Understanding the Toxicity Profile of Approved ADCs
Pharmaceutics,
Год журнала:
2025,
Номер
17(2), С. 258 - 258
Опубликована: Фев. 14, 2025
Background:
Antibody-drug
conjugates
(ADCs)
represent
a
novel
therapeutic
class
that
combines
an
antibody
against
tumor-associated
antigen
(TAA),
payload,
and
linker
binds
these
two
components.
Serious
adverse
events
(SAEs),
particularly
those
of
grade
3
(G3)
or
higher,
frequently
contribute
to
the
abandonment
ADCs
during
clinical
development.
Methods:
In
this
study,
we
analyzed
toxicity
profiles
all
approved
ADCs,
aiming
uncover
correlations
between
their
safety
specific
characteristics
Results:
our
analysis,
dose
reductions,
delays,
treatment
discontinuations,
≥G3
toxicities
were
not
significantly
different
across
payload
types.
Similarly,
no
association
was
found
mechanism
action
toxicities,
including
anemia,
neutropenia,
febrile
thrombocytopenia,
diarrhea.
By
exploring
observed
by
organ,
identified
most
related
action,
like
diarrhea
in
10%
patients
treated
with
sacituzumab
govitecan
(the
SN-38
is
active
metabolite
irinotecan),
very
few
presence
TAA
normal
tissue
(presence
Nectin-4
skin
rash
14%
enfortumab
vedotin).
line
this,
major
differences
studies
levels
(trastuzumab
deruxtecan
Destiny
Breast
Studies
HER2
expression
levels).
Conclusions:
Our
analysis
reveals
ADC
are
driven
payload's
effects
on
non-transformed
tissues;
however,
detailed
each
component
should
be
taken
into
consideration.
Язык: Английский
Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing
Cancer Drug Resistance,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 6, 2025
Antibody-drug
conjugates
(ADCs)
are
a
transformative
approach
in
breast
cancer
therapy,
offering
targeted
treatment
with
reduced
toxicity
by
selectively
delivering
cytotoxic
agents
to
cells.
While
ADCs
like
trastuzumab
emtansine
(T-DM1),
deruxtecan
(T-DXd),
and
sacituzumab
govitecan
have
shown
significant
efficacy,
resistance
mechanisms
such
as
antigen
loss,
impaired
internalization,
efflux
of
payloads
challenge
their
effectiveness.
This
review
discusses
these
explores
advanced
strategies
overcome
them,
including
innovations
linker
chemistry,
multi-antigen
targeting,
biomarker-driven
personalization.
Additionally,
therapeutic
sequencing
-
determining
the
optimal
order
other
treatments
chemotherapy,
endocrine
immunotherapy
is
examined
crucial
maximize
ADC
efficacy
manage
resistance.
Evidence-based
strategies,
particularly
for
human
epidermal
growth
factor
receptor
2
(HER2)-positive
triple-negative
(TNBC),
supported
clinical
trials
demonstrating
benefits
both
early-stage
metastatic
settings.
The
potential
combination
therapies,
immune
checkpoint
inhibitors
(ICIs),
further
highlights
evolving
landscape
treatment.
As
technology
advances,
personalized
approaches
integrating
biomarkers
optimized
protocols
offer
promising
avenues
enhance
outcomes
combat
cancer.
Язык: Английский
Structural Insights into Lipoate Ligase A-Mediated Antibody Modifications
Biochemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 20, 2025
Enzyme-mediated
site-specific
protein
modification
is
gaining
attention
in
biopharmaceuticals
due
to
its
high
specificity
and
mild
conditions.
Lipoic
acid
ligase
A
(LplA)
has
been
widely
studied
for
conjugating
short-chain
fatty
acids
lysine
residues,
traditionally
using
LAP
tags.
Recent
advances
have
enabled
tag-free
LplA
modifications,
expanding
applications
antibody-drug
conjugates
(ADCs)
beyond.
This
study
investigates
the
selective
of
Lys188
trastuzumab
by
LplA.
Spatial
analysis
molecular
modeling
suggest
that
D151
H189
facilitate
nucleophilic
attack
stabilize
intermediates
via
electrostatic
π-cation
interactions.
These
insights
enhance
our
understanding
enzyme-driven
site
selectivity,
guiding
rational
design
antibody
modifications.
The
findings
support
broader
ADC
production,
diagnostics,
next-generation
biopharmaceuticals,
emphasizing
role
local
amino
environments
enzymatic
Язык: Английский
Current advances in separation chemistry for antibody purification and analysis
Analytical Sciences,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 24, 2025
Язык: Английский
Exo-Cleavable Linkers: Enhancing Stability and Therapeutic Efficacy in Antibody-Drug Conjugates
Journal of Synthetic Organic Chemistry Japan,
Год журнала:
2024,
Номер
82(11), С. 1117 - 1124
Опубликована: Ноя. 1, 2024
Customized
drug
delivery
systems
are
essential
for
precision
medicine,
with
antibody-drug
conjugates
(ADCs)
representing
a
pivotal
approach
that
integrates
cytotoxic
payloads
monoclonal
antibodies
(mAbs)
through
sophisticated
chemical
linkers.
However,
optimizing
ADC
stability
while
achieving
controlled
payload
release
remains
challenging.
The
FDA-approved
valine-citrulline
(Val-Cit)
linker
commonly
used
in
ADCs,
suffers
from
issues
such
as
hydrophobicity-induced
aggregation,
limited
drug-antibody
ratio
(DAR),
and
premature
release.
