Safety and efficacy of arcitumomab imaging in colorectal cancer after repeated administration.
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In pivotal phase III clinical trials for detecting recurrent or metastatic colorectal cancer, most patients received a single arcitumomab injection. However, the early detection of postsurgical recurrence or metastases with arcitumomab will necessitate serial studies for surveillance. We present immunogenicity, safety, and imaging data supporting the use of multiple administrations of arcitumomab. METHODS: Human antimouse antibody (HAMA) response, adverse events, clinical laboratory values, and diagnostic imaging results were evaluated in 44 patients (24 men, 20 women; age range, 2878 y) after repeated arcitumomab administration (44 second and 3 third injections). Most patients initially had Dukes' class B or C colorectal cancer and had known or occult disease recurrence and elevated serum carcinoembryonic antigen levels at the time of the repeated injection. RESULTS: At the repeated injection, in no patient did elevated HAMA titers develop, hematology and serum chemistry changes were clinically insignificant, and only 1 adverse event (eosinophilia) was judged at least possibly related to arcitumomab. Arcitumomab imaging results at the second injection were comparable with those obtained in phase III trials after a single injection of arcitumomab, having a 78% per-lesion concordance with CT in the abdomen and pelvis and a 73% sensitivity and 94% specificity based on 9 patients with cancer confirmed surgically at 11 anatomic sites and excluded at 16 sites. CONCLUSION: These data indicate that at least 2 injections of arcitumomab can be given safely to patients with colorectal cancer, without increased immunogenicity and with imaging efficacy equivalent to the first administration. (+info)
Interferon-alpha-2b immunoconjugate for improving immunoscintigraphy and immunotherapy.
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A pretreatment with a single dose of an immunoconjugate (IC) that promises to enhance tumor uptake and decrease liver uptake of radiolabeled monoclonal antibodies (MAbs) might be of use in radioimmunodetection and radioimmunotherapy (RIT). We have shown previously that an interferon (IFN)-MAb (1:1) immunoconjugate (IC) enhances tumor uptake by a factor of 2 or more and reduces liver uptake by 50% in nude mice bearing human tumors. The aim of this study was to determine whether IFN modulates antigenic expression and to ascertain the most effective route of its administration, the optimal quantity to be administered, and the optimal duration of time to lapse between the administration of IC and the radiolabeled MAb. METHODS: IFN-alpha-2b and anticarcinoembryonic antigen-F6 (IgG2a) MAb were conjugated (1:1), and F(ab')2 of the MAb was labeled with 99mTc. Human colorectal tumors were grown in nude mice by implanting 5 x 10(6) LS174T confluent cells grown in culture. Mice, 5 in each group, received 20 x 10(3) IU intravenously, intramuscularly, or intraperitoneally and 40 x 10(3), 60 x 10(3), and 80 x 10(3) IU intravenously 30 min before the intravenous administration of 25.9 MBq 99mTc/20 microg F(ab')2. Mice in the control groups received 99mTc-F(ab')2 but not the conjugate. Twenty-four hours later mice were killed and imaged, and tissues were removed for quantitative (percentage injected dose/g [% ID/g]) distribution of 99mTc. RESULTS: In all conjugate-receiving mice, the tumor uptake was higher and the liver uptake was lower (P < 0.01) than that in the control mice with the exception of liver uptake, which was not significantly different in mice receiving 80 x 10(3) IU conjugate. The optimal results were apparent in mice pretreated with 40 x 10(3) IU conjugate in which tumor uptake was enhanced by a factor of 2.3 (4.8 +/- 0.5 %ID/g versus 11 +/- 0.7 %ID/g; P < 0.01). The renal uptake remained unchanged, and the tumor-to-muscle ratios increased from 11.5 +/- 6.8 to 14.6 +/- 3.9, and the tumor-to-blood ratios increased from 4.4 +/- 1.8 to 8.3 +/- 2.4. The liver uptake decreased from 9.5% +/- 1% to 5% +/- 1.6%. Results were attributed to enhanced tumor blood flow, increased antigenic expression, and blocking of hepatic nonspecific Fc receptors. CONCLUSION: A pretreatment with IFN-MAb conjugate is a worthwhile approach to consider in radioimmunoscintigraphy and RIT. (+info)
Safety and biodistribution of 99mTechnetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients.
