Download Immunotoxin Therapy of Small-Cell Lung Cancer

Immunotoxin
Therapy
N901-Blocked
Cancer
ThoniasJ.
Ricin for Relapsed
Lynch,
Despite
of Small-Cell
Jr.,
its initial
Lung Cancer*
Small-Cell
M.D.
chemosensitivity,
small-cell
lung
cancer
PATI-ERNS
(SCLC)
is rarely cured with chemotherapy
alone,
and fewer
than
5% of patients
are
alive
at 5 years.
Immunotoxin
therapy
appears
to offer promise
in treating
the minimal
residual
disease
that remains
after induction
chemotherapy.
We have
studied
N901-bR
N901-bR
consists
of the
in patients
N901
nonspecific
binding
binding
MoAb
which
muscle,
natural
N901-bR
showed
the
of the
of ligands.
binds
CD56-positive
negative
cell
molecule
B-chain
are
is an anti-NCAM
blocked
and
cells,
line
line.
to
patients
with
as a 7-day
continuous
capillary
leak
patients
treated
mum
infusion.
syndrome
The
observed
dose,
relapsed
(PR)
response
to N901-bR.
clinically
plan
to
significant
begin
a
peripheral
phase
II
chemotherapy
x 7 days,
with
of small-cell
first
challenge
quite
does
relapse,
and
improve
in patients
focused
using
regimens,4
and
maxi-
achieved
remarkable
the 1990s,
SCLC,
with
years
of
bone
marrow
and
history
modalities
that
differences
between
*From
the
Institute,
This work
on
escalation
with
even
designing
future
Division
stage
of
support.’
Clearly
if we
ofSCLC,
SCLC
Clinical
and
and
initial
to
therapy.
5 percent
50%
to make
exploit
disease
problem
normal
Oncology
Harvard
Medical
School,
Boston.
is sponsored
by ImmunoGen,
mc,
within
an impact
therapeutic
biologic
tissue.”
Dana-Farber
not
to
response
Mass.
range
is
no
be
clearly
with
had
and
kidneys,
The
lenge.
treatment
Overall,
on
Oncology
ranged
by the
among
as
from
the
FOR
survival.
As
is a major
of involvement
at time
of
achieved
a CR.
The
in relapsed
SCLC
disease
at autopsy
and the
include
frethe
to
27%
performance
SCLC
SCLC
rates
in
study
.
this
as
prior
response
of
relapse
was
Immunotoxin
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21670/ on 05/14/2017
as many
Therapy
with
study,
status
well
optimistic
is a monumental
a recent
South
in patients
‘ ‘ In
time
most
on
metastasis
RELAPSED
(SWOG)
9%
of relapse
the
rate,
and bone marrow,
44.8%;
adrelymph
nodes,
28.2%;
pancreas,
of relapsed
response
Group
from
(PCI),
Despite
8.1%.
ThERAPY
2
in
the CNS-relapse
previously
involved
metastatic
50%.”
impact
incidence
who
who
relapse
irradiation
to
to reduce
following:
liver, 60%; bone
nals,
31.6%;
retroperitoneal
13.6%;
25%
leptomeningeal
a 24%
disease
disease
cranial
from
demonstrated
in patients
stage
in
control,
nervous
system
(CNS)
metaswith SCLC
is almost
80%.” In
ofPCI
expected,
initial
site of relapse
in SCLC.
that the actuarial
prob-
prophylactic
rates
modality
importance
excellent
experience
period
receiving
remaining
organs
quency
of finding
survival
Cambridge,
will
central
ability
influenced
Cancer
of great
limited
with
a CR
a 2-year
relapse
relapse
has shown
the
in
partial
combined
are
Despite
patients
of developing
As we enter
of patients
to develop
increased
on overall
transplantation
from
following
disease
therapies.
of
during
there
agents
die
rate
failure
stage
achieved
demonstrated
would
non-cross-resistant
of patients
we need
innovative
at
with
Yet SCLC
are
CNS
of optimism;
Efforts
of chemotherapeutic
majority
of
limited
increased
chemotherapy
the chest.
