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1.
Int J Oncol ; 34(2): 511-6, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19148487

RESUMO

Like rituximab, monoclonal antibodies reactive with human leukocyte antigen have potent antilymphoma activity. However, size limits their vascular and tissue penetration. To mimic monoclonal antibody binding, nanomolecules have been synthesized, shown specific for the beta subunit of HLA-DR10, and selective for cells expressing this protein. Selective high affinity ligands (SHALs) containing the 3-(2-([3-chloro-5-trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid (Ct) ligand residualized and had antilymphoma activity against expressing cells. Herein, we show the extraordinary potency in mice with human lymphoma xenografts of a tridentate SHAL containing this ligand. After titrating antilymphoma activity in cell culture, a randomized preclinical study of a tridentate SHAL containing the Ct ligand was conducted in mice with established and aggressive human lymphoma xenografts. Mice having HLA-DR10 expressing Raji B- or Jurkat's T-lymphoma xenografts were randomly assigned to receive either treatment with SHAL at a dose of 100 ng i.p. weekly for 3 consecutive weeks, or to be untreated. Primary end-points were cure, overall response rates and survival. Toxicity was also evaluated in these mice, and a USFDA general safety study was conducted in healthy Balb/c mice. In Raji cell culture, the threshold and IC50 concentrations for cytotoxic activity were 0.7 and 2.5 nmol (pm/ml media), respectively. When compared to treated Jurkat's xenografts or untreated xenografts, Raji xenografts treated with the SHAL showed an 85% reduction in hazard of death (P=0.014; 95% confidence interval 32-95% reduction). There was no evidence for toxicity even after i.p. doses 2000 times greater than the treatment dose associated with cure of a majority of the mice with Raji xenografts. When compared with control groups, treatment selectively improved response rates and survival in mice with HLA-DR10 expressing human lymphoma xenografts at doses not associated with adverse events and readily achievable in patients.


Assuntos
Antígenos HLA-DR/imunologia , Imunoglobulinas/imunologia , Leucemia/imunologia , Linfoma/imunologia , Animais , Linhagem Celular Tumoral/patologia , Linhagem Celular Tumoral/transplante , Sobrevivência Celular , Humanos , Células Jurkat , Leucemia/tratamento farmacológico , Leucemia/mortalidade , Leucemia/patologia , Linfoma/tratamento farmacológico , Linfoma/mortalidade , Linfoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Análise de Sobrevida , Transplante Heterólogo
2.
Bioconjug Chem ; 19(6): 1211-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18517234

RESUMO

Dextran and PEG-coated iron oxide nanoparticles (NP), when suitably modified to enable conjugation with molecular targeting agents, provide opportunities to target cancer cells. Monoclonal antibodies, scFv, and peptides conjugated to 20 nm NP have been reported to target cancer for imaging and alternating magnetic field (AMF) therapy. The physical characteristics of NPs can affect their in vivo performance. Surface morphology, surface charge density, and particle size are considered important factors that determine pharmacokinetics, toxicity, and biodistribution. New NanoFerrite (NF) particles having improved specific AMF absorption rates and diameters of 30 and 100 nm were studied to evaluate the variation in their in vitro and in vivo characteristics in comparison to the previously studied 20 nm superparamagnetic iron oxide (SPIO) NP. SPIO NP 20 nm and NF NP 30 and 100 nm were conjugated to (111)In-DOTA-ChL6, a radioimmunoconjugate. Radioimmunoconjugates were conjugated to NPs using 25 microg of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified and characterized by PAGE, cellulose acetate electrophoresis (CAE), live cell binding assays, and pharmacokinetics in athymic mice bearing human breast cancer (HBT 3477) xenografts. RINP (2.2 mg) were injected iv and whole body; blood and tissue data were collected at 4, 24, and 48 h. The preparations used for animal study were >90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40-60% compared to (111)In-ChL6. Specific activities of the doses were 20-25 microCi/2.2 mg and 6-11 microg of mAb/2.2 mg of NP. Mean tumor uptakes (% ID/g +/- SD) of each SPIO 20 nm, NF 30 nm, and 100 nm RINP at 48 h were 9.00 +/- 0.8 (20 nm), 3.0 +/- 0.3 (30 nm), and 4.5 +/- 0.8 (100 nm), respectively; the ranges of tissue uptakes were liver (16-32 +/- 1-8), kidney (7.0-15 +/- 1), spleen (8-17 +/- 3-8), lymph nodes 5-6 +/- 1-2), and lung (2.0-4 +/- 0.1-2). In conclusion, this study demonstrated that 100 nm NF NP could be conjugated to (111)In-mAb so that the resulting RINP had characteristics suitable for AMF therapy. Although 100 nm RINP targeted tumor less than 20 nm SPIO RINP, their heating capacity is typically 6 times greater, suggesting the 100 nm NF RINP could still deliver better therapy with AMF.


