Hani
H. Abdel-Nabi, MD, PhD #{149}Geoffrey Levine, PhD #{149}Lamk M. Lamki, MD #{149}James Newlon Tauxe, MD #{149}Ajit N. Shah, MD #{149}Yehuda Z. Patt, MD #{149}Ralph J. Doemr, MD Herbert A. Klein, MD #{149}Jayakumami Gona, MD #{149}Michael J. Rosenblum, PhD #{149}Michael Linda M. Smith, MSc #{149}Sally A. Schweighardt, CNMT #{149}E. Bruce Merchant, MD, PhD
L. Murray,
MD
#{149}
w.
Colorectal Detection Monoclonal
T
advent of the hybnidoma technology by Kohler and Milstein (i) has led to the large-scale commercial production and development of monoclonal antibodies (MoAbs) and has promoted their use in clinical practice. HE
In the past several years, different MoAbs to carcinoembryonic antigen (CEA) or the tumor-associated glycoprotein (TAG)-72 (present on appmoximately 80% of adenocancinomas)
have
been
urn,
Colon,
radioactive
761.1299
#{149} Liver,
#{149} Liver
Lung, neoplasms,
secondary,
Radio!ogy
60.33
1990;
PhD
a variety
of
imaging
of
PATIENTS
methods
on
086 is an IgGi
761.33
MoAb reacts with lan-weight species present in colonic does not react with
anti-
757.32
antigen MoAbs
176:117-122
different 19.9 or
tissues seen
MoAb
From
the
New
York,
Buffalo,
of Pittsburgh
M.D. ed,
Department
San
NY;
Diego
(M.J.U.,
15; revision Department
Hall,
Main 1990
3435 RSNA,
Pittsburgh
St.
Cancer
Houston,
L.M.S.,
S.A.S.,
NY
(L.M.L.,
Medicine,
W.N.T.,
J.L.M.,
Received accepted State
J.G.)
and
Biomedical
Minimal
of seven and samples.
Ia-
by
tional
eight
and
9, 1989;
19.
Address
means
chelating
scribed
technique
antibody-DTPA
was
was (185
of New
York
The
labeled
MBq)
by
of In-
by
a 30-minute
chromatography
with
use
of a silica
gel
strip placed in a tank filled with a solution of equal parts of methanol and water containing 5% of ammonium acetate. This
and
nonspecific 50% of maximal
than
Finally,
the
was diluted in (infusate volume,
mean
± standard
travenous
antigens, binding
CCR
In-ill
anation saline
100
mL 119.4
deviation)
infusion
Patient
Veterans
over
was at 0.2
086 prepof normal mL ± 8.2,
prior
to in-
60 minutes.
Evaluation histologically and at least
Adof
University of Texas
Hybritech
Incorporatrequested
requests
at Buffalo,
de-
(14).
4.0 mL of a neu-
Thin-layer
performed
acid
bifunc-
Tucker
conjugate
incubation.
so-
previously
and
the addition of 5.0 mCi 1 1 1 citrate (2.0 mL) and tralizing buffer followed
zg/mL.
by im-
University
revision
1 1 nor-
of a modified
by Krejcarek
specific more
by ca-
University
reprint
of
of
indicated that at least 85% of the In-ill was bound to the antibody-DTPA conjugate. Immunoreactivity of the final product as determined with ELISA (enzymelinked immunosorbent assay), both for
immuof a hu086
Hospital.
H.A.K.);
M.J.R.);
November March
(R.J.D.), State
University A.N.S.,
Y.Z.P.,
University
Surgery
sar-
reactivity
specimens
albumin in 2 mL of an aqueous already bound to the chelating diethylenetniaminepentaacetic
lution), agent
multiple high-molecu(200 kd on less) carcinomas. CCR 086 CEA and detects an
Sciences,
Presbyterian
(CL.,
7, 1990;
14214.
and
Institute,
E.B.M.).
March
of Nuclear Buffalo,
(H.H.A.N.,
of Medicine Pittsburgh
Center received
Medicine
School
of Medicine,
Cancer
H.H.A.N., C
Center,
School
Anderson
cember
of Nuclear
Medical
and
tissues. CCR 80% of the codid not react malignant or
Seventeen patients with proved colonectal carcinoma I
of
The antibody to be labeled with In-ill (Hybnitech, San Diego) was provided in vials (2 mg of MoAb and 2.2 mg of human
immunoglobulin
assessed
two
panels
melanoma,
tested.
in
prostate carcinoma ma! colon tissue
METHODS
086 was
lymphomas,
serum
from that recognized B72.3 (13). The binding
of CCR
thyroid,
(DTPA)
produced from a BALB/C mouse nized with the cytosol fraction man colon carcinoma (13). CCR
pacity
ministration
#{149}
from normal coa variety of neolung, prostate,
comas), and benign human 086 binds to approximately lon carcinomas tested but with the majority of other was
1 i, was evaluatknown metascarcinoma. The I/I! clinical the safety and CCR 086 its potential the detection of metastases.
