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PubMed1999

Radioimmunodetection: technical problems and methods of improvement.

Radioimmunodetection (RAID) is a technique which uses radiolabelled antibodies to visualize tumours, taking advantage of antigens preferentially expressed by malignant tissue. Gamma radiation emitted by radioisotopes can be detected using an external gamma camera (RAID), or intraoperatively with a hand-held Geiger counter (radioimmunoguided surgery, RIGS). RAID has significant inherent problems. Many have been overcome as a result of nearly 50 years of research, and others still remain as obstacles precluding the routine use of the technique. This article summarizes the technical limitations of RAID and outlines the relative successes of the methods evolved to overcome them.

Antibodies, Monoclonal↗
PubMed1997

Radioimmunodetection with 111In-labeled monoclonal antibody Nd2 in patients with pancreatic cancer.

This report summarizes results from an initial clinical evaluation of radioimmunodetection (RAID) in patients with pancreatic cancer using murine monoclonal antibody Nd2, directed against mucins from pancreatic cancer. Nd2 (2 mg) was labeled with 111In (2 mCi) and injected into 19 patients suspected of having pancreatic cancer. Planar scintigrams were taken 3 days post-infusion. As for final diagnoses after surgery, 14 cases were pancreatic cancer, and one case each was chronic pancreatitis, neurilemmoma, islet cell carcinoma, cholangioma, and apparent absence of suspected recurrent lesion of pancreatic cancer. Of 14 patients with pancreatic cancer, RAID was positive in 10 cases (71.4%). Cases other than pancreatic cancer were all negative, so the specificity was 100%. These results demonstrate that RAID using 111In-Nd2 can be useful in differentiating exocrine pancreatic cancer from benign conditions and other types of carcinomas in the pancreatoduodenal regions.

Adenocarcinoma↗
PubMed1993

Radioimmunodetection of prostate cancer by 111In-labeled monoclonal antibody against prostatic acid phosphatase.

Purified human prostate acid phosphatase (PAP) was used to generate a specific monoclonal antibody (FC 3001) for detection of PAP expressed by some prostatic carcinomas. DTPA derivatives of MoAb-F(ab')2-fragments were labeled with indium-111 chloride. This labeled antibody was tested in 15 prostate cancer patients who underwent staging pelvic lymphadenectomy; 9 of them received labeled antibody alone whereas 6 received simultaneous injections of labeled and unlabeled antibody with two dose levels (40 or 80 mg). Biodistribution data obtained by direct blood measurements and imaging procedures indicated that simultaneous injection of unlabeled antibody reduced both the blood elimination rate and the accumulation in the liver. Accumulation of the radionuclide in pelvic lymph node metastases was observed in some patients but in a couple of patients accumulation was noted also in normal lymph nodes. The method cannot in its present design replace staging pelvic lymphadenectomy and further studies are needed for elaboration of clinically useful radioimmunodetection methods.

Acid Phosphatase↗
PubMed2000

CaNa2EDTA for improvement of radioimmunodetection and radioimmunotherapy with 111In and 90Y-DTPA-anti-CEA MAbs in nude mice bearing human colorectal cancer.

UNLABELLED: 111In and 90Y, dissociated from 111In-labeled-monoclonal antibody (MAb) and 90Y-labeled MAb, may cause deterioration of the image quality in radioimmunodetection (RID) and undesirable irradiation of nontargeted tissue in radioimmunotherapy (RIT), respectively. The aim of this study was to investigate any improvement in RID and RIT with 111In-MAb and 90Y-MAb by pre- and postadministration of calcium disodium ethylenetriaminetetraacetic acid (CaNa2EDTA). METHODS: Murine MAb F33-104 against carcinoembryonic antigen (CEA) was labeled with 111In or 90Y by the diethylenetriamine pentaacetic (DTPA)-anhydride method. The influence of CaNa2EDTA on loss of radioactivity from 111In-MAb or 90Y-MAb in serum was investigated in vitro. The effects of CaNa2EDTA, administered before and after 111In-MAb or 90Y-MAb, on the biodistribution of radioactive isotopes in nude mice bearing human colon adenocarcinoma LS 180 tumor expressing CEA, or human pulmonary carcinoma PC 9 tumor expressing no CEA, were then examined. As a control, 0.9% NaCl was used in both the in vitro and in vivo studies. RESULTS: CaNa2EDTA did not cause any decrease in levels of radioactivity of radiolabeled MAbs. Pre- and post-treatment with CaNa2EDTA reduced radioctivity in both specific and nonspecific tumors at 72 h after 111In-MAb injection resulting in an increase of the specific tumor-to-nonspecific tumor radioactivity ratio. The levels of hepatic and renal radioactivity were also subsequently decreased by CaNa2EDTA. On the other hand, CaNa2EDTA pre- and post-treatment reduced levels of bony, hepatic, and renal radioactivity at 24, 72, and 72 h, respectively, after 90Y-MAb injection, although it had no effect on tumor radioactivity. CONCLUSION: Pre- and post-treatment with CaNa2EDTA would be of great use in humans who undergo RID or RIT with 111In-MAb and 90Y-MAb accompanied by disassociation of the labeled radionuclides.