Assuntos
Compostos Férricos/química , Imunoconjugados/química , Imunoconjugados/farmacocinética , Nanopartículas/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Linhagem Celular Tumoral , Feminino , Temperatura Alta/uso terapêutico , Humanos , Imunoconjugados/metabolismo , Radioisótopos de Índio , Magnetismo , Camundongos , Tamanho da Partícula , Fótons , Polietilenoglicóis/química , Radioimunoensaio , Análise Espectral , Distribuição Tecidual
3.
J Clin Invest ; 66(5): 869-77, 1980 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7430349

RESUMO

Onset of lung edema is usually associated with increase in the pulmonary transvascular flux of water and proteins. Clinical measurement of these parameters may aid in early diagnosis of pulmonary edema, and allow differentiation between "cardiogenic" and "noncardiogenic" types base on the magnitude of the detected changes. We have previously described a noninvasive method for estimating transvascular protein flux in lung (Gorin, A. B., W. J. Weidner, R. H. Demling, and N. C. Staub, 1978. Noninvasive measurement of pulmonary transvascular protein flux in sheep. J. Appl. Physiol. 45: 225-233). Using this method we measured the net transvascular flux of [113mIn]transferrin (mol wt, 76,000 in lungs of nine normal human volunteers. Plasma clearance of [113In]transferrin occurred with a T1/2 = 7.0 +/- 2.6 h (mean +/- SD). The pulmonary transvascular flux coefficient, alpha, was 2.9 +/- 1.4 X 10(-3) ml/s (mean +/- SD) in man, slightly greater than that previously measured in sheep (2.7 +/- 0.7 X 10(-3) ml/s; mean +/- SD). The pulmonary transcapillary escape rate is twofold greater than the transcapillary escape rate for the vascular bed as a whole, indicating a greater "porosity" of exchanging vessels in the lung than exists for the "average" microvessel in the body. Time taken to reach half-equilibrium concentration of tracer protein in the lung interstitium was quite short, 52 +/- 13 min (mean +/- SD). We have shown that measurement of pulmonary transvascular protein flux in man is practical. The coefficient of variation of measurements of alpha (between subjects) was 0.48, and of measurements of pulmonary transcapillary escape rates was 0.39. In animals, endothelial injury commonly results in a two- to threefold increase in transvascular protein flux. Thus, external radioflux detection should be a suitable means of quantitating lung vascular injury in human disease states.


Assuntos
Edema Pulmonar/diagnóstico , Adulto , Humanos , Isótopos , Masculino , Capacidade de Difusão Pulmonar , Valores de Referência , Transferrina
4.
Curr Opin Immunol ; 11(5): 563-9, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10508716

RESUMO

Radioimmunotherapy (RIT), a therapy targeted to tumor cells, is a modality that can currently deliver radiation to tumor cells at levels 3-50-times higher than to the normal tissue with the next highest dose. RIT appears promising for future cancer therapy. Clinical responses in patients with advanced cancer have frequently been achieved with RIT as a single agent. Extended complete remissions and even increased survival have been achieved in lymphoma. Similar results in other cancers seem likely with RIT in combination therapy.