AND
munohistochemical unfixed frozen sections lons, colon carcinomas, plasms (breast, stomach,
benign
carcinoma in man. Excellocalization has been and no major toxicities
beled with indium-i ed in 17 patients with tases from colorectal purposes of this phase trial were to determine toxicity of In-ill-labeled MoAb and to evaluate clinical usefulness in colorectal carcinoma
#{149} Lung
#{149} Monoc!ona!
neop!asms,
permit
have been reported (2-i2). CCR 086, an antimucin
studies,
60.1299
with
to
colorectal lent tumor achieved,
#{149} mdi-
secondary,
studies,
#{149} Rectum,
75.32
radionuc!ide
neoplasms,
radionuclide
bodies
neoplasms,
labeled
radionuclides
CCR terms:
Unger,
Carcinoma Metastases: with In- 1 1 1 -labeled Antibody CCR 080’
A phase I/Il clinical trial with mdium-lil-labeled antimucin murine monoclonal antibody (MoAb) CCR 086 was conducted. Seventeen patients with histologically proved colorectal carcinoma and known metastatic disease underwent external scintigmaphy after administration of 5.5 mCi (203.5 MBq) of In-ill CCR 086 at doses of 5 and 20 mg. Of 25 known lesions, 17 were detected (sensitivity, 68%). The smallest detected lesion in the lung was 1 cm and in the liver was 1.5 cm. The serum half-life of In-ill-labeled CCR 086 MoAb was approximately 64 hours. The formation of human antimouse antibody (HAMA) was detected in the serum of four of five patients who received 20 mg of MoAb. No HAMAs were detected in four patients receiving 5 mg of MoAb. No side effects were encountered. Because of effective detection of liver and lung metastases with lower doses (5-20 mg) of CCR 086 conjugated with In-ill, further investigations are warranted to assess clinical and therapeutic potentials of CCR 086 in the management of colorectal cancer. Index
J.
Abbreviations: Dc-
to 105
Parker
gen.
DTPA
acid,
ELISA
assay, MoAb photon =
CEA
carcinoembryonic
anti-
diethy!enetriaminepentaacetic
= =
enzyme-linked
immunosorbent
HAMA human antimouse antibody, = monoclona! antibody, SPECT single emission computed tomography, TAG
tumor-associated
glycoprotein.
117
Table 1 Findings
at
Immun
oscintigraphy
with
C CR 086 in Patients
In-ill
with
Colorectal
Cancer
(ng/mL)
Diagnosis
1/58/M
3/71/M
Liver mets Lung mets Liver mets Lung mets Liver mets
4/64/M
Lung (R hilum) Rectum, unresectible
2173/M
5/69/M 6/65/M 7/62/M
CT, liver
1.5
65 60
Mixed
+t
NA
9/63/M
R lobe liver mets
10/49/M
R lung mets Liver mets
62.8
li/39/M
Liver
i9
and
biopsy
6i
L/S Intraoperative biopsy, CT
111.5
CT, intraoperative
12/60/M
in porta Penipancreatic Sacralmass
13/68/M
R hip
R lobe mets
biopsy,
bone
17/60/F
Lung
Note.-Mets Cold
*
-
Spots
radioactivity t
Two
12.7
lesion
metastases,
areas accumulation
unsuspected
NA
in
areas
mets,
Initial
evaluation
physical try
included
examination.
survey,
complete tial and profiles
liver
and
history
Results renal
function
118
diagnostic
eight
Radiology
#{149}
-
chest
=
procedures,
at intraoperative
in-
biopsy
3-6 (diam)
Hot
NA
spot
NA NA NA
and
L/S
is either
liver. and
or
at CT-guided 1). CEA or sera of patients were means of a solid-phase kit (Abbott-CEA-RIA; North
Chicago,
to 3.5 ng/mL by
means
of an
that
R
Abbott
hot spots.