Animals↗
PubMed1999

[Radioimmunodetection in the diagnosis of trophoblastic disease].

OBJECTIVE: To study the efficiency of radioimmunodetection (RID) to locate the loci of trophoblastic disease. METHOD: 24 RIDs were performed with 131I labeled mouse anti-hCG monoclonal antibodies on 21 patients with trophoblastic disease. RESULTS: Of 24 RIDs performed, 13 were positive, including one false positive; 11 were negative, including two false negative. The sensitivity of RID was 85.7%, the specificity was 90.0%, the accuracy was 87.5%. In 8 patients who underwent operations after RID, the findings of RID were in accordance with the pathologic and immunohistologic findings. CONCLUSIONS: RID is an efficient imaging method for trophoblastic disease. In some cases, RID showed its value as a functional diagnostic method.

Adult↗
PubMed2002

Radioimmunodetection of cervical carcinoma xenografts with (111)In-labeled MAb Cx-99 detected by a hand-held gamma detector.

PURPOSE: To establish a radioimmunodetection (RAID) system for localization of cervical cancer by labeling 111-indium ((111)In) to a monoclonal antibody against cytokeratin 19 (MAb Cx-99), and detecting it with a hand-held gamma detector in an animal model. METHODS: MAb Cx-99 was labeled with 111-Indium by the DTPA chelating method. From the second day to the seventh day after injection of this immunoconjugate into athymic nude mice bearing cervical cancer cell line CC7T xenografts, the biodistribution ratios of tumor and non-tumor radioactivity were detected by a hand-held gamma detector. Data were also correlated with the data detected by the conventional gamma counter. RESULTS: The labeling efficiency of this (111)In-labeled MAb Cx-99 and (111)In-labeled MOPC was 91.6% and 95.5%, respectively. After injection, the liver, kidney and lung were initially noticed to have high radioactivity, but the localization of tumor/tissue ratios increased progressively as time passed, indicating the effect of delayed detection for distinguishing tumor from non-tumor tissues. Except for the spleen, the range of tumor/tissue ratios was 1.18-32.7 and 1.14-39.35 for the fourth day and the seventh day, respectively. The tumor/spleen ratio remained low until the seventh day after injection, thus indicating that the spleen might have a different excretion rate. CONCLUSION: This study indicated the feasibility of a hand-held detection system in the localization of cervical cancer after injection of (111)In-labeled MAb Cx-99. The effect of delayed detection was obvious by the decreasing high bindings in the liver, spleen and kidney, with the applicable detection time being four to seven days after injection.

Animals↗
PubMed1992

[Radioimmunodetection of colorectal cancer, using anti-CEA monoclonal antibody CEA 102: whole IgG versus F(ab')2 fragments].

In order to improve cancer imaging with radiolabeled antibodies, three factors appeared to be of particular importance: (1) The selection of the most favorable monoclonal antibody directed to tumor-associated antigen. (2) The use of F(ab')2 or Fab fragments. (3) Selection of the most convenient isotope. Monoclonal antibody CEA 102 was produced by immunization by purified CEA, and its F(ab')2 fragments were compared with whole IgG as a radiotracer for radioimmunodetection of the colorectal cancer. Fragments were eliminated from the circulation twice as fast as whole IgG, and tumor-to-background ratio was achieved more than 1 at 2-3 days with F(ab')2, but 6-7 days with whole IgG in tumor bearing nude mice. In clinical study, F(ab')2 demonstrated clear image on the 1 at day after injection, whereas achievement of the image was possible on the 3rd day in whole IgG. These results indicated that fragments are preferred over whole IgG. Therefore fragments make it possible to preclude dual isotope subtraction methods, and omit the long delays before imaging. They also make it possible to use short half life radionuclides with excellent photon properties, such as 123I and 99mTc.

