| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Department of Internal Medicine [M. T.], University of California San Francisco, San Francisco, California 94115; Department of Radiation Oncology [P. L., J. B-K.], Pathology and Microbiology [S. A., J. W., D. C.], Preventive and Societal Medicine [J. A.], and Radiology [K. H.], University of Nebraska Medical Center, Omaha, Nebraska 68198; and Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland 20892 [J. S.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and ß half-lives of
111In-labeled MAb CC49 and 90Y-labeled MAb CC49
in the blood were similar. Absorbed radiation dose estimates in
metastatic tumor sites ranged from 180 to 3000 cGy. The percentage of
injected dose/kg of tumor ranged from 1.12 to 18.14; however,
tumor:normal liver ratios were consistently <1. No objective responses
were observed. Doses of up to 0.5 mCi/kg could be administered with
reversible grade IV myelotoxicity. Absorbed radiation dose in tumor was
suboptimal, even at the highest administered activity level. Deposition
of 90Y in liver was high, and estimates of absorbed dose in
liver equaled or exceeded that which could be achieved in metastatic
tumor sites. Strategies to enhance access of radioimmunoconjugates in
tumor and diminish deposition in the liver need to be developed for
effective treatment using MAb CC49 with chelated radiometals. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
40% (e.g.,
5-FU3
-based regimens in metastatic gastric cancer; Ref. 2
).
External beam radiotherapy is commonly used for either local control or
palliative intent in patients with unresectable or metastatic
gastrointestinal tract cancers. Because of the local nature of external
beam radiotherapy, this therapy does not often affect the natural
history of the disease or overall survival in patients with metastatic
gastrointestinal tract cancers. However, the use of radiation,
particularly in combination with chemotherapy, has proved to be of
major importance for local control and possibly survival in esophageal
(3)
, pancreatic (4)
, and rectal cancer
(5)
. Obviously, a major disadvantage of radiation therapy
lies in the necessary limitation of treatment volume or dose delivery
in an effort to spare normal tissues. Systemic radioimmunotherapy is an experimental approach that allows for selective targeting of radioactivity to tumor tissue while hopefully sparing normal organs. MAbs that target selective tumor-associated antigens have been developed for the purposes of cancer imaging and therapy. In solid tumors, the use of radioimmunoconjugates for radioimmunodetection has proved to be successful; clinical studies have documented that it is possible to identify occult disease in patients suspected of having metastases when other conventional imaging studies, i.e., computerized tomography, fail (6) . There are now two Food and Drug Administration-approved reagents commonly available for imaging of colorectal carcinoma metastases. These include 111In-conjugated MAb B72.3 and 99mTc-conjugated anti-carcinoembryonic antigen [F(ab')2 fragments].
MAb B72.3 was initially developed by Colcher et al. (7) using a membrane-enriched fraction of human metastatic mammary carcinoma tissue as a immunogen. The antibody recognizes a mucin antigen, TAG-72, which, based on immunohistochemical and immunocytochemical techniques, is preferentially expressed in adenocarcinomas (8) . The antigen is uncommonly expressed in normal tissues, with the exception of secretory endometrium (9) . In an effort to improve on the parental MAb B72.3, Muraro et al. (10) and Colcher et al. (11) developed and described a series of second generation MAbs that also react with TAG-72. Murine MAb CC49 is a member of the initial library of antibodies produced and was selected for further clinical studies because of its higher affinity and more rapid plasma clearance compared with MAb B72.3. MAb CC49 recognizes an epitope distinct from MAb B72.3 and exhibits higher reactivity to gastric, colonic, and pancreatic adenocarcinomas (12) . Preclinical studies in athymic mice bearing human tumor xenografts showed improved targeting and a 3–5-fold greater therapeutic efficacy for MAb CC49 labeled with either 131I (13) or 90Y (13) than similarly labeled B72.3.
The following report details a Phase I trial of dose escalation of 90Y-labeled MAb CC49 in a setting of hematopoietic stem cell support in patients with metastatic gastrointestinal adenocarcinomas. Because 90Y has a pure ß energy emission, 111In-labeled MAb CC49 was used as a surrogate for radiometal-labeled MAb uptake for biodistribution and dosimetric calculations.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Treatment Schedule.
