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PubMed1990

Clinical radioimmunodetection, 1978-1988: overview and suggestions for standardization of clinical trials.

In the last decade of radioimmunodetection studies the radiolabeled antibody preparations used have gradually changed from polyclonal antibodies labeled predominantly with 131I to monoclonal antibodies labeled with diverse radionuclides including 131I, 111In, 123I, and 99mTc. Over this period progressive improvement in tumor imaging has been observed when one compares the best examples of early studies, performed with 131I labeled heterosera, to the best of modern images, obtained with 123I, 99mTc, or 111In labeled monoclonal antibodies. Important findings in 61 clinical studies reviewed include the reports from several centers which demonstrate occult disease in patients with carcinoma of colon, melanoma, and lymphoma, and the improved sensitivity and specificity of radioimmunodetection in comparison to transmission computerized tomography in the lymph nodes and abdomen, in lymphoma and colon cancer, and ovarian cancer. Evaluation of the liver remains a difficult problem with this technique and standard approaches are superior in most reports. The general principle of targeting radioactivity to tumor with radiolabeled antitumor antibody and the feasibility of developing practical clinical methodology which will add new diagnostic information have clearly been established. Toxicity, particularly for index studies, is reassuringly limited. In all the studies with surgical confirmation after i.v. injection, uptake in tumor is in the range of 0.005% injected dose/g tumor, and this low tumor uptake remains the single greatest limitation of the method. A second important problem is the prompt development of human anti-mouse antibody, which reduces the usefulness of follow-up studies. A serious criticism of the information currently available on radioimmunodetection is that the clinical studies reported to date vary greatly in approach and results. The vast majority of studies are early Phase I clinical trials, from which toxicity information and biodistribution data can be derived but which give limited information about impact on clinical management. Standardization in the study design is needed in order to establish the efficacy of radioimmunodetection in adequate and well controlled clinical trials.

Antibodies, Monoclonal↗

PubMed1991

Radioimmunodetection of human colon cancer in nude mice by a new monoclonal antibody A7 against human colorectal cancer.

The in vivo localization of a monoclonal antibody A7 against a human colorectal cancer was studied in nude mice bearing human solid carcinomas, to evaluate potential applications of this antibody for radioimmunodetection of cancer. The tissue distribution of 125I-labeled A7 MoAb at 3 days after i.v. injection into mice bearing five different kinds of human solid tumors revealed a high uptake ratio by colon cancer, mammary cancer, and glioblastoma. In contrast, the uptake ratio by murine colorectal cancer (Colon-38) was extremely low. In immunoscintigraphic studies, HCT-15, one of the human colon cancer, was clearly visualized with 111In-DTPA-A7 MoAb. Glioblastoma was also imaged with the same extent. These results suggest that A7 MoAb would be applicable to the in vivo radioimmunodetection of colon- and mammary-cancer, and of glioblastoma.

Adenocarcinoma↗

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↗

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↗

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↗

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↗

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↗

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↗

PubMed1986

Radioimmunodetection of human colon carcinoma xenografts in visceral organs of congenitally athymic mice.

The LS-174T human colon carcinoma line and A375 human melanoma line were used to establish primary tumor xenografts at three sites (subcutaneous, spleen, and kidney) in congenitally athymic mice. A monoclonal antibody (MAb) reactive with the LS-174T line, B72.3 IgG, was labeled with iodine 125, and an isotype-identical control antibody MOPC-21, was labeled with iodine 131. Labeled antibodies were injected intravenously in tumor-bearing mice, and animals were killed at varying intervals. Tumor-to-blood and tumor-to-organ ratios of MAb 72.3 indicated no significant difference at any of the three primary tumor sites in LS-174T tumor-bearing mice. The percent injected dose per gram was higher at visceral sites on day 3, but was similar on days 5 and 7 at all sites. Localization indices on all days ranged from 4 to 1 to greater than 16 to 1, confirming the specificity of the B72.3 reactivity at all sites. Athymic mice bearing tumor xenografts were scanned on day 7, and the LS-174T spleen and kidney tumors were imaged, with efficacy similar to that of the subcutaneous site. The visceral tumor model is more representative of the human disease, and may therefore be a better model for evaluation of monoclonal antibodies for radioimmunodetection and therapy for cancer in intra-abdominal organs.

