RESUMO
PURPOSE: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. METHODS: We designed F(ab')2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab')2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab')2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab')2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. RESULTS: Radiolabeling procedure did not change F(ab')2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab')2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab')2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab')2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab')2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. CONCLUSIONS: 111In-DOTAGA-F(ab')2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab')2-cetuximab is an interesting theranostic tool allowing therapy and imaging.
Assuntos
Cetuximab/farmacologia , Neoplasias Colorretais , Imunoconjugados/farmacologia , Radioimunodetecção/métodos , Neoplasias Cutâneas , Nanomedicina Teranóstica/métodos , Animais , Cetuximab/farmacocinética , Humanos , Imunoconjugados/farmacocinética , Fragmentos Fab das Imunoglobulinas/farmacologia , Radioisótopos de Índio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Detection of bone metastases indicates poor prognosis for patients with prostate cancer. The immunotherapy with monoclonal antibody has been an important advance in the treatment of the cancer in the last years. Nimotuzumab is a humanized IgG1 monoclonal antibody directed against epidermal growth factor receptor that has been evaluated in solid tumors. The authors show images of 2 patients with bone metastases secondary to prostate cancer, "pre-cold therapy" with nimotuzumab. Immunoscintigraphic images were acquired 4 and 24 hours after the intravenous administration of 1110 MBq (30 mCi) of Tc-labeled nimotuzumab. Bone metastases expressing the receptor are visualized.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Radioimunodetecção , Compostos Radiofarmacêuticos , Tecnécio , Idoso , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Humanos , Imunoterapia , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapiaRESUMO
The progression of atherosclerosis is favored by increasing amounts of chondroitin sulfate proteoglycans in the artery wall. We previously reported the reactivity of chP3R99 monoclonal antibody (mAb) with sulfated glycosaminoglycans and its association with the anti-atherogenic properties displayed. Now, we evaluated the accumulation of this mAb in atherosclerotic lesions and its potential use as a probe for specific in vivo detection of the disease. Atherosclerosis was induced in NZW rabbits (n = 14) by the administration of Lipofundin 20% using PBS-receiving animals as control (n = 8). Accumulation of chP3R99 mAb in atherosclerotic lesions was assessed either by immunofluorescence detection of human IgG in fresh-frozen sections of aorta, or by immunoscintigraphy followed by biodistribution of the radiotracer upon administration of (99m)Tc-chP3R99 mAb. Immunofluorescence studies revealed the presence of chP3R99 mAb in atherosclerotic lesions 24 h after intravenous administration, whereas planar images showed an evident accumulation of (99m)Tc-chP3R99 mAb in atherosclerotic rabbit carotids. Accordingly, (99m)Tc-chP3R99 mAb uptake by lesioned aortic arch and thoracic segment was increased 5.6-fold over controls and it was 3.9-folds higher in carotids, in agreement with immunoscintigrams. Moreover, the deposition of (99m)Tc-chP3R99 mAb in the artery wall was associated both with the presence and size of the lesions in the different portions of evaluated arteries and was greater than in non-targeted organs. In conclusion, chP3R99 mAb preferentially accumulates in arterial atherosclerotic lesions supporting the potential use of this anti-glycosaminoglycans antibody for diagnosis and treatment of atherosclerosis.