Initial evaluation included a physical examination, histology review,
immunohistochemistry, baseline blood work, chest X-ray examination, and
CT scan of the abdomen and/or thorax. Subsequently, prior to treatment
all patients underwent collection and cryopreservation of hematopoietic
stem cells adequate for one autologous transplant. On day -3, an
imaging dose of 111In-labeled MAb CC49 (5 mCi;
5 mg of IgG) was given i.v. Whole-body exposure rate measurements were
obtained using triplicate readings with standard geometry at distances
of 1 meter from the mediastinum using a calibrated dose rate meter.
These readings were continued daily until
90Y-labeled MAb CC49 was administered. In
addition, blood samples (serum and whole blood) were obtained
immediately after administration and at 30 min and 1, 2, and 3–4 h and
daily for quantification of circulating
111In-labeled MAb CC49 activity. Daily total
urine samples were obtained for 3 days after the infusion for
pharmacokinetic measurement. Daily planar image acquisitions were
performed for 5 days. SPECT images were acquired on the second and
fifth day (-2 and +1). Both planar and SPECT image acquisition were
performed using a dual-headed gamma camera system. For regional SPECT
acquisitions, the number of counts ranged from approximately
50,000–100,000 counts/frame. In planar views, a minimum of 1 million
counts was acquired from the diagnostic and posttherapy studies.
On test day 0, the selected therapy activity of 90Y-labeled MAb CC49 was administered through one port of a double lumen, indwelling central line. Blood samples were obtained for pharmacokinetic studies for 7 days after the therapy dose, and 24-h urine samples were collected for 3 days. Bone marrow aspirates and biopsies of accessible liver metastases and uninvolved liver were obtained 5–7 days after treatment.
Posttreatment Follow-Up.
Patients were evaluated weekly for toxicity by clinical examination,
complete blood count, and chemistry profile. Toxicity was graded
according to the National Cancer Institute Common Toxicity Criteria and
the Supplementary Toxicity Criteria for Bone Marrow Transplantation.
Patients who achieved grade IV neutropenia received supportive care
with prophylactic ciprofloxacin and granulocyte-colony stimulating
factor. In addition, routine support for myelosuppression was provided
including administration of appropriate blood products. Patients were
admitted to the hospital only for fever that could not be controlled
with outpatient antibiotic therapy. The protocol called for infusion of
cryopreserved hematopoietic stem cells if patients did not recover to
grade III neutropenia within 5 days of the initiation of
granulocyte-colony stimulating factor. CT scans of the abdomen and/or
thorax were repeated at 8-week intervals to determine response to
treatment.
90Y-labeled MAb CC49 Activity Selection, Definition of
Maximum Tolerated Dose, and Evaluable Patients.
Administered activities selected for study were 0.3, 0.4, and 0.5
mCi/kg. The specific activity of the radiolabeled MAb was 9.6 mCi/mg
(range, 8.1–11.9). Each dose was checked for the lack of pyrogens and
the radiochemical purity of the MAb prior to administration. Each
administered dose was adjusted to give a total protein dose of 5 mg and
diluted with 0.9% NaCl injection to 15–25 ml and infused i.v. over
20–30 min through an indwelling central line. Patients were
prehydrated with 1–2 liters of 5% dextrose in 0.45% NaCl for
injection.
If no grade III or IV extrahematopoietic toxicity occurred over a 4-week observation period among the initial three patients placed on a given activity level, the amount of 90Y activity was escalated for the successive group of three patients. If any instance of grade III or IV extrahematopoietic toxicity had been observed, three additional patients would have been treated at the existing dose level, and the dose would have been escalated only if no further instances of grade III or IV toxicity was observed. If at any time two instances of grade III or IV extrahematopoietic toxicity and/or grade IV or V bone marrow supplementary toxicity had been observed at a given dosage level, entry onto that level would be terminated. The maximum tolerated dose was defined as the highest dose in which no more than one instance (maximum sample size, 6) of grade III or IV extrahematopoietic toxicity or grade IV or V bone marrow supplementary toxicity was observed.