Animals↗

PubMed1989

Radioimmunodetection of lymph node invasion in prostatic cancer. The use of iodine 123 (123I)-labeled monoclonal anti-prostatic acid phosphatase (PAP) 227 A F(ab')2 antibody fragments in vivo.

The therapeutic indications in prostatic cancer depend on the regional and distant extension of the cancer and are difficult to assess before lymphadenectomy. Radioimmunodetection of lymph node involvement with monoclonal anti-prostatic acid phosphatase (PAP) antibodies can be proposed as a noninvasive alternative to lymphadenectomy. Fifteen patients with various stages of histologically proven prostatic cancer were examined by immunolymphoscintigraphy (ILS) before treatment to detect lymph node metastases. These patients had Stage A (n = 7), Stage B (n = 3), Stage C (n = 2), and Stage D (n = 3) tumors. They received between 100 and 400 micrograms of monoclonal antibody 227 A in the form of F(ab')2 fragments labeled with iodine 123 (123I). The antibody was injected directly into the periprostatic area. ILS images were obtained after 1, 3, 6, and 24 hours. Three days later, each patient underwent a lymphadenectomy for histologic examination. The results of the histologic examination and ILS were compared. In ten patients, the examination did not show any images capable of being interpreted as lymphadenopathy and histologic examination confirmed the integrity of the nodes examined. In five cases, scintigraphy suggested the presence of lymph node invasion by prostatic cancer and this was confirmed by histologic examination in three of the five cases. Overall, in terms of lymphadenopathy, this examination had a sensitivity of 100% and a specificity of 83%. Therefore, ILS appears to be capable of detecting lymph node metastases in prostatic cancer.

Acid Phosphatase↗

PubMed1985

Radioimmunodetection of murine mammary adenocarcinoma (TA3/Ha) lung and liver metastases with radioiodinated PNA.

Organ-specific lung and liver metastatic variants of the murine TA3/Ha mammary adenocarcinoma cell line were selected by sequential in vivo growth with intervening in vitro cell culture. These variants readily formed specific lung or liver metastatic lesions upon i.v. injection into A/J mice. TA3/Ha cells produce a large cell surface glycoprotein called epiglycanin, which contains a high proportion of Thomsen-Friedenreich (TF) antigenic structures. The presence of non-cryptic TF has been associated with malignancy in humans and animals. We used peanut lectin agglutinin (PNA), which has a preferential affinity for TF antigenic structures, to determine whether these selected metastatic variants retained the TF antigen expression. In vitro, the TA3/Ha metastatic variant lines exhibited strong PNA binding similar to that seen with human RBC after neuraminidase treatment to expose the cryptic TF antigen. In contrast, the non-epiglycanin-producing TA3/St subline did not bind PNA appreciably. Autoradiography of liver sections with TA3/Ha metastatic lesions after 125I-PNA i.v. indicated an avid uptake throughout the viable tumor mass and FITC-PNA staining of these tissue sections readily identified the metastatic tumors under fluorescence microscopy. Tissue biodistribution studies revealed that lung or liver containing the TA3/Ha metastatic variant nodules retained about 7 to 8 times as much of an i.v. dose of radioiodinated PNA as did controls, allowing for clear delineation of tumor-infiltrated lung or liver by gamma scintigraphy. These in vitro and in vivo tests confirm that the selected organ-specific TA3/Ha variants retained the binding characteristics of the parent TA3/Ha line. These observations illustrate the potential utility of radiolabelled PNA for the detection of TF-antigen-expressing tumors and metastases. This murine system with organ-specific TA3/Ha metastatic variants also provides a model for evaluation of various other macromolecular probes for tumor radioimmunodetection of metastatic lesions.

