RESUMEN
UNLABELLED: Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (111In/90Y-2IT-BAD-Lym-1). METHODS: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111In- and 90Y-2IT-BAD-Lym-1; 111In was used as a surrogate tracer for 90Y, which emits no gamma-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111In in organs and tumors. RESULTS: Metabolites and complexes were observed in the plasma of every patient who received 111In-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111In in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111In-2IT-BAD-m170, 91% and 94% of 111In in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111In/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. CONCLUSION: Metabolites of 111In/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111In/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/radioterapia , Adulto , Anciano , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Radioisótopos de Indio/metabolismo , Masculino , Persona de Mediana Edad , Radioinmunoterapia , Dosificación Radioterapéutica , Radioisótopos de Itrio/metabolismoRESUMEN
PURPOSE: Over 31,000 Americans die of androgen-independent metastatic prostate cancer each year. New strategies that do not involve hormonal manipulation but instead recognize the biochemical and molecular characteristics of prostate cancer are needed. Radioimmunotherapy (RIT) uses a tumor-specific monoclonal antibody to deliver systemic, targeted radiation to cancer. The objectives of this Phase I study of (111)In-2IT-BAD-m170 (for imaging) and (90)Y-2IT-BAD-m170 (for therapy) were to determine the toxicity and maximum tolerated dose (MTD), the specificity for targeting metastatic prostate cancer, and the efficacy for palliation of pain. EXPERIMENTAL DESIGN: M170 is a mouse monoclonal antibody that targets adenocarcinomas. Patients with adequate renal and liver function, rising prostate-specific antigen, and androgen-independent metastatic prostate cancer were eligible. After estimation of dosimetry and pharmacokinetics with (111)In-2IT-BAD-m170, a single dose of (90)Y-2IT-BAD-m170 (0.185, 0.370, 0.555, or 0.740 GBq/m(2)) was administered to cohorts of three patients. Pain was assessed objectively by questionnaires before and for 8 weeks after RIT; weekly prostate-specific antigen levels were obtained for 2 months after RIT. RESULTS: The MTD of (90)Y-2IT-BAD-m170 was 0.740 GBq/m(2) for patients that had up to 10% of the axial skeleton involved with prostate cancer. Toxicity was almost exclusively confined to reversible myelosuppression. Metastatic prostate cancer was targeted by (111)In-2IT-BAD-m170 in all 17 patients. The mean radiation dose delivered to 39 bone and 18 nodal metastases by (90)Y-2IT-BAD-m170 was 10.5 Gy/GBq (range 2.8-25.1). Thirteen of 17 patients reported pain before (90)Y-2IT-BAD-m170; 7 of these 13 had a partial or complete resolution of pain that lasted an average of 4.3 weeks. CONCLUSIONS: This study determined the MTD of (111)In/(90)Y-2IT-BAD-m170 in patients with metastatic prostate cancer. The drugs were well tolerated, targeted metastases, and temporarily palliated pain.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Terapia Combinada , Radioisótopos de Indio , Neoplasias de la Próstata/terapia , Radioinmunoterapia , Radioisótopos de Itrio/uso terapéutico , Adenocarcinoma/terapia , Anciano , Animales , Anticuerpos Monoclonales/farmacocinética , Estudios de Cohortes , Humanos , Radioisótopos de Indio/farmacocinética , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Dolor/tratamiento farmacológico , Antígeno Prostático Específico/biosíntesis , Radiometría , Factores de Tiempo , Resultado del Tratamiento , Radioisótopos de Itrio/farmacocinéticaRESUMEN
Radioimmunotherapy of cancer utilizes anti-tumor antibodies or antibody fragments conjugated to radionuclides to deliver radiation selectively to tumors. However, radiolabeled proteins deposit radioactivity in normal organs that metabolize or conserve proteins and peptides, primarily liver and kidneys. To accelerate the clearance of radioactivity from normal tissues, linkers between the antibody or antibody fragment and the radioactive moiety have been designed for cleavage in the liver and kidneys, to liberate low molecular weight radioactive species for rapid excretion. Modest success in improving the tumor-to-liver and tumor-to-kidney radiation dose ratios have been achieved in preclinical studies. Such changes when taken to clinical studies have suggested useful impact on therapeutic work. Recent advances in the development of cleavable linkers are described.
Asunto(s)
Inmunoconjugados/farmacocinética , Neoplasias/terapia , Radioinmunoterapia , Radiofármacos/farmacocinética , Animales , Reactivos de Enlaces Cruzados , Humanos , Inmunoconjugados/química , Riñón/metabolismo , Hígado/metabolismo , Tasa de Depuración Metabólica , Radiofármacos/químicaRESUMEN
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.
