RESUMO
PURPOSE: To evaluate total blood radioactivity (BR) after SIR-Spheres yttrium-90 (90Y) radioembolization and differences in BR based on delivery method. MATERIALS AND METHODS: Twenty participants with hepatic metastases undergoing first radioembolization were prospectively enrolled from December 2017 to June 2018. Blood samples were drawn at baseline and 0, 10, 20, 60, and 120 minutes after 90Y administration. BR was measured with a γ-counter and scaled by estimated blood volume. Percentage of instilled radioactivity in the bloodstream was calculated as area under the fitted curve, and differences between delivery methods were examined with nonparametric statistical tests. RESULTS: In 10 participants, resin microspheres were instilled with 50% Isovue 300 diluted in saline solution in the D line, and 10 others were treated with dextrose 5% in water (D5W) in the D line. Median administered activities were 944 MBq (range, 746-1,993 MBq) and 1,213 MBq (range, 519-2,066 MBq), respectively. Fraction of 90Y in blood was significantly higher with dilute contrast agent than with D5W (median, 0.5% of injected activity vs 0.2%; P = .001). Among all participants, the maximum activity delivered was 2,066 MBq, and a maximum of 1% of administered radioactivity was measured as free 90Y in blood. Assuming these highest-case values and complete decay of all free 90Y in bone, a dose to red marrow of 132.3 mGy was calculated by Organ Level INternal Dose Assessment/EXponential Modeling. CONCLUSIONS: Blood sampling after radioembolization allowed for estimation of the time-activity curve and BR. Delivery with 50% contrast agent in saline solution resulted in a significant increase in BR vs D5W, even though the total BR for both groups was nominal.
Assuntos
Embolização Terapêutica , Neoplasias Hepáticas/radioterapia , Doses de Radiação , Compostos Radiofarmacêuticos/administração & dosagem , Radioisótopos de Ítrio/administração & dosagem , Adulto , Idoso , Embolização Terapêutica/efeitos adversos , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/sangue , Fatores de Tempo , Resultado do Tratamento , Radioisótopos de Ítrio/efeitos adversos , Radioisótopos de Ítrio/sangueRESUMO
Finding improved therapeutic strategies against T-cell Non-Hodgkin's Lymphoma (NHL) remains an unmet clinical need. We implemented a theranostic approach employing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with 86Y for positron emission tomography (PET) imaging and 90Y for targeted radionuclide therapy (TRT) of T-cell NHL. PET imaging and biodistribution performed in mouse models of T-cell NHL showed in vivo selective tumor uptake and retention of 86Y-NM600. An initial toxicity assessment examining complete blood counts, blood chemistry, and histopathology of major organs established 90Y-NM600 safety. Mice bearing T-cell NHL tumors treated with 90Y-NM600 experienced tumor growth inhibition, extended survival, and a high degree of cure with immune memory toward tumor reestablishment. 90Y-NM600 treatment was also effective against disseminated tumors, improving survival and cure rates. Finally, we observed a key role for the adaptive immune system in potentiating a durable anti-tumor response to TRT, especially in the presence of microscopic disease.