range
nonsmokers) kit
up
or
(Hybnitech)
(normal values up to 5.0 ng/mL for healthy nonsmokers). CEA levels ranged from 1.5 to 2,295 ng/mL in patients eval1). Laboratory
with
evaluations
existing
policies
estab-
lished tution, labeled
by the review boards of each instipatients received 1 mg of CCR 086 with approximately 5.5 mCi
(203.5
MBq)
of In-ill
in
100-200
mL
of
normal saline administered intravenously over 1 hour. In 13 patients (patients 1-8, 1 1, and 14-17), 19 mg of unlabeled CCR 086 was coinfused with the labeled CCR 086. Four patients (patients 9, 10, 12, and 13)
were
randomly
selected
to receive
4.0
mg of unlabeled CCR 086 with 1.0 mg of labeled MoAb. Vital signs were monitored every 15 minutes during infusion and then every 30 minutes for the next 2
hours.
-
NA NA NA
-
NA
+
-
L
left,
4.5X3
NA LN
norma! liver. positive scan, -
External
Laborato-
(normal
right,
-
of surrounding
radioimmunoassay
Ill)
ELISA
scanning,
than
needle aspiration levels in the plasma determined by
in healthy
(Table
Hot spot Cold spot
+ +
cold and nodes.
-
lymph
(Table
ties,
less
Mixed
celiac
two
biopsy
NA
liver-spleen
absent
normal liver
+
CT, CR
radiography,
consistent
10), pelvis (n = 1), and chest (n 1) were obtained. Sulfum-colloid liver-spleen scans were obtained for five patients, bone scans for two, and abdominal magnetic resonance (MR) images for one. At MoAb infusion, four patients had liver metastases, two had lung metastases, four had both liver and lung metastases, three had liver and lymph node metastases, three had local tumor recurrence, and one patient had metastases to bone. All 17 patients had known lesions detected at
Hot spot
scan
(complete blood cell count, platelet count, liver function and kidney function tests, and urinalysis) were repeated 1-3 days after MoAb infusion. After providing an informed consent
tests,
were obtained. Computed tomographic (CT) scans of the liver and abdomen (n
cluding
97
uated
and
of chemis-
blood cell counts with differenplatelet counts, and coagulation were studied. Chest radiographs
conventional
1.5
which radioactivity accumulation is greater than that of surrounding of MoAb accumulation seen in the
one known metastatic lesion larger than 1 cm at the time of antibody infusion were studied. Other patient eligibility criteria included a performance status of greater than 70% on the Kamnofsky scale and discontinuation of chemotherapy and/or immunotherapy for 1 week prior to and 3 days after the MoAb infusion. Fifteen patients were men, aged 39-73 years (mean, 61 years ± 8.9). The study also included two women, aged 28 and 60 years.
CT
Intraoperative biopsy, CT, L/S CT CT Intraoperative biopsy, CT, MR imaging biopsy
NA
bilobar CR
-
-
Bone
mets
not available,
1.2 (diam) .25-1 (diam)
-
Bonescan
8.6
19.8
LN
3.5 (diam)
+
mets
Inguinal
Hot spots
CT
L lobe liver mets Peripancreatic LN Liver mets, biobar
16/28/F
NA
6 (diam)
Mixed
biopsy CR CT, intraoperative biopsy, L/S Intraoperative
hepatis LN
Mass
15/61/M
10 X 5 1 (diam)
+
8/63/M
(diam)
7 X 5
Mixed +
L/S
intraoperative
Liver mets Liver mets
Liver
1.5-6
+
invasion
14/51/M
NA 2.5 (diam) i.5 (diam)
biopsy,
CT, cystoscopy,
2295
NA
Mixed +
CR
2.0
spot -
biopsy,CT CT, biopsy,
534
Cold
biopsy
CR L/S scan CR Intraoperative L/S, CT CT, CR Intraoperative
59
Liver mets R lung metastases Pelvic recurrence and bladder
of Diagnosis
Method
Lesion Size (cm)
MoAb Scan Results*
CEA
Patient No./Age (y)/Sex
!ymph
-
nodes.
Hot Spots negative scan.
-
areas
in which
Immunoscintigraphy
Planar imaging was performed with large-field-of-view scintillation cameras fitted with parallel hole, medium-energy collimators, using both photopeaks of Inill (174 and 247 KeV), and a 20% window. Images were acquired in the anterior and
posterior
projections
for
7.5
mm-
utes over the head, thorax, abdomen, and pelvis. Imaging was usually performed at 48-72 hours, and again at 96-144 hours after administration of In-ill CCR 086. Single photon emission computed tomography (SPECT) of the liver was usually performed at 48-72 hours. SPECT of the
lower
abdomen,
pelvis,
and other
areas
suspected to be involved with tumor were obtained at the later imaging session.
