Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently produced the monoclonal antibody E48 as a specific reagent for squamous cell carcinomas. In our ongoing investigations to use E48 for clinical tumor detection and therapy, fundamental aspects of the antigen have to be elucidated and practical applications of the antibody have to be tested in a preclinical model. Immunoelectron-microscopic studies localized the E48 antigen along the cell surface and in between desmosomes, suggesting that the antigen serves as an adhesion molecule. To evaluate the usefulness of E48 for radioimmunodetection of neck node metastases, nodes from 20 neck dissection specimens were tested. A strong reactivity was observed. Furthermore, F(ab')2 fragments of E48 were compared with the complete IgG E48 for selective tumor detection in an animal model. It was demonstrated that E48 F(ab')2 fragments localize faster and reach higher tumor-nontumor ratios than the whole molecule.
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PMID:Detection of squamous cell carcinoma xenografts in nude mice by radiolabeled monoclonal antibody E48. 174 35

In our laboratory, a solid-phase synthesis of 186Re-mercaptoacetyltriglycine for reproducible and aseptic production of stable 186Re-monoclonal antibody conjugates was recently developed. Monoclonal antibody (MAb) E48 IgG, when labeled with 99mTc according to the same labeling procedure, was recently shown to be highly capable of detecting recurrent and metastatic disease in patients with head and neck squamous cell carcinoma. In the present study, MAb E48 was labeled with 186Re and tested for its capacity to eradicate established human head and neck squamous cell carcinoma xenografts growing s.c. in nude mice. Experimental groups received a single bolus injection of 200 [number of mice (n) = 6, number of tumors (t) = 11], 400 (n = 6, t = 11), 500 (n = 6, t = 12), or 600 (n = 5, t = 9) microCi 186Re-labeled MAb E48 IgG; control animals were given diluent (n = 4, t = 8). In the 200 microCi group, 5 of 11 tumors showed regression while the remaining tumors showed a decreased growth rate. In the other treatment groups, all tumors regressed. In all treatment groups, remissions were observed (no regrowth within 4 months after injection). The number of remissions in the 200, 400, 500, and 600 microCi group were 2 of 11 (18.2%), 3 of 11 (27.3%), 6 of 12 (50%), and 3 of 9 tumors (33.3%), respectively. In comparison with the median tumor volume doubling time of the controls, the tumor volume doubling time in the remaining tumors in the groups receiving 200, 400, 500, or 600 microCi was increased 5.5-, 7.8-, 8.7-, and 11.3-fold, respectively. Dosimetry was based on the biodistribution of 200 microCi 186Re-labeled MAb E48 IgG. In the group receiving 600 microCi, the absorbed cumulative radiation dose was 3432 cGy for tumor and 1356 cGy for blood. In other tissues, the accumulated dose was < 17% of the dose delivered to tumor. The whole-body dose was 11-fold lower than the dose delivered to tumor. Apparent toxicity was limited to weight loss, which did not exceed 12% and which returned to control levels within 2 weeks. No treatment-related deaths occurred. These data suggest radioimmunotherapy with 186Re-labeled MAb E48 IgG to be a feasible approach for the treatment of head and neck cancer.
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PMID:186Re-labeled monoclonal antibody E48 immunoglobulin G-mediated therapy of human head and neck squamous cell carcinoma xenografts. 833 58

Preliminary data from recent clinical radioimmunoscintigraphy studies indicate that 99mTc-labelled murine monoclonal antibodies (MAbs) E48 and U36 have a similar ability to target squamous cell carcinoma of the head and neck (HNSCC) selectively. In the present study we describe additional aspects of murine and chimeric MAb (mMAb and cMAb) E48 and U36, which might influence the selection of one MAb for adjuvant radioimmunotherapy. To make direct comparison possible, ten patients received 11.2 +/- 0.3 and 11.1 +/- 0.2 mg (n = 5) or 51.1 +/- 0.1 and 51.0 +/- 0.4 mg (n = 5) of both mE48 IgG and mU36 IgG labelled with 131I and 125I simultaneously and underwent surgery 7-8 days after injection. The mean uptake of iodine-labelled mE48 IgG and mU36 was highest in tumour tissue, 8.9 +/- 8.9 and 8.2 +/- 4.4 %ID kg(-1) respectively. Tumour to non-tumour ratios for oral mucosa, skin, muscle, blood and bone marrow aspirate were 2.5, 5.5, 25.2, 4.7 and 4.0 respectively in the case of mE48 IgG and 2.3, 4.1, 21.0, 5.8 and 5.8 respectively in the case of mU36 IgG. The distribution of mMAbs E48 and U36 throughout tumours that had been collected in previous studies was heterogeneous when administered at a dose of 1 or 12 mg, and homogeneous when administered at a dose of 52 mg. Administration of mE48 IgG (1-52 mg) resulted in a human anti-mouse antibody response in 12 out of 28 patients, while for mU36 IgG (1-52 mg), this figure was three out of 18 patients. cMAb E48 was shown to be highly effective in mediating antibody-dependent cellular cytotoxicity in vitro, while cMAb U36 and mMAbs E48 and U36 were not effective at all. Rationales are provided that give priority to the start of adjuvant radioimmunotherapy trials with 186Re-labelled cMAb U36 IgG in head and neck cancer patients who are at high risk for the development of locoregional recurrences and distant metastases.
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PMID:Selection of monoclonal antibody E48 IgG or U36 IgG for adjuvant radioimmunotherapy in head and neck cancer patients. 908 42