All patients were evaluable for toxicity. The protocol also demanded that a minimum of three patients would be evaluable for dosimetry estimates at each dose level. Because of the anticipated problem of 111In deposition in liver, a minimum of at least three patients with extrahepatic metastases evaluable for dosimetry estimations in tumor were entered onto each dose level.
Response Criteria.
Tumor measurements were recorded in centimeters using the longest
diameter and perpendicular diameter at the widest portion of the tumor.
A complete response was defined as total resolution of all measurable
sites of disease for a minimum of 8 weeks. A partial response was
defined as a 50% or greater decrease in the sum of the products of the
perpendicular dimensions of all measurable lesions for a minimum of 4
weeks without the appearance of new lesions. Stable disease was defined
as no change in measurable lesions or <50% decrease or <25%
increase in the sum of the products of the perpendicular dimensions of
all measurable lesions and no development of new lesions over 8 weeks.
Progressive disease was defined as a >25% increase in the sum of the
products of the perpendicular dimensions of all measurable lesions or
the appearance of new lesions. Duration of response was measured from
the time of achievement of response to progression.
Preparation and Administration of the Radioimmunoconjugate.
MAb CC49 modified with an average of two
2-p-aminophenyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''tetraacetic
acid residues per molecule antibody (CC49-PA-DOTA) was stored at
-70°C in sterile 2-ml plastic vials. All procedures were performed
in a biological safety cabinet using aseptic techniques. Prior to
radiolabeling, the antibody solution was brought to room temperature,
and the vial was swabbed with alcohol.
To 1 mg of CC49-PA-DOTA in 0.2 ml of 0.05 M ammonium
acetate (pH 6), 111InCl3
(10 mCi) in 0.05 M HCl was added. An aliquot of
indium[III] to produce a metal:PA-DOTA molar ratio of 1:1 was added
to improve the incorporation of the radiometal into the MAb chelate
complex. The mixture was incubated at 37°C for 30 min. The reaction
progress was monitored at 20 and 30 min on ITLC strips (developed with
0.9% saline). The reaction was terminated by the addition of 0.05 ml
of 0.01 M DTPA in water. The 111In
incorporation yield was verified on ITLC strips. The purification of
111In-labeled CC49-PA-DOTA was done on a sterile
Sephadex G-50 column (1.5 x 30 cm) equilibrated with 0.05
M PBS (pH 7.4). The radioimmunoconjugate eluting in the
void volume was collected into sterile vials, and the radioactivity was
assayed in a Capintec dose calibrator.
The radiolabeling of CC49-PA-DOTA with 90Y was accomplished in an identical manner as described for 111In with the following minor modifications; the amount of CC49-PA-DOTA was increased to 4 mg and the reaction time was increased to 45 min.
Radiolabeled antibody preparations had to contain <5% free radionuclide (ITLC) and <175 endotoxin units/dose. The samples are also tested for immunoreactivity (solid-phase RIA) using the RhoChek assay (RhoMed, Albuquerque, NM), purity integrity [SDS-PAGE (5–20% gradient gel, SDS-PAGE) and high-performance liquid chromatography], and sterility; this set of tests were completed after the administration of the radiolabeled antibody.
The specified amount of radiolabeled MAb CC49 to be administered to the patient was diluted to 25 ml of saline containing 1% human serum albumin and then given over 20–30 min, followed by a 25-ml flush of normal saline infused over 15 min. Although the amount of MAb CC49 was different for each of the 111In-labeled MAb CC49 and 90Y-labeled MAb CC49 administrations, the total amount of administered protein was kept constant at 5 mg for each administration by the addition of unlabeled MAb. We have shown previously (14) that there was no apparent difference in the pharmacokinetics of MAb CC49 administered at 1–1.6 mg/patient for the diagnostic studies and MAb doses of up to >70 mg given as the therapy dose. The T1/2 ß was 39.7 ± 10.4 versus 46.1 ± 10.6 h. Because 5 mg was sufficient to conjugate the desired amount of 90Y activity, it was decided to standardize the administered amount of protein to the highest amount necessary for the studies. The amount of radiolabeled MAb given to the patient was determined by measuring the amount of the 111In or 90Y in the syringe prior to and after patient administration; the difference of these numbers was used as the patient dose.
