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PubMed1980

Radioimmunodetection of gastrointestinal neoplasms with antibodies to carcinoembryonic antigen.

Primary and secondary gastrointestinal tumors have been identified using sheep immunoglobulin G antibody to carcinoembryonic antigen radiolabeled with 131I. 99mTc-pertechnetate and 99mTc-human serum albumin were used to identify tissue spaces and blood pool and to facilitate external substraction imaging. In 13 patients with tumors, 4 of 5 primary sites and 8 of 11 secondary sites were successfully demonstrated. Two patients with benign disease had negative scans. Comparison with conventional methods of scanning showed good correlation.

Antibodies, Neoplasm↗
PubMed1980

Imaging approach in radioimmunodetection.

External in vivo imaging of tumors with radioactively labeled antibodies to tumor-associated antigens requires processing to remove interfering nontarget radioactivity. Processing entails the use of simulated nontarget compounds labeled with a radionuclide physically different from that on the antibody and substraction of the simulated nontarget activity from the nontargeted antibody. A 2-fold increase of the target to nontarget radioactivity is achieved that has made possible a greater than 70% tumor detection rate.

Antibodies, Neoplasm↗
PubMed1995

Improved tumor radioimmunodetection using a single-chain Fv and gamma-interferon: potential clinical applications for radioimmunoguided surgery and gamma scanning.

Previous studies have shown that (a) single-chain antibody binding proteins, or sFvs, localize experimental tumor xenografts (D.E. Milenic et al, Cancer Res., 51: 6363-6371, 1991) and (b) the administration of gamma-interferon (IFN-gamma) increases the expression of a high molecular weight glycoprotein, tumor-associated glycoprotein 72 (TAG-72), which improves mAb-based tumor targeting as well as radioimmunotherapy (J. W. Greiner et al., Cancer Res., 53: 600-608, 1993). The present experimental study was designed to determine whether exploiting those two observations in combination could augment tumor detection. Initial results revealed significant localization of a single-chain antibody binding protein of CC49 (i.e., CC49 sFv), a second generation anti-TAG-72 mAb, to human colon tumor xenografts (HT-29), which express low constitutive TAG-72 levels. IFN-gamma treatment of mice bearing HT-29 tumors significantly increased TAG-72 levels in the tumor xenografts. Increased TAG-72 expression was accompanied by a 2-4-fold augmentation of CC49 sFv localized to the HT-29 tumors, measured by direct quantitation of 125I-labeled CC49 sFv tumor deposition as well as tumor:normal tissue ratios. Enhanced CC49 sFv tumor localization improved HT-29 tumor visualization by external scintigraphy as well as when using a hand-held gamma-detecting probe to discriminate between normal (i.e., heart, hind leg) and tumor tissue. The gamma-detecting probe was the same as that used intraoperatively with 125I-labeled CC49 IgG to identify occult tumors in patients. The present experimental findings indicate that the efficiency by which 125I-labeled CC49 sFv localizes tumor in vivo can be enhanced with IFN-gamma. Results of the present study suggest that (a) the incorporation of an IFN-gamma treatment schema prior to radioimmunscintigraphy may increase the signal from the tumor site(s), thus providing a better discrimination between tumor and background, and (b) combining 125I-labeled CC49 sFv with IFN-gamma will not only reduce the time interval between antibody injection and surgery, but will also increase the efficiency of tumor localization using the intraoperative gamma-detecting probe.

Animals↗
PubMed1997

Combination of monoclonal antibodies for radioimmunoguided surgery.

The use of a cocktail of monoclonal antibodies in intraoperative radioimmunodetection of colorectal tumour has been evaluated in 14 patients. Eight patients had primary and six recurrent colorectal cancer. Three different monoclonal antibodies were used included B72.3, recognizing TAG72 antigen, FO23C3 and FO23C5 directed against two epitopes of CEA. The antibodies were labeled with 125I. During surgery the radioactive emission of tumour and normal tissue was evaluated by a gamma detecting probe. Ten patients showed positive intraoperative results and in particular 6 (75%) of the 8 patients with primary tumour and 4 (67%) of the 6 patients with recurrence, with a mean tumour to normal tissue ratio of 2.2. Intraoperative radioimmunodetection was instrumental in modifying the therapeutic approach in two patients with recurrent cancer but in none of the patients with a primary presentation. Immunohistochemical analysis, to evaluate TAG72 and CEA antigen expression, was performed in 13 cases. CEA antigen was expressed in 8/13 cases and TAG72 in 5/13. Thus the sensitivity was 38.5% and 61.5% with B72.3 and anti-CEA monoclonal antibodies respectively, while in combination the sensitivity was 71.4%. The use of a cocktail of different antibodies improved the sensitivity of intraoperative radioimmunodetection of colorectal tumours, when compared with a single antibody injection. This approach might improve the clinical use of radioimmunodetection.