Assuntos
Anticorpos Antineoplásicos/uso terapêutico , Neoplasias/radioterapia , Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Humanos , Leucemia/radioterapia , Linfoma/radioterapia , Neoplasias Ovarianas/radioterapia
5.
Cancer Res ; 55(23 Suppl): 5916s-5920s, 1995 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-7493370

RESUMO

Radioimmunotherapy (RAIT) using a humanized murine monoclonal antibody, chimeric L6 (ChL6), has produced objective tumor reduction in 50% of chemotherapy-refractory patients with metastatic breast cancer in our prior studies. Because myelosuppression limited dose escalation, we evaluated the ability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cell (PBPC) transfusions to ameliorate this problem. 131I-labeled ChL6 was given at a starting dose of 150 mCi/m2 (2,5 times the maximum tolerated dose without PBPCs) for a planned three treatments. When blood radioactivity declined to less than 1 microCi/ml after treatment, PBPCs were transfused, and G-CSF was administered. Patient 1 had minimal myelosuppression, received two cycles of therapy, and then developed human antimonoclonal antibody (HAMA). Patient 2 had prolonged thrombocytopenia that resolved after additional PBPC transfusion. Progressive disease as well as HAMA prevented further treatment. Patient 3 received all three cycles of 150 mCi/m2 at 8-week intervals. Thrombocytopenia (< 25,000/microliter) occurred but was transient (0-7 days). Because HAMA developed in all prior patients who received G-CSF with ChL6 RAIT, including patients 1 and 2, who received PBPC, patient 3 was given cyclosporin for 14 days. She did not develop HAMA or significant toxicity following 3 cycles of RAIT. Cumulative radiation doses to her lungs and tumor were estimated at 3,100 and 11,200 cGy, respectively. For 9 months, she had a reduction in bone pain, a decline in serum tumor markers, and decreased tumor uptake of F-18-deoxyglucose on a positron emission scan. Her performance status improved, and she had no pulmonary toxicity. We conclude that: (a) PBPC transfusion can modify the myelotoxicity of RAIT and can permit repetitive dosing; (b) cyclosporin is a promising means to abrogate HAMA; and (c) fractionation of intensive-dose RAIT may increase the antitumor effect and reduce normal organ toxicity.


Assuntos
Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Radioisótopos do Iodo/uso terapêutico , Radioimunoterapia , Anticorpos Monoclonais/uso terapêutico , Terapia Combinada , Feminino , Humanos , Dosagem Radioterapêutica
6.
Cancer Res ; 50(3 Suppl): 1014s-1016s, 1990 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-2297713

RESUMO

Eighteen patients with Stage 4 B-cell malignancies, which were primarily of intermediate or high grade and progressive despite multiple drug chemotherapy and external irradiation, were treated with fractionated doses of 131I-labeled Lym-1. Lym-1 is an IgG2a monoclonal antibody that was produced by immunizing mice with Raji cell nuclei that originated from a patient with African Burkitt's lymphoma. Despite advanced disease, 10 of the patients had objective evidence for a complete or partial remission. Toxicity was very modest except in one patient who developed hypotension. Dose-dependent hepatic uptake of Lym-1 was observed in the patients and in BALB/c mice suggesting receptor-mediated recognition of this murine antibody.


Assuntos
Anticorpos Monoclonais/imunologia , Imunoglobulina G/imunologia , Radioisótopos do Iodo/administração & dosagem , Leucemia de Células B/radioterapia , Linfoma/radioterapia , Anticorpos Anti-Idiotípicos/análise , Humanos , Radioisótopos do Iodo/uso terapêutico , Taxa de Depuração Metabólica
7.
Cancer Res ; 49(7): 1707-11, 1989 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-2493983

RESUMO

In patients, the pharmacokinetic behavior of murine monoclonal antibodies has been observed to vary with the amount of antibody administered. It has been suggested that this reflects human recognition of the foreign mouse protein. We have found that the amount of antibody administered also influenced pharmacokinetic behavior when murine monoclonal antibody was administered to mice. p-Isothiocyanatobenzyl-EDTA, a new chelator which forms complexes with 111In that are stable in vivo, was conjugated to Lym-1, a murine anti-Burkitt's lymphoma monoclonal antibody. The pharmacokinetics of two doses (20 and 0.2 micrograms) of the 111In labeled radiopharmaceutical were studied in non-tumor bearing BALB/c mice. About 20% (0.04 microgram) of the 0.2-microgram dose, compared with 8% (1.6 micrograms) of the 20-micrograms dose, was found in the liver at 48 h after injection. Both doses demonstrated a biological half-life of approximately 120 h. At least 75% of the 111In was excreted by the kidneys, and essentially all 111In in the urine remained chelated by the EDTA portion of p-isothiocyanatobenzyl-EDTA. From these observations of a dose dependent uptake of this radiopharmaceutical by the liver we conclude that there is a recognition phenomenon in mice for this murine monoclonal antibody.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Ácido Edético/administração & dosagem , Radioisótopos de Índio , Fígado/metabolismo , Animais , Relação Dose-Resposta Imunológica , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Baço/metabolismo , Distribuição Tecidual
8.
Cancer Res ; 55(23 Suppl): 5893s-5898s, 1995 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-7493366