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The CD44 protein family consists of isoforms, encoded by standard exons and up to nine alternatively spliced variant exons (v2-v10), which are expressed in a tissue-specific way. Expression of v6-containing variants (CD44v6) has been related to aggressive behavior of various tumor types and was shown to be particularly high in squamous cell carcinoma (SCC). Therefore, CD44v6 might be a suitable target for radioimmunoscintigraphy (RIS) and therapy. The present study evaluates the novel high-affinity murine anti-CD44v6 monoclonal antibody (MAb) BIWA 1 for its safety and targeting potential in patients with SCC of the head and neck (HNSCC). Twelve HNSCC patients, who had planned to undergo resection of the primary tumor and neck dissection, were included. Preoperatively, 2, 12, or 52 mg of 99nTc-labeled MAb BIWA 1 was administered. RIS results obtained 21 h after injection were compared with palpation, computed tomography, and magnetic resonance imaging, with histopathology as the gold standard. Moreover, biodistribution of BIWA 1 was evaluated by radioactivity measurement in blood and bone marrow and in biopsies from the surgical specimen obtained 40 h after injection. The distribution of BIWA 1 in tumor biopsies was analyzed by immunohistochemistry. BIWA 1 integrity in the blood was assessed by high-performance liquid chromatography and related to soluble CD44v6 levels in serum samples. No drug-related adverse events were observed. Human antimouse antibody responses were observed in 11 patients. The diagnostic efficacy of RIS appeared to be comparable for the three BIWA 1 dose levels and for the four diagnostic methods. Besides activity uptake in tumor tissue, minimal accumulation of activity was observed in mouth, lungs, spleen, kidney, bone marrow, and scrotal area. Analysis of tissue biopsies revealed high uptake in tumors, with a mean value of 14.2+/-8.4% of the injected dose/kg tumor tissue and a mean tumor:blood ratio of 2.0+/-1.4 at 40 h after injection. Differences among the three dose groups were not statistically significant, although a trend toward lower uptake in the highest dose group was noted. Distribution of BIWA 1 throughout the tumor was heterogeneous for all dose groups, which might be related to the high affinity of the MAb. The mean biological half-life in blood (34.5+/-6.1 h) was not dose dependent. Extensive complex formation of BIWA 1 was observed in the 2-mg group, most probably with soluble CD44v6 present in the blood, and complex formation relatively diminished upon increase of the MAb dose. BIWA 1 is a promising MAb for targeting HNSCC because it can be safely administered to HNSCC patients, while it shows high and selective tumor uptake. However, BIWA 1 is immunogenic, and therefore a chimerized or humanized derivative of BIWA 1 with intermediate affinity will be used in future clinical trials. (+info)
Applicability of carcinoembryonic antigen-specific monoclonal antibodies to radioimmunoguided surgery for human colorectal carcinoma.
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Two carcinoembryonic antigen (CEA)-specific monoclonal antibodies (MAbs), PR1A3 and T84.66, were tested to determine whether they could accurately localize colorectal carcinoma and therefore be applicable in radioimmunoguided surgery (RIGS). Twenty-one tumors by three human colorectal carcinoma cell lines with various levels of CEA expression (KM-12c, C75, and Clone A) were successfully implanted in the intra-abdominal organs of 15 nude mice. The tumors was localized using a portable radioisotope detector (Neoprobe 1000) 48 h after injection of radiolabeled MAbs (10 mCi/mouse) when the precordial counts were <20 per 2 s. Histopathological identification of radiolabeled MAbs were also performed using immunohistochemistry and microautoradiography. Radioactivity counted on a portable radioisotope detector correlated well with that on a gamma counter. The distribution in the blood was significantly greater than in other organs (P < 0.001). Localization indices of the tumor in various organs was from 1.1 to 8.5 in the PR1A3-pretreated mice and 3.0 to 8.6 in the T84.66-pretreated mice. Silver grains and immune staining were distributed in the tumor cells of the PR1A3-pretreated mice, whereas they were in the necrotic debris as well as the tumor cells of the T84.66-pretreated mice. There were significantly more silver grains in the liver in the T84.66-pretreated mice than in the PR1A3-pretreated mice (P = 0.004). The sensitivity and specificity of tumor localization by RIGS were 71.4 and 91.4% in the PR1A3-pretreated mice, whereas they were 60 and 76% in the T84.66-pretreated mice. A study using specific anti-CEA MAbs suggested PR1A3 as an efficient immune probe for RIGS in colorectal carcinoma with a low rate of false-positive detection. (+info)
FDG PET and immunoscintigraphy with 99mTc-labeled antibody fragments for detection of the recurrence of colorectal carcinoma.
