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PubMed1998

Tumor pretargeting for radioimmunodetection and radioimmunotherapy.

UNLABELLED: The limited success of the sole use of monoclonal antibodies for cancer detection and treatment has led to the development of multistep methods using antibodies in conjunction with low molecular weight agents. For tumor pretargeting, it is important to optimize dose and schedule of relevant agents and to understand barriers to targeted delivery. Here, we address these issues for the anti-carcinoembryonic antigen bifunctional antibody-hapten and the streptavidinylated antibody-biotin systems using a recently developed physiologically based pharmacokinetic model. METHODS: For baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used in conjunction with the Medical Internal Radiation Dosimetry schema to: estimate absorbed doses in tumor and normal tissues; determine the dose dependence of effector agent accumulation in tumor; simulate tumor-to-background effector agent uptake ratio; and calculate the therapeutic ratio for different antibody forms and radionuclides. Alternative drug administration schemes and variable tumor physiological conditions were considered. RESULTS: Model simulations showed that 131I-labeled biotin with the streptavidinylated F(ab')2 provided the highest therapeutic ratio under the optimized conditions. The simulations also showed that biotin with the bifunctional streptavidinylated immunoglobulin G provided the highest tumor-to-liver uptake ratio during the early period. Sensitivity analysis showed that antibody extravasation was the major factor limiting the accretion of the effector agent in tumor, whereas antigen expression in normal tissues and tumor antigen shedding had little effect on the absorbed doses. CONCLUSION: Tumor pretargeting should provide a definite advantage over direct antibody targeting with up to a 200% increase in tumor-to-background ratio in radioimmunodetection and up to a 76% increase in tumor-to-bone marrow therapeutic ratio in radioimmunotherapy. Rapid antibody clearance from the bloodstream before effector agent injection is expected to improve the therapeutic ratio marginally (3%-10%). However, continuous plasmapheresis dramatically increased the tumor-to-background ratio by a factor of 10 in RAID and the tumor-to-bone marrow therapeutic ratio by more than 110% for short-lived radionuclides in RAIT. Apart from drastic measures such as extended plasmapheresis, pretargeting selectivity was neither sensitive enough for radioimmunodetection nor effective enough for radioimmunotherapy in patients with typical solid tumors even using the optimized protocols.

Animals↗
PubMed1981

Experimental studies of tumor radioimmunodetection using antibody mixtures against carcinoembryonic antigen (CEA) and colon-specific antigen-p (CSAp).

Experiments with the GW-39 human colonic carcinoma growing in hamsters showed that injection of radioactive antibody to a colorectal-specific, tumor-associated antigen, CSAp, results in better tumor radiolocalization than was seen previously with radioantibodies to carcinoembryonic antigen (CEA). However, a mixture of both radioactive antibodies resulted in potentiation of CEA-tumor radioimmunodetection without affecting CSAp-tumor radiolocalization. Hence, multi-marker antibody mixtures may be the method of choice in cancer radioimmunodetection.

Animals↗
PubMed1983

Antitumor monoclonal antibodies for radioimmunodetection of tumors and drug targeting.

Developments in hybridoma technology leading to the production of monoclonal antibodies recognizing tumor-associated antigens are providing new approaches for the radioimmunodetection of, and drug targeting to, metastases. These developments are illustrated in a series of studies on the in vivo localization of an antihuman-osteogenic sarcoma monoclonal antibody (791T/36) in human tumor xenografts maintained in immunodeprived mice. 131I-labelled 791T/36 antibody localized specifically in osteogenic sarcomas but not in xenografts of other tumors, such as bladder carcinoma T24, which do not express the antigen identified by this antibody. Developing from these studies, various parameters influencing antibody localization in tumors were examined including the kinetics of antibody uptake, the relationship between tumor size and antibody binding, and the site of antibody deposition. This provides a basis for considering the potential of antitumor monoclonal antibodies for targeting antitumor agents. Of particular importance here is the observation that antibody is principally located at the periphery of tumors since this will influence the population of cells within a tumor which can be attacked by antibody-drug or antibody-toxin conjugates. Experiments with human tumor xenografts demonstrate tumor localization of radioisotope-labelled 791T/36 monoclonal antibody. Tumor localization by external gamma camera imaging of osteogenic sarcoma xenograft-bearing mice was also demonstrated. These studies illustrate the potential of antitumor monoclonal antibodies for imaging primary and metastatic tumors. This approach is further emphasized by the radioimmunodetection of primary and metastatic colorectal carcinomas.