Animals↗
PubMed2004

Radiolabeling, biodistribution, and dosimetry of (123)I-mAb 14C5: a new mAb for radioimmunodetection of tumor growth and metastasis in vivo.

UNLABELLED: This study reports on the in vitro evaluation, biodistribution, and dosimetry of (123)I-labeled monoclonal antibody (mAb) 14C5, a new antibody-based agent proposed for radioimmunodetection of tumor growth and metastasis in vivo. METHODS: (123)I-mAb 14C5 was prepared by direct iodination and tested for stability in vitro. Binding assays were performed on human SK-BR-3 and HeLa carcinoma cells to investigate the antigen expression, antibody affinity, and kinetics of tracer binding. For the biodistribution and dosimetry study, 3- to 4-wk-old NMRI mice were injected intravenously with (123)I-mAb 14C5 (148.0 +/- 7.4 kBq per mouse) and killed at preset time intervals. Organs, blood, urine, and feces were counted for radioactivity uptake, and the data were expressed as the percentage injected dose per gram tissue (%ID/g tissue) or %ID. The MIRDOSE3.0 program was applied to extrapolate the estimated absorbed radiation doses for various organs to the human reference adult. RESULTS: (123)I-mAb 14C5 was obtained in radiochemical yields of 85.0% +/- 2.5% and radiochemical purities were >97%. The iodinated antibody demonstrated good in vitro stability with 93.6% +/- 0.1% of (123)I-mAb 14C5 remaining intact at 24 h after radiolabeling. (123)I-mAb 14C5 bound to SK-BR-3 cells (dissociation constant [K(d)] approximately 0.85 +/- 0.17 nmol/L) and HeLa cells (K(d) approximately 1.71 +/- 0.17 nmol/L) with nanomolar affinity and high specificity, whereas both cell types exhibited a high CA14C5 antigen expression (maximum number of binding sites [B(max)] = 40.6 +/- 5.2 and 57.1 +/- 9.6 pmol/L, respectively). In mice, (123)I-mAb 14C5 accumulated primarily in lungs (20.4 %ID/g), liver (15.1 %ID/g), and kidneys (11.1 %ID/g) within 5 min after injection. A delayed uptake was observed in stomach (12.8 %ID/g) and urinary bladder (8.7 %ID/g) at 3 and 6 h, respectively, after injection. Radioactivity clearance was predominantly urinary, with 44.9 +/- 4.5 %ID excreted during the initial 48 h after administration (cumulative amount). The highest absorbed radiation doses determined for the human reference adult were received by the urinary bladder wall (0.1200-0.1210 mGy/MBq), liver (0.0137-0.0274 mGy/MBq), uterus (0.0196-0.0207 mGy/MBq), and lower large intestine wall (0.0139-0.0258 mGy/MBq). The average effective dose resulting from a single (123)I-mAb 14C5 injection was estimated to be 0.017-0.022 mSv/MBq. CONCLUSION: (123)I-mAb 14C5 shows good in vitro biologic activity and favorable biodistribution properties for imaging carcinomas of different origin and provides an acceptable radiation dose to the patient.

Animals↗
PubMed1991

[Immunohistochemical study on human epithelial ovarian carcinoma after radioimmunodetection with 131I-labelled polyclonal antibodies].

We report the results of our immunohistochemical study on the distribution and the retention time of the injected labelled antibodies in both primary and recurrent ovarian epithelial carcinomas and the regional lymph nodes, following the radioimmunodetection with injection of 131I-labelled polyclonal antibodies (including 5 cases of intravenous injection group and 35 cases of subcutaneous injection group). Six other tumors or tumor-like lesions, 8 normal ovaries and 7 normal fallopian tubes were used for control. The results demonstrated: 1. The labelled antibodies were specific for ovarian epithelial carcinoma, 2. The concentration of the labelled antibodies in the lymph node metastasis was higher in the subcutaneous injection group than in the intravenous injection group. Therefore, the subcutaneous route should be used both for imaging and radioimmunotherapy of lymph node metastasis, 3. The retention time of the antibodies in the lymph node metastasis was not more than 24 days. With this reference, the total dose of radioimmunotherapy can be calculated.