The
percentage
of radioactivity
ac-
cumulating in the liver was estimated by manually drawing regions of interest over the anterior and posterior aspects of the liver. A box region of interest was also drawn over a standard spot source of known amount of radioactivity. The percentage of the dose of In-ill CCR 086 that accumulated in the liver was estimated from the geometric means of the anterion
and
posterior
ter taking total
into
linear
1 1 1 and
aspects
attenuation
the
of the
consideration
patient
liver,
af-
the effective coefficient
for
In-
thickness.
July
1990
I
Figure
liver
Patient
1.
with
5.
SPECT
selected
coronal
images
of the
projections
after
In-il 1-labeled CCR 086 (a) and Tc-99m sulfur-colloid (b) administration. A rim of In1 1 1 MoAb activity (open arrow) is seen at the inferior aspect of the left lobe (which is mostly occupied ing defect (solid
tern
(hot
and with
patients
5-7
days.
seen tent,
by a large tumor) as a fillarrows, a and b). Mixed pat-
cold spots) is seen liver metastases.
Prominent
in the in the
activity
was
also
liven and, to a lessen exspleen and bone marrow.
MoAb images experienced
a.
in 25% of
were nuclear
interpreted medicine
by an physi-
cian at each site. Results of conventional imaging and/or intraoperative reports were available to the reader prior to MoAb scan interpretation. In-i 1 1 CCR 086 imaging showed positive MoAb accumulation in 17 of 25 known
lesions
(68%
detection
rate) in the patients evaluated, excluding photopenic liven lesions in two patients. The smallest lesion detected in the lung measured 1 cm in diameter and in the liver (hot spot), 1.5 cm. The largest was approximately b.
cation
of lesions
CCR
Pharmacokinetics Biodistnibution
CCR 086 was measured
and
obtained
at 2-4
weeks Serum half-lives were determined blood
samples
240 minutes
of In-i
1 1 CCR
by drawing
086
whole
at 0, 60, 90, 120,
150, and
and at 3 and either
6 or 7
days after infusion. Blood samples were centrifuged, aliquoted, and counted in an automatic gamma well counter against a known standard, which was usually a 1:10,000 dilution of the original injected dose. Serum half-lives of In-i 1 1 CCR 086
were and
calculated
individually
least-square
and standard for seven (patients
patient
fit analysis;
deviations
the
were
graphic mean
calculated
patients receiving the high dose 2, 3, 5, 7, 11, 14, and 17) and one
receiving
10). The
istered
with
the lower
cumulative
dose
dose
percentage
remaining
mulative
percentage
formula.
dose
and
!ution
tested
for
which
of the
404 nm
above
that of the background).
signal
the
was
remaining
The cuin
Safety
and
No
adverse
preinfusion
were
The
gamma
Antibodies
Number
#{149}
antibody (HAMA) administration of
1
regions for 2-3 a moderate
camera
images activity
of the heart and major days following infusion, decrease
discovered
in
new
le-
at MoAb
imag-
ing in three patients (patients 4, 11, and 17). In patient 4, a follow-up CT scan confirmed liver and celiac lymph imaging.
node metastases seen at MoAb However, clinical follow-
up and confirm
subsequent a right
lung
1 1 non a presacral of recurrent rectal tient
CT scans lesion
did not in patient
lesion, suggestive carcinoma, in pa-
17.
Twelve
patients
had
liver
metasta-
ses. These were confirmed by means of surgery, CT, and liven-spleen scanning in four patients; surgery and CT in five patients; CT only in one patient; and liven-spleen scanning only in the remaining two patients. Liver
and
over
in two
15), while
tients
patients
in four
2, 3, 5, and
were seen and “hot”
(patients
patients
7), liver
1
(pa-
metastases
as a combination of “cold” lesions (Fig 1). In four pa-
tients, liver metastases were detected as areas of positive In-ill CCR 086 accumulation (hot), coinciding with cold defects on a previous technetium-99m sulfur-colloid liver-spleen scan (Fig 2). In-i 1 1 CCR 086 imaging
Findings
blood-pool
four
lo-
11
is summarized
In addition,
mulation
ob-
at 1-3 similar to
Immunoscintigraphic significant
176
density
significantly
reactions
values.
