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Biomedical subjects

D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 91 records · Page 5Linked to original sources
PubMed1997

Prospects of radioimmunotherapy in epithelial ovarian cancer: results with iodine-131-labeled murine and humanized MN-14 anti-carcinoembryonic antigen monoclonal antibodies.

OBJECTIVES: Epithelial ovarian cancer (EOC) is known to produce carcinoembryonic antigen (CEA), and the plasma CEA level is frequently elevated in patients with advanced stage and bulk of tumor. This study reports the results of a phase I therapy trial with intravenously administered 131I-MN-14 anti-CEA monoclonal antibody (MAb) in patients with EOC. METHODS: Fourteen patients with advanced refractory EOC were given escalating intravenous doses (two received 30 mCi/m2, six 40 mCi/m2, and six 50 mCi/m2) of 131I-MN-14 IgG. All patients received a diagnostic study with 8 mCi (0.6 mg) of 131I-MN-14 IgG 1 week prior to their therapy infusion. Tumor targeting was assessed by external scintigraphy, toxicity according to the Radiation Therapy Oncology Group criteria, and therapy responses by CT and serum CA-125. RESULTS: The MAb scan was positive in all 14 treated patients. Myelosuppression was the only observed treatment-related toxicity. Dose-limiting toxicity, defined as grade 4 leukopenia or thrombocytopenia of any duration, or grade 3 leukopenia or thrombocytopenia of > 2 weeks, was not seen at the 30 or 40 mCi/m2 dose levels. However, 2 of 6 patients treated at 50 mCi/m2 had a grade 4 thrombocytopenia or a grade 3 thrombocytopenia lasting 18 days. Of the 14 patients, 1 with diffuse peritoneal implants of < or = 2 cm had a complete clinical remission by CT and CA-125 for 8 months, following an initial partial remission for 10 months, both at the 40 mCi/m2 dose level. Another patient had a mixed response for 1 month. CONCLUSION: MN-14 anti-CEA MAb is a suitable agent for tumor targeting and may have a therapeutic potential in patients with chemotherapy-refractive EOC, especially those with minimal disease.

Adult↗
PubMed1997

Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22.

LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiolabeled, has a high sensitivity for detecting B-cell, non-Hodgkin's lymphoma (NHL), as well as an antitumor efficacy in therapeutic applications. The aim of this study was to determine whether intracellularly retained radiolabels have an advantage in the diagnosis and therapy of lymphoma with LL2. In vitro studies showed that iodinated LL2 is intracellularly catabolized, with a rapid release of the radioiodine from the cell. In contrast, residualizing radiolabels, such as radioactive metals, are retained intracellularly for substantially longer. In vivo studies were performed using LL2-labeled with radioiodine by a non-residualizing (chloramine-T) or a residualizing method (dilactitol-tyramine, DLT), or with a radioactive metal (111In). The biodistribution of a mixture of 125I (non-residualizing chloramine-T compared to residualizing DLT), 111In-labeled LL2 murine IgG2a or its fragments [F(ab')2, Fab'], as well as its humanized, CDR-grafted form, was studied in nude mice bearing the RL human B-cell NHL cell line. Radiation doses were calculated from the biodistribution data according to the Medical International Radiation Dose scheme to assess the potential advantage for therapeutic applications. At all assay times, tumor uptake was higher with the residualizing labels (i.e., 111In and DLT-125I) than with the non-residualizing iodine label. For example, tumor/blood ratios of 111In-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non-residualizing iodinated IgG on days 3, 7 and 14, respectively. Similar results were obtained for DLT-labeled IgG and fragments with residualized radiolabels. Tumor/organ ratios also were higher with residualizing labels. No significant differences in tumor, blood and organ uptake were observed between murine and humanized LL2. The conventionally iodinated anti-CD20 antibody, 1F5, had tumor uptake values comparable to those of iodinated LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies such as LL2, labeling with intracellularly retained isotopes has an advantage over released ones, which justifies further clinical trials with residualizing 111In-labeled LL2 for diagnosis, and residualizing 131I and 90Y labels for therapy.