Adult↗
PubMed1997

Perspectives on oncologic imaging with radiolabeled antibodies.

BACKGROUND: The contributions of nuclear imaging tests to the management of cancer are expanding, especially in terms of detection (staging and recurrence), diagnosis, and qualification of patients for certain forms of therapy, and particularly with regard to the tests' ability to identify tumors on a functional basis. METHODS: This article is a selective review of the advances and clinical management applications of cancer imaging with radiolabeled antibodies (radioimmunodetection or immunoscintigraphy), with the objective of demonstrating how this new imaging technology can contribute to oncologic practice. The contribution of another functional imaging modality, positron emission tomography (PET), also is discussed. RESULTS: Radioimmunodetection and PET imaging have shown particular management contributions in patients with colorectal, breast, or lung carcinoma, as well as in patients with non-Hodgkin's lymphoma (NHL). Two antibody imaging agents, OncoScint and CEA-Scan, currently are available for the detection of colorectal carcinoma, and have shown particular application for disease staging and disclosure of occult lesions. Each of these agents has different characteristics and potential applications. Recent results with CEA-Scan in patients with mammary carcinoma suggest that it may be a useful complementary tool to screening mammography by adding very high specificity. In patients with lung carcinoma, technetium-99m-labeled NR-LU-10 antibody has been shown to be useful in preoperative staging. LymphoScan is under investigation as a staging agent and for revealing residual disease in patients with NHL; it also provides, with a different radioisotope attached and in a humanized antibody form, a therapeutic option for patients with NHL. Similar results can be shown for PET, but this method may not provide the specificity of an antibody-based functional imaging agent, although PET may have a higher lesion sensitivity. CONCLUSIONS: Both radioimmunodetection and PET provide new exciting opportunities for earlier and more sensitive functional imaging tests for cancer. In contrast to PET, antibody agents also can serve to qualify a patient as a candidate for an antibody-based therapy.

Humans↗
PubMed1996

Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion.

UNLABELLED: The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments. METHODS: The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique). RESULTS: The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group. CONCLUSION: The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.

Aged↗
PubMed1988

Targeting of cancer with radiolabeled antibodies. Prospects for imaging and therapy.

This article reviews the current status, including problems and some proposed solutions, of the targeting of cancer with radioactive antibodies for use in antibody imaging (radioimmunodetection) and radioimmunotherapy. The problems and results are similar for purified polyclonal and murine monoclonal antibodies. Foremost among the problems are the low accretion of antibody (0.01% to 0.001% of injected dose per gram) in tumor and the nonspecific deposition of radiometals that are more ideal for imaging or therapy after antibody conjugation. Despite these limitations, radioimmunodetection appears to be a safe and useful method, even at this early stage of development. Sensitivity, specificity, and accuracy rates of 80% to 90% have been achieved in some studies involving radioiodine labels and polyclonal or monoclonal antibodies, whereas lower percentages have been achieved with indium 111 or technetium Tc 99m radioconjugates. Even at a usual tumor resolution of 1.5 to 2.0 cm, occult cancers have been disclosed by radioimmunodetection when missed by traditional detection measures, including computed tomography and magnetic resonance imaging. Radioimmunotherapy is somewhat less developed as a treatment modality, but encouraging remissions have been observed, thus stimulating further active pursuit of this technology. These targeting results have been achieved with antibodies that are not truly cancer specific, but only exploit quantitative differences in antigen expression between tumor and adjacent normal tissues. Circulating target tumor antigens do not appear to prevent successful tumor targeting of the radioactive antibodies.

Antibodies, Monoclonal↗
PubMed1986

[Localization of radiolabeled antibody to carcinoembryonic antigen in patients with gastrointestinal carcinoma].