Biodistribution and pharmacokinetics of radiolabeled mAb E48 IgG and E48 F(ab')2 were analyzed and compared in 39 patients with histologically proven squamous cell carcinoma of the head and neck who were included in a radioimmunoscintigraphy study and underwent surgery 44 h after injection. Three groups of patients were distinguished: group 1 (n = 19) received technetium-99m (99mTc)-labeled E48 F(ab')2, group 2 (n = 9) received 99mTc-labeled E48 IgG, and group 3 (n = 11) received 99mTc- and 131I-labeled E48 IgG as well as 125I-labeled F(ab')2. Two patients in group 1 and four patients in group 3 received a high mAb dose (10-50 mg), while all other patients received a low mAb dose (1-4 mg). From all patients in groups 2 and 3 biopsies from the surgical specimen were obtained 44 h postinjection. Tumor uptake of 99mTc-labeled E48 IgG was high, ranging from 0.007 to 0.082% of the injected dose/g, with a mean of 0.031 +/- 0.020% of the injected dose/g. The mean tumor:nontumor ratio of this conjugate was 2.8 for mucosa, 4.6 for bone marrow aspirate, 4.1 for blood, 20.3 for fat, and 21.0 for muscle. Activity uptake in tumor positive lymph nodes was 4.7 times higher as compared to negative lymph nodes. Sixteen h postinjection radioimmunoscintigraphy revealed activity uptake in the primary tumor, lymph node metastases, oral cavity, and adrenal glands. Using regions of interest, the uptake in the adrenal glands was estimated to be 0.050% of the injected dose/g. If a high mAb dose was used, no adrenal glands were visualized and the uptake in the oral cavity was clearly diminished, while the tumor uptake and tumor:nontumor ratios were increased. The mean elimination half-lifes t1/2 alpha and t1/2 in plasma were: for E48 IgG (n = 20) 6.6 +/- 2.6 and 54.1 +/- 24.3 h and for E48 F(ab')2 (n = 19) 2.3 +/- 0.4 and 19.9 +/- 4.6 h, respectively. Tumor uptake of 131I-labeled E48 IgG was 49% higher than of 125I-labeled F(ab')2. For most tissues except normal oral mucosa, tumor:nontumor ratios were slightly higher for F(ab')2 than for IgG. The present study shows that mAb E48 accumulates selectively and to a high level in head and neck squamous cell carcinoma. Although no definite conclusions can be drawn as to which mAb form is more suitable, IgG or F(ab')2, mAb E48 seems to have potential for radioimmunotherapy in head and neck squamous cell carcinoma patients.
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PMID:Biodistribution of radiolabeled monoclonal antibody E48 IgG and F(ab')2 in patients with head and neck cancer. 981 83

So far, mAb E48 is the most promising antibody described for specific targeting of head and neck squamous cell carcinoma (HNSCC) in patients. On the basis of its more homogeneous reactivity pattern on HNSCC, the novel mAb U36 may be even better suited for targeting. In this study the biodistribution of mAb U36 was evaluated by radioimmunoscintigraphy (RIS) and biopsy measurements in 10 patients who were suspected of having neck lymph node metastases from a histologically proven HNSCC and who had been scheduled to undergo resection of the primary tumor and neck dissection. Patients received 1.8-53.0 mg mAb U36 IgG labeled with 756 +/- 95 MBq technetium-99m i.v. Preoperatively, palpation, computerized tomography, magnetic resonance imaging, and RIS were performed. RIS images included planar and single-photon emission computerized tomography images of the head and neck and planar images of the whole body. The diagnostic findings were recorded per side as well as per lymph node level of the neck and compared to the histopathological outcome. Radioactivity in blood samples and biopsies from the surgical specimens were measured. All 10 primary tumors were visualized by RIS. All diagnostic modalities were correct in 7 of 14 tumor-involved lymph node levels. The missed lymph node metastases comprised micrometastases, small tumor-involved nodes (<9 mm), and tumor-involved nodes with much necrosis, keratin, or fibrin. There were no false-positive observations with mAb U36. Besides activity uptake in tumor tissue, only a slight accumulation of activity was observed in the mouth, lungs, liver, spleen, kidneys, and scrotal area. Biopsies from the surgical specimen showed a high tumor uptake of 20.4 +/- 12.4% of the injected dose/kg (range, 8.0-43.0% of injected dose/kg), 44 h postinjection. An increase in the mAb dose did not influence uptake of activity in tumor tissue. The mean tumor:nontumor ratio at this time point was 2.3 for mucosa, 2.8 for blood, 3.0 for bone marrow aspirate, 12.9 for fat, and 13.0 for muscle tissue. The present clinical study shows that technetium-99m-labeled U36 IgG accumulates selectively and to a high level in HNSCC. The tumor-targeting results for U36 IgG are comparable to those previously described for E48 IgG. On the basis of the results of ongoing biodistribution studies in which both mAbs E48 and U36, labeled with different iodine isotopes, are simultaneously evaluated for tumor uptake and retention in HNSCC patients, one of these mAbs will be selected for future adjuvant radioimmunotherapy trials.
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PMID:Radioimmunoscintigraphy and biodistribution of technetium-99m-labeled monoclonal antibody U36 in patients with head and neck cancer. 981 20