Animals↗
PubMed1997

Improved selection of patients for reoperation for medullary thyroid cancer by imaging with radiolabeled anticarcinoembryonic antigen antibodies.

BACKGROUND: This study examined the utility of using radiolabeled anticarcinoembryonic antigen (CEA) monoclonal antibodies (MAbs) as a noninvasive imaging method to aid in the selection of patients for reoperation after operation for medullary thyroid carcinoma (MTC). METHODS: Sixteen patients with persistent or recurrent hypercalcitoninemia since operation or MTC, but had negative or equivocal conventional imaging study results, were given 99mTc-, 123I-, or 131I-labeled NP-4 or MN-14 anti-CEA MAbs. Scintigraphic images were then performed to determine detection of tumor lesions. RESULTS: The MAb scans were positive in 13 (81%) of the 16 patients studied. However, in only three of 13 patients was disease confined to the cervical or mediastinal nodes. In 10 patients, disease was additionally or solely found in distant organs such as liver (five patients), bone (four patients), and periaortic nodes (one patient). On the basis of our studies, only three of the 13 patients with positive scans would benefit from repeat neck exploration, another three would possibly benefit from neck or mediastinal exploration and hepatic resection, and the remaining seven patients would not benefit from any reoperation with curative intent. CONCLUSIONS: MTC imaging with anti-CEA MAbs could be very useful in determining the ideal candidates for repeat neck exploration.

Adult↗
PubMed1997

Radioimmunotherapy of solid tumors: a review "of mice and men".

Radioimmunotherapy in lymphoma is crossing the threshold to become a standard mode of treatment. Whereas in solid tumors in preclinical studies, radioimmunotherapy has proven to be superior to conventional chemotherapy, clinical success is still limited. The purpose of this brief review is to analyze recent developments in preclinical as well as clinical radioimmunotherapy of solid, CEA-expressing tumors. Advances in experimental radioimmunotherapy are characterized by the development of metastatic, rather than subcutaneous, tumor models in nude mice, which seem to reflect the actual clinical situation much more accurately. Furthermore, the recent development of strategies to reduce the renal accretion of antibody fragments and peptides enables the use of such smaller molecules for therapy, especially those also labeled with radiometals and other forms of intracellularly retained radionuclides. Recent developments in clinical radioimmunotherapy are characterized by a trend toward the treatment of small-volume and micrometastatic disease, as is the case, e.g., in adjuvant settings. Interestingly, despite dramatic differences in size, weight and percent-of-injected-dose-per-gram uptake values, only small differences between animal models and the actual patient situation exist with respect to activity concentrations (in microCi/gram) in the tumors and tissues. Because the activity concentration over time determines the radiation absorbed dose, and thus biological effects, we postulate that animal models should be able to predict actual clinical scenarios fairly well. These findings could be used as guidelines in the design of future preclinical, as well as clinical, trials.

Animals↗
PubMed1997

Structure determination of N-linked oligosaccharides engineered at the CH1 domain of humanized LL2.