RESUMO

The Ann Arbor staging classification has proven less useful in nonHodgkin's lymphoma, because this malignancy is inherently a multifocal disorder. Since 1985, 57 adult patients with advanced B-lymphocytic malignancies that progressed despite standard therapy entered into one of three different therapy trials using radiolabeled Lym-1 antibody. Tumor regression in 31 (54%) of these patients fulfilled conventional requirements for an oncological response to the therapy. To define the role of radioimmunotherapy in B-lymphocytic malignancies better and to find opportunities for improving its therapeutic efficacy, the records of these patients were reviewed to assess the significance of various parameters as prognostic indicators. Twenty-one pretherapy characteristics were evaluated, including age at diagnosis, age at study entry, sex, Karnofsky performance status, prior chemotherapy and radiation therapy, interval since diagnosis, histology, constitutional B symptoms, extranodal malignancy (excluding marrow), bone marrow malignancy, tumor bulk, and circulating malignant cells; blood tests included lymphocyte, granulocyte, platelet, hematocrit, serum lactate dehydrogenase (LDH), interleukin 2 receptor, and human antimouse antibody levels. In the multivariate analysis, LDH and Karnofsky performance status were the parameters that best predicted survival, complete and partial remission, and time to progression; interleukin 2 receptor and LDH best predicted complete remission. These prognostic factors for radioimmunotherapy outcome are consistent with the pretherapy characteristics observed to be significant for chemotherapy.


Assuntos
Linfoma de Células B/radioterapia , Radioimunoterapia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Linfoma de Células B/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores Sexuais
9.
Cancer Res ; 55(4): 878-84, 1995 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-7850803

RESUMO

Trial therapy for lymphoma with the radiolabeled chelate-antibody conjugate 67Cu-2IT-BAT-Lym-1 has been promising. It is desirable to deliver therapeutic doses of radiometal using a minimum amount of 2IT-BAT-Lym-1 to minimize the risks of adverse patient reaction and antigenic response to antibody. This is readily accomplished by increasing the number of metal-binding sites (i.e., chelating agents) conjugated per antibody, but the ability of the antibody to bind antigen and target tumor cells in vivo must not be impaired by the conjugation reaction. To determine the maximum chelator:antibody ratio (c/a) of 2IT-BAT-Lym-1 at which functional integrity is preserved, immunoconjugates with a c/a of 1.3-23 were prepared and examined by radioimmunoassay and competitive antigen binding versus lightly iodinated Lym-1. The biodistribution in tumored mice of conjugates with c/a of 2.1, 4.3, 8.4, and 11.4 also was examined. Conjugates with c/a up to 5 exhibited no loss of immunoreactivity, and conjugates with c/a up to 11 retained 75% or greater immunoreactivity relative to unmodified Lym-1. All conjugates examined competed less effectively than did unmodified Lym-1 for antigen binding, but the effect at c/a 5 was slight. Tumor uptake declined with increasing c/a, but the effect was insignificant at c/a 2.1 and 4.3. Conjugates of c/a 4-5 were found to be optimal for the preparation of radioimmunoconjugate of high specific activity with minimal, if any, loss of functional integrity.