Asunto(s)
Compuestos Heterocíclicos/uso terapéutico , Oligopéptidos/uso terapéutico , Neoplasias de la Próstata/radioterapia , Radioinmunoterapia/normas , Radiofármacos/uso terapéutico , Itrio/uso terapéutico , Animales , Anticuerpos Monoclonales/uso terapéutico , Peso Corporal , Relación Dosis-Respuesta en la Radiación , Femenino , Compuestos Heterocíclicos/sangre , Compuestos Heterocíclicos/farmacocinética , Humanos , Recuento de Leucocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oligopéptidos/sangre , Oligopéptidos/farmacocinética , Recuento de Plaquetas , Radioinmunoterapia/efectos adversos , Radiofármacos/sangre , Radiofármacos/farmacocinética , Organismos Libres de Patógenos Específicos , Células Tumorales Cultivadas , Recuento Corporal Total , Itrio/sangre , Itrio/farmacocinética , Radioisótopos de Itrio/sangre , Radioisótopos de Itrio/farmacocinética , Radioisótopos de Itrio/uso terapéuticoRESUMEN
UNLABELLED: Several monoclonal antibodies, including Lym-1, have proven effective for treatment of hematologic malignancies. Lym-1, which preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma (NHL) when labeled with 131. Because radiometal-labeled monoclonal antibodies provide higher tumor radiation doses than corresponding 131I-labeled monoclonal antibodies, the radiation dosimetry of 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyc lododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (90Y-21T-BAD-Lym-1) is of importance because of its potential for radioimmunotherapy. Although 90Y has attractive properties for therapy, its secondary bremsstrahlung is less suitable for imaging and pharmacokinetic studies in patients. Thus, the pharmacokinetic data obtained for 111In-21T-BAD-Lym-1 in patients with NHL were used to calculate dosimetry for 90SY-21T-BAD-Lym-1. METHODS: Thirteen patients with advanced-stage NHLwere given a preload dose of unmodified Lym-1 followed by an imaging dose of 111In-21T-BAD-Lym-1. Sequential imaging and blood and urine samples obtained for up to 10 d after infusion were used to assess pharmacokinetics. Using 111In pharmacokinetic data and 90Y physical constants, radiation dosimetry for 90Y-21T-BAD-Lym-1 was determined. RESULTS: The uptake of 111In-21T-BAD-Lym-1 in tumors was greater than uptakes in the lung and kidney but similar to uptakes in the liver and spleen. The biologic half-time in tumors was greater than in lungs. The mean radiation dose to tumors was 6.57 +/- 3.18 Gy/GBq. The mean tumor-to-marrow (from blood) radiation ratio was 66:1, tumor-to-total body was 13:1, and tumor-to-liver was 1:1. Images of 111In were of excellent quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 3 patients. CONCLUSION: Because of the long residence time of 111In-2IT-BAD-Lym-1 in tumors, high 90Y therapeutic ratios (tumor-to-tissue radiation dose) were achieved for some tissues, but the liver also showed high uptake and retention of the radiometal.
Asunto(s)
Radioisótopos de Indio/uso terapéutico , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia , Radioisótopos de Itrio/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosificación RadioterapéuticaRESUMEN
UNLABELLED: Preliminary evaluations of 125I-labeled Lym-1, an anti-lymphoma mouse IgG2a monoclonal antibody, demonstrated favorable tumor uptake in mice bearing human Burkitt's lymphoma (Raji) tumors. In this study, the pharmacokinetics of 125I- and 131I-Lym-1, and the dosimetry, efficacy, and toxicity of 131I-Lym-1 in Raji-tumored mice were evaluated. METHODS: Lym-1 was radioiodinated by the chloramine-T method and analyzed for monomeric fraction and immunoreactivity (antigen cell binding, relative to unmodified Lym-1). Nude mice bearing Raji tumors (20-500 mm3) received 1.5 MBq (40 microCi) 125I-Lym-1, or 1.5, 7.4, 14.8, or 18.5 MBq (40, 200, 400, or 500 microCi) 131I-Lym-1. Pharmacokinetic data (total body and blood clearance and biodistribution) were used to estimate radiation dosimetry. Mini-thermoluminescent dosimetry (TLD) was also used to measure radiation dosimetry directly for 7 days after injection of 131I-Lym-1. Tumor size, survival, body weight, and blood counts were monitored for 60 days to evaluate therapeutic efficacy and toxicity of 131I-Lym-1. RESULTS: At the time of injection, the mean quality assurance (QA) values for 125I-Lym-1 were 100% monomer and 100% relative immunoreactivity; the corresponding values for 131I-Lym-1 were 73% and 66%, indicating that radiolysis had occurred during the interval between radiolabeling and injection. 