Patients with advanced stages of head and neck cancer frequently develop locoregional recurrence as well as distant metastases. These data indicate that traditional diagnostic methods such as histopathology and radiology are not sensitive enough to detect the small numbers of tumor cells which are left behind, defined as minimal residual disease (MRD). Sensitive diagnostic assays based on molecular markers appear to be powerful tools to improve the staging of these patients. At the DNA level, tumor-specific p53 mutations seem to have great potential for the detection of "occult" tumor cells at surgical margins and lymph nodes. At the RNA level HNSCC associated antigens like the E48 antigen, allow the detection of rare HNSCC cells in blood and bone marrow and, it is hoped, also in lymph nodes and lymph node aspirates. However, the molecular assays which are used to detect MRD are subject to certain (technical) problems which affect their sensitivity and specificity. In this paper we will present examples of molecular assays such as the plaque assay using p53 mutations and the E48 RT-PCR, and show their use for MRD detection in cervical lymph nodes. In addition, we will discuss the problems and pitfalls associated with these sensitive techniques.
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PMID:Molecular diagnosis of head and neck cancer. 1085 64

The presence of lymph node metastases is the major determinant for prognosis in head and neck squamous cell carcinoma (HNSCC). It is at present unknown whether the same holds true for the presence of histologically undetectable micrometastases. We analyzed 456 histologically tumor-negative lymph nodes of 23 HNSCC patients without (pN0) and 18 patients with one or two tumor-positive lymph nodes (pN+) in their neck dissection specimens at histopathologic examination. To detect the presence of disseminated tumor cells and micrometastases in these lymph nodes, we used real-time quantitative RT-PCR with E48 (Ly-6D) transcripts as a squamous cell-specific molecular marker. The results were compared with histopathologic examination and clinical outcome. E48 transcripts were detected in lymph nodes of 5 (22%) of 23 patients in the pN0 group, and in histologically negative lymph nodes of 10 (56%) of 18 patients in the pN+ group. In the pN0 group, the presence of E48-positive lymph nodes was significantly associated with a distinctly poor cause-specific survival as compared with those with E48-negative lymph nodes. Our results indicate that E48 real-time quantitative RT-PCR is a suitable method for the detection of micrometastases in lymph nodes of patients with HNSCC. Moreover, detection of micrometastases seems clinically relevant but should be confirmed in a large multicenter trial.
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PMID:Assessment and clinical significance of micrometastases in lymph nodes of head and neck cancer patients detected by E48 (Ly-6D) quantitative reverse transcription-polymerase chain reaction. 1292 Feb 52

There is an urgent need for an effective adjuvant systemic therapy for the treatment of patients with advanced head and neck cancer. This study shows that therapy based on the use of monoclonal antibodies (MAbs) is developing to a realistic option. A few years ago the first MAbs with specificity for squamous cell carcinoma of the head and neck (HNSCC) were produced, among which was MAb E48. In animal and patient studies, in which localization of radiolabelled MAb E48 was analysed qualitatively and quantitatively, it was demonstrated that a high percentage of the injected dose accumulated selectively in the tumour. These targeting properties, when exploited for delivery of toxic agents to the tumour, give MAb E48 potential for tumour therapy. Especially the application of MAb E48 in radioimmunotherapy (RIT) seems to be attractive due to the intrinsic radiosensitivity of HNSCC. Armed with 186-Rhenium, a radionuclide recently introduced in the field of RIT, MAb E48 IgG was shown to be highly capable of eradicating established HNSCC tumours in nude mice. Complete ablation of small HNSCC was observed in this animal model by a single bolus injection. In an effort to make MAb E48 less antigenic for human application a chimeric human/mouse MAb (cMAb) has been constructed by use of recombinant DNA techniques. This modification strongly improved the capacity of MAb E48 for mediating antibody-dependent cellular cytotoxicity (ADCC). When using this cMAb E48 for RIT of minimal residual disease it can be anticipated that ADCC activity may be supportive to irradiation, especially in the ablation of single disseminated cells or small cell aggregates. Extrapolating results obtained in nude mice to patients and taking into account the good targeting in patients, RIT with E48 IgG seems to have potential for the elimination of minimal residual disease. Based on this encouraging progress, preparations are being made to evaluate the efficacy of Re-186-labelled cMAb E48 as an adjuvant in a phase III study for the treatment of patients who are at high risk for developing distant metastases.
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PMID:Progress in radioimmunotherapy of head and neck-cancer (review). 2160 50