Two humanized antibody mutants, hLL2HCN1 and hLL2HCN5, engineered with CH1 domain-appended carbohydrates (CHOs) were generated to facilitate site-specific conjugation of radionuclides and anti-cancer drugs to antibodies. Such site-specific conjugation may minimize the incidence of immunoreactivity perturbation as is often observed with random conjugation. Since the compositions and structures of CHOs are important in determining the chemistry, efficiency, and extent of conjugation, the sequences of the CH1-appended CHOs were determined by exoglycosidase digestions and fluorophore-assisted CHO electrophoresis (FACE). The CHO species attached at HCN1 and HCN5 sites in hLL2HCN1 and hLL2HCN5, respectively, were distinct from each other, heterogeneous, and extensively processed. All of these CHOs were core-fucosylated complex-type oligosaccharides and contained Gal (galactose) and GlcNAc (N-acetylglucosamine) residues in the outer branches. Some of the outer branches were composed of Gal alpha1-3Galbeta1-4GlcNAc structure, also known as alpha-galactosyl epitope. Most of the CHOs were sialylated. While all HCN1-CHOs were biantennary, the majority of HCN5-CHOs (>60%) were triantennary. The CH1-appended CHOs have favorable structural characteristics suitable for site-specific conjugation. For efficient conjugation of large drug complexes, hLL2HCN5 is preferable to hLL2HCN1 because the attached CHO is larger in size and more remotely positioned from the V region. The effects of the alpha-galactosyl epitope found in these CHOs on the immunological properties of the immunoconjugates as efficient cancer diagnostics and therapeutics are being studied.

Antibodies, Monoclonal↗
PubMed1997

Use of carcinoembryonic antigen radioimmunodetection and computed tomography for predicting the resectability of recurrent colorectal cancer.

OBJECTIVE: The objective was to determine the role of arcitumomab (CEA-Scan; Immunomedics, Morris Plains, NJ), an anticarcinoembryonic antigen (CEA) Fab' labeled with technetium-99m, in the presurgical evaluation of patients with recurrent or metastatic colorectal carcinoma. SUMMARY BACKGROUND DATA: Surgical resection is the only method known to cure recurrent or metastatic colorectal carcinoma. The location and extent of disease must be determined before surgery. The role of antibody imaging, a new cancer detection modality, in preoperative evaluation for resection of locally recurrent or metastatic colorectal cancer has not been established, either alone or in combination with standard diagnostic modalities. METHODS: In a blinded analysis of 209 patients with known or suspected colorectal cancer, the accuracy of arcitumomab, alone and combined with computed tomography (CT), was compared to that of CT for predicting abdominopelvic tumor resectability by correlating the results with surgical and histopathologic findings. RESULTS: Arcitumomab alone or combined with CT was found to be significantly more accurate for predicting surgical outcome than CT alone. When the results of CT and arcitumomab were concordant for abdominopelvic resectability, nonresectability, or absence of disease, the prediction was accurate in 67%, 100%, and 64%, respectively. Thus, the concordance for nonresectability (100% correct) may obviate the need for other diagnostic modalities or exploratory surgery. When the two tests were discordant, arcitumomab was correct substantially more often than CT. Because the liver is the most common site of distant metastasis in colorectal cancer, a subset of patients with hepatic disease was also analyzed; findings were similar to the overall resectability results. The product's safety profile was excellent: the incidence of induction of an immune response against arcitumomab was <1% and that of potentially adverse events was 1.2%. CONCLUSIONS: The accuracy of arcitumomab for assessing resectability status is greater than that of CT, both in all patients undergoing evaluation for curative abdominopelvic resection of colorectal cancer and in the subset of patients with suspected or proven liver metastases. The additional use of arcitumomab with CT potentially doubles the number of patients who could be saved the cost, morbidity, and mortality of unnecessary abdominopelvic surgery and increases those who are potentially resectable for cure by 40%.

Adult↗
PubMed1997

Changes in tumor vascular permeability in response to experimental radioimmunotherapy: a comparative study of 11 xenografts.