Assuntos
Memória Imunológica/efeitos da radiação , Linfoma de Células T/radioterapia , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos de Ítrio/uso terapêutico , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Memória Imunológica/imunologia , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Distribuição Tecidual/imunologia , Distribuição Tecidual/efeitos da radiação , Carga Tumoral/imunologia , Carga Tumoral/efeitos da radiação , Proteína Tumoral 1 Controlada por Tradução , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/farmacocinéticaRESUMO
PURPOSE: To perform a detailed analysis of microsphere distribution in biopsy material from a patient treated with (90)Y-labeled resin spheres and characterize microsphere distribution in the hepatic artery tree, and to construct a novel dichotomous bifurcation model for microsphere deposits and evaluate its accuracy in simulating the observed microsphere deposits. METHODS AND MATERIALS: Our virtual model consisted of arteries that successively branched into 2 new generations of arteries at 20 nodes. The artery diameter exponentially decreased from the lowest generation to the highest generation. Three variable parameters were optimized to obtain concordance between simulations and measure microsphere distributions: an artery coefficient of variation (ACV) for the diameter of all artery generations and the microsphere flow distribution at the nodes; a hepatic tree distribution volume (HDV) for the artery tree; and an artery diameter reduction (ADR) parameter. The model was tested against previously measured activity concentrations in 84 biopsies from the liver of 1 patient. In 16 of 84 biopsies, the microsphere distribution regarding cluster size and localization in the artery tree was determined via light microscopy of 30-µm sections (mean concentration, 14 microspheres/mg; distributions divided into 3 groups with mean microsphere concentrations of 4.6, 14, and 28 microspheres/mg). RESULTS: Single spheres and small clusters were observed in terminal arterioles, whereas large clusters, up to 450 microspheres, were observed in larger arterioles. For 14 microspheres/mg, the optimized parameter values were ACV=0.35, HDV = 50 cm(3), and ADR=6 µm. For 4.6 microspheres/mg, ACV and ADR decreased to 0.26 and 0 µm, respectively, whereas HDV increased to 130 cm(3). The opposite trend was observed for 28 microspheres/mg: ACV = 0.49, HDV = 20 cm(3), and ADR = 8 µm. CONCLUSION: Simulations and measurements reveal that microsphere clusters are larger and more common in volumes with high microsphere concentrations and indicate that the spatial distribution of the artery tree must be considered in estimates of microsphere distributions.
Assuntos
Artéria Hepática/fisiologia , Fígado/irrigação sanguínea , Fígado/metabolismo , Microesferas , Modelos Cardiovasculares , Radioisótopos de Ítrio/sangue , Velocidade do Fluxo Sanguíneo/fisiologia , Simulação por Computador , Humanos , Infusões Intra-Arteriais/métodos , Tamanho da Partícula , Doses de Radiação , Distribuição Tecidual , Radioisótopos de Ítrio/administração & dosagemRESUMO
INTRODUCTION: Radioimmunotherapy (RIT) with 90Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of 111In labeled anti-CD66 antibody. Equal pre-therapeutic and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients. AIMS: The aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetry in 90Y-labeled anti-CD66 RIT, 2) that pre-therapeutic and therapeutic biodistributions differ, and most importantly 3) that this difference in biodistributions can be accurately predicted using a refined model. MATERIALS AND METHODS: Two new PBPK models were developed considering fully, half and non-immunoreactive antibodies and constraints for estimating the RM antigen number. Both models were fitted to gamma camera and serum measurements of 27 patients. Akaike weights were used for model averaging. Time-integrated activity coefficients for total body, liver, spleen, RM and serum were calculated. Model-based predictions of the serum biokinetics during therapy were compared to actual measurements. RESULTS: Variability of the RM time-integrated activity coefficients ((37.3 ± 7.5) h) indicates the need for patient-specific dosimetry. The relative differences between pre-therapeutic and therapeutic serum time-activity curves were (-25 ± 16)%. The prediction accuracy of these differences using the refined PBPK models was (-3 ± 20)%. CONCLUSION: Individual treatment is needed due to biological differences between patients in RIT with 90Y-labeled anti-CD66 antibody. Differences in pre-therapeutic and therapeutic biokinetics are predominantly caused by different degrees of saturation due to different amounts of administered antibody. These differences could be predicted using the PBPK models.