125I-Lym-1 exhibited high and sustained concentration in tumors relative to normal organs, whereas 131I-Lym-1 did not. Assuming identical pharmacokinetic behavior to 125I-Lym-1, 131I-Lym-1 would deliver radiation doses of 3.45, 0.83, 1.03, 0.34, and 0.56 Gy per MBq injected (12.8, 3.1, 3.8, 1.3, and 2.1 rad/microCi), to tumor, liver, lungs, total body, and marrow, respectively. When the actual pharmacokinetic data for 131I-Lym-1 (1.5 MBq) were used to estimate dosimetry, corresponding values of 0.51, 0.72, 0.49, 0.31, and 0.41 Gy/MBq (1.9, 2.7, 1.8, 1.1, and 1.5 rad/microCi) were obtained. Similar values were obtained for mice receiving 7.4 or 14.8 MBq of 131I-Lym-1. Similarly, TLD data indicated little preferential radiation dosimetry to tumor. Response rates (cure + CR + PR) for mice receiving 0, 7.4, 14.8, and 18.5 MBq of 131I-Lym-1 were 8%, 7%, 21%, and 45%, respectively. The LD50/30 dose of 131I-Lym-1 was 12.7 MBq (343 microCi). CONCLUSIONS: 125I-Lym-1 exhibited high and sustained concentration in Raji tumors in mice, indicating excellent therapeutic potential for 131I-Lym-1. However, in vitro QA results for 131I-Lym-1 indicated that radiolysis had occurred, and 131I-Lym-1 demonstrated little accumulation in tumor, or preferential radiation dosimetry to tumor in the same model.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Especificidad de Anticuerpos/efectos de la radiación , Linfoma de Burkitt/metabolismo , Radioisótopos de Yodo/farmacocinética , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Linfoma de Burkitt/radioterapia , Niño , Femenino , Humanos , Radioisótopos de Yodo/inmunología , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Control de Calidad , Dosis de Radiación , Radioinmunoterapia , Dosificación Radioterapéutica , Análisis de Supervivencia , Células Tumorales CultivadasRESUMEN
BACKGROUND: Prior clinical trials proved that all histologic grades of chemotherapy-resistant B-cell non-Hodgkin's lymphoma (NHL) could respond to radio-immunotherapy (RIT) with 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1. This Phase I study was conducted to determine the safety and maximum tolerated dose (MTD) of 90Y-2IT-BAD-Lym-1. METHODS: Lym-1 is a mouse monoclonal antibody that preferentially targets malignant B-lymphocytes. 90Y has beta emissions suitable for therapy but no gamma emissions, therefore, 111In-2IT-BAD-Lym-1 is used for imaging. The macrocyclic chelator, DOTA, bound 90Y tightly to form a stable drug. Patients with chemotherapy-resistant NHL received 90Y-2IT-BAD-Lym-1 at administered doses of: 0.185, 0.278, or 0.370 GBq/m2. RESULTS: Myelotoxicity, especially thrombocytopenia, was dose-limiting. No significant non-hematologic toxicity occurred. Human anti-mouse antibody (HAMA) developed in 3/8 patients. The mean radiation dose to the 33 imaged tumors was 7.0 Gy/GBq. Lung, kidney and liver received mean radiation doses of 1.3, 2.4, and 6.4 Gy/GBq, respectively from 90Y-2IT-BAD-Lym-1. The tumor: body and tumor:bone marrow (by imaging) ratios were 16.4:1 and 5.8:1, respectively. In this Phase I study, 5/8 patients that failed prior chemotherapy had a partial response or stabilization of NHL after RIT. CONCLUSION: The safety and toxicity of 90Y-2IT-BAD-Lym-1 were determined and the MTD was 0.370 GBq/m2, a dose used in 4 patients. 90Y-2IT-BAD-Lym-1 may be useful for future clinical trials because 90Y is readily available and can deliver potent beta emissions to NHL. Bone marrow support however, will be required for further dose escalation.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia/efectos adversos , Radioisótopos de Itrio/efectos adversos , Adulto , Anciano , Animales , Anticuerpos Heterófilos/sangre , Femenino , Humanos , Linfoma no Hodgkin/diagnóstico por imagen , Masculino , Ratones , Persona de Mediana Edad , Selección de Paciente , Cintigrafía , Dosificación Radioterapéutica , Seguridad , Trombocitopenia/etiologíaRESUMEN
Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ((67)Cu), iodine-131 ((131)I), or yttrium-90 ((90)Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although (131)I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using (67)Cu-2IT-BAT-Lym-1, (131)I-Lym-1, or (111)In-2IT-BAD-Lym-1. Because (90)Y does not have good emissions for imaging, indium-111 ((111)In), its analogue, was used as a surrogate to estimate (90)Y-2IT-BAD-Lym-1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received (67)Cu- and (131)I-labeled Lym-1 or (111)In- and (131)I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. (67)Cu-2IT-BAT-Lym-1 and (90)Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did (131)I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for (67)Cu-2IT-BAT-Lym-1, (131)I-Lym-1, and (90)Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from (67)Cu-2IT-BAT-Lym-1, (131)I-Lym-1, and (90)Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because (90)Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from (67)Cu-2IT-BAT-Lym-1 and (131)I-Lym-1 to normal tissues were similar except that the liver received a higher dose from (67)Cu-2IT-BAT-Lym-1 than from (131)I-Lym-1; radiation doses to normal tissues from (90)Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for (67)Cu-2IT-BAT-Lym-1, and less generally for (90)Y-2IT-BAD-Lym-1, were more favorable when compared to those for (131)I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. (67)Cu-2IT-BAT-Lym-1 showed more potential than (131)I-Lym-1 or (90)Y-2IT-BAD-Lym-1 for non-Hodgkin's lymphoma radioimmunotherapy.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Compuestos Heterocíclicos/farmacocinética , Radioisótopos de Yodo/farmacocinética , Linfoma no Hodgkin/metabolismo , Compuestos Organometálicos/farmacocinética , Radioisótopos de Itrio/farmacocinética , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/uso terapéutico , Femenino , Compuestos Heterocíclicos/uso terapéutico , Humanos , Radioisótopos de Yodo/uso terapéutico , Linfoma no Hodgkin/radioterapia , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Radioinmunoterapia , Dosificación Radioterapéutica , Radioisótopos de Itrio/uso terapéuticoRESUMEN