Volume
optical
served after In-i 1 1 CCR 086 administration. Blood cell counts, liven and renal function test results, and un-
the
the
were
at In-i
metastases were demonstrated as aneas of absent In-i 1 1 CCR 086 accu-
mined as follows: [cumulative radioactivity (.tCi) in urine (at t0, t1, t2 . . .) + (dose administered residual activity in syringe and/or intravenous fluid bag)1 X 100.
antimouse after
sions
Toxicity
evaluated were
Human development
at 7-9
of a solid-
RESULTS
was
nalysis findings days after infusion
Antimouse
2.
phase ELISA assay method described by Schawlem et al (15) and modified by Hybnitech. Baseline samples were obtained prior to the injection; each patient served as his or her own control. Serial dilutions of each sample were incubated with goat antihuman IgG conjugated to alkaline phosphatase followed by the addition of a color substrate. The optical density of the color reaction was read with an automatic ELISA reader at 404 nm. Results are expressed as endpoint titers (ie, the last di-
the body is 100 minus the cumulative percentage eliminated. The latter is deter-
Human
again
by means
detected
imaging
Table
(patient
in the body
to the following
weeks
infusion
086
samples
of admin-
estimated from aliquots of urine samples collected at intervals of 0-5, 5-9, 9-24, and 24-48 hours after In-ill CCR 086 infusion. The cumulative percentage remaining in the body was calculated ac-
cording
after
in serum
lesion detected 7 X 5 cm. The
showed in the
did
vessels with
tasis, 1.2 cm in diameter in one patient (patient 9) on multiple, small metastases in another patient (patient
a period
of
not
depict
a solitary
liven
Radiology
metas-
119
#{149}
b.
a.
c.
Figure 2. Patient 10. (a) Anterior scan of the liver 3 days after In-i 1 1 CCR 086 administration shows normal liver uptake. (b) Concurrent Tc-99m sulfur-colloid scan shows two cold defects in the left and right lobes (arrows). (c) Image obtained by subtracting Tc-99m image from In-l i 1 image shows positive accumulation in the liver lesions (arrows).
16). In summary,
In-ill
munoscintignaphy
fication
CCR
086 im-
permitted
of liven
identi-
metastases
in 10 of 12
patients (sensitivity of 83%, ing both hot and cold lesions positive results, or sensitivity considering only hot lesions positive results). In addition, CCR 086 imaging demonstrated previously undetected liven in one patient (patient 4).
Four sions
patients
had
isolated
one
lobe
involving
both lobes was difficult lesions
since
lung
sidered
one
lung (n
le-
3) or
=
= 1). In two patients, to evaluate individual
(n
multiple
lesions
scattered throughout fields. For the purpose diffuse
consideras trueof 25%, as trueIn-i 11 two lesions
was
In-i
imaging demonstrated lung lesions (sensitivity,
of the liver confirmed CCR 086 findings.
Metastases
were
both lung of this study,
involvement
lesion.
it
suspected
086
the
five of seven 71%). Char-
second.
of the
accumulation This area
tient right
cinoma
a metastatic lesion in the is seen in Figure 3. Tu-
mom recurrence urinary bladder
in the pelvis with invasion was present
in one patient, and sacral invasion was found in another. In-i 1 1 CCR
086 scans enabled correct identification of the location and extent of the lesions in these two patients. Figure 4 is an In-i 1 1 CCR 086 scan of patient 4, demonstrating
carcinoma
a large
of the
sulfum-colloid
CT scan
of the
months
prior
were
rectum.
scan
of the
abdomen to the
A Tc-99m liver
and
obtained
MoAb
a
3
imaging
unremarkable
for liven
metasta-
depicted of the
a lesion right
120
Radiology
#{149}
CCR
were
based
on
an
1 1 CCR
patient was
a moderately
086
showed
in the excised
positive
left inguinal and found
differentiated
consistent
imaging
adenocar-
with
from
a primary
colon
scan
in patient
13 was
area. to be
a metastasis
tumor.
A bone
suggestive
of a
metastatic lesion lowing resection
in the right hip folof rectal adenocanci-
noma.
In-l
However,
1 1 CCR
086
did
not localize in this lesion, and further work-up of the patient to confirm the nature of this lesion (benign versus malignant) was not possible.
suggestive of liven me5). A follow-up CT scan
HAMA
Results of HAMAs was patients. In all pa-
tients, results the antibody
were negative infusion. Four
patients
who
received
086
detectable
had
administration.
No
Pharmacokinetics Biodistribution
and
In all cases, intravenously
more than administered
was
ance
bound
to CCR
of the
achieved first-order
HAMAS
CCR
086
086.