Assuntos
Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Marcação por Isótopo , Leucemia/radioterapia , Modelos Biológicos , Radioimunoterapia , Radioisótopos de Ítrio/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Humanos , Fatores de Tempo , Distribuição Tecidual , Radioisótopos de Ítrio/sangueRESUMO
BACKGROUND: CC49, an antibody (mAb) reactive to tumor-associated glycoprotein (TAG-72), has been extensively studied for radioimmunotherapy for colon cancer. Myelotoxicity has been dose-limiting because of prolonged circulation time in the plasma, and human anti-mouse antibody responses were observed in the majority of patients. A CH2 domain deleted and humanized CC49 (HuCC49ΔCh2) was developed to ameliorate these problems. This study reports biodistribution and dosimetry of (111)In/(90)Y-HuCC49ΔCh2 (IDEC-159). MATERIALS AND METHODS: Five (5) patients with colon cancer were enrolled. Each patient received intravenous administration of 185 MBq (111)In-HuCC49ΔCh2, followed by sequential gamma camera imaging, and blood counting. Uptakes and clearance half-lives for organs and tumors were quantified from images. Absorbed doses for (90)Y-HuCC49ΔCh2 were derived from (111)In-HuCC49ΔCh2 kinetic data. RESULTS: Compared to reported (111)In/(90)Y-CC49 data in the literature, median blood circulation T(1/2ß) was less at 38 (31-43) hours for (90)Y-HuCC49ΔCh2, than 50 hours for (90)Y-CC49. Median tumor-to-marrow absorbed dose ratio was 18 for (90)Y-HuCC49ΔCh2, and 9.53 for (90)Y-CC49. Median tumor-to-liver absorbed dose ratio was 3.14 for (90)Y-HuCC49ΔCh2, and 1.0 for (90)Y-CC49. Median tumor-to-spleen absorbed dose was 3.19 for (90)Y-HuCC49ΔCh2, and 1.07 for (90)Y-CC49. CONCLUSIONS: A humanized and CH2 domain-deleted CC49 antibody radiolabeled with (111)In/(90)Y showed improved tumor-to-normal dose ratios over those reported from studies with intact CC49.
Assuntos
Adenocarcinoma/radioterapia , Neoplasias Colorretais/radioterapia , Imunotoxinas/farmacocinética , Radioisótopos de Índio/administração & dosagem , Radioisótopos de Índio/farmacocinética , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/farmacocinética , Adenocarcinoma/sangue , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Antineoplásicos/administração & dosagem , Anticorpos Antineoplásicos/imunologia , Anticorpos Antineoplásicos/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/imunologia , Radioisótopos de Índio/sangue , Masculino , Radioimunoterapia/métodos , Radiometria/métodos , Cintilografia/métodos , Distribuição Tecidual , Radioisótopos de Ítrio/sangueRESUMO
UNLABELLED: Radioimmunotherapy (RIT) is a new and effective treatment modality in patients with non-Hodgkin's lymphoma. The monoclonal antibody (mAb) hLL2 (epratuzumab), a humanized mAb directed against the CD22 antigen, and which internalizes, can be labeled with various radionuclides. The biodistribution of hLL2 labeled with (131)I, (186)Re, (177)Lu, and (88)Y was studied in nude mice with subcutaneous human lymphoma xenografts in order to determine the most suitable of these four radionuclides for RIT with hLL2. METHODS: Human Ramos lymphoma xenografts were transplanted in cyclophosphamide-pretreated athymic BALB/c mice. Four groups of mice were injected intravenously with (131)I-, (186)Re-, (88)Y-, or (177)Lu-labeled hLL2, respectively. To determine the nonspecific tumor uptake, two groups of mice received (88)Y-labeled or (131)I-labeled control antibody, cG250. The biodistribution of the radiolabel was determined 1, 3, and 7 days postinjection (p.i.). RESULTS: Radiolabeled hLL2 had a higher tumor uptake than the nonspecific mAb at all time-points, irrespective of the radiolabel used. Tumor accretion of (88)Y- and (177)Lu-hLL2 was higher than tumor uptake of (131)I- and (186)Re-hLL2. Activity in the bone, represented by the femur without bone marrow, was higher for (177)Lu- and (88)Y-hLL2 than for (131)I- and (186)Re-hLL2 on day 7 p.i. CONCLUSION: The use of the residualizing radiolabels (88)Y and (177)Lu in combination with a mAb directed against an internalizing antigen resulted in higher uptake and better retention of the radiolabel in the tumor.