Single and fractionated doses of radioimmunotherapy (RAIT) and standard chemotherapy (0.6 mg 5-FU/day and 0.36 leucovorin/day on days 1-5) result in decreases in vascular permeability (VP) in the GW-39 human colonic xenograft. The effect of a single dose of RAIT (MN-14 anticarcinoembryonic antigen, Mu-9 anticolon-specific antigen, PAM-4 anti-MUC-1, RS-7 and RS-11 antiepithelial glycoprotein labeled with 131I) has also been evaluated in 10 other tumors. Fourteen days after a fixed 1,500-cGy dose of RAIT, 3 colonic tumors (LS174T, HT-29 and MOSER) all exhibited decreases in VP (58, 75 and 70%, respectively). Two colonic (LoVo and GS-7) and 1 breast tumor (MDA-468) did not exhibit any change in VP, and 1 lung (CALU-3), 1 cervical (ME-180), 1 pancreatic (CaPan-1) and 1 breast cancer line (ZR-75) exhibited increases in tumor VP (214, 289, 170 and 139%, respectively). The differences in VP response to RAIT do not appear to be related to the type of tumor, the size of tumor or the antigen being targeted by RAIT. The differences in tumor VP response to RAIT are discussed in terms of the ability to achieve significant tumor accretion of a second dose of radioantibody on a multiple-dosing regimen. We have begun to investigate the mechanism(s) which regulate the varying responses of tumor VP to RAIT by assessing the role that nitric oxide plays. Administration of arginine, a substrate for nitric oxide synthase, results in increases in both baseline and RAIT-modified VP in GW-39 and ME-180 tumors.

Animals↗
PubMed1997

Detection of hepatocellular carcinoma with a new alpha-fetoprotein antibody imaging kit.

PURPOSE: The aim of this phase II study was to assess the clinical utility and safety of AFP-Scan (Immunomedics, Inc, Morris Plains, NJ), a technetium-99m (99mTc)-labeled anti-alpha-fetoprotein (AFP) Fab' imaging kit, in the evaluation of hepatocellular carcinoma (HCC), in comparison to computed tomography (CT). PATIENTS AND METHODS: Twenty-five consecutive patients with a history of HCC were examined by planar and single-photon emission computed tomography (SPECT) imaging at 6 and 24 hours after intravenous (I.V.) injection of 1 mg AFP-Scan labeled with 925 MBq 99mTc. RESULTS: In 20 patients, there was a specific binding of the Fab' antibody to the tumor, whereas in four patients who presented with elevated serum AFP levels, no specific targeting was found and no malignant lesions were evident by CT or biopsy. One patient was diagnosed as false-negative by AFP-Scan. In five of six patients with normal serum AFP levels, focal uptake was demonstrated. In one case, metastatic disease in the lower abdomen was found. In all patients, diagnostically relevant information was provided by the 24-hour antibody images, especially with SPECT. Comparing AFP-Scan versus CT, the former showed a higher sensitivity (95% v 63%) and specificity (67% v 17%), with an overall accuracy of 88% versus 52% for AFP-Scan versus CT, even in patients with normal serum AFP titers. No adverse reactions or human antimouse antibody (HAMA) elevations were found in any of the patients. CONCLUSIONS: AFP-Scan appears to be a promising new antibody imaging kit for the disclosure of sites of HCC and should aid in the management of these patients by revealing primary, recurrent, and metastatic disease with a single imaging modality.

Adult↗
PubMed1997

Regression of advanced refractory ovarian cancer treated with iodine-131-labeled anti-CEA monoclonal antibody.

Advanced chemotherapy-resistant ovarian cancer has a poor prognosis, thus requiring new therapeutic modalities. A complete clinical remission, using two cycles of 131I-labeled murine MN-14 anti-CEA monoclonal antibody (MAb), given intravenously, is reported in a patient with advanced ovarian cancer refractory to paclitaxel (Taxol) therapy. The patient first received radioimmunotherapy with approximately 74 mCi 131I-MN-14 IgG, followed 4 mo later by a similar dose of radiolabeled MAb. A partial remission was seen by CT 1 mo after the first radioimmunotherapy, and a further objective response was documented after the second radioimmunotherapy. CT scans performed 6 and 11 mo after the second radioimmunotherapy showed stable and minimal residual changes. However, a whole-body PET scan with [18F]fluorodeoxyglucose (FDG-PET) was negative in these regions. The CA-125 also decreased to only 13 U/ml, compared to the baseline value of 7700 U/ml. Based on CT, FDG-PET, serum CA-125 and physical exam, the patient was in complete clinical remission for 8 mo when the CA-125 levels rose. CT also showed a new suspicious lesion, presumably a peritoneal implant. No toxicity was seen after the first injection, and only Grade 1 thrombocytopenia and Grade 2 leukopenia developed after the second injection, both reversing within 6 wk. This is a report of a complete clinical remission with radiolabeled anti-CEA antibodies in a patient with chemotherapy-refractive metastatic ovarian cancer.