85% of the In-ill Blood
radioactivity
by means kinetics.
component
of biexponential The long liver
represented had
clear-
was
by In-i
a mean
effective
11 serum
half-life of 63.4 hours ± 13.2 (n 8). In addition, a rapidly cleared component, probably representing In-i 11 DTPA, was cleared with a half-life of 10-26 minutes. A second less chamacterized
3-5
The development evaluated in nine
(1:40-1:1,000)
086
were detected (up to 80 days) in the sera of the four patients who meceived only 5 mg of CCR 086.
component,
which
could
be a
metabolic by-product of In-ill CCR 086, cleaned with a serum half-life of
unresectable
ses. In-ill CCR 086 in the inferior aspect
lobe, highly tastases (Fig
nodes
patients
In-i
latter
actenistics of the lung lesions imaged with CCR 086 are summarized in Table 2. An In-i 1 1 CCR 086 scan of pa3 with hilum
to lymph in two
In-ill
abnormal CT scan in the first patient and on physical examination of an enlanged left inguinal lymph node in
con-
1 1 CCR
the
20 mg of CCR HAMA
16-67
prior to of five
days
titers
after
In-ill
hours.
ministered the
urine
Less
dose during
than
was the
10%
of the
ad-
eliminated first
in
48 hours.
DISCUSSION This study demonstrates bility of detecting colomectal
the feasicarcino-
July
1990
a.
b.
Figure
3. Patient
tion in a large prahilar region.
3.
Anterior
metastasis
(a) and
in the
right
posterior suprahilar
c.
(b) images
of the chest 7 days (arrow). (c) Anteroposterior
region
after
In-i
1 1 CCR
chest
086
infusion
radiograph
show
positive
a 9 X 5-cm
shows
MoAb
lesion
mated and did not age interpretation. that approximately istened dose remained the end of 48 hours,
accumula-
in the
night
su-
interfere with imOur data showed 93% of the adminin the body at presumably as
In-ill MoAb on In-lli-MoAb-Ag complex. Comparison of liver radioactivity to a standard source of known radioactivity showed that 17%-22% ed dose and day ly. This
of this Figure
5. Patient
of the
Figure 4. Patient 4. Posterior planar image of the pelvis, 3 days after infusion of In-ill
CCR
086,
shows
the patient’s
intense
rectal
radiolocalization
tumor
in
(arrows).
4.
Anterior
planar
image
liver,
3 days after infusion of In-i 11 CCR 086, shows two areas of positive uptake (hot spots) in the right and left lobes of the liver (arrows), consistent with liver metastases. Hot-spot liver metastases were seen in 33% of patients studied with CCR 086 MoAb.
CCR
086
confirms ports
ing
with
In-i
11-labeled
immunoscintigmaphy
the (16,17).
of previous
External
planar
following
ministration
and
findings the
imag-
intravenous
of In-ill
mead-
CCR
086
showed blood-pool distribution and normal accumulation in liver, spleen, and bone marrow, similar to the distribution of In-i 1 1-labeled anti-CEA ZCE 025 (5,7) and B72.3 GYK-DTPA
anti-TAG (18,19).
difference between and In-ill ZCE 025, DTPA (12), or B72.3 the total absence of all 17 patients studied The reason for this accumulation
of bowel which Volume
In-ill CCR B723-SCN-BZ-
086
GYK-DTPA
is
bowel activity in with CCR 086. absence of bowel
is not
activity
ministration
known.
after
is a clear
could 176
allow #{149} Number
72 In-ill A major
CCR
The
lack
086 ad-
advantage,
the
detection 1
of
primary on recurrent bowel with a greater confidence, obviating prescriptions cuants to patients. The serum half-life 086 (approximately
somewhat
longer
tumors
as well
of bowel of In-i 64 hours)
than
that
as eva-
1 1 CCR is
seen
for
other whole antibodies such as ZCE 025 labeled with In-i 1 1 and use of the same bifunctional DTPA method (serum half-life, approximately 24 hours) (5) or B72.3 MoAb labeled with In-i 1 1 at the site specific covalent agent GYK-DTPA (serum halflife, approximately 38 hours) (18,19). Nonetheless, excellent images were
obtained then
days
on day
3, as well
6 or 7 following CCR 086 administration. not bound to the MoAb administered dose) was
as on ei-
In-i 11 The In-i 11 (15% of the quickly elim-
antibody,
compared
with
3
In-
1 1 1 ZCE 025 as discussed above. The mean liver localization of In-i 1 1 ZCE 025 was found to be 1 1 .7% at 3 days after infusion (20).