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The aim of this study was to compare FDG PET with a new monoclonal antibody-based imaging agent that comprises an anti-carcinoembryonic antigen (CEA) monoclonal antibody Fab' fragment directly labeled with 99mTc. METHODS: Twenty-eight patients who were previously treated for colorectal carcinoma and in whom recurrence was suspected were examined with FDG PET and immunoscintigraphy. The most common indications were an elevation of serum CEA (13 patients), suggestive lesions documented by CT (9 patients), sonography (4 patients), and severe constipation (2 patients). Planar imaging and SPECT were performed 4-6 h after intravenous injection of the new imaging agent. Whole-body PET was performed 45-60 min after intravenous injection of FDG. The findings were confirmed by conventional diagnostic modalities, surgery, and histology. RESULTS: Histology confirmed local tumor recurrence in 9 of 28 patients. Clinical follow-up or CT confirmed the presence of liver metastases in 9 patients and lymph node involvement, lung metastases, and bone metastases in 2 patients each. The new agent correctly detected 8 of 9 local recurrences, whereas FDG PET was able to detect all 9 cases and in 1 case was false-positive. Liver metastases were confirmed in 9 patients by FDG PET but in only 1 patient by the new agent. Two cases with lymph node metastases and 2 cases with lung metastases were correctly identified by FDG PET, but none were detected by the new agent. Finally, bone metastases were identified in 1 patient by FDG PET but not with the new agent, whereas bone marrow infiltration (n = 1) was diagnosed by both imaging modalities. CONCLUSION: These results indicate that FDG PET and 99mTc-labeled anti-CEA Fab' are suitable for the diagnosis of local recurrence of colorectal carcinoma but that FDG PET is clearly superior in the detection of distant metastases (liver, bone, and lung) and lymph node involvement. (+info)
Specific and rapid scintigraphic detection of infection with 99mTc-labeled interleukin-8.
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Interleukin-8 (IL-8) is a chemotactic cytokine involved in activation and recruitment of neutrophils to areas of infection. In our previous studies in rabbits we tested 123I-labeled IL-8 for its potential to image infections and showed that IL-8 rapidly and efficiently accumulated in infectious foci. However, labeling of IL-8 with 123I is costly and laborious and the specific activity of the preparation was low. In this study IL-8 was labeled with 99mTc through the hydrazinonicotinamide (HYNIC) chelator. METHODS: The leukocyte receptor-binding capacity of the preparation was determined in vitro. Rabbits with Escherichia coli abscesses were injected intravenously with 7 MBq 99mTc-HYNIC-IL-8. Biodistribution of the radiolabel was determined by gamma camera imaging and tissue counting at 8 h after injection. 99mTc-HYNIC-lysozyme was used as a size-matched control. RESULTS: The leukocyte receptor-binding capacity of the 99mTc-HYNIC-IL-8 preparation was preserved as determined in vitro, but labeling efficiency was modest with a specific activity of 3 MBq/microg. 99mTc-HYNIC-IL-8 accumulated rapidly in the abscess up to 0.33 +/- 0.06 percentage injected dose per gram (%ID/g) at 8 h after injection (vs. 0.025 +/- 0.003 %lD/g for 99mTc-HYNIC-lysozyme). Total uptake in the abscess was 4.9 +/- 0.7 %ID (vs. 0.44 +/- 0.05 %ID for 99mTc-HYNIC-lysozyme). Abscess-to-contralateral muscle ratios increased up to 127 +/- 23 (compared with 6.7 +/- 1.1 for 99mTc-HYNIC-lysozyme) and abscess-to-blood ratios increased to 11.9 +/- 2.2 (0.24 +/- 0.03 for 99mTc-HYNIC-lysozyme). The radiolabel was excreted renally, with a retention in the kidneys of 28 %ID. Gamma camera imaging rapidly visualized the abscess from 1 h after injection onward, with abscess-to-background ratios improving with time up to 22 at 8 h after injection (vs. 2.7 for 99mTc-HYNIC-lysozyme), as determined by quantitative analysis of the images. Most important, only a transient (30 min) moderate drop of leukocyte counts and no leukocytosis were observed after injection of an imaging dose of 99mTc-HYNIC-IL-8. CONCLUSION: IL-8 can be labeled with 99mTc using HYNIC as a chelator. By this method the leukocyte receptor-binding capacity is preserved. The preparation allows rapid visualization of infection in a rabbit model with high target-to-background ratios. The mild transient drop of leukocyte counts and the absence of leukocytosis suggest that 99mTc-HYNIC-IL-8 may be used as an imaging agent with only mild and transient side effects. (+info)
Immunoscintigraphy of aortic dissection with 99mTc-labeled murine anti-smooth muscle myosin monoclonal antibody in rats.