Adenocarcinoma↗
PubMed1995

Improving the balance between treatment and diagnosis: a role for radioimmunodetection.

Despite major advances in diagnostic testing, including the introduction and widespread availability of high-resolution computed tomography (CT) and magnetic resonance imaging, inadequate diagnostic information still interferes with proper management of many patients with cancers. This is particularly true for recurrent colorectal cancer, for example. In the course of this symposium, significant advances have been reported which are likely to improve management of this clinical situation. 111In, oncoscint for colorectal and ovarian cancer imaging, has been approved for single use only, and is a product licensed by the Food and Drug Administration. It has been shown to be significantly more effective than CT for detecting the presence of disease that is confined to the abdomen outside the liver. This agent is very useful in a limited role. A larger opportunity awaits other preparations reported at this conference, especially 99mTc-labeled Immu-4 carcinoembryonic antigen, which is significantly better than CT for determining resectability of recurrent cancer (T. Behr et al., Cancer Res. 55 (Suppl.): 5777S-5785S, 1995). The 99mTc-labeled compound preparations offer the advantages of low immunogenicity, excellent imaging energies of 99mTc, and "same-day" imaging. Even the most effective cancer treatment such as surgical resection, if applied to a patient who basically does not need it, can be a needless expense and a trauma to the patient. To date, our emphasis in oncology research has been heavily weighted toward developing new therapies. The success of radioimmunodetection is one indication of why it is time for a paradigm shift, during which we can move toward a more balanced program that emphasizes both diagnosis and therapy. To achieve this we must urge research institutions such as the National Cancer Institute and American Cancer Society to make major investments in the diagnostic aspects of cancer care. With the knowledge base that we have now, we can make improvements in patient care by emphasizing development of improved diagnostic methods and support for cost-effectiveness studies for developed methods, in order that currently available treatments can be more intelligently applied.

Humans↗
PubMed1993

[Radioimmunodetection of prostatic cancer: in vivo 131I-gamma-seminoprotein for diagnosis of prostatic cancer by nuclear imaging].

69 patients with prostatic cancer were subjected to radioimmunodetection (RAID) with 131I-labeled antibody against gamma-seminoprotein (gamma-Sm), the images of malignant tumor sites was obtained by single photon emission computed tomography (SPECT) with dual radionuclide and computer processing. Of the 69 patients 66 were confirmed by RAID. The ratio of tumor tissue to normal tissue (T/N) 6.9 and the best time for incaging was 96 hours after injection of anti-gamma-Sm. The diameter of the minimum tumor in RAID was 0.5 cm. metastatic prostatic cancer in the pelvis or bone location as well as the origin tumors were also detected in 13 cases. Anti-gamma-SmRAID can differentiate benign from malignant prostatic neoplasms. In 37 cases of benign prostate hyperplasia, only two were positive. The positive detective rate of B-ultrasound and CT was 70.8% and 73.1% respectively.

Dextrans↗
PubMed1994

Direct labeling of monoclonal antibodies with 99mTc and radioimmunodetection of a murine mammary carcinoma with 99mTc-B2C114.

Two anti-CEA antibodies, B2C114 and IORCEA1, were radiolabeled with 99mTc by two direct methods (mercaptoethanol and ascorbic acid reduction), and the radio-immunoimaging properties of B2C114 were assessed in mice bearing an M3-reactive tumor. The labeling efficiency was greater than 90% as measured by ITLC in saline, methylethylketone and with serum albumin impregnated sheets using ethanol: water: NH4OH (2:5:1). The label was stable to challenge with excess DTPA, and in the case of ascorbic acid reduction, serum analysis showed that 10-15% of the radioactivity was lost during incubation. In vitro studies demonstrated that the radiolabeled antibodies retained their immunoreactivity. Biodistribution studies in normal Balb/c mice showed that the pattern of uptake was quite similar for both antibodies. Biodistribution of the 99mTc-B2C114 and image studies in the animal model showed that the tumor was clearly visualized and that B2C114 labeled with 99mTc is a possible candidate for human radioimmunodetection of CEA-expressing tumors.