Assuntos
Anticorpos Monoclonais/farmacocinética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Moléculas de Adesão Celular , Lectinas/imunologia , Linfoma/radioterapia , Radioimunoterapia , Radioisótopos/farmacocinética , Análise de Variância , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Duodeno/metabolismo , Feminino , Fêmur/metabolismo , Humanos , Radioisótopos do Iodo/sangue , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Lutécio/sangue , Lutécio/farmacocinética , Linfoma/química , Linfoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Músculos/metabolismo , Transplante de Neoplasias , Neoplasias/metabolismo , Radioisótopos/sangue , Radioisótopos/uso terapêutico , Rênio/sangue , Rênio/farmacocinética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Baço/metabolismo , Fatores de Tempo , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/farmacocinética , Radioisótopos de Ítrio/uso terapêuticoRESUMO
Ethiodol (or lipiodol) is selectively retained in hepatocellular carcinoma and is used as a vehicle to deliver radioactive agents following intraarterial hepatic infusion. We prepared the lipophilic complex 90Y-oxine with a radiolabeling efficiency of 97.6+/-1.1%. After extraction into ethiodol, a stability test in serum at 37 degrees C showed that 87.8% of the 90Y remained ethiodol-bound for 7 days. Bremsstrahlung imaging of a rabbit for 48 h confirmed that the homogeneous mixture of radiolabeled 90Y-oxine and ethiodol stayed in the targeted liver lobe. This radiopharmaceutical is thus a potential candidate for the treatment of non-resectable liver cancer.
Assuntos
Óleo Etiodado/química , Neoplasias Hepáticas Experimentais/radioterapia , Oxiquinolina/química , Compostos Radiofarmacêuticos/uso terapêutico , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/química , Angiografia , Animais , Cromatografia em Camada Fina , Estabilidade de Medicamentos , Óleo Etiodado/administração & dosagem , Óleo Etiodado/farmacocinética , Artéria Hepática , Radioisótopos de Índio/química , Injeções Intra-Arteriais , Marcação por Isótopo/métodos , Fígado/diagnóstico por imagem , Especificidade de Órgãos , Oxiquinolina/administração & dosagem , Oxiquinolina/sangue , Oxiquinolina/farmacocinética , Coelhos , Cintilografia , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/farmacocinéticaRESUMO
The pharmacokinetics and dosimetry of (86)Y-DOTA(0)- d-Phe(1)-Tyr(3)-octreotide ((86)Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of (86)Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. (86)Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly ( P<0.05) reduced (86)Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3+/-1.3 vs 4.4+/-1.0 mGy/MBq; P<0.05) and was further enhanced upon prolonging the infusion to 10 h (2.1+/-0.4 vs 1.7+/-0.2 mGy/MBq; P<0.05). Infusion of Lys-Arg but not of l-lysine was more effective in reducing renal uptake than mixed AA. Infusion of AA did not result in reduced tumour uptake. The amount of (90)Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10-114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9-37%; P<0.05) with prolonged infusion and by a mean of 16% (2-28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys.
Assuntos
Aminoácidos/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Tumores Neuroendócrinos/metabolismo , Octreotida/análogos & derivados , Octreotida/farmacocinética , Radiometria/métodos , Radioisótopos de Ítrio/farmacocinética , Adulto , Idoso , Aminoácidos/efeitos adversos , Arginina/administração & dosagem , Estudos de Coortes , Estudos Cross-Over , Tontura/etiologia , Combinação de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Lisina/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/efeitos adversos , Octreotida/sangue , Octreotida/urina , Especificidade de Órgãos , Doses de Radiação , Lesões por Radiação/etiologia , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão , Vômito/etiologia , Radioisótopos de Ítrio/efeitos adversos , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/urinaRESUMO
BACKGROUND: Radioimmunotherapy (RIT) is a new therapeutic modality capable of systemic delivery of radionuclides specifically to sites of metastatic cancer. The L6 monoclonal antibody has been shown to target prostate cancer in preclinical studies and, along with chimeric L6 (ChL6), has been used for RIT in breast cancer patients. METHODS: Pharmacokinetics, blood counts, body weight, and antitumor activity of RIT with (90)yttrium-((90)Y)-DOTA-peptide-ChL6 (75-260 microCi) were determined in nude mice bearing human prostate cancer (PC3) xenografts. RESULTS: RIT produced durable, dose-dependent antitumor effects with a 100% response rate using 112 microCi and 150 microCi (the maximum tolerated dose) of (90)Y-DOTA-peptide-ChL6. Myelotoxicity was reversible, dose-limiting, and dose-related. RIT was associated with improved survival (P = 0.05). All 5 mice in the 150-microCi group survived the 84-day study period vs. 1/8 (13%) for untreated, tumored control mice. CONCLUSIONS: (90)Y-DOTA-peptide-ChL6 targets PC3 human prostate cancer xenografts in nude mice and has an antitumor effect. These results provide a basis for future RIT trials for patients with metastatic prostate cancer.