Aged↗
PubMed1997

Advantage of a residualizing iodine radiolabel for radioimmunotherapy of xenografts of human non-small-cell carcinoma of the lung.

UNLABELLED: Attachment of 131I to MAbs through adducts such as dilactitol-tyramine (DLT), which remain lysosomally trapped after catabolism of the labeled MAb, can greatly increase the residence time of the radiolabel at the tumor site. Our previous studies demonstrated a marked increase in accretion of 131I in a human lung-cancer xenograft model, using 131I-DLT in comparison to 131I linked to MAb by the conventional chloramine-T methodology. METHODS: In this study, biodistribution experiments were performed to evaluate the effect of protein dose on the accretion of 131I-DLT-labeled MAb RS11 in tumor and nontumor tissues, and in vivo radioimmunotherapy experiments compared the effect of single injections of 131I-DLT-labeled MAb RS11 to conventional 131I-labeled RS11 and an untreated control group. RESULTS: Dosimetry calculations based on the biodistribution data indicate only small changes in absorbed dose-to-tumor and nontumor tissues with increasing protein dose up to 100 micrograms, with a predicted absorbed dose to tumor of from 21,000 to 25,000 cGy/mCi. A single dose of 100 microCi of 131I-DLT-RS11 was found to cause tumor regression. At 7 wk postinjection of the radiolabeled MAbs, tumor volume in 73% of the animals administered 131I-DLT-labeled RS11 remained smaller than at the time of MAb injection. This is compared to 14% of the tumors in the conventionally labeled 131I-RS11 group and none in the untreated group. CONCLUSION: The use of the residualizing radiolabel DLT provides a therapeutic advantage in comparison to conventional 131I-labeled RS11.

Animals↗
PubMed1997

Variables influencing tumor dosimetry in radioimmunotherapy of CEA-expressing cancers with anti-CEA and antimucin monoclonal antibodies.

UNLABELLED: In this study, we examined the factors that may influence tumor dosimetry in the radioimmunotherapy of solid, CEA-expressing cancers. METHODS: Data from 119 tumors in 93 patients with CEA-expressing cancers were analyzed. The patients underwent radioimmunotherapy with the 131I-labeled IgG1 anti-CEA antibodies NP-4 (Ka = 10(8) M-1) or MN-14 (Ka = 10(9) M-1), its humanized form hMN-14, as well as the anticolon-specific antigen-p (CSAp) antibody, Mu-9. For dosimetry, the biodistribution, targeting kinetics and cumulated activity of tumors and organs were determined from planar and SPECT imaging. RESULTS: An inverse logarithmic relationship between tumor size and antibody uptake was found for both anti-CEA antibodies, whereas no such relationship was found for Mu-9. The absolute tumor uptake was identified as the most important factor determining the radiation dose to the tumor (r = 0.9), with the biological half-life of the antibody in the tumor being of secondary importance (r = 0.5). No significant difference in tumor uptake was found between both anti-CEA antibodies, despite their tenfold difference in affinity. At comparable masses, colorectal and medullary thyroid cancers had significantly higher tumor uptakes (p = 0.02), as well as tumor-to-red marrow dose ratios, than other cancer types. The tumor half-lives of the anti-CEA antibodies were significantly lower in colorectal than in all other tumor types (p = 0.01). CONCLUSION: In radioimmunotherapy, tumor uptake appears to be the most important dose-determining factor. Differences in antibody affinity are reflected by differences in the biological half-life, not the absolute uptake. Especially favorable conditions for anti-CEA antibodies seem to prevail in colorectal cancer patients having minimal disease, as well as in medullary thyroid cancer, where cytotoxic tumor doses might be expected. Antimucin antibodies may have a particular advantage in the treatment of patients with larger colorectal tumors.