Image Interpretation.
111In-labeled MAb CC49 planar and SPECT images
were interpreted with full knowledge of known disease sites and with
direct comparison to CT images. Localization of activity in tumor sites
were classified as minimal, moderate, or marked. A region of interest
was drawn around the area of uptake and another in a representative
background area. The mean counts/pixel in each region of interest was
used to determine uptake ratios. Minimal localization was defined as
faintly seen above background activity. Moderate localization was
defined as easily identified, but activity was no more than
approximately two to four times greater than background. Marked
localization was defined as an intense activity more than four times
greater than background.
Pharmacokinetic Studies.
To determine the pharmacokinetics of radiolabeled MAb CC49, blood
samples were drawn immediately after administration and then at 0.5, 1,
2, and 3–4 h and at 1, 2, 3, 4, 5, and 7 days. The concentration of
111In-labeled and
90Y-labeled MAb CC49 in these samples was
measured in a well-type NaI (Tl) gamma scintillation counter calibrated
with 90Y standard from the National Institute for
Science and Technology. 111In was counted using a
window of 150–510 keV. When measuring the activity of
90Y-labeled MAb CC49 in blood samples, a 511-2000
keV window was used on a gamma scintillation counter to measure
Bremsstrahlung radiation resulting from the 90Y
decay. At these high-energy settings, there was virtually no crossover
from the 111In-labeled MAb CC49 that was also
present in these samples.
Measurement of HAMA.
Serial blood samples were screened for the presence of HAMA using a
sandwich solid-phase RIA as described previously
(15)
. This assay uses an isotype-matched MAb [B6.2
(IgG1)] not related to the TAG-72 antigen. Serum from a cynomolgus
monkey positive for antimouse immunoglobulin antibodies is used as a
reference standard to determine the amount of immunoglobulins bound by
the serum samples (expressed as ng of immunoglobulin bound per ml of
serum).
Analysis of Bone Marrow Aspirates and Tissue Biopsies.
When possible, sternal bone marrow aspirates and needle biopsies of
liver and liver metastases of 10 mg in mass were obtained at 3–7
days after the administration of 90Y-labeled MAb
CC49 (approximately 8–10 days after
111In-labeled MAb CC49 administration). The
Bremsstrahlung radiation resulting from the 90Y
decay in these samples was measured using a gamma scintillation counter
(511–2000 keV) to eliminate any possible crossover from the residual
111In activity. All of the samples were adjusted
to 1 ml and counted to obtain a consistent sample size to obtain a
reproducible counting efficiency for the 90Y.
There were virtually no indium counts detected in the biopsies after
the passage of three to four physical half-lives of the radionuclide.
The needle biopsies were placed in 1 ml of formalin prior to counting.
Radiation Dosimetry for Tumors and Normal Tissues.
A complete description of the methodology for determining radiation
absorbed dose estimates for tumors and normal tissues in this study has
been presented elsewhere (16)
. Quantitative gamma camera
imaging of 111In-labeled MAb CC49 and direct
measurements of the activity of 90Y-labeled MAb
CC49 in blood, tumors, and normal liver were used in absorbed dose
calculations. Whole-body imaging commenced in <2 h after
administration of 111In-labeled MAb CC49 and was
repeated at 24, 48, and 72 h. SPECT acquisitions were carried out
at 24 and 72 h. Administered activities of
111In-labeled MAb CC49 ranged from 3 to 5 mCi,
and all images were acquired on a dual-headed gamma camera system.
Energy windows of 15% were used in all planar and SPECT acquisitions
and were centered on the two photopeaks of 111In.