Assuntos
Quelantes/farmacologia , Compostos Heterocíclicos/farmacocinética , Imidoésteres/farmacocinética , Imunotoxinas/imunologia , Imunotoxinas/farmacocinética , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Ligação Competitiva , Quelantes/farmacocinética , Radioisótopos de Cobre , Reagentes de Ligações Cruzadas/farmacocinética , Reagentes de Ligações Cruzadas/farmacologia , Feminino , Compostos Heterocíclicos/farmacologia , Imidoésteres/farmacologia , Focalização Isoelétrica , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Radioimunoterapia , Distribuição Tecidual , Transplante Heterólogo
10.
Cancer Res ; 55(23 Suppl): 5837s-5841s, 1995 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-7493356

RESUMO

Radioimmunotherapy (RIT) in breast cancer patients using I-131-chimeric L6 (ChL6) and in human breast cancer xenografts in nude mice using Y-90-1,4,7,10-tetraazacylododecant N,N',N",N"'-tetraacetic acid-peptide ChL6 (Y-90-ChL6) has shown promise. Tumor cell response to low-dose rate (5-25 rads/h) irradiation from Y-90-ChL6 RIT, therefore, was correlated with levels of tumor cell mRNA for selected genes linked to programmed cell death (apoptosis). Three groups of 10-16 mice with 1-2 HBT 3477 xenograft tumors were treated with 100, 150, or 250 microCi Y-90-ChL6. Three tumors were taken before and two tumors each were taken 3, 6, and 24 h after injection of 150 microCi Y-90-ChL6. Tumor expression of mRNA was amplified by PCR for p53, PIC1, c-myc, and transforming growth factor-beta 1; quantitated; and standardized to N-ras. Tumors received radiation doses of 2000, 3000, and 5000 rads, respectively, for the groups of mice that received 100, 150, and 250 microCi Y-90-ChL6, and tumor regression occurred in each group, with mean tumor volumes decreased by 10, 50, and 95% at nadir after Y-90-ChL6 injection. At the highest dose level, 30% of mice had complete remissions, and no treatment deaths occurred, although tumors subsequently recurred. Continuous up-regulation of transforming growth factor-beta 1 and c-myc mRNA expression was observed from 3 to 24 h after treatment. Expression of p53 and PIC1 increased at 3 h and subsequently decreased to the untreated control levels. These observations are consistent with previous observations of early responses of p53 and PIC1 to cellular DNA damage and subsequent G1 cell cycle arrest or apoptosis. Apoptosis-associated gene expression patterns observed in this tumor model provide evidence that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 rads. These preliminary data suggest that insight into the molecular basis of RIT-induced tumor regression may be gained by further studies using different radiation doses.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Apoptose/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , RNA Mensageiro/biossíntese , Radioimunoterapia , Radioisótopos de Ítrio/uso terapêutico , Animais , Sequência de Bases , Neoplasias da Mama/genética , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Transplante de Neoplasias , RNA Mensageiro/genética , Transplante Heterólogo
11.
J Clin Oncol ; 14(4): 1383-400, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8648397

RESUMO

PURPOSE: To review antibody structure, function, and production; suitable radioisotopes for radioimmunotherapy; challenges facing the field; recent clinical results; toxicity; and future directions. DESIGN: The radioimmunotherapy literature was reviewed, with an emphasis on clinical results and future directions. RESULTS: The highest complete response rates (overall, approximately 50%) have been achieved in patients with B-cell non-Hodgkin's lymphoma. Challenges that currently face radioimmunotherapy include circulating free antigen, binding of antibodies to nonspecific Fc receptors, insufficient tumor penetration, antigenic heterogeneity and insufficient antigen expression, antigenic modulation, and development of human antimouse antibodies. Possible approaches to these challenges, including high-dose radioimmunotherapy and chemotherapy followed by autologous bone marrow transplantation, the use of radionuclides such as yttrium 90 (90Y) and copper 67 (67Cu), and the development of humanized and bifunctional antibodies, are under investigation. CONCLUSION: Although radioimmunotherapy is a relatively new field, substantial progress has been made. Additional research will ultimately resolve many of the challenges that currently face radioimmunotherapy and hopefully lead to the cure of some currently incurable malignancies.