Adenocarcinoma↗
PubMed1997

99Tcm-LL1: a potential new bone marrow imaging agent.

LL1, a monoclonal antibody (MAb) to HLA Class-II-like antigen (li determinant) on the surface of B-lymphocytes, monocytes and histiocytes, was evaluated as an agent for bone marrow imaging. Six patients with diverse diseases (non-Hodgkin's lymphoma, n = 2; multiple myeloma, n = 1; polycythaemia vera, n = 1; lung cancer, n = 1; breast cancer, n = 1) were given low protein doses (< 1 mg) of 99Tcm (30 mCi) labelled Fab' of LL1. 99Tcm-sulphur colloid (SC) imaging was performed in three patients for comparison. Both planar and single photon emission tomographic images were acquired using Sopha gamma cameras. As early as 2 h post-MAb injection, excellent bone marrow images were achieved in all patients, demonstrating both normal or hyperproliferative marrow, as well as 'cold' bone marrow abnormalities such as radiation defects or cancer metastases. Similar to SC, relatively high uptake of LL1 was found in the liver and spleen. However, the bone marrow-to-liver and -spleen uptake ratios were approximately 19-fold higher (0.75 vs 0.04) and 6-fold higher (1.23 vs 0.22), respectively, with LL1 than with SC. The higher bone marrow uptake allowed clearly superior visualization of the thoracic spine when compared to SC. The mean T1/2 of blood and whole-body clearance were 0.4 and 66 h, respectively. The highest radiation absorbed doses (in cGy mCi-1) were observed in the spleen (0.47 +/- 0.24), kidneys (0.25 +/- 0.09) and liver (0.14 +/- 0.04). The bone marrow dose was only 0.05 +/- 0.02 cGy mCi-1. These results indicate that bone marrow imaging with 99Tcm-LL1 is feasible, and that LL1 may be a suitable alternative to SC because of better visualization of the lower thoracic spine. Potential applications include the improved detection of bone marrow metastases of solid tumours and the assessment of haematological disorders.

Animals↗
PubMed1997

Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG.

UNLABELLED: The aim of this study was to determine, in a Phase I/II clinical trial, the pharmacokinetics, dosimetry and toxicity, as well as antitumor activity, of the 131I-labeled murine anti-carcinoembryonic antigen (CEA) monoclonal antibody, NP-4 (IgG1 subtype). METHODS: A total of 57 patients with CEA-expressing tumors (29 colorectal, 9 lung, 7 pancreas, 6 breast and 4 medullary thyroid cancer patients), mostly in very advanced stages, were treated. The patients underwent a diagnostic study (1-3 mg of IgG and 8-30 mCi of 131I) to assess tumor targeting and to estimate dosimetry, followed by the therapeutic dose (4-23 mg and 44-268 mCi), based on the radiation dose to the red marrow. Imaging was performed from 4-240 hr postinjection (planar and SPECT). Blood and whole-body clearance were determined; radiation doses were calculated by the Medical Internal Radiation Dose scheme. RESULTS: Red marrow doses ranged from 45 to 706 cGy, and whole-body doses ranged from 31 to 344 cGy. Differences in pharmacokinetics were found between different types of CEA-producing tumors: blood T 1/2 was significantly lower in colorectal cancer when compared to all other tumor types (21.4 +/- 11.1 hr versus 35.8 +/- 13.2 hr, p < 0.01), as was also whole-body t 1/2. Myelotoxicity was dose-limiting, and its severity was related to the types of prior therapy and extent of bone marrow involvement. In patients without prior radiation or chemotherapy, marrow doses as high as 600 cGy were tolerated without evidence of dose-limiting toxicity. No major toxicity to other organs was observed. Tumor doses were inversely related to the tumor mass and ranged between 2 and 218 cGy/mCi. Modest antitumor effects were seen in 12 of 35 assessable patients (1 partial remission, 4 minor/mixed responses and 7 with stabilization of previously rapidly progressing disease). CONCLUSION: These results suggest that prior chemotherapy or external beam radiation is an important risk factor for the development of hematological toxicity in radioimmunotherapy and that higher radiation doses may be delivered to tumors of patients without prior therapy compromising the bone marrow reserve. The different and, in the individual cases, unpredictable clearance rates suggest the necessity of dosimetry-based treatment planning rather than mCi/m2 dosing. Small tumors seem to be more suitable for radioimmunotherapy because of their favorable dosimetry, but to achieve better therapeutic results in patients with bulky disease, the application of higher, potentially myeloablative doses is indicated.