Animals↗
PubMed1986

Preliminary findings in the evaluation of hepatic malignancies by radioimmunodetection, X-ray computed tomography, and magnetic resonance imaging.

In 12 consecutive patients with suspected metastatic carcinoma of the liver, we evaluated the sensitivity of radiolabeled antibodies to tumor antigens, magnetic resonance imaging, and X-ray computed tomography imaging in the detection of hepatic malignancies. Studies were performed with 131I labeled antibodies to CEA and/or CSAp; polyclonal, monoclonal and F(ab')2 antibodies were used. Nontarget radioactivity was diminished by administration of 99mTc reagents simulating nontumor distribution and use of a computer subtraction method. In nine patients with confirmed liver neoplasms, radioimmunodetection disclosed the foci of hepatic malignancies. In three patients with suspected liver neoplasms, the antibody studies were positive, but at this time have not been confirmed. X-ray computed tomography each disclosed mass lesions in five patients and magnetic resonance in three. These findings suggest that radioimmunodetection provides greater accuracy in the detection and localization of cancer than other diagnostic modalities currently used.

Adenocarcinoma↗
PubMed1983

Improved radioimmunodetection of tumours using liposome-entrapped antibody.

The discrimination of radioimmunodetection of tumours is reduced by the presence of circulating radiolabelled antibody (primary antibody). We have prepared liposomes containing an antibody to the primary antibody (secondary antibody), with the intention of complexing and delivering to the liver primary antibody which is not associated with the tumour. In mice bearing xenografts of human tumours which secrete the marker carcinoembryonic antigen (CEA), liposomally entrapped secondary antibody was able to reduce the blood levels of 125I-labelled anti-CEA within 2 h, without reducing the amount of anti-CEA bound to the tumour. We therefore suggest that the use of liposomally entrapped secondary antibody would improve the diagnostic potential of radioimmunodetection of tumours and their metastases.

Animals↗
PubMed1988

Limits of sensitivity for the radioimmunodetection of colon cancer by means of a hand held gamma probe.

This study was undertaken to define the limits for the radioimmunodetection of minimal deposits of colorectal cancer cells using a hand held gamma probe. 125I labeled monoclonal antibody 17-1A and its F(ab')2 fragments were reacted in vitro with cells of the human colorectal cancer line SW 1116. The limits of sensitivity of the probe were determined by injecting doubling dilutions of 125I-antibody coated SW 1116 cells ranging from 10(7) to 3.9 x 10(4) subserosally at 2 cm intervals into 60 cm segments of freshly obtained autopsy or surgical specimens of human colon. A linear relationship was observed between the number of cells injected and the number of counts obtained with either the probe or well counter. As few as 6.25 x 10(5) 125I-antibody coated cells (less than 1 mm3) were detected under experimentally defined conditions by an earlier version of the probe, and 3.9 x 10(4) coated cells (much less than 1 mm3) could be detected by the currently available model. Although the count rates were less than 5% of those obtained by well counter, nevertheless, these were 10-25 times greater than background and allowed the detection of tumor cell deposits that otherwise would not have been discernible by either palpation or external scintigraphy. These findings, in conjunction with ongoing clinical studies, suggest that the hand held gamma probe may increase the usefulness of monoclonal antibodies for the radioimmunodetection of cancer.

Antibodies, Monoclonal↗
PubMed2001

Immunoscintigraphy and intra-operative radioimmunodetection in the treatment of colorectal carcinoma.

