpressed
CHO-K1
(CHO/CD44v3–10)
oral
squamous
carcinoma
lines
(HSC-2
SAS)
flow
cytometry.
exerted
superior
antibody‐dependent
cellular
cytotoxicity
(ADCC)
CD44v3–10.
contrast,
showed
complement‐dependent
(CDC)
A
similar
tendency
observed
ADCC
CDC
HSC-2
SAS.
Furthermore,
administering
or
significantly
suppressed
CD44v3–10,
HSC-2,
SAS
xenograft
growth
control
IgG2a.
These
results
indicate
that
could
be
therapeutic
regimen
CD44v10-positive
tumors.
Cancers,
Journal Year:
2024,
Volume and Issue:
16(23), P. 3979 - 3979
Published: Nov. 27, 2024
Background/Objectives:
Human
epidermal
growth
factor
receptor
2
(HER2)
is
overexpressed
in
several
malignancies,
such
as
breast,
gastric,
ovarian,
and
lung
cancers,
where
it
promotes
aggressive
tumor
proliferation
unfavorable
prognosis.
Targeting
HER2
has
thus
emerged
a
crucial
therapeutic
strategy,
particularly
for
HER2-positive
malignancies.
The
present
study
focusses
on
the
design
optimization
of
peptide
inhibitors
targeting
HER2,
utilizing
machine
learning
to
identify
enhance
candidates
with
elevated
binding
affinities.
aim
provide
novel
options
malignancies
linked
overexpression.
Methods:
This
started
extraction
structural
examination
protein,
succeeded
by
designing
sequences
derived
from
essential
interaction
residues.
A
technique
(XGBRegressor
model)
was
employed
predict
affinities,
identifying
top
20
possibilities.
underwent
further
screening
via
FreeSASA
methodology
free
energy
calculations,
resulting
selection
four
primary
(pep-17,
pep-7,
pep-2,
pep-15).
Density
functional
theory
(DFT)
calculations
were
utilized
evaluate
molecular
reactivity
characteristics,
while
dynamics
simulations
performed
investigate
inhibitory
mechanisms
selectivity
effects.
Advanced
computational
methods,
QM/MM
simulations,
offered
more
understanding
peptide–protein
interactions.
Results:
Among
principal
peptides,
pep-7
exhibited
most
DFT
values
(−3386.93
kcal/mol)
maximum
dipole
moment
(10,761.58
Debye),
whereas
pep-17
had
lowest
value
(−5788.49
minimal
(2654.25
Debye).
Molecular
indicated
that
steady
−12.88
kcal/mol
consistently
bound
inside
pocket
during
300
ns
simulation.
showed
overall
total
system,
which
combines
both
QM
MM
contributions,
remained
around
−79,000
±
400
kcal/mol,
suggesting
entire
protein–peptide
complex
stable
state,
maintaining
strong,
well-integrated
binding.
Conclusions:
Pep-7
promising
peptide,
displaying
strong
stability,
favorable
energy,
stability
HER2-overexpressing
cancer
models.
These
findings
suggest
viable
candidate
offering
potential
treatment
strategy
against
HER2-driven
