Cancer Research,
Год журнала:
2024,
Номер
84(9), С. 1475 - 1490
Опубликована: Фев. 6, 2024
Trastuzumab
emtansine
(T-DM1)
was
the
first
and
one
of
most
successful
antibody-drug
conjugates
(ADC)
approved
for
treating
refractory
HER2-positive
breast
cancer.
Despite
its
initial
clinical
efficacy,
resistance
is
unfortunately
common,
necessitating
approaches
to
improve
response.
Here,
we
found
that
in
sensitive
cells,
T-DM1
induced
spindle
assembly
checkpoint
(SAC)-dependent
immunogenic
cell
death
(ICD),
an
immune-priming
form
death.
The
payload
mediated
ICD
by
inducing
eIF2α
phosphorylation,
surface
exposure
calreticulin,
ATP
HMGB1
release,
secretion
ICD-related
cytokines,
all
which
were
lost
resistance.
Accordingly,
gene
signatures
pretreatment
samples
correlated
with
response
T-DM1-containing
therapy,
increased
infiltration
antitumor
CD8+
T
cells
posttreatment
better
Transforming
acidic
coiled-coil
containing
3
(TACC3)
overexpressed
T-DM1-resistant
responsive
patients
had
reduced
TACC3
protein
expression
whereas
nonresponders
exhibited
during
treatment.
Notably,
genetic
or
pharmacologic
inhibition
restored
T-DM1-induced
SAC
activation
induction
markers
vitro.
Finally,
vivo
elicited
a
vaccination
assay
potentiated
efficacy
dendritic
maturation
enhancing
intratumoral
cytotoxic
cells.
Together,
these
results
illustrate
key
mechanism
action
targeting
can
restore
T-DM1-mediated
overcome
Trends in cancer,
Год журнала:
2023,
Номер
9(4), С. 339 - 354
Опубликована: Фев. 4, 2023
Antibody-drug
conjugates
(ADCs)
have
become
a
credentialled
class
of
anticancer
drugs
for
both
solid
and
hematological
malignancies,
with
regulatory
approvals
mainly
as
single
agents.
Despite
extensive
preclinical
clinical
efforts
to
develop
rational
ADC-based
combinations,
date
only
limited
number
demonstrated
survival
improvements
over
standard
care.
The
most
appealing
partners
ADCs
are
those
that
offer
additive
or
synergistic
effects
on
tumor
cells
their
microenvironment
without
unacceptable
overlapping
toxicities.
Coadministration
antiangiogenic
compounds,
HER2-targeting
drugs,
DNA-damage
response
agents
immune
checkpoint
inhibitors
(ICIs)
represent
active
forerunners.
Through
the
identification
targets
tumor-specific
expression,
improved
conjugation
technologies,
novel
linkers
payloads
offering
superior
therapeutic
indices,
next
generation
brings
optimism
combinatorial
approaches.
Cancers,
Год журнала:
2023,
Номер
15(15), С. 3886 - 3886
Опубликована: Июль 30, 2023
Antibody-drug
conjugates
(ADCs)
are
an
innovative
family
of
agents
assembled
through
linking
cytotoxic
drugs
(payloads)
covalently
to
monoclonal
antibodies
(mAbs)
be
delivered
tumor
tissue
that
express
their
particular
antigen,
with
the
theoretical
advantage
augmented
therapeutic
ratio.
As
June
2023,
eleven
ADCs
have
been
approved
by
Food
and
Drug
Administration
(FDA)
on
market.
These
added
armamentarium
acute
myeloblastic
lymphoblastic
leukemias,
various
types
lymphoma,
breast,
gastric
or
gastroesophageal
junction,
lung,
urothelial,
cervical,
ovarian
cancers.
They
proven
deliver
more
potent
effective
anti-tumor
activities
than
standard
practice
in
a
wide
variety
indications.
In
addition
targeting
antigen-expressing
cells,
bystander
effects
engineered
extend
killing
low-antigen-expressing
negative
cells
heterogenous
milieu.