In-i raphy
known
1 1 CCR
086 immunoscintig-
enabled
detection
lesions
cluding
two ma metastases
and ii%-14% of the injectlocalized in the liver at day 7 after infusion, respectiveconfirms the slow clearance
photopenic
patients.
of 17 of 25
(sensitivity,
68%),
liven
Excellent
lesions
exin
localization
in
lung lesions consistent with metastases was seen in six patients. In-i 11 CCR 086 imaging enabled detection of five of seven lesions and was panticularly helpful in establishing the diagnosis of pulmonary metastasis, which was surgically confirmed in patient 6. More lung lesions were detected with In-ill CCR 086 than with In-ill ZCE 025, irrespective of the dose of MoAb injected. Also, 10
of 12 liver
lesions
were
detected
with
In-ill seen
CCR 086, but only four were as focal areas of increased In- 111 CCR 086 accumulation on planar scans (hot lesions) without the aid of computer-assisted background subtraction. In this study, more liven lesions were detected as hot lesions with a lower dose of CCR 086 (20 mg) than were detected with ZCE 025. In our previous report, all documented
Radiology
#{149} 121
liven sions
lesions with
use
were detected In-i 1 1 ZCE 025
of the
20-mg
only 25% ed as hot
doses (40-80 are compatible studies could
on less,
lesions at higher
with ZCE 025 have significant
with There
improvement
detection
with
in this
group
SPECT
provided
use
except
better
anatomic
was
def-
DTPA (19). However, Lamki et al meported improved lesion detection with the use of SPECT (23). Only two of five lesions were detected in the four patients receiving the 5-mg MoAb dose, compared with
dose.
The
to make
regarding
series.
This
has been previously other In-i 1 i-labeled The overall rate tion tients
MoAb
CCR
ported (22)
by others
with
MoAb
associated with fects. Although ed
in the
sera
5 mg
(11)
and
of CCR
086,
of five
the
menot
of In-i
1 1 CCR
that
122
IgGs
(24).
further
Radiology
#{149}
Our
investigations
findings
6.
side efdetectpatients
086 comneceiv-
small
086
and
Kohler G, Mi!stein tures of fused cells
the
Berche
C, Mach
Mach
suggest
are war-
and
monoclonal
JP,
by
Nature
15.
1975;
JP,
Lumbroso
JD,
16.
et al.
Wilson
JA,
Chang
AE,
iodine-131
cancer.
of in-
labeled in
J Nucl
B72.3
patients
Med
with
1989;
BS,
Diveley
J, Halverson
C, et a!.
Characterization of a mouse monoclonal antibody CCR 086 for imaging of colon cancer. J Biol Response Mod 1989; 8:325. Krejcarek GE, Tucker KL. Covalent attachment of chelating groups to macroBiochem
Biophys
Res
Commun
Buchegger
F, Forni
M, et a!.
Use
monoclonal anti-CEA antidetection of human carcino-
external
photoscanning
and
to-
19.
HH,
Schwartz
AN,
Higano
CS, Wechter DG, Unger MW. Co!orectal carcinoma: detection with indium-i 1 1 anticarcinoembryonic antigen monoclonal antibody ZCE 025. Radiology 1987; 164:617-621. Abdel-Nabi HH, Schwartz AN, Goldfoge! G, et al. Colorectal tumors: scintigraphy with In-lll anti-CEA monoclona! antibody and correlation with surgical, histopathologic, and immunohistochemical Radiology
Lamki
LM,
Patt
1988,
findings
indium-i
JL, et a!.
of colonic
1 1 labeled
20.
21.
166:747-752.
YZ, Murray
cancer
anti-CEA
clonal antibody ZCE 025 combined unlabeled antibody (abstr). J Nuc!
mono-
with 22.
Med
1986; 27:1021. 8.
Patt
9.
proved tumor localization with increasing dose of indium-ill labeled anti-carcinoembryonic antigen monoclonal antibody ZCE 025 in metastatic colorectal cancer. Clin Oncol 1988; 6:1220-1230. Nuti M, Teramoto YA, Mariani-Constan-
YZ,
Lamki
R, Horan
LM,
Hand
Hayme
P. Colcher
TM,
et a!.
Im23.
D, Schlom
J. A monoclonal patterns associated carcinoma
antibody (B72.3) defines of distribution of a novel tumorantigen in human mammary cell population. Int J Cancer
24.
29:539-545.
Carrasquillo
JA,
Sugarbaker
Shawler DL, Bartholomew RM, Smith LM, Dillman RO. Human immune response to multiple injections of murine monoclonal IgG. J Immunol 1985; 135:1530-1535. Abde!-Nabi H, Doerr R, Roth SC, et al. Localization of colorectal carcinomas with In-ill CCR 086 monoclonal antibody. Nucl
17.
