RESUMEN
The aims of this prospective, nonrandomized phase I/II study were to evaluate (1) the safety and (2) the detection rate of tissue culture-derived, 111In-labelled anti-CEA monoclonal antibody IVP ZCE 025 in patients with primary, metastatic and occult colorectal carcinomas. 111In-IVP ZCE 025 imaging correctly identified 31 of 37 primary colorectal carcinomas, 10 of 19 hot liver metastases, 11 of 16 distant metastases and seven of seven local tumour recurrences. Previously unsuspected tumours were detected by IVP ZCE 025 imaging in 11 of 34 patients. The scans were also true negative in four patients. The overall performance characteristics of IVP ZCE 025 at monoclonal antibody doses of 1.0-5.0 mg were comparable to those obtained with 40.0 mg ascites-produced ZCE 025. No clinical or biochemical adverse reactions were encountered in the 61 patients entered into this study.
Asunto(s)
Neoplasias Colorrectales/diagnóstico por imagen , Radioisótopos de Indio , Radioinmunodetección , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Even with the advancement of radiologic techniques, metastatic cancers can still be difficult to detect. In this study, 48 patients suspected of having occult metastases were studied by radioimmunodetection following the administration of 92.5 to 181.3 MBq of indium 111-labeled monoclonal anticarcinoembryonic antigen antibody. All but seven patients were thought to have metastatic colorectal carcinoma. In the majority of cases, physical examinations and computed tomographic scans had failed to detect a lesion. At least one lesion that was later proved to exist was detected in 34 of the 50 studies performed on these patients. Seven of eight patients with normal radioimmunodetection scans remain free of disease. One hundred one sites were detected overall; 60 were considered true-positive sites and 27 false-positive sites. Fourteen sites remained in question. Nineteen false-negative sites occurred. Radioimmunoimaging appears valuable for the detection of occult cancer where standard, noninterventional techniques have failed to detect the suspected disease.
Asunto(s)
Antígeno Carcinoembrionario/inmunología , Radioisótopos de Indio , Metástasis de la Neoplasia/diagnóstico por imagen , Radioinmunodetección , Antígeno Carcinoembrionario/análisis , Reacciones Falso Positivas , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas , Inmunoglobulina G , Masculino , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
The safety and clinical utility of repeated administrations of 111In-ZCE 025 were evaluated in 25 patients who have undergone colorectal carcinoma resection. Fifteen patients were clinically and radiologically free of recurrences and asymptomatic while 10 had rising CEA and/or symptoms. We repeatedly imaged the patients following intravenous administrations of 40 mg ZCE 025, every 4 to 6 mo. Side effects occurred in 16% of patients who received two or more infusions. Sixteen lesions were detected by immunoscintigraphy in 11 patients who were free of disease by CT scans or other imaging modalities. Ten recurrences were surgically confirmed in seven patients. Radiographic and clinical follow-up confirmed the remaining 6 Mab-positive lesions. Elevated human anti-mouse antibody (HAMA) titers were detectable in the sera of 30% and 64% of patients following the 1st and 2nd Mab injection respectively, but did not interfere with successful immunoscintigraphy nor correlated with the occurrence of side effects. This study suggests that a negative Mab scan indicates that a patient will remain free of recurrence; conversely, a positive scan was associated with recurrences of disease.
Asunto(s)
Antígeno Carcinoembrionario/inmunología , Neoplasias del Colon/diagnóstico por imagen , Radioisótopos de Indio , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Recurrencia Local de Neoplasia/diagnóstico por imagen , Radioinmunodetección/métodos , Neoplasias del Recto/diagnóstico por imagen , Adulto , Anciano , Neoplasias del Colon/cirugía , Femenino , Humanos , Radioisótopos de Indio/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Estudios Prospectivos , Neoplasias del Recto/cirugíaRESUMEN
In clinical studies we have evaluated a unique monoclonal antibody-based drug delivery system, a bifunctional antibody designed to deliver imaging or therapeutic agents, such as radioisotopes, drugs, or biologics, to tumor cells, while minimizing the dose to normal tissue. The bifunctional antibody, with one specificity to a tumor-associated antigen (carcinoembryonic antigen) and another specificity to a hapten, is injected and allowed to localize at a tumor site for 4 days. A hapten, tagged with a radioisotope, is subsequently injected for delivery to and capture by the prelocalized antibody at the tumor site. In studies reported here, the sulfhydryl groups of Fab' fragments of ZCE-025 and CHA-255 were linked with bis-maleimidomethyl ether to form an F(ab')2 bifunctional antibody coupled by a stable thioether linkage. EOTUBE, a hydroxyethylthiourido derivative of benzyl EDTA, was used as the hapten carrier of 111In. Fourteen patients 62-82 years old with recurrent or metastatic adenocarcinoma of the colon were studied. Twenty of 21 known lesions were imaged, and eight of nine new lesions were confirmed. With this fundamentally new approach to drug delivery, clearance from normal tissue is rapid, and high tumor:normal tissue ratios are expeditiously achieved.
Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Anticuerpos , Quelantes , Neoplasias del Colon/diagnóstico por imagen , Ácido Edético/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antígeno Carcinoembrionario/inmunología , Quelantes/farmacocinética , Reactivos de Enlaces Cruzados , Ácido Edético/inmunología , Ácido Edético/farmacocinética , Haptenos , Humanos , Fragmentos Fab de Inmunoglobulinas , Radioisótopos de Indio , Persona de Mediana Edad , CintigrafíaRESUMEN
Metastatic colorectal cancer was detected with stabilized F(ab')2 fragments of ZCE-025, an anti-carcino-embryonic antigen (CEA) monoclonal antibody (MoAb). The fragments were prepared by cross-linking Fab' with a bifunctional cross-linking agent, bis-(maleimido)methyl ether. The authors labeled 2 mg of ZCE-025 with 5 mCi (185 MBq) of indium-111 and injected the material intravenously, either alone or with unlabeled F(ab')2, into 16 patients. Lesion detection, pharmacokinetics, and relative body distribution were evaluated and compared with those of the intact immunoglobulin (IgG1) antibody. Stabilized F(ab')2 fragments were more useful than the intact antibody in detection of lesions: Overall sensitivity of F(ab')2 fragments for all the patients was 79.4%, whereas overall sensitivity of the intact IgG1 antibody was 32%. This anti-CEA-stabilized F(ab')2 fragment may be a powerful diagnostic tool that can achieve higher sensitivity at smaller protein doses than the intact IgG1 antibody.
Asunto(s)
Anticuerpos Monoclonales , Antígeno Carcinoembrionario/inmunología , Neoplasias Colorrectales/secundario , Fragmentos Fab de Inmunoglobulinas , Radioisótopos de Indio , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Neoplasias Colorrectales/diagnóstico por imagen , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , CintigrafíaRESUMEN
Liver uptake of 111In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an 111In-labeled anti-melanoma antibody 96.5 (111In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of 111In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to 111In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of 111In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to 111In-96.5 infusion demonstrated a significant drop [P less than 0.001] in the liver/heart ratio of radioactivity [2.81 +/- 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 +/- 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (Vd) and the plasma t1/2 both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration X time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P less than 0.05). Although tissue distribution of 111In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.