Inevitably,
myelosuppression
is
common
side
effect
most
due
payload.
Also,
other
unique
specific
antigen
targeted
for,
such
as
cardiac
toxicity
Her-2
ADCs,
hemorrhagic
factor
(TF)
Tisotumab
vedotin.
Further
exciting
developments
centered
strategies
improve
tolerability
efficacy
window;
well
development
novel
payloads
including
(1)
peptide-drug
(PDCs),
peptide
replacing
antibody,
rendering
greater
penetration;
(2)
immune-stimulating
antibody
(ISACs),
which
upon
conjugation
cause
influx
pro-inflammatory
cytokines
activate
dendritic
harness
T-cell
response;
(3)
use
radioactive
isotopes
payload
enhance
activity.
Frontiers in Pharmacology,
Год журнала:
2023,
Номер
14
Опубликована: Сен. 18, 2023
Antibody-Drug
Conjugates
(ADCs)
represent
an
innovative
class
of
potent
anti-cancer
compounds
that
are
widely
used
in
the
treatment
hematologic
malignancies
and
solid
tumors.
Unlike
conventional
chemotherapeutic
drug-based
therapies,
mainly
associated
with
modest
specificity
therapeutic
benefit,
three
key
components
form
ADC
(a
monoclonal
antibody
bound
to
a
cytotoxic
drug
via
chemical
linker
moiety)
achieve
remarkable
improvement
terms
targeted
killing
cancer
cells
and,
while
sparing
healthy
tissues,
reduction
systemic
side
effects
caused
by
off-tumor
toxicity.
Based
on
their
beneficial
mechanism
action,
15
ADCs
have
been
approved
date
market
approval
Food
Drug
Administration
(FDA),
European
Medicines
Agency
(EMA)
and/or
other
international
governmental
agencies
for
use
clinical
oncology,
hundreds
undergoing
evaluation
preclinical
phases.
Here,
our
aim
is
provide
comprehensive
overview
features
revolving
around
strategy
including
structural
targeting
properties,
role
tumor
microenvironment
review
providing
discussion
regarding
toxicity
profile,
manifestations
novel
combination
therapies.
Finally,
we
briefly
pathological
contexts
information
manufacturing
analytical
characterization.
Journal of Hematology & Oncology,
Год журнала:
2024,
Номер
17(1)
Опубликована: Янв. 4, 2024
Antibody-drug
conjugates
(ADCs)
represent
an
important
class
of
cancer
therapies
that
have
revolutionized
the
treatment
paradigm
solid
tumors.
To
date,
many
ongoing
studies
ADC
combinations
with
a
variety
anticancer
drugs,
encompassing
chemotherapy,
molecularly
targeted
agents,
and
immunotherapy,
are
being
rigorously
conducted
in
both
preclinical
clinical
trial
settings.
Nevertheless,
combination
therapy
does
not
always
guarantee
synergistic
or
additive
effect
may
entail
overlapping
toxicity
risks.
Therefore,
understanding
current
status
underlying
mechanisms
is
urgently
required.
This
comprehensive
review
analyzes
existing
evidence
concerning
ADCs
other
classes
oncology
medicines.
Here,
we
discuss
biological
different
strategies,
provide
prominent
examples,
assess
their
benefits
challenges.
Finally,
future
opportunities
for
practice.
Bioconjugate Chemistry,
Год журнала:
2023,
Номер
34(11), С. 1951 - 2000
Опубликована: Окт. 11, 2023
Antibody–drug
conjugates
(ADCs)
are
targeted
immunoconjugate
constructs
that
integrate
the
potency
of
cytotoxic
drugs
with
selectivity
monoclonal
antibodies,
minimizing
damage
to
healthy
cells
and
reducing
systemic
toxicity.
Their
design
allows
for
higher
doses
drug
be
administered,
potentially
increasing
efficacy.
They
currently
among
most
promising
classes
in
oncology,
efforts
expand
their
application
nononcological
indications
combination
therapies.