PURPOSE: Intra-operative radioimmunodetection of malignant involved lymph nodes follows the pre-operative immunoscintigraphy in the treatment of patients with colorectal carcinoma. The aims of this clinical study were to determine the sensitivity of the method, to compare the results in study when using Oncoscint and CEA-Scan and to evaluate the importance of the method of surgery and postoperative adjuvant therapy. PATIENTS AND METHODS: 121 patients with colorectal tumours (106 primary and 15 recurrent) were operated on using radioimmunoguided surgery (RIGS). The study compared results of pre-operative immunoscintigraphy, intra-operative radioimmunodetection and postoperative histological examination. Histological investigation used classical H&E staining. In histologically negative and RIGS positive cases the immunohistochemical investigation was supplemented. Two radiopharmaceuticals were used Oncoscint CR 103 (MAb B72.3, Satumomab Pendetide), labelled with 111In in 56 patients and CEA-Scan (IMMU 4-Fab' fragments MAb against CEA, Arcitumomab), labelled with 99mTc in 65 patients. RESULTS: The relationship between RIGS positive results and histological examination was statistically assessed after 38 operations and the most acceptable RIGS evaluating index was determined. All subsequent results were evaluated by this index. Immunoscintigraphy of tumour was positive in 112 cases (92.6%). Fifty-five RIGS positive cases of malignant infiltrated lymph nodes were confirmed by 43 histologically positive examinations (78%). In this group 9 cases were discovered only by immunohistochemistry. Sixty-six remaining RIGS negative results were confirmed in 62 (94%) cases by negative histology. CONCLUSIONS: Both immunoscintigraphy and RIGS enable one to make a more accurate diagnosis. While treating the primary disease the use of RIGS may help in assessment of necessary extent of operation performance and in staging of the disease by revealing occult lymph nodes involved. Pre-operative immunoscintigraphy seems to be a useful diagnostic method for detection of tumour recurrence. When comparing two radiopharmaceuticals used, CEA-Scan seems to be more suitable for diagnostic studies, but using the Oncoscint for tumour recurrence detection had some specific benefit, too.

Journal Article↗
PubMedDate not supplied

Radioimmunodetection of melanoma: preliminary results of a prospective study.

A prospective study to evaluate the clinical usefulness of radioimmunodetection of melanoma in clinical practice is ongoing at the National Cancer Institute of Milan, Italy. Technical conditions for the application of the method were previously reported. In this trial, 99mTc-labelled F(ab')2 fragments of the 225.28S monoclonal antibody were used against a high molecular weight melanoma associated antigen (HMW-MAA). Retrospective studies on radioimmunodetection of melanoma have already been made by our group and by other Centers in about 300 patients. This study concerns the evaluation of the regional extension of primary melanoma. 23 patients with 32 suspected lymphatic involvements of melanoma on the trunk and arms underwent immunoscintigraphy. No false positive results were observed; 3 false negatives, one corresponding to a micrometastasis, were noticed. Specificity corresponds to 100% and sensitivity to 78.6%.

Adolescent↗
PubMed2002

[Radioimmunodetection of 188Re-labeled anti-carcinoembryonic antigen chimeric antibody in nude mice bearing human colon carcinoma].

BACKGROUND & OBJECTIVE: Carcinoembryonic antigen(CEA), is highly expressed in many kinds of carcinomas, especially in colon carcinoma. Anti-CEA antibodies have great application in diagnosis and therapy of the patients with colon carcinoma. This study was designed to investigate the biodistribution and radioimmunodetection in nude mice bearing human colon carcinoma using 188Re-labeled anti-CEA chimeric antibody. METHODS: CEA chimeric antibody and its parent McAb C50 were labeled with 188Re by a stannous chloride reduction method. The radiochemical purity of them were determined by ITLC. The biodistribution and whole body gamma scintigraphy imaging of 188Re-CEA chimeric antibody in nude mice bearing human colon carcinoma were fulfilled. The effect of radioimmunoimage between these two antibodies was compared. RESULTS: 188Re-CEA chimeric antibody showed high radiochemical purity of more than 95%. The specific reactivity of 188Re-CEA chimeric antibody was 356 MBq/mg. Immunoreactivity of 188Re-CEA chimeric antibody was 61% as determined by ELISA. Tumor/kidney ratio (0.75) and tumor/blood ratio(0.99) of 188Re-CEA chimeric antibody were observed in 24 h; compared to the orther organs, the ration is over 1.78. Tumor/kidney ratio (1.02) and tumor/blood ratio (1.12) of 188Re-CEA chimeric antibody were observed in 48 h; compared to the other organs more than 2.08. High uptake of 188Re-CEA chimeric antibody was observed in 20 hours after injection. The radioimmunodetection effect of these two antibodies was approximately same. CONCLUSIONS: 188Re-CEA chimeric antibody showed high specific tumor uptake and could fast display clear image in the nude mice bearing human colon carcinoma. Comparing with McAb C50, CEA chimeric antibody has good effect in clinic because of reducing of immunogenicity.