Assuntos
Anticorpos Monoclonais/farmacologia , Aterosclerose/tratamento farmacológico , Glicosaminoglicanos/antagonistas & inibidores , Proteínas Recombinantes de Fusão/farmacologia , Administração Intravenosa , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Combinação de Medicamentos , Imunofluorescência , Glicosaminoglicanos/metabolismo , Humanos , Masculino , Camundongos , Compostos de Organotecnécio , Fosfolipídeos , Coelhos , Radioimunodetecção/métodos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética , Sorbitol , Sulfatos/metabolismo , Tecnécio , Fatores de Tempo , Distribuição TecidualRESUMO
INTRODUCTION The availability of monoclonal antibodies in Cuba has facilitated development and application of innovative techniques (immunoscintigraphy and radioimmunotherapy) for cancer diagnosis and treatment. Objective Review immunoscintigraphy and radioimmunotherapy techniques and analyze their use in Cuba, based on the published literature. In this context, we describe the experience of Havana's Clinical Research Center with labeled monoclonal antibodies for cancer diagnosis and treatment during the period 1993-2013. EVIDENCE ACQUISITION Basic concepts concerning cancer and monoclonal antibodies were reviewed, as well as relevant international and Cuban data. Forty-nine documents were reviewed, among them 2 textbooks, 34 articles by Cuban authors and 13 by international authors. All works published by the Clinical Research Center from 1993 through 2013 were included. Bibliography was obtained from the library of the Clinical Research Center and Infomed, Cuba's national health telematics network, using the following keywords: monoclonal antibodies, immunoscintigraphy and radioimmunotherapy. RESULTS Labeling the antibodies (ior t3, ior t1, ior cea 1, ior egf/r3, ior c5, h-R3, 14F7 and rituximab) with radioactive isotopes was a basic line of research in Cuba and has fostered their use as diagnostic and therapeutic tools. The studies conducted demonstrated the good sensitivity and diagnostic precision of immunoscintigraphy for detecting various types of tumors (head and neck, ovarian, colon, breast, lymphoma, brain). Obtaining different radioimmune conjugates with radioactive isotopes such as 99mTc and 188Re made it possible to administer radioimmunotherapy to patients with several types of cancer (brain, lymphoma, breast). The objective of 60% of the clinical trials was to determine pharmacokinetics, internal dosimetry and adverse effects of monoclonal antibodies, as well as tumor response; there were few adverse effects, no damage to vital organs, and a positive tumor response in a substantial percentage of patients. CONCLUSIONS Cuba has experience with production and radiolabeling of monoclonal antibodies, which facilitates use of these agents. Studies in Cuba conducted by the Clinical Research Center over the past 20 years have yielded satisfactory results. Evidence obtained suggests promising potential of monoclonal antibodies and nuclear medicine, with immunoscintigraphy and radioimmunotherapy techniques providing alternatives for cancer diagnosis and treatment in Cuba.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/diagnóstico , Radioimunodetecção/métodos , Radioimunoterapia/métodos , Cuba , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapiaRESUMO
OBJECTIVES: The aim of this study was to assess the use of anti-CD3, labelled with technetium-99m scintigraphy, for evaluating the joints of patients with RA, juvenile idiopathic arthritis (JIA), OA and gouty arthritis, and to establish the diagnosis parameters for each disease. METHODS: We evaluated 2044 joints from 77 patients with rheumatic diseases. The clinical evaluation consisted of laboratory assays; examination for joint inflammation (pain and/or oedema); and for patients with RA, the disease activity score of 28 joints. To evaluate the sensitivity and specificity of 99mTc-anti-CD3 in detecting disease activity, patients received an injection of the radiopharmaceutical compound 99mTc-anti-CD3, and underwent a scintigraphy scan 1 h later. Scanning was repeated 3 h later. As a control, after 2 days, the patient was injected with 99mTc-non-specific human immunoglobulins, and scintigraphy scanning performed at 1 and 3 h after the injection. The intensity of uptake and the pattern of activity were defined, and Spearman's correlation and analysis of variance used for statistical evaluation. RESULTS: Diagnosis criteria were established for 99mTc-anti-CD3 uptake in different diseases. RA and JIA showed joint uptake with progressive increase in late images. Gouty arthritis showed joint uptake with decrease during the late images. Joint uptake was low or absent in patients with OA, although when present the joint uptake decreased during the examination. CONCLUSION: 99mTc-anti-CD3 scintigraphy is a useful method in the differential diagnosis of rheumatic diseases.