Assuntos
Neoplasias/radioterapia , Radioimunoterapia , Animais , Anticorpos Antineoplásicos/biossíntese , Anticorpos Antineoplásicos/fisiologia , Ensaios Clínicos como Assunto , Humanos , Leucemia/radioterapia , Linfoma/radioterapia , Neoplasias/imunologia , Radioimunoterapia/efeitos adversos , Radioimunoterapia/métodos , Radioimunoterapia/tendências , Radioisótopos/uso terapêutico , Dosagem Radioterapêutica
12.
J Clin Oncol ; 16(10): 3246-56, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9779698

RESUMO

PURPOSE: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS: Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS: Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION: (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoglobulina G/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Linfoma não Hodgkin/radioterapia , Radioimunoterapia , Adulto , Idoso , Animais , Anticorpos Monoclonais/efeitos adversos , Transfusão de Sangue , Feminino , Humanos , Imunoglobulina G/efeitos adversos , Radioisótopos do Iodo/efeitos adversos , Masculino , Camundongos , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/terapia , Radioimunoterapia/efeitos adversos , Dosagem Radioterapêutica , Trombocitopenia/etiologia , Trombocitopenia/terapia
13.
Clin Cancer Res ; 5(10 Suppl): 3088s-3094s, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10541348

RESUMO

Radioimmunotherapy (RIT) has demonstrated potential for improving clinical cancer therapy. Optimizing the approach has proven difficult thus far. Antibody phage display libraries provide unique molecules that could improve RIT. A phage display library of single chain antibody fragments (scFv) against the MUC-1 mucin molecule, which is expressed on 90% of human breast cancers, was produced from the spleen cells of MUC-1 hyperimmunized BALB/c mice. Increased serum IgG levels, 15 times baseline, were detected following the third immunization. RNA from the spleen cells was isolated, cDNA was made, and variable heavy and variable light immunoglobulin chain gene regions were amplified using PCR technology. The variable heavy and variable light chain gene regions were combined with a flexible linker, ligated into the pCANTAB 5E phagemid vector, and electroporated into TG1 Escherichia coli cells. A library of 10(7) initial colonies was compiled. Forty-six of 288 colonies screened for reactivity demonstrated binding to MUC-1-expressing MCF-7 breast cancer cell membrane fragments. Anti-MUC-1 library diversity evaluated by BstNI digest demonstrated that 52% of the anti-MUC-1 scFv binding MCF-7 possessed individual banding patterns representative of approximately 5 x 10(5) colonies likely able to recognize distinct epitopes present on MUC-1 positive human breast cancers. In summary, the anti-MUC-1 scFv antibody phage library contains diverse scFv molecules, which should provide unique characteristics and epitope recognition. These molecules will be used in the development of pretargeting RIT strategies designed to improve the clinical outcome of patients with breast cancer.


Assuntos
Anticorpos Monoclonais/genética , Neoplasias da Mama/radioterapia , Fragmentos de Imunoglobulinas/genética , Mucina-1/imunologia , Radioimunoterapia , Animais , Bacteriófagos/genética , Impressões Digitais de DNA , Feminino , Biblioteca Gênica , Humanos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Células Tumorais Cultivadas
14.
Clin Cancer Res ; 3(1): 71-9, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9815540

RESUMO

Radioimmunotherapy has shown promising results for treatment of radiosensitive malignancies such as lymphoma. Positive responses have been reported in patients with non-Hodgkin's lymphoma treated with 131I-radiolabeled Lym-1, a mouse anti-lymphoma monoclonal antibody. In this study, the efficacy of 67Cu-radiolabeled Lym-1 was examined. Nude mice bearing human Burkitt's lymphoma (Raji) tumors (20-524 mm3) were treated with 12.4, 14.8, 18.5, and 23.3 MBq of 67Cu-2IT-BAT-Lym-1. Tumor size was measured to assess efficacy, and mouse weight, blood counts, and mortality were monitored to assess toxicity. In mice treated with 12.4, 14.8, and 18.5 MBq of 67Cu-2IT-BAT-Lym-1, 50% (9 of 18), 42% (5 of 12), and 50% (3 of 6) of tumors achieved remission or cure; 33% of tumors were cured overall; and significant regrowth delay was observed. The 23.3 MBq dose group did not yield meaningful efficacy data because of high mortality. In control groups receiving 14.8 and 18.5 MBq of the isotype-matched nonspecific monoclonal antibody radioimmunoconjugate, 67Cu-2IT-BAT-L6, 0% (0 of 15) and 17% (2 of 12) of tumors achieved a response; hence, targeted delivery of radiation was the dominant antitumor mechanism of 67Cu-2IT-BAT-Lym-1. LD50/30 for mice treated with 67Cu-2IT-BAT-Lym-1 and -L6 were 21.6 and 20.6 MBq, respectively. In conclusion, 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice with modest toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Compostos Heterocíclicos/uso terapêutico , Imunoconjugados/uso terapêutico , Compostos Organometálicos/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Contagem de Células Sanguíneas/efeitos dos fármacos , Linfoma de Burkitt/metabolismo , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/toxicidade , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/toxicidade , Camundongos , Transplante de Neoplasias , Compostos Organometálicos/farmacocinética , Compostos Organometálicos/toxicidade , Radiometria , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/toxicidade , Redução de Peso/efeitos dos fármacos
15.
Clin Cancer Res ; 3(8): 1253-60, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9815807