Radioimmunoconjugates of 170H.82 (m170), a panadenocarcinoma monoclonal antibody, are effective for imaging primary and metastatic breast cancer. To evaluate m170 as a targeting agent for therapy, we developed (111)In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-m170 immunoconjugates with 99% purity by molecular sieving and immunoreactivity comparable to unmodified antibody. (111)In-m170 pharmacokinetic studies were performed prior to each therapy to determine the maximum dose of 90Y-m170 that could be administered without exceeding a limit of 800 rad to the liver, lungs, or kidneys or 250 rad to the whole body or bone marrow for each of three cycles of treatment. Peripheral blood stem cells (PBSCs) were harvested and cyclosporin A (5 mg/kg twice daily) was administered as strategies to ameliorate myelosuppression and prevent the development of HAMA, respectively. An (111)In imaging/pharmacokinetic study was performed, and the 90Y dose was calculated and administered. The liver was the 90Y dose-limiting organ. The mean and range of calculated doses (in rad/mCi) for the five patients evaluated were as follows: whole body, 2.3 (2.1-2.4); liver, 17.8 (12.7-22.2); lung, 6.4 (4.8-7.2); kidney, 6.9 (6.3-11.5); marrow, 3.6 (1.9-4.4); and tumors (n = 25), 71.5 (14.1-141.5). Of the three patients treated, with doses of 37, 54, and 57 mCi of 90Y, one had a partial response, one had measurable tumor reduction but less than a partial response, and one had stable disease for more than 1 month. PBSCs prevented prolonged myelosuppression. The therapeutic responses, coupled with an absence, thus far, of significant adverse sequelae, suggest that this dosimetry-based approach combined with PBSCs may lead to effective therapy when higher 90Y doses are reached.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/terapia , Ciclosporina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Radioinmunoterapia , Dosificación Radioterapéutica , Radioisótopos de Itrio/uso terapéutico , Adulto , Animales , Femenino , Humanos , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Trasplante AutólogoRESUMEN
Copper-67 (67Cu) has ideal properties for radioimmunotherapy. The 62-h half-life is similar to the residence time of antibodies in tumor, and the therapeutic beta emission of 67Cu is comparable to that of 131I. 67Cu, however, has gamma emissions similar to 99mtechnetium that are favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) binds 67Cu tightly and selectively, facilitating linkage to Lym-1, a mouse monoclonal antibody that preferentially targets malignant lymphocytes. The safety, efficacy, and practicality of 67Cu-2-iminothiolane (2IT)-6-[p-(bromoacetamido)benzyl]-TETA (BAT)-Lym-1 was assessed in this Phase I/II clinical trial for patients with non-Hodgkin's lymphoma (NHL) who had failed standard therapy. Up to four doses of 67Cu-2IT-BAT-Lym-1, 25 or 50-60 mCi/m2/dose (0.93 or 1.85-2.22 GBq/m2/dose, respectively) were administered; the lower dosage was used when NHL was detected in the bone marrow. 67Cu-2IT-BAT-Lym-1 provided good imaging of NHL, had favorable radiation dosimetry, and had a response rate of 58% (7 of 12). Hematological toxicity was dose-limiting, but no significant nonhematological toxicity was observed. The ability to image and treat NHL patients with a single radiopharmaceutical with useful physical properties makes 67Cu-labeled monoclonal antibody an option for future clinical trials, as this study showed that 67Cu-2IT-BAT-Lym-1 was safe, effective, and practical.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Radioisótopos de Cobre/uso terapéutico , Antígenos HLA-DR/inmunología , Inmunoglobulina G/uso terapéutico , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia , Adulto , Anciano , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Radioinmunoterapia/efectos adversos , Dosificación RadioterapéuticaRESUMEN
Antilymphoma mouse monoclonal antibody (MoAb) Lym-1, labeled with 67Cu or 131I, has demonstrated promising results in radioimmunotherapy (RIT) for lymphoma. Although 131I has played a central role in RIT thus far, some properties of 67Cu are preferable. A subset of our patients received both 67Cu- and 131I-labeled Lym-1, allowing a comparative evaluation of the two radiopharmaceuticals administered to a matched population of patients. Four patients with B-lymphocytic non-Hodgkin's lymphoma that had progressed despite standard therapy entered trials of 67Cu- and 131I-labeled Lym-1, which were injected 3-26 days apart. Lym-1 was conjugated to 6-[p-(bromoacetamido)benzyl]-1,4,7,11-tetraazacyclotetradecane-N,N ',N",N'"-tetraacetic acid (BAT) via 2-iminothiolane (2IT) and radiolabeled with 67Cu to prepare 67Cu-2IT-BAT-Lym-1; 131I-Lym-1 was preparred by the chloramine-T reaction. Planar imaging was used to quantitate 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 in organs and tumors daily for 3 days or longer. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in 92% (12 of 13) of tumors and a longer biological half-time in every tumor than 131I-Lym-1. The mean tumor concentration (%ID/g) of 67Cu-2IT-BAT-Lym-1 was 1.7, 2.2, and 2.8 times that of 131I-Lym-1 at 0, 24, and 48 h after injection, respectively. The mean biological half-times of 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 in tumor were 8.8 and 2.3 days, respectively. Consequently, the mean tumor radiation dose delivered by 67Cu-2IT-BAT-Lym-1 was twice that of 131I-Lym-1, 2.8 (range 0.8-6.7), and 1.4 (range 0.4-35) Gy/GBq, respectively. 67Cu-2IT-BAT-Lym-1 delivered a lower marrow radiation dose than 131I-Lym-1; hence, the tumor:marrow therapeutic indices were 29 and 9.7, respectively. Radiation doses from 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 to normal tissues were similar except for liver, which received a higher dose from 67Cu-2IT-BAT-Lym-1. Images obtained with 67Cu-2IT-BAT-Lym-1 were superior. Radiation dosimetry data for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 agreed with corresponding data from the larger populations of patients from which the matched population for the current study was drawn. In conclusion, 67Cu-2IT-BAT-Lym-1 given to non-Hodgkin's lymphoma patients in close temporal proximity to 131I-Lym-1 exhibited greater uptake and longer retention in tumor, resulting in higher radiation dose and therapeutic index than 131I-Lym-1. These as well as other factors suggest that 67Cu-2IT-BAT-Lym-1 may be superior to 131I-Lym-1 for RIT.
Asunto(s)
Compuestos Heterocíclicos/farmacocinética , Linfoma no Hodgkin/metabolismo , Compuestos Organometálicos/farmacocinética , Radiofármacos/farmacocinética , Adulto , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/uso terapéutico , Compuestos Heterocíclicos/uso terapéutico , Humanos , Radioisótopos de Yodo/farmacocinética , Radioisótopos de Yodo/uso terapéutico , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/radioterapia , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Radioinmunoterapia , Radiofármacos/uso terapéutico , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
UNLABELLED: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 1311. Radiometal-labeled antibodies provide higher tumor radiation doses than corresponding 1311 antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu-21T-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-21T-BAT-Lym-1 in patients with lymphoma was initiated. METHODS: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-21T-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood, urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. RESULTS: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-21T-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-21T-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor-to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. CONCLUSION: Because of the long residence time of 67Cu-21T-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-21T-BAT-Lym-1.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Radioisótopos de Cobre/uso terapéutico , Linfocitos/inmunología , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Radioisótopos de Cobre/efectos adversos , Radioisótopos de Cobre/farmacocinética , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Linfoma no Hodgkin/diagnóstico por imagen , Masculino , Persona de Mediana Edad , CintigrafíaRESUMEN
UNLABELLED: Encouraged by the results of 131I-Lym-1 therapy trials for patients with B-cell non-Hodgkin's lymphoma (NHL), this phase I/II clinical trial of 67Cu-2IT-BAT-Lym-1 was conducted in an effort to further improve the therapeutic index of Lym-1-based radioimmunotherapy. Lym-1 is a mouse monoclonal antibody that preferentially targets malignant lymphocytes. 67Cu has beta emissions comparable to those of 131I but has gamma emissions more favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid binds 67Cu tightly to form a stable radioimmunoconjugate in vivo. METHODS: All 12 patients had stage III or IV NHL that had not responded to standard therapy; 11 had intermediate- or high-grade NHL. At 4-wk intervals, patients received up to four doses of 67Cu-2IT-BAT-Lym-1, 0.93 or 1.85-2.22 GBq/m2 (25 or 50-60 mCi/m2), with the lower dose used when NHL was detected in the bone marrow. RESULTS: 67Cu-2IT-BAT-Lym-1 provided good imaging of NHL and favorable radiation dosimetry. The mean radiation ratios of tumor to body and tumor to marrow were 28:1 and 15:1, respectively. Tumor-to-lung, -kidney and -liver radiation dose ratios were 7.4:1, 5.3:1 and 2.6: 1, respectively. This 67Cu-2IT-BAT-Lym-1 trial for patients with chemotherapy-resistant NHL had a response rate of 58% (7/12). No significant nonhematologic toxicity was observed. Hematologic toxicity, especially thrombocytopenia, was dose limiting. CONCLUSION: 67Cu remains an option for future clinical trials. This study established 67Cu-2IT-BAT-Lym-1 as a safe, effective treatment for patients with NHL.