Adenocarcinoma↗

PubMed1987

Antibody protein dose and radioimmunodetection of GW-39 human colon tumor xenografts.

This study investigates the influence of antibody protein dose on the radioimmunodetection of a CEA-producing, human colonic tumor xenograft (GW-39) using affinity-purified goat anti-carcinoembryonic antigen (CEA) antibody and a murine monoclonal anti-CEA antibody (NP-2). Hamsters bearing GW-39 tumors were given an equal mixture of 131I-labelled antibody and 125I-labelled irrelevant IgG at doses varying from 0.01 to 1.0 mg (0.1 to 10 mg/kg body weight) for each antibody preparation. No differences were found in the percentage of antibody in the tumor or the clearance rate from the blood as the antibody dose was increased. The concentration of antibody in the tumor increased proportionally with the antibody dose and maintained a linear relationship with increasing dose, indicating that antigenic sites in the tumor were not saturated with antibody. The concentration of irrelevant IgG in the tumor also increased proportionally as the dose was increased, but the concentration of irrelevant IgG in the tumor was less than the antibody and was removed more rapidly from the tumor than the antibody. By considering the amount of irrelevant IgG in the tumor as a measure of the amount of antibody non-specifically bound, we determined that there was no change in the amount of antibody in the tumor between days 3 and 7, and the amount of antibody increased uniformly for both the tumor and non-tumor tissues, resulting in no improvement in the tumor/non-tumor ratios with increasing antibody dose. External scintigraphy verified that the dose of the antibody did not influence tumor imaging. Thus, tumor accretion of antibody in this model is not dependent principally on the antibody protein dose, and other factors such as accessibility to antigen and antibody metabolism may play important roles in regulating the uptake of antibody in tumor.

Animals↗

PubMed1988

Radioimmunodetection of human pancreatic tumor xenografts using DU-PAN II monoclonal antibody.

The potential of DU-PAN II, monoclonal antibody (IgM), which was raised against the human tumor cell line, was evaluated for radioimmunodetection of human pancreatic tumors (PAN-5-JCK and EXP-58) grown in nude mice. 125I-labeled DU-PAN II was accumulated into PAN-5-JCK producing DU-PAN II antigen with a tumor-to-blood ratio of 2.72 +/- 3.00, but it did not localize in EXP-58 because of insufficient DU-PAN II. There was no significant uptake of 125I-nonimmunized IgM in PAN-5-JCK. These facts indicated the specific tumor uptake of DU-PAN II. Excellent images of the tumor PAN-5-JCK were obtained 3 days after the injection of 125I-DU-PAN II. Gel chromatography was also investigated with respect to the plasma taken from mice injected with antibody, or incubated with antibody in vitro. The results indicate that circulating antigen affected the tumor uptake of DU-PAN II: The more the tumor grew, the higher the amount of antigen excreted into the blood, leading to the degradation of DU-PAN II before it reached the tumor sites. Consequently, the immunoscintigram of the small tumor was remarkably clear. The catabolism and the radiolysis of the labeled IgM injected are critical points in applying immunoscintigraphy.

Animals↗

PubMed1988

Anti-fibrin monoclonal antibodies for radioimmunodetection: preliminary assessment in a rat model system.

The D Dimer (DD) site formed by linkage of D domains from adjacent fibrin (FN) molecules is unique to cross-linked FN and its degradation products and is not found in FN monomer or fibrinogen (FB). Thus monoclonal antibodies (MAb) reactive to DD should have a very suitable specificity for in vivo thrombus detection. Two anti-DD MAbs have been labelled with 131-I and assessed as scintigraphic agents in a normal rat model system. Each rat received 3 sc implants of antigen covalently coupled to Sepharose beads: 1) Human DD 2) Human FB 3) Glycine (GL) (control). Scintigraphic images taken 7 days after injection of 131-I anti DD MAb showed clear localisation of both anti-DD MAbs to the DD implant rather than to the FB or GL implants with no localisation in normal tissues. This was confirmed in biodistribution studies. Injection of anti-DD MAbs DD-3B6/22 and DD-IC3/108 resulted in DD: blood ratios of 10.4 +/- 0.6 and 4.9 +/- 0.3 respectively. These results suggest that anti-DD MAbs will have potential for thrombus radioimmunodetection.