Animals↗
PubMed1993

Radioimmunodetection of prostatic cancer: in vivo use of antibody against r-seminoprotein for diagnosis of prostatic cancer.

Forty patients (25 cases of prostatic cancer and 15 cases of benign prostatic hyperplasia) were examined with radioimmunodetection (RAID) using antibody against r-Seminoprotein (r-Sm). The images of malignant tumor sites were revealed from the scan of single photon emission computerized tomography with the tracing of dual radionuclide and computer digital subtraction technique. Of the 25 patients with prostatic cancer tested, twenty-four were demonstrated in RAID with a positive rate of 96%. The ratio of taking in nuclide radioactivity between the tumor tissue and normal tissue (T/N) was 6.9 and the best showing time was the 96th hr from injection of radioactive antibody against r-Sm. The minimum diameter of the tumor detected in RAID was 0.5 cm. All of the 8 cases of metastatic prostatic cancer in pelvic or bone location were detected, with a rate of 100%. Of the 15 cases of benign prostatic hyperplasia, only one showed mild positive result. B-ultrasonography and CT showed a positive detective rate of 72.7% and 65%, respectively. Our results have indicated that RAID using 131I-labeled antibody against r-Sm possesses more advantages in specificity, because RAID not only defines the involved sites, but also shows the sites of the original tumors, and the metastatic location as well as the relationship between them.

Antineoplastic Agents↗
PubMed1993

Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEA/anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer.

Two-step radioimmunotargeting using a bispecific anti-CEA/anti-in-DTPA monoclonal antibody and an 111In-labeled DTPA dimer (diDTPA-TL) was evaluated nine times in eight patients with medullary thyroid cancer (MTC). Immunoscintigraphy was performed 5 and 24 hr after injection of 111In-diDTPA-TL. For five patients, radioimmunoguided surgery (RIGS) was performed using a hand-held gamma probe (sodium iodine), and a biodistribution study was performed 48 hr (four times) and 24 hr (one time) after injection of 111In-diDTPA-TL. Mean tumor uptake (%ID/kg in tumor) was 39 (range 2.75-139). In these five patients, immunoscintigraphy visualized all known tumors and detected unknown foci (US and CT were negative) in the neck (once) and neck and liver (once). Immunoscintigraphy, performed four times in search of a recurrence, detected unknown localizations in the mediastinum and neck (twice) and was negative twice. There were no false-positives. In three of five patients who had surgery, RIGS localized tumor foci not detected by the surgeon. RIGS failed to detect two small lesions (10 x 10 mm) corresponding to sites of fibrosis and microscopic cancer infiltration. Bispecific anti-CEA/anti-In-DTPA mediated targeting of 111In-diDTPA-TL provided elevated tumor uptake and tumor-to-normal tissue ratios. Radioimmunodetection of small MTC lesions is thus possible even when morphological imaging techniques prove negative.

Carcinoma↗
PubMed1996

Factors influencing the pharmacokinetics, dosimetry, and diagnostic accuracy of radioimmunodetection and radioimmunotherapy of carcinoembryonic antigen-expressing tumors.