Asunto(s)
Compuestos Heterocíclicos/uso terapéutico , Linfoma no Hodgkin/radioterapia , Compuestos Organometálicos/uso terapéutico , Radioinmunoterapia , Médula Ósea/efectos de la radiación , Femenino , Compuestos Heterocíclicos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organometálicos/efectos adversos , Dosificación RadioterapéuticaRESUMEN
Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfoma Relacionado con SIDA/radioterapia , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia/métodos , Radiofármacos/uso terapéutico , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Humanos , Linfoma Relacionado con SIDA/diagnóstico , Linfoma Relacionado con SIDA/diagnóstico por imagen , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Dosis de Radiación , Tolerancia a Radiación , Radioinmunoterapia/efectos adversos , Cintigrafía , Radiofármacos/efectos adversos , Radiofármacos/farmacocinética , Distribución Tisular , Radioisótopos de Itrio/efectos adversos , Radioisótopos de Itrio/uso terapéuticoRESUMEN
UNLABELLED: Use of a single lot of monoclonal antibody (MoAb) or immunoconjugate for clinical studies provides efficiency of scale and consistent characteristics for MoAb-based pharmaceuticals. Lym-1, an anti-lymphoma mouse IgG2 alpha chimeric L6 (ChL6), an anti-adenocarcinoma mouse IgG2 alpha-human IgG1 chimera, and the immunoconjugate 2IT-BAD-Lym-1 were examined for stability following storage. METHODS: Lym-1, ChL6, and 2IT-BAD-Lym-1 were aliquotted with filtration and stored at -70 degrees C for up to 8.5 years. 2IT-BAD-Lym-1 stored for 6.3 years (lot A) was compared to freshly prepared 2IT-BAD-Lym-1 (lot B). MoAbs were thawed and examined yearly by gel filtration high performance liquid chromatography (HPLC), polyacrylamide gel electrophoresis (PAGE), cellulose acetate electrophoresis (CAE), and Scatchard analysis of antigen binding. 2IT-BAD-Lym-1 was evaluated by HPLC, CAE, and radioimmunoassay. To assure the in vivo significance of the in vitro studies, 2IT-BAD-Lym-1 lots A and B were labeled with 111In and their pharmacokinetics in BALB/c mice were compared. RESULTS: Lym-1 demonstrated stability over 8.5 years, providing the following ranges of data over the interval: 98-100% chemical purity (HPLC), 96-100% monomeric fraction (CAE), 8.18-8.46 antigen binding pKa (Scatchard). Similar results were obtained for ChL6 for 7.4 years. HPLC and PAGE of Lym-1 and ChL6 have not changed from original manufacturer specifications, and both MoAbs remain sterile and apyrogenic. No significant differences between 2IT-BAD-Lym-1 lots A and B were observed by in vitro evaluation or pharmacokinetics in mice. CONCLUSIONS: Lym-1, ChL6, and 2IT-BAD-Lym-1 as manufactured and stored for 8.5, 7.4, and 6.3 years, respectively, demonstrated retention of structural and functional integrity.
Asunto(s)
Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacocinética , Animales , Anticuerpos Monoclonales de Origen Murino , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Femenino , Congelación , Humanos , Ratones , Ratones Desnudos , Distribución TisularRESUMEN
UNLABELLED: Radioimmunotherapy (RIT) with 90Y-labeled immunoconjugates has shown promise in clinical trials. The macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) binds 90Y with extraordinary stability, minimizing the toxicity of 90Y-DOTA immunoconjugates arising from loss of 90Y to bone. However, reported 90Y-DOTA immunoconjugate product yields have been typically only < or =50%. Improved yields are needed for RIT with 90Y-DOTA immunoconjugates to be practical. METHODS: (S) 2-[p-(bromoacetamido)benzyl]-DOTA (BAD) was conjugated to the monoclonal antibody Lym-1 via 2-iminothiolane (2IT). The immunoconjugate product, 2IT-BAD-Lym-1, was labeled in excess yttrium in various buffers over a range of concentrations and pH. Kinetic studies were performed in selected buffers to estimate radiolabeling reaction times under prospective radiopharmacy labeling conditions. The effect of temperature on reaction kinetics was examined. Optimal radiolabeling conditions were identified and used in eight radiolabeling experiments with 2IT-BAD-Lym-1 and a second immunoconjugate, DOTA-peptide-chimeric L6, with 248-492 MBq (6.7-13.3 mCi) of 90Y. RESULTS: Ammonium acetate buffer (0.5 M) was associated with the highest uptake of yttrium. On the basis of kinetic data, the time required to chelate 94% of 90Y (four half-times) under prospective radiopharmacy labeling conditions in 0.5 M ammonium acetate was 17-148 min at pH 6.5, but it was only 1-10 min at pH 7.5. Raising the reaction temperature from 25 degrees C to 37 degrees C markedly increased the chelation rate. Optimal radiolabeling conditions were identified as: 30-min reaction time, 0.5 M ammonium acetate buffer, pH 7-7.5 and 37 degrees C. In eight labeling experiments under optimal conditions, a mean product yield (+/- s.d.) of 91%+/-8% was achieved, comparable to iodination yields. The specific activity of final products was 74-130 MBq (2.0-3.5 mCi) of 90Y per mg of monoclonal antibody. The immunoreactivity of 90Y-labeled immunoconjugates was 100%+/-11%. CONCLUSION: The optimization of 90Y-DOTA chelation conditions represents an important advance in 90Y RIT because it facilitates the dependable and cost-effective preparation of 90Y-DOTA pharmaceuticals.