The information about the activity of
111In-labeled MAb CC49 in SPECT slices, and
whole-body images was used to generate time-activity curves for
90Y-labeled MAb CC49, in conjunction with
measurements in tissue samples. The tissue activities calculated from
the SPECT images of the 111In-labeled MAb CC49
correlated with absolute measurements made of liver and tumor biopsies
(17)
.
Radiation absorbed dose estimates in this study were, therefore, based on planar whole-body and regional SPECT imaging, scaling from 111In-labeled MAb CC49 to 90Y-labeled MAb CC49, direct activity measurements, and the average ß-particle energy of 90Y. Absorbed dose calculations for tumors and normal organs were made for complete absorption of 90Y ß-particle energy and complete biological removal and physical decay of this radionuclide. However, for red marrow the absorption of 90Y ß-particle energy is incomplete, and the method of absorbed fractions was used in marrow dosimetry (17) . Additionally, marrow absorbed dose calculations were based on activity measurements in whole blood. It has been suggested that a reduction factor of 0.2–0.4 be used for the activity in blood to account for the difference in activity concentrations in blood and red marrow (15) . In this study, a reduction factor of 0.3 was used to scale from blood activity to marrow activity in absorbed dose calculations.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. One patient with extensive locoregional involvement with pancreatic
adenocarcinoma did not have metastatic disease. Eight patients had
prior treatment. This included two patients who received 5-FU alone or
in combination with levamisole, leucovorin, or both. Six patients
received multiple drug therapies. Two patients received prior
radiation: sites included esophagus (patient 08) and rectum (patient
11). All patients underwent collection of hematopoietic stem cells.
|
6.2 mCi/mg (range, 3.1 to 8.2) of CC49-PA-DOTA, which corresponds to
approximately 1 in 50 molecules of antibody carrying
111In. The 90Y-labeled
conjugates were prepared with a specific activity of 9.6 mCi/mg (range,
8.1 to 11.9), which corresponds to about 1 in 30 molecules of antibody
having one 90Y. The immunoreactivity of the radiolabeled MAbs were evaluated in a solid-phase immunoassay. The binding assay results indicated a slightly greater retention of immunoreactivity for 111In-labeled CC49-PA-DOTA compared with the 90Y-labeled CC49-PA-DOTA, 87.9 ± 4% versus 79.1 ± 4.4%, respectively.
Imaging Results.
Table 1
also profiles the extent of disease in 12 patients enrolled in
the study along with the imaging information obtained from images
acquired after the diagnostic dose. Three patients had no detectable
localization of labeled antibody, and an additional three patients had
no more than minimal localization in any known lesion. Six patients had
at least one focus of moderate activity at a known disease site. Only
one patient had marked localization at any site, this being in the
primary tumor.
In general, liver lesions were difficult to identify because of the
high nonspecific activity seen in normal liver with
111In. Lesions were more likely to be seen as
photopenic regions rather than enhanced activity, although patients 11
and 12 did have some small areas of increased activity peripheral to
photopenic liver lesions. Pancreatic lesions were often difficult to
differentiate from immediately adjacent normal liver activity. Fig. 1
is a typical planar image from a patient with peritoneal
carcinomatosis.
|
and ß for
111In-labeled MAb CC49 were 5.44 h (range,
1.91–9.35) and 59.83 h (range, 33.21–89.93), respectively. For the
90Y-labeled MAb CC49, the
T1/2 and ß were 3.89 h
(range, 1.48–7.93) and 47.38 h (range, 28.14–65.69), respectively.
Biopsy Data.
Sternal aspirates were obtained on all patients. Biopsies from liver
metastases and of normal liver were obtained on 8 and 10 patients,
respectively. Although the percentage of injected dose/kg (range,
1.12–18.14) was somewhat higher than we had observed with
131I, the tumor:normal liver ratio was
consistently <1 because of the retention of the
111In and 90Y in the normal
liver. Table 2
shows the percentage of injected dose/kg for the tumor, normal liver,
and the tumor:normal liver ratios, tumor:blood, and bone marrow:blood.