RESUMO

This study was designed to evaluate dosimetric, pharmacokinetic, and other treatment-related parameters as predictors of outcome in patients with advanced B-lymphocytic malignancies. Fifty-seven patients were treated with radiolabeled Lym-1 antibody in early phase trials between 1985 and 1994. Logistic regression and proportional hazards models were used to evaluate treatment parameters for their ability to predict outcome, taking into account patient risk group based on Karnofsky performance status and serum lactic dehydrogenase. The occurrence of a partial or complete response (31 of 57 patients) and development of human antimouse antibody (HAMA) predicted improved survival using a time-dependent proportional hazards model. The final multivariate model for survival with parameters significant at P

Assuntos
Compostos Heterocíclicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/radioterapia , Linfoma de Células B/radioterapia , Compostos Organometálicos/uso terapêutico , Radioimunoterapia , Compostos Radiofarmacêuticos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Heterófilos/sangue , Anticorpos Monoclonais , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/uso terapêutico , Feminino , Compostos Heterocíclicos/farmacocinética , Humanos , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Compostos Organometálicos/farmacocinética , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos/farmacocinética , Análise de Regressão , Resultado do Tratamento
16.
Clin Cancer Res ; 5(10 Suppl): 3010s-3014s, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10541336

RESUMO

Radioimmunotherapy using monoclonal antibodies against tumor-associated antigens has been particularly promising in the treatment of radiosensitive malignancies such as lymphoma. 67Cu has excellent physical and biochemical properties for radioimmunotherapy. 67Cu-2IT-BAT-Lym-1 has been used in preclinical and clinical trials, where an exceptionally long residence time of 67Cu on tumor was observed. BCL-2, a proto-oncogene that promotes cell survival by blocking apoptotic cell death, is overexpressed in most B-cell lymphomas including Raji human Burkitt's lymphoma cells. In this study, therapeutic efficacy and BCL-2 gene and protein expression levels were examined in Raji xenografts in mice after 67Cu-2IT-BAT-Lym-1 radioimmunotherapy. 67Cu-2IT-BAT-Lym-1 therapy induced a response rate (complete and partial responses) of approximately 50%. BCL-2 gene expression was decreased 3 h after radioimmunotherapy, followed by a decrease in Bcl-2 protein by 24 h. Decreases in BCL-2 gene and protein expression preceding observations of 67Cu-2IT-BAT-Lym-1 therapeutic effect suggest that down-regulation of BCL-2 leaves cells more likely to be killed by low dose-rate radiation from radioimmunotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Radioisótopos de Cobre/uso terapêutico , Genes bcl-2 , Antígenos HLA-DR/imunologia , Linfoma/radioterapia , Radioimunoterapia , Animais , Humanos , Camundongos , Transplante de Neoplasias , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-bcl-2/análise , Transplante Heterólogo , Células Tumorais Cultivadas
17.
Clin Cancer Res ; 5(10 Suppl): 3213s-3218s, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10541366