Aged↗
PubMed1997

Studies of breast cancer imaging with radiolabeled antibodies to carcinoembryonic antigen. Immunomedics Breast Cancer Study Group.

Multiple imaging methods are currently used to detect the presence, location, and extent of breast cancer, either at initial presentation or during follow-up. Even at initial diagnosis, more specific methods are needed to complement the high sensitivity of mammography in the detection and diagnosis of mammary carcinoma. Therefore, the current study evaluates the potential use of a new monoclonal antibody-based imaging agent, arcitumomab (CEA-Scan), which comprises an anti-carcinoembryonic antigen monoclonal antibody Fab' fragment labeled directly with technetium-99m, in the detection of primary, recurrent, or metastatic mammary cancer. A prospective, non-randomized, open-label, multicenter trial was conducted in 123 women 100 with primary breast cancer confirmed by histology or cytology, and 23 with a prior history and who were under evaluation for possible recurrence or metastasis. A 1-mg dose of arcitumomab labeled with 20-25 mCi Tc-99m was injected i.v., and planar images were acquired at 5-8 hr, as well as single-photon emission computed tomography. Additional planar scanning was performed optionally at 18-24 hr. The imaging studies were interpreted as positive if there was abnormal focal activity, and were correlated, wherever possible, with histopathology or conventional imaging tests. In 78 evaluable patients with primary breast carcinoma arcitumomab showed an imaging sensitivity and specificity of 82% and 88%, respectively, even detecting lesions < 1 cm in 61% of the cases. Among 58 patients evaluable for axillary node involvement, 30 were positive by histopathology, of which arcitumomab was correct in 19 with cancer (63% sensitivity) and in 25 of 28 without cancer (89% specificity). Among 88 primary operable patients, arcitumomab showed additional sites of focal uptake outside of the breasts and axillae in 10, or 11%. In a total of 19 breast cancer patients with known or suspected recurrence or metastatic disease, 13, or 68%, showed one or more focal sites of uptake, involving the typical sites of spread of mammary cancer. No significant adverse effects or induction of human antimouse antibodies were observed in these patients. Arcitumomab immunoscintigraphy is a simple, same-day, and safe new imaging modality for the detection of sites of breast cancer, including lesions < 1 cm, with a reasonably high rate of sensitivity and specificity. It may be used to complement mammography in the differentiation of malignant from benign disease.

Adult↗
PubMed1997

Cancer imaging with radiolabeled antibodies: new advances with technetium-99m-labeled monoclonal antibody Fab' fragments, especially CEA-Scan and prospects for therapy.