Assuntos
Compostos Heterocíclicos/uso terapêutico , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/radioterapia , Radioimunoterapia/normas , Compostos Radiofarmacêuticos/uso terapêutico , Ítrio/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Peso Corporal , Relação Dose-Resposta à Radiação , Feminino , Compostos Heterocíclicos/sangue , Compostos Heterocíclicos/farmacocinética , Humanos , Contagem de Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Contagem de Plaquetas , Radioimunoterapia/efeitos adversos , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Organismos Livres de Patógenos Específicos , Células Tumorais Cultivadas , Contagem Corporal Total , Ítrio/sangue , Ítrio/farmacocinética , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/farmacocinética , Radioisótopos de Ítrio/uso terapêuticoRESUMO
Intrapatient variation in the biodistribution of the chimeric monoclonal antibody cT84.66 was assessed in 19 patients having a variety of carcinoembryonic antigen (CEA) positive tumors. The two studies, including whole-body imaging and blood and urine specimen collections, were conducted within 14 days of each other using (111)In-cT84.66 at a fixed total protein dose of 5 mg per patient per study. An initial pretherapy infusion of (111)In-cT84.66 was administered followed by a therapy coinfusion of (111)In-ct84.66 and 90Y-cT84.66 A closed five-compartment model was used to integrate source organ activity curves as residence time inputs into the MIRDOSE3 program. Normal organ absorbed doses were estimated for 90Y-cT84.66, the corresponding radiotherapeutic agent. For the two (111)In-cT84.66 biodistributions, all data were modeled with a R2 value of between 0.72 and 1.00 with the exception of the urine data taken during therapy. This was due to the need of diethylenetriaminepentaacetic acid during the therapy phase because of the possibility that yttrium might escape from the chelator attached to the antibody. With the assurance that the biodistributions were reproducible, we were able to estimate the 90Y-cT84.66 absorbed doses on a per-patient basis. Concordance coefficients showing the agreement between the imaging and therapy phase dose estimates were between the 0.60 and 0.99 levels for liver, spleen, red marrow, total body, and other organ systems. Median results were: 27, 17, and 2.7 rad/mCi of 90Y-cT84.66 for liver, spleen, and red marrow, respectively. Because of decreases in platelets and white cells as the amount of 90Y was increased, dose-limiting toxicity was found at 22 mCi/m2. We conclude that patient biodistributions were consistent over time to 14 days so as to allow absorbed dose estimation in a radioimmunotherapy trial involving the cT84.66 anti-CEA antibody.