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Compuestos Heterocíclicos con 1 Anillo , Compuestos Heterocíclicos/síntesis química , Compuestos Organometálicos/síntesis química , Radioinmunoterapia/métodos , Radiofármacos/química , Radioisótopos de Itrio , Tampones (Química) , Cromatografía Líquida de Alta Presión , Compuestos Heterocíclicos/química , Indicadores y Reactivos , Cinética , Estructura Molecular , Compuestos Organometálicos/química , Proteínas Recombinantes de Fusión , TermodinámicaRESUMEN
PURPOSE: Lym-1, a monoclonal antibody (MoAb) that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine-131 (131I). Radiometal labeled antibodies provide a higher tumor radiation dose than the corresponding 131I labeled antibodies. Based on the strategy of fractionating the total radiation dose, this study was designed to define the maximum tolerated dose (MTD) of the first 2, of a maximum of 4, doses of 67Cu-2IT-BAT-Lym-1 given 4 weeks apart. Additionally, toxicity, radiation dosimetry and efficacy were assessed. MATERIALS AND METHODS: Patients had Ann Arbor stage IVB NHL, resistant to standard therapy, including multiple chemotherapy regimens. Each dose of 67Cu-2IT-BAT-Lym-1 was given after a preload of unmodified Lym-1. A 10 mCi imaging dose of 67Cu-2IT-BAT-Lym-1 was given in order to assess pharmacokinetics and radiation dosimetry prior to therapy. Based on the MTD for 131I-Lym-1 and comparative dosimetry for 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1, the trial was initiated at 60 millicuries per square meter of body surface area (mCi/m2) in cohorts of 3 patients. RESULTS: A single cohort of patients proved sufficient to define the MTD as 60 mCi/m2 for each of the first 2 doses of 67Cu-2IT-BAT-Lym-1. The dose-limiting toxicities were grade 3-4 thrombocytopenia and neutropenia. Neutropenic sepsis and bleeding did not occur. Mean radiation dose contributed to the bone marrow by 67Cu in the body and blood was 0.2 (range, 0.2 to 0.3) rads/mCi. Copper-67 incorporated into ceruloplasmin contributed 25% of the dose to marrow from blood. Non-hematologic toxicities did not exceed grade 2. The three patients had substantial tumor regression even after imaging doses of 67Cu-2IT-BAT-Lym-1. After therapy, one response was complete with a duration of 12 months. Radiation doses to tumors in this patient varied from 7.0-21.9 rads/mCi or 5420-7000 total rads from the course of therapy. CONCLUSION: 67Cu-2IT-BAT-Lym-1 provided good imaging, favorable radiation dosimetry and a remarkably high therapeutic index (ratio of tumor to marrow radiation doses). The non-myeloablative MTD for each of 2 doses was 60 mCi/m2.
Asunto(s)
Compuestos Heterocíclicos/toxicidad , Compuestos Heterocíclicos/uso terapéutico , Linfoma no Hodgkin/radioterapia , Compuestos Organometálicos/toxicidad , Compuestos Organometálicos/uso terapéutico , Radiofármacos/toxicidad , Radiofármacos/uso terapéutico , Adulto , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/toxicidad , Ceruloplasmina/análisis , Cromatografía Líquida de Alta Presión , Radioisótopos de Cobre/sangre , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/uso terapéutico , Radioisótopos de Cobre/toxicidad , Fraccionamiento de la Dosis de Radiación , Femenino , Compuestos Heterocíclicos/sangre , Compuestos Heterocíclicos/farmacocinética , Humanos , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/diagnóstico por imagen , Masculino , Concentración Máxima Admisible , Persona de Mediana Edad , Compuestos Organometálicos/sangre , Compuestos Organometálicos/farmacocinética , Proyectos Piloto , Radioinmunoterapia/efectos adversos , Cintigrafía , Radiofármacos/sangre , Radiofármacos/farmacocinética , Albúmina Sérica/análisis , Resultado del TratamientoRESUMEN
UNLABELLED: The novel radioimmunoconjugate, 90Y-DOTA-peptide-chimeric L6 (ChL6), was designed to reduce radiation to critical normal tissues with an exceptionally stable 90Y chelate moiety and a biodegradable linker. Human breast cancer tumors (HBT 3477) in mice were treated with 90Y-DOTA-peptide-ChL6 to examine the effects of increasing dose on the therapeutic efficacy and toxicity of this new agent. METHODS: Groups of athymic mice bearing HBT 3477 xenografts received 4.1- to 14.1-MBq doses of 90Y-DOTA-peptide-ChL6 intravenously. The lethal dose (LD)(50/30), general well-being (weight loss), hematotoxicity and therapeutic efficacy were studied. RESULTS: The LD(50/30) was 12.8 MBq, which corresponded to doses of 17.9 and 50.9 Gy to the total body and tumor (200 mm3), respectively. Deaths were associated with hematotoxicity; no deaths occurred at doses of 9.6 MBq or less. At sublethal doses, the rate of tumor response (cures +/- complete responses + partial responses) increased with increasing dose: 4.1 MBq, 27%; 5.9 MBq, 41%; 8.5 MBq, 69%; and 9.6 MBq, 79% (maximum tolerated dose, MTD). In mice receiving doses of 4.1-9.6 MBq, 6 of 74 (8%) of tumors were cured. Increasing the 90Y dose led to smaller tumor size at nadir and longer tumor regrowth delay but no increase in cure. Although the HBT 3477 p53 gene was found to be mutant resulting in p53 protein not binding DNA breaks, tumors at MTD demonstrated evidence of apoptosis. CONCLUSION: In the human breast cancer athymic mouse model, 90Y-DOTA-peptide-ChL6 had a high therapeutic index and LD(50/30) leading to a 79% response rate at the MTD. The evidence of apoptosis as a mechanism for this tumor response in p53 mutant breast cancer warrants further studies because these observations are relevant to the treatment of lethal breast cancer.