The use of radiolabeled anticancer antibodies to detect cancer sites by external scintigraphy has had a relatively long history. With the advent of monoclonal antibodies (MAbs), which precluded the need for purifying the antibodies by laborious purification steps, there was a surge of interest and efforts to develop these reagents for both imaging and therapy applications (1). Today, many thousands of patients have received different forms and doses of MAbs for various purposes, and four MAb-based products have been licensed for manufacture and sale in the U.S. (2,3). This article describes the most recent MAb product to be approved in the U.S. for colorectal cancer imaging, including discussions of using this agent and its therapeutic counterpart in several cancer types.

Antibodies, Monoclonal↗
PubMed1997

Manipulation of blood clearance to optimize delivery of residualizing label-antibody conjugates to tumor cells in vivo.

UNLABELLED: We have attempted to improve the therapeutic index of radioimmunotherapy by manipulating the blood clearance rate and the catabolism of the radiolabel. The general strategy is to allow the antibody (Ab) to circulate in the blood for 2-3 days, then to clear it rapidly by a method that delivers the Ab to hepatocytes. In addition, the radiolabel selected has two key properties: it is a residualizing label (which is lysosomally trapped after catabolism), so it is retained well by tumor cells, but is excreted rapidly by hepatocytes into bile. METHODS: In initial experiments, three residualizing radiolabels were tested for their rate of excretion after specific delivery in vivo to either hepatocytes, via galactosylated Ab, or Kupffer cells, via immune complexes. A label showing rapid biliary excretion only after delivery to hepatocytes, (111)In-benzyl-diethylenetriamine tetraacetic acid, was then used for radioimmunodetection in a protocol of delayed rapid blood clearance in which clearance was by hepatocytes. This was achieved by using galactosylated Ab, combined with temporary inhibition of the asialo-glycoprotein receptor on hepatocytes. Ab RS11 and the lung adenocarcinoma Calu-3 xenograft in nude mice were used. Control experiments were performed with a conventional 125I label and with 125I-dilactitol-tyramine. RESULTS: Indium-benzyl-diethylenetriamine tetraacetic acid was identified as a label that was excreted more rapidly from hepatocytes than from Kupffer cells, by biliary excretion. Using this radiolabel with delayed rapid blood clearance, very high tumor/blood ratios were obtained, 166:1 at day 3, but tumor/normal tissue ratios for other tissues were not as high. There appeared to be some uptake of the radiolabel by all normal tissues tested, including the lungs and muscle. Dosimetry calculations suggested that the therapeutic index was no better than with a simple Ab injection. CONCLUSION: Antibody catabolism can be directed towards either hepatocytes or Kupffer cells, and this difference can strongly affect the excretion rate of radiolabels, since only hepatocytes can excrete degradation products into bile. Processing will also depend on the particular radiolabel. These factors are particularly important for protocols involving delayed rapid blood clearance, since liver uptake is so rapid. The methods described should stimulate other approaches of manipulating Ab blood clearance and radiolabel catabolism to achieve improved therapeutic results.

Animals↗
PubMed1996

Internalization and catabolism of radiolabelled antibodies to the MHC class-II invariant chain by B-cell lymphomas.

The fate of antibody (Ab) LL1, which reacts with the invariant chain (Ii) subunit of the immature MHC class-II antigen (CD74) after binding to the surface of B-cell lymphomas was investigated. This Ab was internalized and catabolized very rapidly, much faster than other Abs that are considered to be rapidly internalized, such as CD19, CD22 and anti-(transferrin receptor). Such internalization did not depend on Ab cross-linking. The capacity of this uptake process was determined in long-term experiments by increasing the Ab concentration: in 1 day, approx. 8 x 10(5) Ab molecules per cell were catabolized. This analysis was facilitated by the use of radiolabels that are trapped within cells after catabolism of the Abs to which they were conjugated. If the Ab is a reliable marker for the Ii antigen, which is likely, we can conclude that Ii directed to the cell surface appears to be sufficient, indeed more than sufficient, to account for the cell content of mature class-II molecules.

Antibodies↗