RESUMO

Pretargeting techniques have shown promise for enhancement of the therapeutic index of radioimmunotherapy for cancer. However, methods to vary and compare antibody configurations and select optimal combinations have proved rather formidable. New options for the construction of pretargeting molecules are provided by sophisticated use of the diversity and malleability of antibody genes. Diverse arrays of single-chain antibody fragments (scFvs) can now be obtained reactive with virtually any target antigen by selection from human naive phage antibody libraries. ScFvs can also be cloned directly from hybridoma for construction of phage libraries that facilitate subsequent manipulation: e.g., affinity maturation and modification of specificity. ScFvs affinity selected from these sources to their specific antigen targets have demonstrated a wide spectrum of binding characteristics. ScFvs selected from a large human naive phage antibody library by binding Cu-1,4,8,11-tetra-azacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) or Y-1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) have shown diversity by DNA fingerprints. DNA sequence information confirmed that the anti-TETA scFv represented diverse scFv gene families. ScFvs for Y-DOTA and those for lymphoma-associated HLA DR10 (Lym-1) were selected in a similar manner from mouse antibody gene libraries derived from hybridoma. ScFv clones for each of these antigens were chosen for further study based on the results of ELISA assays involving the respective cell membrane or metal chelate antigens. A PCR primer system built to pCANTAB 5E expression vector sequence was designed to facilitate cloning of antibody heavy (V(H)) and light (V(L)) genes from selected scFvs as cassettes into diabody modules. Thus, chosen scFvs could be expressed in the same diabody format for comparative study. Selected mouse anti-DOTA scFv and Lym-1 scFv genes were linked as V(HA) anti-DOTA-link-V(LB) Lym-1; V(HB) anti-DOTA-link-V(LA) Lym-1 and ligated into the pCANTAB 5E vector. Corresponding diabodies were expressed in Escherichia coli and purified by affinity chromatography. Here we provide a perspective on the power of antibody phage libraries and the possibilities of creating simple molecular formats that can be used en route to the development of new tumor targeting and pretargeting molecules.


Assuntos
Bacteriófagos/genética , Biblioteca Gênica , Fragmentos de Imunoglobulinas/genética , Neoplasias/radioterapia , Radioimunoterapia , Animais , Ensaio de Imunoadsorção Enzimática , Antígenos HLA-DR/genética , Humanos , Camundongos , Peso Molecular
18.
Clin Cancer Res ; 5(10 Suppl): 3219s-3223s, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10541367

RESUMO

Single-agent radioimmunotherapy (RIT) has proven efficacy as a treatment for hematological malignancies, particularly non-Hodgkin's lymphoma. Although promising, RIT has been less effective for solid tumors, in part because they are less radiosensitive. Bone marrow transplantation permits the administration of larger radiopharmaceutical doses, but the results of bone marrow transplantation-supported RIT for solid tumors have been marginal. The purpose of this publication is to provide an overview of promising RIT strategies for solid tumors. It is apparent that combination therapy is required, but optimization of the radiopharmaceutical should be the first step. Metallic radionuclides provide higher tumor radiation doses but not necessarily an improved therapeutic index, that is, the ratio of tumor:normal tissue radiation doses. Biodegradable peptide linkers between the chelated metal and the antibody improve the therapeutic index. Further improvements depend on identification of synergistic therapies which recognize that: (a) continuous, low-dose radionuclide therapy acts through apoptosis; and (b) apoptosis is often blocked because most tumors have ineffective p53 and increased Bcl-2. Taxanes are particularly attractive as synergistic agents for RIT because they induce cell cycle arrest in the radiosensitive G2-M phase and p53-independent apoptosis. Optimal sequence and timing for combined modality RIT are critical to achieve synergy. Data from preclinical and clinical studies will be reviewed to illustrate the potential of these strategies.


Assuntos
Neoplasias/radioterapia , Radioimunoterapia , Animais , Transplante de Medula Óssea , Quelantes , Humanos , Camundongos
19.
Clin Cancer Res ; 5(10 Suppl): 3330s-3336s, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10541382

RESUMO

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.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Radioisótopos de Cobre/uso terapêutico , Antígenos HLA-DR/imunologia , Imunoglobulina G/uso terapêutico , Linfoma não Hodgkin/radioterapia , Radioimunoterapia , Adulto , Idoso , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Radioimunoterapia/efeitos adversos , Dosagem Radioterapêutica
20.
Clin Cancer Res ; 5(3): 533-41, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10100704

RESUMO

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.


Assuntos
Compostos Heterocíclicos/farmacocinética , Linfoma não Hodgkin/metabolismo , Compostos Organometálicos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/uso terapêutico , Compostos Heterocíclicos/uso terapêutico , Humanos , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/radioterapia , Pessoa de Meia-Idade , Compostos Organometálicos/uso terapêutico , Radioimunoterapia , Compostos Radiofarmacêuticos/uso terapêutico , Planejamento da Radioterapia Assistida por Computador
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