Although there may be heterogeneity in the biopsies, the measured
activities in the tissues correlated well with the SPECT image
analyses. The tumor:blood ratio ranged from 1 to >36:1.
|
. Within the range of administered activities of
90Y-labeled MAb CC49, the absorbed dose estimates
observed were 200-3000 cGy, averaging 35 cGy/mCi administered (range,
7–81).
|
summarizes the toxicities seen on this trial. The predominant toxicity,
as expected, is hematopoietic. None of the patients reached the
criteria for hematopoietic stem cell rescue. However, cryopreserved
bone marrow was returned to patient 2 for prolonged thrombocytopenia
after therapy and patient 9 in an attempt to shorten aplasia in the
face of rapidly progressing disease.
|
HAMA Studies.
The formation of a humoral response to the injected MAbs was measured
in a double determinant RIA that was developed to measure antibodies
reactive to murine IgG1. None of the patients had any evidence of a
preexisting immune response, nor did any demonstrate a measurable
response between the administration of the diagnostic dose and therapy
dose (each 5 mg). Adequate sampling was available in eight patients to
determine that there was no detectable HAMA response for up to 30 days
after administration of the diagnostic dose of
111In-labeled MAb CC49 (followed by therapeutic
90Y-labeled MAb CC49) in six of eight patients
evaluated. The median HAMA quantitation was 521 mg/ml (range, 1–22,374
ng/ml) at 2 months after the study; 2 patients remained negative, 2
patients had modest levels of HAMA (<1000 ng/ml), 3 patients had
between 1000 and 10,000 ng/ml HAMA, and one patient had 10,000 ng/ml
HAMA.
Response to Treatment.
There were no objective responses observed in this trial. Two patients
(nos. 10 and 11) demonstrated stable disease durable for 4 and 2 months
after treatment, respectively.
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In addition to suboptimal absorbed dose estimates, another concern arose from studying autoradiographs of 131I-labeled MAb CC49 in tumor biopsies after treatment. Although these biopsies showed good penetration of radiolabel throughout the core biopsy fragments, areas of low or no activity resulting from heterogeneous antibody uptake were evident. Although it is possible that the heterogeneity seen in tissues may have been a result of a low administered antibody dose, it is also possible that other factors, such as high osmotic pressure, prevented antibody access to these sites. Thus, this finding prompted us to study 90Y in this subsequent Phase I trial. 90Y has a higher average energy ß emission compared with 131I (937 keV versus 183 keV). This property can potentially permit more bystander radiotoxicity to overcome heterogeneous targeting to antigen. Furthermore, this radiometal can be stably chelated to the antibody using a macrocyclic structure. This stable linkage provides a theoretical advantage over directly labeled 131I, which can undergo some dehalogenation in vivo.
Although there can be variations between the normal biodistribution of 111In- and 90Y-conjugated antibodies, preclinical studies support the use of 111In as a surrogate for 90Y deposition in tumor sites. Using patient specific dosimetry of 111In/90Y-conjugated MAb CC49, we have calculated absorbed dose estimates in metastatic tumor sites of up to 3000 cGy for the highest administered activity levels. This dose delivery is comparable with absorbed dose estimates with very high administered activities of 131I-labeled MAb CC49 (20) . However, the administered activities of 131I-labeled MAb CC49 required to achieve this dose deposition caused severe myelosuppression requiring administration of hematopoietic stem cell support. Reversible myelosuppression was observed with the administered activities of 90Y-labeled MAb CC49 used in this trial. Thus, within the range of activities studied, it would appear that higher tumor dose deposition can be achieved with 90Y using administered activities that are less toxic than observed with 131I.