Animals↗
PubMed1990

Radioimmunodetection of human melanoma.

Radioimmunodetection has been shown to be an invaluable method in the diagnosis of primary and metastatic malignant disease. Fourteen patients, consisting of four men and 10 women with clinical suspicion of metastatic malignant melanoma or ocular melanoma were prospectively evaluated with the technique. Ten (71%) had positive and four (29%) had negative scintigrams. There was one false-positive scintigram. The overall sensitivity and specificity were 100% and 80%, respectively. SPET was necessary for the radioimmunodetection of patients with ocular melanoma. Combined immunoscintigraphy and immunolymphoscintigraphy enhanced the diagnosis of small, cutaneous melanoma and metastatic lymph node disease.

Adult↗
PubMedDate not supplied

Radioimmunodetection of gliomas by administration of radiolabelled monoclonal antibodies. Experimental data.

Radiolabelled monoclonal antibodies (McAbs) raised against membrane components of an experimental rat glioma (79FR-G-41) were administered parenterally to immunodeficient mice bearing glioma grafts for tumor radioimmunodetection by external imaging. Purified McAbs (14AC1) of IgG2a isotype were labelled with Na131I (2mCi/50ml) using the Chloramin-T method. As control, for non-specific uptake of proteins in the tumor, normal mouse IgG were also iodinated. For radioimaging, nude mice bearing gliomas in the thigh muscle were injected intravenously with 15 micrograms of the 131I-McAb with an activity of approximately 150 mu Ci. Control tumor-bearing animals received the same amount of mouse 131I-IgG. Scans obtained immediately after injecting the intact 131I-14AC1 antibody and at 24, 48, 72, and 96 hours demonstrated accumulation in the tumor. The tumor was clearly visible 48 hours following injection of 131I-labelled antibody. At 96 hours after injection, the McAb showed a clearly higher uptake into the tumor as the control IgG. The biodistribution of the injected antibody was studied at 96 hours after injection following the last gamma-imaging. At this time the blood activity was still high, but the maximum activity was found in the tumor for the specific McAb. Using the 131I-14AC1 to image glioma transplants, it could be shown that grafts are permeable for the McAb. The time-course experiments administering 131I-14AC1 antibody and normal mouse 131I-IgG, demonstrated that the localization of 131I-I4AC1 antibody in glioma grafts is the result of specific antigen binding. The scintigrams using intact antibody without background subtraction provided adequate tumor visualization, but the activity in the blood was high even 96 hours after injection. More rapid clearance of blood - pool radioactivity would possibly be achieved with F(ab')2 fragments. These in vivo glioma imaging studies, together with related in vitro binding tests, indicate the potential value of monoclonal antiglioma antibodies not only for clinical tumor radioimmunodetection, but also for the evaluation of immunotherapeutic approaches to the glioma disease of man.

Animals↗
PubMed1981

The role of radioimmunodetection in the management of testicular cancer.