The brain is also a major
Autopsy
studies
have demonstrated
tumors
chemotherapy
cycles
vast
are
of
marrow
standard-dose
conversion
of
of limited
tases
are
this
majority
combining
to c-onventional
to cure less than
the
diagnosis.
natural
vast
intensity,
needed.
therapy
initially
presents
Tumors
a 77%
patterns
ability
yet
The
alternating
resistance
we are able
oncology.
bone
with
are
The
40%
103:436S-39S)
witnessed
a period
SCLC
was imminent.
dose
autologous
with
436$
the
developed
(SCLC)
chemotherapy,
persist.
early
1980s
a cure for
outcome
radiation2I
to
not
cures
are rare. ‘ The
many
felt that
cancer
in clinical
responsive
sensitivity
lung
dose
etopo-
on outcome
approaches
is
SCLC.
1993;
increasing
with
impact
given
or central
neuropathy.
We
study
of N901-bR
following
in patients
alternating
to complete
response
(CR) and a disease-free
survival
benefit,
but ultimately,
the overall
survival
benefit
was too
small to be statistically
significant.”
Clearly,
new drugs
and
patients
he treatment
a unique
the
has
has
alternating
(cyclophospha-
and late intensification
have
have not impacted
significantly
of autologous
yielded
However,
a dramatic
the
therapy
with
into a
of
at the
No patient
(Chest
T
thirds
patient
A trial
included
as CAV/EP
vincristine
Furthermore,
of therapy,
rates, but
have
combination
model.
has not had
compared
this
such
and
cisplatin)
(ABMT)
SCLC
toxicity
two
One
30 p.gfkg/day
a partial
induction
in
at 40 .tgfkg/day.
tolerated
dose-limiting
doxorubicin,
and
phenotype
is the
and radiotherapy
alternating
Goldie-Coldman
survival.
antigen-
SCLC
IN
to circumvent
chemotherapy
duration
response
nerve.
antigen-negative
Namalwa
cell line. Nineteen
patients
relapsed
and/or
refractory
SCLC have been entered
phase
I study at doses ranging
from 5 to 40 .tgfkg/day
Efforts
the
in SCLC.
cardiac
the
on
mide,
side
FAILURE
non-cross-resistant
based
the
cytotoxicity
to
SCLC.
of
combination
(CD56)
peripheral
than
Nineteen
SCLS.
lines,
in vitro
SE-2
use
OF
emergence
of a drug-resistant
reason
for failure
ofchemotherapy
to cure
(MoAb)
through
cell
and
greater
The
primary
in which
the
which
mediate
N901
tumors
log
cell
Namalwa
ricin
ricin
(NK)
a 2.7
relapsed
antibody
toxin
to SCLC
killer
with
monoclonal
and blocked
ricin, an altered
galactose
binding
sites of the
covalent
Lung
relapse
response
ofpatients
to
chalWest
was
at the
therapy.
Median
study
is
authors
quote
a
br SCLC (Thomas
J. Lynch,
Jr)
16
weeks.
other
This
time
median
relapse
survival
ofonly
7 to 8 weeks
cell-surface-binding
created
for clinical
in patients
experiencing
an interesting
opportunity
12
Small-cell
lung
cancer
presents
for new drug development.
The majority
to achieve
a minimal
disease
state with
otherapy.
A
distinctly
different
would
thus
disease.
new
agent
whose
from
have
that
mechanism
(IT)
may
of
was
chemotherapy
opportunity
mechanism
to impact
represent
action
linked
on this
such
differs
following
effective
upfront
chemotherapy
have
These
ITs
those
cells
have
However,
the
of
for the
majority
specifically
considerations,
Background
toxin
immunoconjugates
lysozome.