Asunto(s)
Adenocarcinoma/radioterapia , Neoplasias de la Mama/radioterapia , Compuestos Heterocíclicos/uso terapéutico , Oligopéptidos/uso terapéutico , Radioinmunoterapia , Radioisótopos de Itrio/uso terapéutico , Itrio/uso terapéutico , Adenocarcinoma/genética , Animales , Anticuerpos Monoclonales/uso terapéutico , Apoptosis , Neoplasias de la Mama/genética , Relación Dosis-Respuesta en la Radiación , Femenino , Compuestos Heterocíclicos/toxicidad , Humanos , Dosificación Letal Mediana , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Oligopéptidos/toxicidad , Radioinmunoterapia/efectos adversos , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/genética , Itrio/toxicidadRESUMEN
Despite effective therapies for non-Hodgkin's lymphoma (NHL), the majority of patients are not cured. Radioimmunotherapy (RIT) has shown good results in preclinical and clinical trials even in patients that are non-responsive to standard chemotherapy. To make RIT more effective, agents such as paclitaxel (Taxol), that can enhance radiation effects, are being tested. Nude mice bearing human Burkitt's lymphoma (Raji) xenografts were treated with: 1) 150 or 200 microCi (5.5 or 7.3 MBq) of 90Y-2IT-BAD-Lym-1 alone, 2) 600 micrograms of Taxol alone, 3) 150 or 200 microCi of 90Y-2IT-BAD-Lym-1 plus 600 micrograms of Taxol given 24 hours after RIT, or 4) no treatment. Tumor size, survival, mouse weight and blood counts were monitored to assess efficacy and toxicity. Survival for mice treated in this 84 day trial was: 71% for 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol, 29% for Taxol alone, 6% for 90Y-2IT-BAD-Lym-1 (200 microCi) alone and 14% in the untreated group. Average tumor volume in the 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol group was reduced by 89 and 99% compared to the RIT alone and Taxol alone groups, respectively. Mice treated with 150 microCi had less toxicity than those treated with 200 microCi of 90Y-2IT-BAD-Lym-1, however, the higher radiation dose, and Taxol, were required for improved survival. Mouse weights and myelotoxicity in the combined modality (RIT plus Taxol) groups were similar to those receiving the same dose of RIT alone. In the Raji tumored nude mouse model, addition of Taxol to 90Y-2IT-BAD-Lym-1, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/radioterapia , Paclitaxel/uso terapéutico , Radioinmunoterapia , Radiofármacos/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacocinética , Terapia Combinada , Femenino , Humanos , Ratones , Ratones Desnudos , Radiofármacos/farmacocinética , Trasplante Heterólogo , Células Tumorales Cultivadas , Radioisótopos de Itrio/farmacocinética , Radioisótopos de Itrio/uso terapéuticoRESUMEN
BACKGROUND: Paclitaxel (Taxol) has demonstrated synergistic enhancement of radioimmunotherapy (RIT) of breast cancer with Y-90 labeled antibody ChL6, in the xenografted mouse model. To determine the optimal sequence and timing of RIT and Taxol for a prospective clinical trial, efficacy and dosimetry in mice, and dosimetry in patients receiving RIT alone, were examined. MATERIALS AND METHODS: Mice bearing human breast cancer xenografts (HBT 3477) received i.v. Y-90-DOTA-peptide-ChL6 (260 microCi), and i.p. Taxol (300 or 600 micrograms) 72, 48, or 24 hours prior to RIT, or 6, 24, 48, or 72 hours after RIT. RESULTS: Taxol after RIT resulted in cure, CR, or PR of all mice (70/70 tumors) and demonstrated greater therapeutic enhancement (p = 0.001) than Taxol before RIT. Mice receiving 600 micrograms Taxol 48 hours after RIT achieved 88% cure (7/8 tumors). In mice, 57% and 42% of the radiation dose to tumor and marrow, respectively, was delivered from 48-336 hours after RIT; in patients receiving 90Y-DOTA-peptide-ChL6, the corresponding values were 56% and 22%. CONCLUSIONS: Taxol given approximately 48 hours after RIT provides coincident peak deposition of Taxol and Y-90 in tumor, and no Taxol in the marrow during the major radiation dose to marrow, resulting in therapeutic enhancement without observable additive toxicity. A clinical trial of low dose Taxol given after RIT to patients with metastatic breast cancer is planned.