Five patients with testicular cancer received an intravenous injection of between 1 and 2.5 mCi of iodine 131-labeled antibody to human chorionic gonadotropin (HCG) or alpha-fetoprotein (AFP), followed by total-body photoscanning to visualize areas of abnormal radioactivity. Blood-pool and nontarget sites of radioactivity were reduced by subtracting the images derived by injection of technetium Tc 99m-labeled components from the iodine 131 scans. The HCG-immune scintiscans proved helpful in tumor localization and in the selection of appropriate therapy, while the AFP scan presented corroborative evidence of widespread tumor. Elevated serum levels of these two markers did not hinder successful tumor detection and localization by this method of radioimmunodetection. Cancer radioimmunodetection with antibodies to HCG and to AFP appears to be a useful procedure for the pretreatment and posttreatment evaluation of patients with testicular cancer and can reveal sites of tumor not detected by other methods.

Adult↗
PubMed1983

[Recent progress in radioimmunodetection for cancer using radio-labeled monoclonal antibodies].

The concept of injecting anti-tumor antibodies to localize tumors was first introduced in experimental systems by Pressman (1957). Since then, various trials for tumor detection have been performed using anti-tumor antibodies. In 1970's, the radioimmunodetection of cancer has rapidly developed by the use of radioantibodies to oncofetal proteins such as CEA, AFP and hCG. Recently, there are papers dealing with animal studies of external scanning by the monoclonal antibodies that bind selectively to tumor cells derived from murine teratocarcinoma, human malignant melanoma, human mammary carcinoma and human osteosarcoma. As clinical trials the radiolabeled monoclonal antibodies against CEA or AFP were also used for the radioimmunodetection in patients with CEA or AFP-producing tumors, and the positive rates of the scanning ranged from 40 to 94%. Various related problems are also discussed.

Animals↗
PubMed1980

Radioimmunodetection of primary and metastatic ovarian cancer using radiolabeled antibodies to carcinoembryonic antigen.

131I-labeled goat immunoglobulin G (IgG) prepared against carcinoembryonic antigen (CEA) was administered at an average dose of 1.0 mCi (180 to 250 microgram IgG protein) to patients with ovarian tumors in order to evaluate this method of tumor detection and localization, termed the radioimmunodetection of cancer. All primary cancers in 13 patients could be localized, whereas the metastases in six of nine cases could be imaged by external scintigraphy. However, only two of these cases showed metastatic spread by more conventional diagnostic techniques, including computer-assisted tomography, ultrasonography, and angiography. Successful tumor radiolocalization appeared to depend on tumor size, with lesions smaller than 2 cm in diameter not being detected. Tumors containing a CEA concentration above 115 ng/g, including a benign neoplasm, could be localized with radioactive anti-CEA antibodies. Administration of radioiodinated normal goat IgG to four patients with malignant or benign ovarian tumors failed to show tumor radioimmunodetection. One of these cases subsequently demonstrated a 4- x 4-cm tumor after receiving specific radiolabeled anti-CEA IgG. This study shows that ovarian neoplasms containing CEA can be detected and localized by external photoscanning after the application of radioiodinated antibodies to CEA and that, in this small series of patients, primary and secondary tumors could be detected in 100 and 67% of the cases, respectively.

Adenocarcinoma↗
PubMed1998

Preoperative and intraoperative radioimmunodetection of cancer pretargeted by biotinylated monoclonal antibodies.

The in vivo post-targeting of tumor by means of anti-carcinoembryonic-antigen (CEA) monoclonal antibodies (MAbs) and the avidin-biotin three-step system was tested by immunoscintigraphy and radioimmunoguided surgery (RIGS) in six patients with primary or recurrent rectal cancer. The patients were preoperatively injected with 1 mg of FO23C5 (anti-CEA) and/or B72.3 anti-tumor-associated glycoprotein (TAG-72) biotinylated MAb; after 24 hours, 1 mg of avidin was administered, and, after a further 24 hours, biotin labeled to Indium-111 (In111) was injected. Preoperative imaging was obtained by means of a gamma camera, and a portable gamma-detecting probe (Neoprobe 1000) was intraoperatively used to count tumor and surrounding normal tissue. Eight tumor sites were localized in the six patients. Four lesions were identified preoperatively and six intraoperatively with a mean tumor-to-normal-tissue (T/NT) ratio of 1:8. This method allowed preoperative scintigraphy and intraoperative radioimmunodetection to be performed with a single radioactive compound injection of biotin labeled to In111 within few days before surgery.