Here
we
provide
a
detailed
overview
recent
advances
ADC
research
consider
future
directions
challenges
promoting
this
platform
widespread
therapeutic
use.
We
examine
data
from
CAS
Content
Collection,
largest
human-curated
collection
published
scientific
information,
analyze
publication
landscape
reveal
exploration
trends
documents
insights
into
area.
also
discuss
evolution
key
concepts
field,
major
technologies,
development
pipelines
company
focuses,
disease
targets,
stages,
investment
trends.
A
comprehensive
concept
map
has
been
created
based
on
Collection.
hope
report
can
serve
as
useful
resource
understanding
current
state
knowledge
field
ADCs
remaining
fulfill
potential.
Journal of Clinical Oncology,
Год журнала:
2023,
Номер
41(21), С. 3747 - 3761
Опубликована: Май 24, 2023
Antibody-drug
conjugates
(ADCs)
are
one
of
the
fastest-growing
oncology
therapeutics,
merging
cytotoxic
effect
conjugated
payload
with
high
specific
ability
and
selectivity
monoclonal
antibody
targeted
on
a
cancer
cell
membrane
antigen.
The
main
targets
for
ADC
development
antigens
commonly
expressed
by
lung
cells,
but
not
in
normal
tissues.
They
include
human
epidermal
growth
factor
receptor
2,
3,
trophoblast
surface
antigen
c-MET,
carcinoembryonic
antigen-related
adhesion
molecule
5,
B7-H3,
each
or
more
ADCs
that
showed
encouraging
results
field,
non-small-cell
than
small-cell
histology.
To
date,
multiple
under
evaluation,
alone
combination
different
molecules
(eg,
chemotherapy
agents
immune
checkpoint
inhibitors),
optimal
strategy
selecting
patients
who
may
benefit
from
treatment
is
evolving,
including
an
improvement
biomarker
understanding,
involving
markers
resistance
response
to
payload,
besides
target.
In
this
review,
we
discuss
available
evidence
future
perspectives
treatment,
comprehensive
discussion
structure-based
drug
design,
mechanism
action,
concepts.
Data
were
summarized
target
antigen,
biology,
efficacy,
safety,
differing
among
according
their
pharmacokinetics
pharmacodynamics
properties.
Abstract
While
strategies
such
as
chemotherapy
and
immunotherapy
have
become
the
first-line
standard
therapies
for
patients
with
advanced
or
metastatic
cancer,
acquired
resistance
is
still
inevitable
in
most
cases.
The
introduction
of
antibody‒drug
conjugates
(ADCs)
provides
a
novel
alternative.
ADCs
are
new
class
anticancer
drugs
comprising
coupling
antitumor
mAbs
cytotoxic
drugs.
Compared
chemotherapeutic
drugs,
advantages
good
tolerance,
accurate
target
recognition,
small
effects
on
noncancerous
cells.
occupy
an
increasingly
important
position
therapeutic
field.
Currently,
there
13
Food
Drug
Administration
(FDA)‒approved
more
than
100
ADC
at
different
stages
clinical
trials.
This
review
briefly
describes
efficacy
safety
FDA-approved
ADCs,
discusses
related
problems
challenges
to
provide
reference
work.
EClinicalMedicine,
Год журнала:
2024,
Номер
68, С. 102415 - 102415
Опубликована: Янв. 5, 2024
Although
the
antibody-drug
conjugates
(ADCs)
have
significantly
improved
survival
outcomes
of
patients
with
human
epidermal
receptor
2
(HER2)-expressing
gastric
or
gastroesophageal
junction
(G/GEJ)
cancer,
efficacy
ADC
used
as
a
single
agent
is
limited.
Therefore,
it
necessary
to
investigate
effective
and
safe
combination
regimens.
Preclinical
data
indicated
synergetic
antitumour
effect
RC48
programmed
cell
death
protein
1
(PD-1)
inhibitors.
We
aimed
evaluate
safety
plus
toripalimab
in
HER2-expressing
G/GEJ
cancer
other
solid
tumours.