Abdel-Nabi
1982;
Med 1988;
30:320-327. 13.
18.
using
10.
D,
of colon B72.3
in biodistribution
antibodies
colorectal
moscintigraphy. Immuno! Today 1981; 2:239-249. De!aloye B, Bischof-Delaloye A, Buchegger F, et a!. Detection of colorecta! carcinoma by emission computerized tomography after injection of 1-123 labeled Fab or F(ab’)2 fragments from monoclonal anticarcinoembryonic antigen antibodies. Clin Invest 1986; 77:301-311.
tini
P. Colcher
K, Carrasquillo Differences
dium-ill
14.
C. Continuous culsecreting antibody of
specificity.
Scintigraphic
are
Sugarbaker
1977; 77:581-585.
findings.
7.
num-
slower than those observed with othen anti-colon cancer whole IgGs Iabeled with In-i 1 1, in the future this problem may be circumvented by the use of F(ab’)2 fragments, all of which have been shown to clear fasten than intact
3.
5.
was
20 mg of CCR of four patients
BSN,
JA,
Yokoyama et al.
the
Tomoscintigraphy for detecting gastrointestinal and medullary thyroid cancers: first clinical results using radiolabeled monoclonal antibodies against carcinoembryonic antigen. Br Med J 1982; 285:14471451.
4.
ben of patients examined does not allow for meaningful conclusions concerning dose effect and HAMA formation. The results of the present study indicate overall tumor targeting in 68% of lesions with In-i 1 1 CCR 086 MoAb. Although serum and urinary clearances
2.
025 MoAb
demonstrable HAMAS were
Roth,
Carrasquillo
et al. Radioimmunoscintigraphy cancer with iodine-l31-labeled monoclonal antibody. J NucI 29:1022-1030.
256:495-497.
not
that
ZCE
of four
who received pared to none ing
from
acknowledge
of Susan
predefined
with (21). forma-
was
different
on B72.3
1.
of
of nine paafter murine
086 infusions
significantly
1 1.
molecules.
phenomenon
in the sera of four (44%) examined
assistance
mas
effect
observed MoAbs of HAMA
We
of radiolabeled bodies for the
dose on tumor detection with this antibody remains to be determined in a larger
then-
References
definite
the
and
support of the Protocol Office of the Pittsburgh Cancer Institute. Our special thanks to Ellen Berg for manuscript preparation and editorial assistance.
detected in 13 pathe 20-mg MoAb
ability
conclusions
clinical
that
inition of lesions seen on planar scmtiscans. This confirms our previous observations with In-ill ZCE 025 (5,6) and In-i 1 i-labeled B72.3-GYK-
15 of 20 lesions tients receiving
the
12.
nursing
of SPECT
of patients,
to assess
technical dedication of Debra Higgins, CNMT, Frank Klasterka, CNMT, Paul Ga!antowicz, CNMT, Lori Redlinski, CNMT, and Deborah Reimers, CNMT, MS. We also acknowledge the
in tu-
the
ranted
apeutic potentials of CCR 086 in the management of patients with cobrectal cancers. U Acknowledgments:
(7,8,21) and implications
of patients metastases.
appreciable
mon
and
were detectMoAb
mg) (5). These findings with other imaging
in the treatment lung and liver no
dose
of liven lesions
as cold lescans with
P. Colcher
et al. Peritoneal carcinomatosis: imaging with intraperitonea! injection of 1-131-labeled B72.3 monoclonal antibody. Radio!ogy 1988; 167:35-40.
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Med
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Lamki
LM,
Murray
JL,
Rosenblum
MG,
Patt YZ, Babaian R, Unger MW. Effect of unlabeled monoclonal antibody (MoAb) on biodistribution of In-i 1 i-labeled MoAb. Nucl Med Comm 1988; 9:553-564. Smith LM, Unger M, Bartholomew R. Anti-mouse responses to monoclonal antibody (MoAb) therapy in human patients (abstr). J Nuci Med 1986; 27:942. Lamki
LM,
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U,
Patt
YZ,
Shanken
U, Unger MW. Comparison photon emission computed (SPECT) and planar imaging
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anti-CEA monoclonal antibody ZCE 025 and its F(ab’)2 fragment. J Nuc! Med 1988; 29:886. Halpern SE, Haind! W, Beauregard J, et al. Scintigraphy with In-ill-labeled monoclonal antitumor antibodies: kinetics, biodistribution,
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1990