In
contrast
be agents
nonspecific
with
to
their
antibodies
has
clinical
supply
has
to tumor
antineoplastic
toxins
for
(2)
a potent
and
only
monoclonal
and
the
avidity,
clinical
trials,
an
it has
normal
to normal
when
bound
linkage
antibody
become
antibody
localization
to be very
equally
occurring
as ricin,
bind
not
cells
to
between
toxin
of binding
of highly
As a result
clear
important.
important.
The
polypeptide
abrin,
saporin,
but
site
Second,
major
on
the
classes
that
the
also
nature
ofthe
toxin
include
naturally
synthesis
protein
natural
substances
kill cells
Whole
ricin and abrin
possess
such
(PAP),
by riboso2 distinct
chains,
1 chain
with lectin-binding
properties,
and another
with cytotoxic
activity.
These
2-chain
toxins are highly
toxic
to
intact
composed
and
cells
in
their
of a single
natural
state.
polypeptide
gelonin)
demonstrate
little
cells because
membranes.
they have
Moreover,
no mechanism
the binding
can
be inactivated
by separating
In
chain
intrinsic
the
contrast,
(eg,
toxins
saporin,
toxicity
PAP,
to intact
for binding
to surface
of ricin to normal
cells
toxic
of the
detoxify
manifest
biologic
antibody
many
enzymatic
toxin
single-chain
degradation
A-chain
from
Blocked
on
in the
the
Ricin
laboratory
studies
examining
toxins
as
linker
and
kill
formed.”'’
toxins
were
These
studies
demonstrated
not very effective
cytotoxic
normal
Ricin
an
chemistry
on
target
tumor
are
of 2 subunits,
linked
enzyme
by
that
the
a single
the
the
B-chain
ubiquitous
sites
the
the
by
ofthe
less
single-chain
even with
and
bond.
and
These
to affect
the ability
chain
with
than
was
100-fold
relative
A-chain,
synthesis
than ricin A-chain
alone.
blocked
ricin is reduced
to whole
ricin
as measured
in a cell-free
,
has
CHEST
even
is identical
by their
system.
a conjugate
but
ricin,
A-chain
is formed
500-fold
a
I 103
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21670/ on 05/14/2017
that
I 4 I APRIL
The nonspeby more
than
the
of native
activity
of
ricin
to inhibit
protein
the blocked
ricin
the
same
cytotoxicity
1993
antiThe
a highly
a toxicity
to that
has
increased
transport
though
capacity
By linking
ricin
appear
the N901
molecule.
in the above
section
produces
the specificity
of N901
with
greater
of free
blocked
toxin
whole
with
do not
linking
ricin
been
the
is seen
to enhance
whole
has
conjugates
with only
for
than
ligands
way
observed
modifications
B-chain
natural
ricin
antibody
biochemical
across
the cell membrane.
N901-bR
is an immunoconjugate
NKH1
antibody
to a ‘blocked”
significantly
cific toxicity
is
antibody-whole
the 2 galactose
stable
more
as described
IT combining
B-chain,
A-chain
of eucaryotic
linking
significantly
ofthe
the
The
subunit
605
in a chemically
cytotoxicity
IT
toxicity,
A-chain
Monoclonal-antibody-blocked
specificity
of the monoclonal
molecule
to N901
that
reagents
toxicity
of monoclonal
chemically
blocking
sites
A-chain
the
of
of ITs to
been
per-
are potent
cytotoxic
agents;
demonstrate
nonspecific
cytoto all cells via the B-chain.
An
ricin-B
binding
developed.
retain
the
process
purified
of
binds
to galactose-terminated
on eucaryotic
cell
surfaces.