Assuntos
Complexo CD3/imunologia , Imunoconjugados , Radioimunodetecção/métodos , Compostos Radiofarmacêuticos , Doenças Reumáticas/diagnóstico , Índice de Gravidade de Doença , Tecnécio , Diagnóstico Diferencial , Humanos , Articulações , Doenças Reumáticas/diagnóstico por imagem , Doenças Reumáticas/fisiopatologiaRESUMO
Patient 28 years old has continued to have a persistent fever (39.2°C), despite ten days treatment by specific antibiotics for bacterial endocarditis associated to a recent claudication of the right lower leg. The persistent fever has motivated a 99mTc-labelled monoclonal anti granulocyte scan which has showed an important uptake in the myocardial septum, and other infection locations in temporal bone and in right tibial arteries. Two days after, a nanocolloids-99mTc WBS showed no uptake in the heart area, a total absence of uptake of the nanocolloids in the bone marrow of right tibia b and cranial SPECT views confirmed the infectious site in the right temporal bone. New antibiotic strategy was adopted successfully associated with surgical amputation of the right lower leg.
Assuntos
Masculino , Adulto , Humanos , Coração , Crânio , Endocardite Bacteriana , Endocardite Bacteriana/complicações , Ossos da Perna , Isquemia/microbiologia , Radioimunodetecção , Anticorpos Monoclonais , Compostos de Tecnécio , Coração/microbiologia , Crânio/microbiologia , Granulócitos , Ossos da Perna/microbiologiaRESUMO
The relevance of certain gangliosides in tumour growth and metastatic dissemination has been well documented, reasons for considering these molecules as potential targets for cancer immunotherapy and diagnosis. GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues according to immunohistochemical studies, using either polyclonal or monoclonal antibodies. But both immunohistochemical and biochemical methods have strongly suggested its over-expression in human breast tumours. Nevertheless, the lack of a direct evidence of this antigenic display in human breast cancer has kept the subject controversial. For the first time, we described herein the "in vivo" detection of GM3(NeuGc) ganglioside in human breast primary tumours using a radioimmunoscintigraphic technique with 14F7, a highly specific anti-GM3(NeuGc) ganglioside monoclonal antibody, labelled with (99m)Tc. In an open, prospective Phase I/II clinical trial, including women diagnosed in stage II breast cancer, the 14F7 monoclonal antibody accumulation in tumours at doses of 0.3 (n=5), 1 (n=5) and 3 mg (n=4) was evaluated. Noteworthy, the immunoscintigraphic study showed antibody accumulation in 100% of patients' tumours for the 1 mg dose group. In turn, the radioimmunoconjugate injected at doses of 0.3 mg or 3 mg of the antibody, was uptaken by 60 and 33.3% of breast tumours, respectively. "In vivo" immune recognition of GM3(NeuGc) in breast tumours reinforces the value of this peculiar target for cancer immunotherapy.
Assuntos
Anticorpos Monoclonais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Gangliosídeo G(M3)/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Radioimunodetecção , Tecnécio/administração & dosagemRESUMO
In the present paper we report the development of a bivalent scFv (single-chain Fv) antibody fragment, starting from a mouse mAb (monoclonal antibody) specific for CEA (carcinoembryonic antigen) that has received approval for in vivo radioimmunodiagnosis in humans. The diabody is well expressed in Escherichia coli, is easily purified by a combination of immobilized metal ion affinity chromatography and gel filtration and exhibits high affinity and specificity for CEA, comparable with those of the original mAb. Biodistribution experiments in athymic nude mice transplanted with human CEA+ cancer cells showed that the 125I-labelled diabody preferentially localizes in the tumour tissue and that retention is still high 48 h after injection. The diabody can be advantageous for some in vivo tumour targeting applications, due to the faster clearance derived from its smaller molecular mass.