However, we also calculated a disappointingly high uptake of 90Y-labeled MAb CC49 in normal liver. There are very few other published studies of treatment using systemic administration of 90Y-conjugated antibody in Phase I and II trials in patients with solid tumors. Wong et al. (21) reported on three patients treated with 90Y-conjugated chimeric T84.66 and anti-carcinoembryonic antigen antibody. Using administered activities of 5 mCi/m2, no serious hematopoietic toxicity was observed. However, even with this low administered activity, the estimated total radiation dose to liver ranged from 234 to 432 cGy. Absorbed dose estimates for tumor were not reported. Although the original goal of our trial was to determine whether extrahematopoietic toxicity occurred with 90Y-labeled MAb CC49, a decision was made to cease dose escalation at 0.5 mCi/kg because of the observation of high absorbed dose estimates in normal liver tissue. Thus, this study provides clinical confirmation for earlier observations by Wang et al. (22) in beagle dogs. In their studies, animals treated with high activities of 90Y-labeled MAb B72.3 antibody experienced liver toxicity including liver failure. Fortunately, this finding may not present a critical hurdle for therapy of hematological malignancies that are more radiosensitive. Experience with an 90Y-conjugated anti-CD-20 antibody in the treatment of lymphoma suggests that therapeutic activity is seen with administered activities in the range used for our study (23) .
Nonetheless, the high deposition of 90Y-labeled MAb CC49 in normal liver is problematic. There are no antigenic targets for MAb CC49 in normal liver, and free 90Y is known to accumulate in bone and/or bone marrow. This finding could have resulted from infusion of antibody damaged during labeling. However, we saw no evidence of such damage in our postlabeling quality assurance assays (high-performance liquid chromatography, ITLC, and immunoreactivity assays). Thus, we assume that the accumulation of 90Y in the liver is a result of normal liver clearance of either the antibody or antigen-antibody complexes carrying the stably chelated 90Y. Paik et al. (24) has suggested that alteration in chelation and linker chemistry may reduce liver uptake of antibodies; thus, it is possible that this liver deposition could be modified using novel chelate-linker conjugates. Other approaches could involve coinfusion of cold antibody or pretargeting. This latter strategy is being pursued in the development of MAb NR-LU-10 for therapy (25) . Streptavidin-conjugated antibody is first administered to bind to the tumor target. Biotin-bound albumin is used to "washout" circulating MAb, which is then followed by 90Y conjugated to biotin. This strategy avoids nonspecific uptake of 90Y and can conceivably reduce both myelosuppression and liver uptake. In fact, the dose-limiting toxicity with MAb-NR-LU-10 and 90Y-labeled biotin (120 mCi/M2) using this strategy is diarrhea.
The HAMA response seen in this trial was predicted by earlier studies. Higher dose deposition in tumors may also require multiple administrations of 131I- or 90Y-conjugated MAb CC49. MAb CC49 has been humanized and further engineered to delete the CH2 portion of the Fc fragment (26) . This antibody is predicted to be less immunogenic and will be the focus of our future studies of radioimmunoconjugate therapy.
To our knowledge, this is the first clinical trial using systemic administration of 90Y-conjugated antibody in which tissue biopsies of tumor targets and organs at risk have been obtained in an effort to validate dosimetry estimates. The extremely low tumor:normal tissue ratios seen in this study raises concern about the future of 90Y-conjugated antibodies for radioimmunoconjugate therapy in solid tumors. Future studies with radiometals will need to focus on strategies to minimize liver uptake or dramatically improve tumor targeting and absolute accumulation of radioactivity in tumor sites. However, high-dose deposition in tumor with a single and well-tolerated administration of 90Y-labeled MAb CC49 raises hope that successful radioimmunotherapy can be achieved using sequential treatments with a less immunogenic engineered antibody.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 This study was supported by Grant U01-CA58272
from the National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at University of California San Francisco Comprehensive
Cancer Center, University of California San Francisco, 2356 Sutter
Street, Suite J708, San Francisco, CA 94115. Phone: (415) 885-3846;
Fax: (415) 353-9636.
3 The abbreviations used are: 5-FU,
5-fluorouracil; MAb, monoclonal antibody; HAMA, human antimurine
antibody; CT, computed tomography; SPECT, single photon emission
tomography; ITLC, instant thin-layer chromatography.