Intact
ricin immunoconjugates
however,
such immunotoxins
toxicity
because
they bind
slightly
effects
modifications
the capacity
cells
have
disulfide
inactivates
ribosomes,
and
oligosaccharides,
into
as
of the highest
avidity
and ability
to internalize.
a new type of toxin was prepared
which
retained
properties
of the intact
ricin
molecule
but had
blocked
the ability
of the B-chain
to bind
to
cells.”'”'
consists
binding
the
well
antibody-toxin
internalize
ricin
antigen
4 These
inactivation.
isotype,
the
inhibitors
of protein
pokeweed-anti-viral
could
by
approach
to limit
ricin
conjugates
conjugate
increasingly
important,
cells
single-chain
which
are
mon-
with
(3) a stable
of
are
are important
in the development
of a
efficacious
IT. First, not only is the specificity
monoclonal
and
appear
components
(1) a specific
does
penetrates
and
that
cytotoxic
to be relatively
simple,
the development
and specific
ITs has been more difficult.
several
variables
therapeutically
the
which
xi’3
concept
toxins
cross-reactivity
to and
antibody;
antibody
Although
of early
toxin
binds
agents
potential
highly
major
Background
antibodies
Therefore
the toxic
chemically
chemotherapeutic
to develop
limited
ho-
monoclonal
of cytotoxic
immunotoxin:
with
of
several
Three
anti-
agents.
use
conventional
be used
limited
of
examining
identified
a successful
antibody
appeared
studies
conjugates.
necessary
cytotoxic
delivery
than
to the
quantities
the
tumor
Extensive
decades,
unlimited
on
that
different
tumors
of monoclonal
the
may
due
to
minimal
advent
Previous
have
potent
antibody-toxin
tissue;
for
cells.
more
Such
oclonal
prove
several
as therapeutic
focused
agents
5 to 7 logs
and
mal
to test
as vehicles
directly
tissue
provided
been
for
ability
not
Additional
agents,
might
impossible
The
antibodies
antibodies
is
were
has
Attention
agents.
specificity,
considered
studies
technology
mogeneous
of
been
of heteroantibodies.
body
the
chemotherapeutic
exquisite
with which
to treat human
tumors
with
toxicity.
Although
the concept
oftreating
extensive
the
conventional
with
did
ITs.
to
antigen.
conjugate
to penetrate
the cell surface
as well as the number
of IT molecules
required
to kill a cell, appeared
to be very
important
in inducing
cell death.
Moreover,
it became
evident
antibodies,
antibodies.
cytotoxicity
efficiency
the
A-
of laboratories
cell-surface
single-chain
including
ricin
monoclonal
relevant
cytotoxic
ofthese
number
to
demonstrated
the
expected
therapy.
on Immunotoxins
toxins
the first ITs
antibodies
or to purified
an increasing
expressing
of
radio-
5 years,
this reason,
monoclonal
toxins
single-chain
that
and
single-chain
the past
linked
a class
from
traditional
cytotoxic
agents,
and they are unlikely
to potenhate
bone
marrow
suppression.
Thus,
ITs may be able to
improve
the cure rate in SCLC by eradicating
drug-resistant
cells
to either
chain.
Over
are able
chem-
of action
of conventional
an excellent
Immunotoxins
Their
drugs.
ofpatients
conventional
B-chain.”
For
trials
utilized
I Supplement
general
for
the
437$
targeted
cell
population
Characteiistics
ofthe
Monoelonal
means
N901
of
the
relationship
For example,
cells
In this
intestinal
tumors
derived
precursor
uptake
and
pheochromocytoma,
led to the generation
investigation
of
from
generating
ing” bone
these
marrow
antibodies
of patients
apy
autologous
which
for
has
against
SCLC.
The
that
NKH1
peripheral
monocytes,
precursors.
of
5i0fl
chosen
is a 180
an
the
IT
IC
values
Four
NKH
with
to
1
to five
have
neural
cells. The
to 15% of
NKH1
the
NKH
1
receptor)
antigen,
receptor
complex.
fractions
of
myocardial
Extensive
express
20%
screening
to
has
also
of frozen
a CD3T1’-cell
mediate
of NK
been
CD3
non-MHC
expression
out
samples.
immuno-
The
noted
changes
humans
The
In addition,
was
staining
observed
by
and
skeletal
cardiac
tional
staining
in the
cytoplasm
In
was
oe
other
and
strongly
transferrm
fibers
ofcortical
stromal
study,
the
antigens,
recel)tor.