Present study was undertaken to investigate accumulation of radiolabeled antibody to CEA in CEA-producing tumor and possibility of radioimmunodetection of cancer with antibody. Nine patients with gastric carcinoma and seventeen colorectal carcinoma were studied. Antibody to CEA were produced in horse by immunization with CEA purified from hepatic metastasis of colorectal carcinoma. The purified antibodies were labeled with 125I or 131I. The patients who entered these studies received radioactive antibodies to CEA intravenously 24-48 hours prior to operation. Radioactivity in tumor tissues and normal mucosal tissues obtained at the operation was counted by gamma-scintillation counter. In four patients with liver metastasis from colorectal carcinoma, external photoscanning was also performed for radioimmunodetection of cancer with 131I-labeled antibody to CEA. The results were as follows. The mean ratio of 125I-uptake of cancer tissue to that of normal mucosal tissue was 3.28 +/- 1.52 (n = 26), and ratio to peripheral blood, liver, skin and fat tissue was 1.91 +/- 1.32, 2.90 +/- 1.47, 5.70 +/- 3.28 and 12.86 +/- 8.48, respectively. Tumor tissue showed the highest uptake. Accumulation of radiolabeled antibody to CEA in tumor tissue was higher in patients with relatively high serum CEA level. High level of circulating CEA did not hinder accumulation of radiolabeled antibody to CEA in tumor tissue. In two out of four patients with liver metastasis from colorectal carcinoma, the tumor location was successfully demonstrated by external photoscanning using gamma-camera. The information obtained in the present study provided possibility of direct radioimmunodetection and immunochemotherapy.

Adult↗
PubMed1992

Detection of occult tumor using indium 111-labeled anticarcinoembryonic antigen antibodies.

Even with the advancement of radiologic techniques, metastatic cancers can still be difficult to detect. In this study, 48 patients suspected of having occult metastases were studied by radioimmunodetection following the administration of 92.5 to 181.3 MBq of indium 111-labeled monoclonal anticarcinoembryonic antigen antibody. All but seven patients were thought to have metastatic colorectal carcinoma. In the majority of cases, physical examinations and computed tomographic scans had failed to detect a lesion. At least one lesion that was later proved to exist was detected in 34 of the 50 studies performed on these patients. Seven of eight patients with normal radioimmunodetection scans remain free of disease. One hundred one sites were detected overall; 60 were considered true-positive sites and 27 false-positive sites. Fourteen sites remained in question. Nineteen false-negative sites occurred. Radioimmunoimaging appears valuable for the detection of occult cancer where standard, noninterventional techniques have failed to detect the suspected disease.

Carcinoembryonic Antigen↗
PubMed2006

Molecular imaging and radioimmunoguided surgery.

Molecular imaging comprises a series of diagnostic modalities that provide information on the physiology and molecular composition of cells and tissues. One of these modalities, radioimmunodetection, uses radiolabeled monoclonal antibodies (mAbs) to image tissues. Two radioimmunodetection modalities are described in this article: immunoscintigraphy and radioimmunoguided surgery (RIGS). In immunoscintigraphy, the radioactivity is measured with the use of an external gamma camera and used to create images. In RIGS, the radioactivity is detected intraoperatively with the use of a handheld gamma probe to help the surgeon detect foci of otherwise occult disease. Both techniques have the potential to improve the preoperative and intraoperative localization of cancer. Multiple studies have been performed on the efficacy of RIGS on different malignancies, especially colorectal cancer. Despite the good sensitivity of the technique, some concerns revolve around the high rate of false positives and the real significance of leaving RIGS-positive tissue behind in terms of long-term outcomes and survival. More studies are warranted to further develop the technique and determine the specific role it will play on the diagnosis and management of surgical disease. Surgeons should actively participate in these studies and in expanding the applications of this promising technology.

Child↗
PubMed1999

In vivo and in vitro characterizations of three 99mTc-labeled monoclonal antibody G250 preparations.

