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.

D,

Med

1988; 29:898.

Tauxe WN, Kirkwood J, Ernstoff G, Unger M. Phase I/Il trial: monoclona! antibody to patients with colorectal cancer. at the 136th Annual Meeting, Pharmaceutical Association, Calif, April 8-12, 1989. H, Doerr R, Roth 5, Hajdu I, Balu I, Gona J. Imaging of colorectal cancers with In-lll B72.3 monoclonal antibody (CYT-l03): preliminary clinical results. Proceedings of Second Conference on Radioimmunodetection and Radioimmunotherapy of Cancer. Newark, NJ: Center for Molecular Medicine and Immunology, 1988; 80. Abdel-Nabi H, Doerr RJ, Chan HW, Balu D, Schmelter RF, Maguire RT. In-ill-labeled monoclonal antibody immunoscintigraphy in colorecta! carcinoma patients: safety, sensitivity, and preliminary clinical results. Radiology 1990; 175:163-171. Reimers D, Roth 5, Gona J, Abdel-Nabi H. Liver uptake following repeated infusions of In-i 1 1 monoclonal antibody ZCE 025 in patients with colorectal carcinoma. J NucI Med Technol 1989; 17:119-120. Levine G, M, Kowal In-ill-labeled mucin in Presented American Anaheim, Abdel-Nabi

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,

Murray

U,

Patt

YZ,

Shanken

U, Unger MW. Comparison photon emission computed (SPECT) and planar imaging

of single tomography in the detec-

tion

cancer

of metastatic

colorecta!

using

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,

Radiology

and

1988;

tumor

detection

(abstr).

168:529-536.

July

1990