SCLC
saml)les.
or
OKTh,
mouse
SCLC
NKI-I1
Most
but
model,
was
in the
also
cells
to possible
and
Toxicity:
which
of
non-small-cell
antigen
et al2
lung
was
noted
for the
cancer
only
some
also
found
SCLC
of myocardial
study.
that
by
total
N901
N901-bR.
infusion.
had
Phase
I Study
clearly
In many
seen
in
attention
be
on nervous
high doses
of
infusion
for
6 days
and
p.g/kg
in
1,000
of motor
conduction
were
destudies.
The monkeys
had no
abnormalities
in either
motor
one
NK
with
at
animal
activity
However,
returned
in
patients.
of 750
monitored
In
days
dose
is consistent
that
using
doses
be
these
is not
but
of N901-bR
is reactive
was
no functional
should
tolerated
These
electromyelographic
until 21 days after therapy.
activity
activity
effect
continuous
At
examined,
after
It
produced
requires
performed
mild abnormalities
by nerve
conduction
clinically
significant
infusion
is specific
inflammatory
in human
the
the
evidence
the
This
of
Of
minimal
of drug
were
monkeys.
NK
diffusely
damage.
phenomena.
similar
to those
To clarify
species,
stained
evidence
and
toxicity
in
infusion
mediated
findings
are
studies
in SCLC
or non-lineage-spe-
bolus
microscopic
of
rejection.
NK
cells,
condition
either
findings
administered
tected
apparent
toxicity.
on cynomolgus
microscopic
cardiac
or sensory
function.
ties did not develop
NK Toxicity:
Since
ovary.
against
were
OKT9
Koros
Addi-
graft
further
.Lg/kg,
of
epithelium
ofthe
MAb
cytokeratins,
NKH1
observed.
of NKH1
other
CNS
light
cardiac
N90i-bR
cells.
Staining
follicular
specimens
and
Schwann
neuropil
expression
of 21
to
methods.
in thyroid
with
with
438$
and
muscle
All
reactec.l
In a nude
of astrocxtes
to a panel
leukocyte
antigens.2’
itself
noted
recent
cific
neuron
immunoperoxidase
was
compared
the
3 had
dose
a
the
over the same
time
a total dose of N901-
during
the
given
cynomolgus
to
that
acute
fibroblasts
not
infusion
received
had any clinical
an immunologically
the pathologic
tissue,
and
by
inflammation
ways,
CNS
strongest
pathologic
arrhythmia
to
on
nonspecific
cardiac
evidence
binding
expressed
reflect
N901-bR
reactivity
from
isoform
6 days,
had
by the
of N901 occurs
with peripheral
nerves
of all types.
It appears
that the N901 antibody
binds
to the intraneural
staining
result
and
at an N901-bR
is well above the likely maximum
due to hepatic
toxicity.
mechanism
of this tissue
response
with
in non-
by
6
or
explained
cells.’
carried
tissue
the
and
8,
insufficiency
rosette
over
cells
respectively.
has demonstrated
of N901-bR
received
No monkeys
further
Although
CD3
of N KH 1 antigen
tissue
staining
able
is characteristic
remaining
al.a
antigen-
SW-2
nmol,
effects
examined
mg/kg
et
N901
be killed
may
or it may
myocardial
changes.
large
of acute
l/E
bR of 900
7.8
can
molecule
the
had
conjugate
Scott
the
towards
and
6 days or by continuous
Of 12 monkeys
who
significant
lymphoid
(Ti
coexpress
both
on
other
CD2
to 25%
are
of NK
20%
of myeloma.
also
cells
that
about
on
period.
as activated
In malignant
expressed
rarely
Interestingly,
NKH1
hematopoietic
l)ut
expres-
This
surface,
we
following
the
by
on
N90i-bR
investigate
who
of
ricin
nmol
cells.
cell
measured
described
of SW-2 cells
nmol.
adhesion
To further
was
of conjugate
required
to kill 63% of
exposure
ofthe
cells to conjugate.