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Aortic dissection is among the most common of fatal conditions of the aorta. Prompt and accurate diagnosis of the site and extent of the lesion is necessary for adequate therapy. However, this catastrophic disease, characterized by extensive damage to smooth muscle cells, lacks specific signs and symptoms. As a result, the diagnosis is still frequently missed today and a new diagnostic method to specifically identify aortic dissection would be attractive. The purpose of this study was to examine the feasibility of radioimmunoscintigraphy using 99mTc-anti-smooth muscle myosin monoclonal antibody (SM-MAb) for the noninvasive diagnosis of aortic dissection in the rat experimental model. METHODS: The accumulation of 99mTc-anti-SM-MAb was studied, and scintigraphic imaging with 99mTc-anti-SMMAb was performed in rats immediately after experimental aortic dissection and 1 and 2 wk later. RESULTS: The radioactivity of 99mTc-anti-SM-MAb in the dissected aorta showed a significant increase compared both with the normal portion of the aorta and with blood 6 h after injection of the radiotracer; the ratio of the percentage injected dose per gram (%lD/g) in the lesion to that retained in the normal portion was 4.17 +/- 1.47. Scintigraphic imaging with 99mTc-anti-SM-MAb allowed distinct visualization of the dissected aorta with specific accumulation of antibody 6 h after tracer injection. Selective accumulation of the tracer in the dissected portion of the aorta persisted even 1 wk after aortic injury, allowing clear visualization of the dissected lesion by scintigraphy. CONCLUSION: Radioimmunoscintigraphy using anti-SM-MAb is a potentially useful noninvasive diagnostic method for imaging aortic dissection. (+info)
In vivo detection of deposition of radiolabeled lupus antikidney antibody and its inhibition by soluble antigen.
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This investigation in an animal model was designed to test the feasibility of using radiolabeled lupus antikidney antibody to show renal deposition in vivo and the ability to block this deposition with a binding peptide. METHODS: BALB/c mice received injections of radiolabeled murine anti-DNA antibody, antibody with no DNA binding capability, and DNA antibody simultaneously with blocking peptide. RESULTS: Significantly higher renal deposition of anti-DNA antibody than of antibody without DNA binding capability occurred in the animals at 48 h after injection (5.21% of the injected dose per gram of tissue versus 2.5%, P < 0.0004) and at 7-8 d after injection (1.44% versus 0.20%, P < 0.00004). The simultaneous injection of blocking peptide with anti-DNA binding antibody significantly reduced the renal deposition of the anti-DNA antibody at 48 h (1.53%, P < 0.00001) and at 7-8 d (0.64%, P < 0.0017). CONCLUSION: This study showed the feasibility of using a radiolabeled antibody to evaluate deposition of anti-DNA antibody in the kidney and the successful use of a peptide to block antibody deposition-a strategy that may be useful for renal preservation in lupus. These data support the possibility of using antikidney-labeled antibodies to evaluate immunologic renal disease in vivo in humans. (+info)