Received 8/20/99; revised 4/25/00; accepted 5/ 8/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  J. Baranowska-Kortylewicz, M. Abe, J. Nearman, and C. A. Enke Emerging Role of Platelet-Derived Growth Factor Receptor-{beta} Inhibition in Radioimmunotherapy of Experimental Pancreatic Cancer Clin. Cancer Res., January 1, 2007; 13(1): 299 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. McCarron, S. A. Olwill, W. M.Y. Marouf, R. J. Buick, B. Walker, and C. J. Scott Antibody Conjugates and Therapeutic Strategies Mol. Interv., December 1, 2005; 5(6): 368 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Baranowska-Kortylewicz, M. Abe, K. Pietras, Z. P. Kortylewicz, T. Kurizaki, J. Nearman, J. Paulsson, R. L. Mosley, C. A. Enke, and A. Ostman Effect of Platelet-Derived Growth Factor Receptor-{beta} Inhibition with STI571 on Radioimmunotherapy Cancer Res., September 1, 2005; 65(17): 7824 - 7831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Sharkey, G. Hajjar, D. Yeldell, A. Brenner, J. Burton, A. Rubin, and D. M. Goldenberg A Phase I Trial Combining High-Dose 90Y-Labeled Humanized Anti-CEA Monoclonal Antibody with Doxorubicin and Peripheral Blood Stem Cell Rescue in Advanced Medullary Thyroid Cancer J. Nucl. Med., April 1, 2005; 46(4): 620 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vallabhajosula, I. Kuji, K. A. Hamacher, S. Konishi, L. Kostakoglu, P. A. Kothari, M. I. Milowski, D. M. Nanus, N. H. Bander, and S. J. Goldsmith Pharmacokinetics and Biodistribution of 111In- and 177Lu-Labeled J591 Antibody Specific for Prostate-Specific Membrane Antigen: Prediction of 90Y-J591 Radiation Dosimetry Based on 111In or 177Lu? J. Nucl. Med., April 1, 2005; 46(4): 634 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shen, A. Forero, A. F. LoBuglio, H. Breitz, M.B. Khazaeli, D. R. Fisher, W. Wang, and R. F. Meredith Patient-Specific Dosimetry of Pretargeted Radioimmunotherapy Using CC49 Fusion Protein in Patients with Gastrointestinal Malignancies J. Nucl. Med., April 1, 2005; 46(4): 642 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Stein, S. V. Govindan, M. Hayes, G. L. Griffiths, H. J. Hansen, I. D. Horak, and D. M. Goldenberg Advantage of a Residualizing Iodine Radiolabel in the Therapy of a Colon Cancer Xenograft Targeted with an Anticarcinoembryonic Antigen Monoclonal Antibody Clin. Cancer Res., April 1, 2005; 11(7): 2727 - 2734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Sharkey and D. M. Goldenberg Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies J. Nucl. Med., January 1, 2005; 46(1_suppl): 115S - 127S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Milowsky, D. M. Nanus, L. Kostakoglu, S. Vallabhajosula, S. J. Goldsmith, and N. H. Bander Phase I Trial of Yttrium-90--Labeled Anti--Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Androgen-Independent Prostate Cancer J. Clin. Oncol., July 1, 2004; 22(13): 2522 - 2531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Graves, E. Dearstyne, Y. Lin, Y. Zuo, J. Sanderson, J. Schultz, A. Pantalias, D. Gray, D. Axworthy, H. M. Jones, et al. Combination Therapy with Pretarget CC49 Radioimmunotherapy and Gemcitabine Prolongs Tumor Doubling Time in a Murine Xenograft Model of Colon Cancer More Effectively Than Either Monotherapy Clin. Cancer Res., September 1, 2003; 9(10): 3712 - 3721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kurizaki, S. Okazaki, S. D. Sanderson, D. Colcher, C. A. Enke, M. A. Tempero, and J. Baranowska-Kortylewicz Potentiation of Radioimmunotherapy with Response-Selective Peptide Agonist of Human C5a J. Nucl. Med., July 1, 2002; 43(7): 957 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Goldenberg Targeted Therapy of Cancer with Radiolabeled Antibodies J. Nucl. Med., May 1, 2002; 43(5): 693 - 713. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