The
Toxicitij:
cell
monkeys
non-MHC-
definition
and
exception
cells
only
killing
with
is commonly
cases,
with
of
operational
leukemias
leukemia
malignancies,
an
that
cells
resting
NK as well
killer
(LAK)
effectors.
lymphocytic
myelogenous
those
function,
include
demonstrated
to
of3.5
N901-blocked
cell line Namalwa
by the same
are presented
as an IC,
which
0.022
myocardial
for
studies
is restricted
logs
Myocardial
stnicture
human
natural
killer
expressed
on 10%
are
modest
N901-antigen-positive
determined
for N901-blocked
cells
concentration
activity
kd surface
200
assay
was
Burkitt’s
lymphoma
Toxicity
values
Namalwa
Previous
cells,
peroxidase
to develop
these
of
the
concentrations
clonogenic
the concentration
cells following
a 24-h
Some
cytotoxicity
on
Cytotoxicity
toxicity
negative
procedure.
as serotherapy.
vitro
varying
is
candidate
The N901
recognizing
SW-2.
the
monkeys,
hematopoietic
restricted
Finally,
provide
line
Nonspecific
in
In
determined
with
using
distin-
goal
cell
N901
a
Anti-N901-bR
was
incubation
N901 antibody.
In this model
into nude mice; the resultant
noted.
with
Toxicity:
(bR)
l)lO()d
lymphocytes
but
not on granulocytes,
erythrocytes,
platelets,
or earlier
hematopoietic
cytolytic
majority
has
the
of
as immunoconjugates.
by normal
is selectively
cells.2
These
lymphokine-activated
granular
reinfusion.21
for SCLC,
(anti-CD56)
antigen
NKH1
restricted
This
and
with
were
Studies
in-Vitro
with
is expressed
antigen
NKH1
as
second
A
Preclinical
SCLC
amine
such
treated
reductions
ricin
is to provide
a means
of “purgprior to high-dose
chemother-
marrow
been
a means
cancers.”
are selective
antib(xly
antigen
in
were
tumor
on
gastro-
(APUD),
as
other
development
monoclonal
the
engaged
immunophenotyping
from
molecules
cells
a
and of
tumors.
neur()blastoma,
and carcinoid.
of MAb reactive
with SCLC
SCLC
with
as
antigens
resembles
decarboxylation
guishing
antibodies,
SCLC
reductions
using the
cell line was introduced
tumors
neural-related
respect,
tumor
SCLC
utilized
of SCLC
and other
SCLC
express
antibody.
been
lineage
between
SCLC
surface.
have
cell
the
by
Antibody
(MAb)
investigating
the
solely
Monoclonal
antilxdies
clarifying
their
specified
by
NK
cells
various
in
days
in
times
which
could
30
abnormali-
be
this
after
was
this
identified
postinfusion,
2
NK
to normal.
in
After
in Patients
the completion
with
Relapsed
SCLC
ofextensive
preclinical
Immunotoxin Therapy
for SCLC
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studies
(Thomas
which
J. Lynch,
Jr)
showed
that
could
safely
of N901-bR
N901-bR
could
be given
to primates,
in patients
Patients
were
design
at
x
assessed
for
serial
with
given
doses
pg’kg/d
specifically
relapsed
N901-bR
ranging
7
days
continuous
cardiac
toxicity
radionuclide
with
measurements.
serial
neurologic
Neurologic
exams,
serial
7
toxicity
nerve
were
cardiac
was
11
with
studies,
12
have
19 patients
found
that
have
this
been
drug
treated
can
be
with
given
N901-bR.
safely
of
cardiac
is the
and neurologic
parameters.
Capillary
leak syndrome
dose-limiting
toxicity
at 40 p.g/kg/d
x 7 days.
Serum
drug
levels
cytotoxic
in
mouse
achieved
vitro.
All patients
and human
of treatment.
have observed
patient
mented
with
drug
patients
are
of a level
response
SCLC.
to tumor
such
in a state
as
to
initiating
N90i-bR
residual
chemotherapy
a
phase
induction
II
be
14
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