Adult↗
PubMed1994

Radioimmunodetection of non-small cell lung cancer using technetium-99m-anticarcinoembryonic antigen IMMU-4 Fab' fragment. Preliminary results.

BACKGROUND: Although computed tomography and magnetic resonance imaging have improved the staging and evaluation of non-small cell lung cancer (NSCLC), mediastinal staging lacks adequate specificity and sensitivity. Radioimmunodetection may augment computed tomography and magnetic resonance imaging. The authors evaluated the ability of the technetium 99m-anticarcinoembryonic antigen IMMU-4 Fab' fragment to localize NSCLC in vivo, measured its pharmacokinetics, and estimated its radiation dose. METHODS: Seventeen patients with carcinoembryonic antigen-positive NSCLC received 16-30 mCi of technetium 99m IMMU-4 Fab'. Planar imaging was performed at 1-7 hours and 20-24 hours. Single-photon emission computed tomography (SPECT) was performed within 8 hours after injection. In 10 patients, blood sampling, urine collection, and quantitative imaging were performed to determine blood and urine pharmacokinetics and radiation dose estimates. Human anti-mouse antibody response was measured for as long as 3 months after administration. RESULTS: Planar and/or SPECT imaging detected 72% of 32 known lesions. SPECT was more sensitive than planar imaging. T1/2 alpha averaged 0.18 +/- 0.33 hours; T1/2 beta averaged 8.02 +/- 5.53 hours. The mean concentration versus time value was 1.11 +/- 0.56 mg.h. The average whole body dose estimated for administration of 30 mCi was 0.45 +/- 0.08 rads. No human anti-mouse antibody responses were detected. CONCLUSION: The tumor detection rate was high, but the persistent blood pool at < 8 hours complicated image interpretation. An intermediate imaging time point (12-16 hours) might be preferable. SPECT is an important adjunct to imaging with this radioimmunoconjugate. The acceptable dosimetry estimated for 30 mCi Technetium 99m IMMU-4 Fab' and the lack of human anti-mouse antibody responses suggest this is a promising localizing tool for NSCLC:

Antibodies, Monoclonal↗
PubMed1995

Radioimmunodetection of human cervical carcinoma xenograft by 111In-labeled monoclonal antibody MAb Cx-99.

Radioimmunodetection (RAID) is more sensitive and specific than conventional diagnostic methods. In this study, a monoclonal antibody against cervical carcinoma antigen, MAb Cx-99, was labeled with 111Indium (111In). This immunoconjugate was intravenously injected into athymic nude mice bearing cervical squamous cell carcinoma (SCC) xenografts. The tissue distribution study showed that the xenograft tumor had higher binding activity than most other tissues after 48 h from injection, demonstrated by localization ratio of tumor of tissues (c.p.m./g) against blood (c.p.m./g). However, this localization ratio was also high in the liver, spleen and kidney. The imaging study by immunoscintigraphy also showed that the tumor and liver were distinct from other background tissues 2 days after injection. This preliminary study showed that 111In-labeled MAb Cx-99 may have potential for RAID of cervical cancer, especially for tumors in the pelvis.

Animals↗
PubMed1994

Current status of radioimmunodetection.

Radioimmunodetection is a nuclear medicine technique that depends on in vivo detection of localization of antibodies and antibody forms carrying radioactivity for the purpose of diagnosis in patients with cancer. Current methods take advantage of tracers suitable for high resolution gamma-camera imaging, such as 99mTc and 111In, for common tumors, such as colon and lung cancers. In addition, tracers such as 125I have been used for the intraoperative detection of metastatic deposits. These methods detect from 75 to 90% of metastatic deposits with high specificity, and typically contribute important diagnostic information, even in 25-40% of patients with occult disease.

Clinical Trials as Topic↗