Assuntos
Radioimunoterapia/métodos , Planejamento da Radioterapia Assistida por Computador , Radioisótopos de Ítrio/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Radioisótopos de Índio/sangue , Radioisótopos de Índio/urina , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Tempo , Distribuição Tecidual , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/urinaRESUMO
Three-step pretargeting for radioimmunotherapy in BALB/c mice with KHJJ tumors was done with monoclonal antibody (mAb) 2D12.5, which is specific for yttrium-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) but nonspecific for the tumor. Tumor uptake was by passive diffusion of mAb through leaky neovasculature in the tumor. The three steps were: (a) anti-hapten mAb 2D12.5 (0 h); (b) polyvalent haptenprotein conjugate chase (20 h); and (c) 88Y-labeled monovalent DOTA or bivalent Janus-DOTA haptens (21 h) and organ and tumor bioassay (24 h). Rapid tumor (T) uptake and high tumor:blood ratio (T:BL) was seen 3 h after injection after step c. For monovalent 88Y-DOTA, T = 1.7%/g* and T:BL = 16:1; for bivalent 88Y-Janus-DOTA, T = 4.41%/g* and T:BL = 21:1 at 3 h (*, P < 0.001). Blood and bone plus marrow were << 1%/g, and liver was < 1%/g. The 24-h whole body retention was approximately 5% of injected dose with 1% in tumor (20% of total), 1.8% in other organs, and 2.2% in carcass; the 24-h whole body retention of covalent nonspecific antibody conjugates was > 80% of injected dose. The biological half-life in the tumor of 0.9 microCi 88Y-Janus-DOTA was approximately 24 h, measured daily for 5 days. Activity in microCi/g of tumor and blood for 90Y equimolar to the amount of 88Y injected (0.9 microCi 88Y = 0.744 pmol = 36.47 microCi 90Y) was used for calculating the area under the curve of tumor and blood in microCi-h/g of 90Y. The 90Y radiation absorbed dose (RAD) from multiplying microCi-h/g x the 90Y absorbed dose constant, 1.99 RAD-g/microCi-h, gave T = 89 RAD and BL = 3.7 RAD. The therapeutic ratio from RAD T:RAD BL = 24:1. These results indicate that pretargeting 90Y hapten-specific mAb for radioimmunotherapy has considerable promise.
Assuntos
Acetatos/farmacocinética , Anticorpos Monoclonais/farmacocinética , Compostos Heterocíclicos/farmacocinética , Neoplasias Mamárias Experimentais/metabolismo , Radioimunoterapia/métodos , Radioisótopos de Ítrio/farmacocinética , Acetatos/sangue , Animais , Anticorpos Monoclonais/sangue , Meia-Vida , Compostos Heterocíclicos/sangue , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/radioterapia , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Tecidual , Radioisótopos de Ítrio/sangueRESUMO
B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation.
Assuntos
Anticorpos Monoclonais , Radioisótopos de Índio/farmacocinética , Oligopeptídeos/farmacocinética , Ácido Pentético/análogos & derivados , Radioisótopos de Ítrio/farmacocinética , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Cães , Feminino , Humanos , Radioisótopos de Índio/administração & dosagem , Radioisótopos de Índio/sangue , Radioisótopos de Índio/toxicidade , Infusões Intravenosas , Masculino , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Oligopeptídeos/toxicidade , Ácido Pentético/administração & dosagem , Ácido Pentético/farmacocinética , Ácido Pentético/toxicidade , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/sangue , Radioisótopos de Ítrio/toxicidadeRESUMO
Resin particles (diameter 45-75 microns) were labelled with 90Y, suspended in a glucose/dextran solution and infused into the kidneys of 3-month-old pigs (tumour model). Both kidneys of each animal were embolized with particles, but only one with active (90Y loaded) particles and the other, for comparison, with inactive particles. The organ measurements showed less than 1% of injected activity in bone, bone marrow, liver and lung compared to greater than 99% retention by the kidneys. Only minimal shunted activity was found in blood (less than 0.27%) and urine (less than 0.07%). There was a clear shrinkage of the 90Y-treated kidneys with a reduction in weight of up to 50%. Histologically, the ischaemic lesions (infarcts and atrophy) were clearly more pronounced and extensive in the 90Y-embolized kidneys than in the non-radioactive embolized kidneys. Furthermore, severe arterial wall changes and fibrotic necrosis due to radiation damage were observed in the 90Y-treated kidneys. It is concluded that with intra-arterially applied particles a dose of about 100 Gy is sufficient to completely destroy tissue-specific structures. Complications due to acute necrosis or inflammatory reactions were not observed, and there were no shunt related alterations seen in the liver or lungs. The 90Y-loaded resin particles are considered suitable for a super selective intra-arterial radioembolization.