Animals↗

PubMed1990

Radioimmunodetection of uterine leiomyosarcoma with 111In-labeled monoclonal antimyosin antibody Fab fragments.

Radioimmunodetection of uterine leiomyosarcoma in a 64-year-old woman with a palpable local recurrence is described. Pathological abdominal, pelvic, and thoracic accumulation of monoclonal 111In-labeled antimyosin was observed. Afterward, these lesions were examined by whole-body X-ray computed tomography. With a double-tracer technique (pulmonary and hepatic/splenic subtractions) the lesions were delineated better and SPECT (radioisotope tomography) was used for more accurate localization of the abdominal and pelvic lesions. These findings indicate that antimyosin scintigraphy might be useful in staging and follow-up of uterine leiomyosarcoma.

Antibodies, Monoclonal↗

PubMed1986

Radioimmunodetection of cutaneous T-cell lymphoma with 111In-labeled T101 monoclonal antibody.

T101 monoclonal antibody recognizes a pan-T-cell antigen present on normal T cells and also found in high concentrations in cutaneous T-cell lymphoma. We used this antibody, radiolabeled with 111In, in gamma-camera imaging to detect sites of metastatic cutaneous T-cell lymphoma in 11 patients with advanced disease. In all patients, [111In]T101 concentrated in pathologically or clinically detected nodes, including those in several previously unsuspected nodal regions. Concentrations (per gram of tissue) ranged from 0.01 to 0.03 percent of the injected dose and were consistently 10 to 100 times higher than previously reported on radioimmunodetection. Focal uptake was seen in skin tumors and heavily infiltrated erythroderma but not in skin plaques. The specificity of tumor targeting was documented by control studies with [111In]chloride or [111In]9.2.27 (anti-melanoma) monoclonal antibody. Increasing the T101 dose (1 to 50 mg) altered distribution in nontumor tissues. These studies suggest that imaging with [111In]T101 may be of value in identifying sites of cutaneous T-cell lymphoma. In contrast to the targeting of solid tumors, the mechanism of localization appears to be related to binding to T cells, which can then carry the radioactivity to involved sites.

Adult↗

PubMed1987

Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council Study.

A radiolabeled murine monoclonal antibody (T101) was used for imaging and therapy of six patients with cutaneous T cell lymphoma (CTCL). Radioimmunodetection was performed with a 5.6 to 13.1 mCi 131I-T101 preparation (9.6 to 10.5 mg). A therapeutic dose of 100.5 to 150.1 mCi 131I on 9.9 to 16.9 mg of antibody was administered to five patients, with subsequent retreatment following plasmapheresis in three patients at the time of disease progression. All patients responded to their initial therapy and two patients responded to retreatment. Regression of skin lesions and peripheral adenopathy was witnessed. All patients reported resolution of their chronic pruritus. The duration of response ranged from 3 weeks to 3 months. Acute toxicity included fevers, pruritus, and mild dyspnea in two instances. Myelosuppression was seen in patients receiving the 144.7 mCi, 145.0 mCi, and 150.1 mCi 131I-T101 doses. Radioimmunodiagnostic and therapy studies included gamma scintigraphy, plasma, urinary, and wholebody antibody clearances, and biodistribution determined from skin, bone marrow, and liver biopsies. Immunologic studies included immunoperoxidase staining of target tissues, immunofluorescent flow cytometric analysis on peripheral blood and bone marrow, assays for serum blocking factors, determination of a human antimouse antibody (HAMA) response, and quantitation of circulating T101 levels. These preliminary data suggest that 131I-T101 has therapeutic potential in CTCL and that myelosuppression will be the limiting toxicity.

Aged↗