UNLABELLED: In previous clinical studies, excellent visualization of tumor lesions has been observed with 131I-labeled monoclonal antibody (mAb) G250 in patients with renal cell carcinoma (RCC). In several cases, 131I-cG250 immunoscintigraphy disclosed tumor lesions that were not visualized by radiography or CT. To improve image quality, we aimed to develop a 99mTc-labeled mAb G250 preparation for radioimmunodetection of RCC. We studied in vitro stability, biodistribution and imaging potential of three 99mTc-labeled G250 preparations in nude mice with subcutaneous RCC xenografts.125I-G250 and the nonspecific mAb 131I-MN14 were used as control antibodies. METHODS: The mAb G250 was labeled with 99mTc according to three methods using: (a) S-hydrazinonicotinamide (HYNIC), (b) S-benzoylmercaptoacetyltriglycine (MAG3) and (c) a direct labeling method (Schwarz method). The stability of all preparations was tested in serum at 37 degrees C during 48 h. In addition, diethylenetriamine pentaacetic acid, cysteine and glutathione challenge assays were performed. RESULTS: All preparations showed good stability in serum during the 48-h incubation period. 99mTc-G250 (Schwarz) showed release of the radiolabel at a 100-fold or higher molar excess of cysteine and at a 10,000-fold or higher molar excess of glutathione. 99mTc-MAG3-G250 showed release of the radiolabel at a 10,000-fold molar excess of cysteine. 99mTc-HYNIC-G250 was stable under all conditions. Tumors were clearly visualized with all preparations. 99mTc-G250 (Schwarz) showed significantly lower blood levels (3.8 %ID/g) compared with all other preparations (11.2, 13.4 and 13.4 %ID/g for 99mTc-HYNIC-G250, 99mTc-MAG3-G250 and 125I-G250, respectively, 48 h postinjection). At 48-h postinjection, mean tumor uptake was very high with all mAb G250 preparations: 92.4 (99mTc-HYNIC-G250), 125.9 (99mTc-MAG3-G250), 29.4 (99mTc-G250 Schwarz) and 75.4 (125I-G250) %ID/g. Mean tumor uptake of the nonspecific 131I-MN14 mAb was 6.6 %ID/g. CONCLUSION: In this study, 99mTc-HYNIC-G250 showed excellent in vitro stability and tumor targeting. Moreover, this preparation could be labeled with high efficiency (>95%) at room temperature within 15 min. Therefore, 99mTc-HYNIC-G250 seems to be an ideal candidate for radioimmunodetection of RCC.

Animals↗
PubMed1997

Tumor pretargeting: role of avidin/streptavidin on monoclonal antibody internalization.

UNLABELLED: Radioimmunodetection of tumor can be improved by introducing a two-step system in which radiolabeled streptavidin is administrated after the injection of a biotinylated monoclonal antibody (MAb) (two-step) or radiolabeled biotin is injected after biotinylated MAb and avidin (three-step). The anti-carcinoembryonic antigen (CEA) MAb FO23C5 has been recently exploited in a three-step protocol based on the avidin-biotin system. The anti-folate receptor (FR) MAb MOv18 has proven suitable for radioimmunodetection of ovarian cancer using directly radiolabeled MAb or in a two-step method. In this study, we analyzed the suitability of MOv18 in a three-step protocol in ovarian carcinoma patients and the internalization events after formation of the MOv18-avidin complex. METHODS: Selected patients with documented metastatic lesions were enrolled in a three-step radioimaging analysis with biotinylated MOv18 and FO23C5, avidin and (111)In-labeled biotin. Two-step internalization experiments were conducted in vitro with MOv18 and MOv19 MAbs on the FR-overexpressing IGROV1 cell line and with the anti-CEA MAb FO23C5 on the LS174T cell line. Cells were incubated sequentially with biotinylated MAb and 125I-labeled streptavidin or with 125I-biotinylated MAb and cold streptavidin. RESULTS: In the in vivo study, SPECT revealed the majority of metastatic lesions in patients injected with biotinylated MOv18; however, the tumor-to-background ratio was relatively low. In the in vitro study, a consistent internalization was induced by antigen-biotinylated MAb-streptavidin complex formation at the cell surface in both antigenic systems analyzed. However, the extent of internalization was lower in the CEA model. CONCLUSION: The internalization ability of avidin suggests its potential clinical application for delivering toxic agents in a two-step approach (biotinylated MAb + avidin conjugate). The suitability of a given MAb for three-step clinical applications (biotinylated MAb + avidin + biotin) should be previously investigated by using appropriate in vitro experiments.

Antibodies, Monoclonal↗