Язык: Английский
Safety Concerns in Neurological Clinical Trials: A Challenge That the FDA Must Resolve
Biomedicines,
Год журнала:
2024,
Номер
12(12), С. 2918 - 2918
Опубликована: Дек. 22, 2024
Background:
Monoclonal
antibodies
approved
by
the
FDA,
lecanemab,
donanemab,
and
aducanumab,
are
failing
to
meet
expected
efficacy
treat
early
Alzheimer’s
disease,
aducanumab
has
been
recalled.
Methods:
Recently,
it
was
reported
that
clinical
trials
of
these
may
have
violated
patient’s
rights
subjected
them
high,
likely
lethal
risk.
The
challenge
with
developing
neurological
disorders
is
their
poor
blood–brain
barrier
(BBB)
penetration
if
antibody
must
enter
brain,
resulting
in
almost
negligible
brain
bioavailability,
requiring
high
dosing
can
be
toxic.
Results:
drugs
should
also
reviewed,
considering
placebo
effects,
since
all
shown
severe
side
effects
not
prevented
responses.
In
this
critical
urgent
advice
I
am
suggesting
a
guideline
amendment
proof
sufficient
bioavailability
at
site
action,
where
known.
Conclusions:
For
cross
barrier,
there
proven
options
such
as
conjugating
transferrin
protein,
making
its
absence
more
questionable.
Язык: Английский
Antibody Modification via Lipoic Acid Ligase A‐Mediated Site‐Specific Labeling
Chemistry & Biodiversity,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 22, 2024
Abstract
Enzymatic
modification,
particularly
utilizing
lipoic
acid
ligase
(LplA),
has
emerged
as
a
transformative
approach
in
biopharmaceuticals,
enabling
precise
and
site‐specific
protein
modifications.
This
review
delves
into
the
innovative
applications
of
LplA
antibody
modifications,
including
creation
antibody‐drug
conjugates
(ADCs)
advancement
tag‐free
conjugation
techniques.
LplA's
ability
to
facilitate
incorporation
bioorthogonal
groups
its
adaptability
various
substrates
underscores
versatility.
Key
developments
include
successful
generation
dual‐labeled
antibodies
application
modifying
fragments.
Additionally,
explores
potential
for
enhance
therapeutic
efficacy
ADCs
through
improved
drug‐to‐antibody
ratios
payload
attachment.
The
implications
these
advancements
are
significant,
suggesting
that
LplA‐mediated
modifications
could
lead
more
effective
targeted
antibody‐based
therapies.
aims
provide
comprehensive
overview
role
expanding
possibilities
enzymatic
conjugation,
setting
stage
future
research
clinical
applications.
Язык: Английский
Immunoconjugates as an Efficient Platform for Drug Delivery: A Resurgence of Natural Products in Targeted Antitumor Therapy
Pharmaceuticals,
Год журнала:
2024,
Номер
17(12), С. 1701 - 1701
Опубликована: Дек. 17, 2024
The
present
review
provides
a
detailed
and
comprehensive
discussion
on
antibody–drug
conjugates
(ADCs)
as
an
evolving
new
modality
in
the
current
therapeutic
landscape
of
malignant
diseases.
principle
concepts
targeted
delivery
highly
toxic
agents
forsaken
stand-alone
drugs
are
examined
detail,
along
with
biochemical
technological
tools
for
their
successful
implementation.
An
extensive
analysis
ADCs’
major
components
is
conducted
parallel
function
impact
stability,
efficacy,
safety,
resistance
profiles
immunoconjugates.
scope
article
covers
classes
currently
validated
natural
compounds
used
payloads,
emphasis
structural
mechanistic
features,
origin,
distribution.
Future
perspectives
design
thoroughly
explored,
addressing
inherent
or
emerging
challenges
limitations.
survey
also
overview
molecular
rationale
active
tumor
targeting
ADC-based
platforms,
exploring
cellular
biology
clinical
relevance
markers
“homing”
mechanism
both
hematological
solid
malignancies.
Язык: Английский
Exo-Linker: Positional Reconfiguration Driving Significant Advances in ADC Stability and Efficacy
ADC Review / Journal of Antibody-drug Conjugates,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 30, 2024
Antibody-drug
conjugates
(ADCs)
have
transformed
targeted
cancer
therapy
by
combining
the
specificity
of
monoclonal
antibodies
with
cytotoxic
potency
small-molecule
drugs.
However,
payload
instability,
hydrophobicity,
and
premature
cleavage
limit
their
efficacy
safety.
This
study
presents
Exo-Linker
technology
as
a
novel
solution
to
these
issues.
By
repositioning
cleavable
peptide
linkers
like
Glu-Val-Cit
Glu-Glu-Val-Cit
at
exo-position
p-aminobenzyl
carbamate
moiety,
Exo-Linkers
improve
stability,
hydrophilicity,
resistance
enzymatic
degradation.
Key
findings
highlight
superior
pharmacokinetics,
tumor-suppressive
efficacy,
stability
ADCs
in
preclinical
models,
significantly
outperforming
traditional
Val-Cit-based
linkers.
Integration
second-generation
AJICAP
platform
broadens
therapeutic
windows,
ensures
precise
drug-to-antibody
ratio
control,
minimizes
aggregation.
establish
new
standard
for
ADC
development,
overcoming
critical
limitations
while
enabling
safer
more
effective
treatments.
innovative
approach
redefines
landscape,
enhances
patient
outcomes,
scope
applications.
Язык: Английский