The aim of this study was to examine factors that may influence the pharmacokinetics, diagnostic accuracy, and dosimetry in radioimmunodetection and radioimmunotherapy with anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs). Data from 275 patients with CEA expressing tumors were analyzed retrospectively. Of these, 69 patients devoid of human antimouse antibody (i.e., 31 colorectal, 9 lung, 7 breast, 4 ovarian, 6 pancreatic, 9 medullary thyroid, 1 gallbladder, and 1 salivary gland cancer, and 1 primary tumor of unknown origin) underwent a low-protein-dose diagnostic study (0.3-2.6 mg of protein; 6.8-28.8 mCi 131I-labeled IgG or fragments), followed within 4 weeks by a high-protein-dose therapy injection (4.0-27.5 mg of protein; 29.8-238.9 mCi). The anti-CEA antibodies NP-4 (Ka=10(8)M-1) and MN-14 (ka=10(9)M-1) were used. Plasma clearance, the molecular composition of radioactivity in the plasma, and the cumulated activity in organs and tumors were determined. Radiation doses were derived from the Medical Internal Radiation Dose scheme. At a low-protein dose and over a similar range of plasma CEA, a significantly higher percentage of MN-14 than of NP-4 was complexed with circulating CEA, consistent with its higher affinity. Complexation was reduced with increasing protein doses. However, the targeting sensitivity was not affected. Profound differences were found in the clearance of the antibody between different types of cancer. Colorectal cancer patients cleared the antibody significantly faster from blood (T1/2=17.6+/-12.6 versus 44.2 +/- 23.7 h) and whole body (t1/2= 53.2 +/- 30.1 versus 114.6+/-59.7 h) than all other tumor types (P <0.001). Consequently, significantly lower red marrow (2.1 +/- 1.0 cGy/mCi versus 4.3 +/- 1.6 cGy/mCi) and whole-body doses (0.5 +/- 0.3 cGy/mCi versus 1.0 +/- 0.4 cGy/mCi) were seen in colorectal cancer patients as compared with other tumor types (P < 0.001). This clearance is probably due to hepatic metabolism of the immune complexes. Clearance rates were especially high in patients with colorectal cancer having large liver metastases and elevated liver enzymes (rapid hepatic clearance with liberation of free I-). In contrast, a disease-stage and plasma CEA-matched cohort of colorectal cancer patients, examined with the 131 I-labeled anti-colon-specific antigen p mAb Mu-9, showed normal murine IgG pharmacokinetics (n=22;3 of them compared intraindividually to MN-14). Only in colorectal cancer patients did complexes between mAb and CEA tend to clear rapidly, whereas Mu-9 had normal kinetics in these patients. This suggests that different CEA-expressing cancer types may produce heterogeneous CEA molecules and that the variability in mAb clearance is due to varying clearance rates of these different circulating CEA subspecies. Disease-related alterations in antibody metabolism are unlikely, given that only anti-CEA antibodies exhibit this phenomenon.

Adolescent↗
PubMed1995

[Construction and radioimmunodetection of nude mouse xenograft of human choriocarcinoma].

Fresh tissue of human choriocarcinoma was injected subcutaneously into the BALB/C nude mouse. The xenografts had grown up with 16-68 passages. The hCG level of the ascites or intratumoral blood was 400-20,000 mIU/ml. Radioimmunodetection was performed using 131I labelled murine anti-hCG McAb. The labelled antibody could be specifically accumulated in the tumor sites and the tumor imaging was acquired. The ideal imaging time was 72-96 hours after the injection of antibody.

Animals↗
PubMed1996

[Anti-human AFP variant McAb in radioimmunodetection for primary hepatocellular carcinoma].

We investigated the affinity and special combination of anti-human AFP variant monoclonal antibody (AFP-R-LCA McAb) for cells of AFP positive hepatocellular carcinoma (HCC). AFP-R-LCA McAb was labeled by 131I radioisotope (131I-AFP-R-LCA McAb injected into the peripheral veins of patients with HCC or liver cirrhosis after hepatitis B. 131I-AFP-R-LCA McAb was gathered in tumor of HCC in 6 AFP positive patients, but there was no positive gathering in HCC in 6 AFP negative or 4 liver cirrhosis patients. AFP-R-LCA McAb has strong affinity and special combination to AFP positive cells of HCC and can be recognized as a carrier for radioimmunodetection and radiommunotherapy.

Adult↗
PubMed1983

Radioimmunodetection of prostatic cancer. In vivo use of radioactive antibodies against prostatic acid phosphatase for diagnosis and detection of prostatic cancer by nuclear imaging.

Radioimmunodetection (RAID) of prostatic cancer is done by injecting 131I-labeled rabbit antibody IgG against prostatic acid phosphatase (PAP) and performing total-body photoscans with a gamma scintillation camera. Of two patients tested, the PAP RAID scintiscans located the primary or recurrent prostatic cancers in both and showed no disease in the lungs of the patient shown subsequently to have lung cancer. The lung tumor nodules showing anti-PAP IgG accretion were assumed to be of prostatic cancer origin, since one of the original tumors removed from this patient's other lung a year earlier stained for PAP by immunohistochemistry. This study showed that PAP RAID can locate primary and metastatic tumors of prostatic origin.

Acid Phosphatase↗