Assuntos
Anticorpos Monoclonais/farmacocinética , Antígeno Carcinoembrionário/imunologia , Fragmentos de Imunoglobulinas/farmacologia , Neoplasias/metabolismo , Proteínas Recombinantes/farmacocinética , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Clonagem Molecular , Escherichia coli/genética , Feminino , Humanos , Fragmentos de Imunoglobulinas/química , Fragmentos de Imunoglobulinas/imunologia , Radioisótopos do Iodo , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Transplante de Neoplasias , Neoplasias/diagnóstico por imagem , Neoplasias/imunologia , Radioimunodetecção , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologiaRESUMO
Se presenta un estudio experimental que tiene por objetivo evaluar la sensibilidad y especificidad de la detección de solución de continuidad del tracto gastrointestinal con la utilización de partículas pesadas marcadas con Tecnecio 99. Se diseñó un estudio experimental prospectivo triple ciego, con un cálculo de tamaño de muestra teniendo en cuenta una sensibilidad y especificidad superiores al 95 por ciento, con un error alfa del 0.05 y una precisión de 0.05. Inicialmente se evaluaron 4 conejos de la raza Nueva Zelanda para determinar: el anestésico y la dosis a utilizar, la capacidad del estómago en mililitros; los tiempos promedios de tránsito gastrointestinal, la capacidad de la cavidad abdominal en mililitros y la biodistribución del radiofármaco (absorción gastrointestinal, diseminación y distribución hemática y eliminación renal). Se utilizaron 40 conejos de la raza Nueva Zelanda y se analizaron en tres estaciones de trabajo independientes, asignando aleatoriamente 20 conejos en cada grupo de estudio (perforados y no perforados). El radiofármaco utilizado fue Tecnecio 99 sulfuro coloidal > 100 nm, 2.5 mCi a 140 Kev de energía preparado en una dilución de solución salina al 0.9 por ciento quedando una concentración de 0.0025 mCi por mililitro. El rastreo se realizó con una sonda gamma a 10X. El análisis estadístico se realizó con el programa Episet V:1 aplicando la prueba de Chi Cuadrado.Todos los 20 conejos que tenían disrupción del estómago, presentaron una prueba positiva para detección de radioactividad en el líquido peritoneal analizado con un valor promedio de 467 y un rango de 37 a 1748. En los 20 conejos restantes que no tenían perforación de la pared gástrica la prueba fue negativa.La sensibilidad de la metodología diagnóstica fue de 0.98 y la especificidad de 0.98 con un intervalo...
Assuntos
Diagnóstico , Fístula do Sistema Digestório , Radioimunodetecção , Cintilografia , RadiocirurgiaRESUMO
AIM: To evaluate the biodistribution, internal radiation dosimetry and toxicity of the humanized MAb h-R3 labelled with Tc in humans. METHODS: Twenty-five patients with suspected epithelial-derived tumours were included in this study and divided into two groups: group I consisted of 10 patients who received 3 mg/1110 MBq (3 mg/30 mCi); and group II consisted of 15 patients who received 6 mg/2220 MBq (6 mg/60 mCi). Single photon emission computed tomography (SPECT) and planar images, and multiple blood and urine samples were collected up to 24 h after injection. Haematological parameters and adverse effects were classified according to the WHO criteria. Biodistribution, human anti-mouse antibody (HAMA) response and absorbed doses were estimated and reported. RESULTS: Liver, spleen, kidneys and heart were identified as source organs. Their higher uptakes were 53.3+/-6.4%ID, 2.0+/-1.4%ID, 9.8+/-4.3%ID and 2.8+/-0.9%ID, respectively. The urinary bladder and large intestine also had a significant uptake. The mean urinary excretion was around 22%ID. The liver received the highest absorbed doses followed by the kidneys and the urinary bladder wall. There were no haematological or biochemical abnormalities with clinical significance related to the product. No patient developed HAMA response. Preliminary analysis of clinical results showed a sensitivity of 76.5% and a specificity of 100%. CONCLUSIONS: The results of this study suggest that Tc-h-R3 could be used in patients in a safe and effective way, for the diagnosis of epithelial-derived tumours at the two evaluated dose levels.