RESUMO
PURPOSE: Radionuclides emitting low-energy electrons (Auger and conversion electrons of <50 keV) are potentially useful for cancer therapy when conjugated to an antibody, because they can irradiate the cell to which they bind while producing relatively little irradiation of surrounding cells and tissues. We showed previously the ability of such antibody conjugates to treat micrometastatic, disseminated human B-lymphoma in a severe combined immunodeficient mouse model using an anti-CD74 antibody. In this study, we have evaluated the ability of such conjugates to treat s.c. tumors. EXPERIMENTAL DESIGN: Severe combined immunodeficient mice were injected s.c. with Raji, Daudi, or RL B-lymphoma human tumor cells. Antibodies to CD74, CD20, or HLA-DR were radiolabeled with (111)In or (125)I and injected i.v. at various times starting at day 5, and tumor growth was monitored. Controls included the testing of unlabeled antibodies, labeled nonreactive antibodies, and a combination of the two. RESULTS: Therapy of s.c. B-lymphoma was more difficult than therapy of tumor cells that had been injected i.v. Although large, macroscopic tumors were not effectively treated, therapy was effective on s.c. Daudi tumors on day 36 after injection of this slowly growing tumor, with an (111)In anti-CD74 antibody given in two doses. An anti-CD20 antibody labeled with either (111)In or (125)I was able to effectively treat s.c. RL tumors when given as late as day 16 after tumor inoculation. The largest tumors that were effectively treated were macroscopic thin discs (<2 mm in diameter) growing on the mesentery. CONCLUSION: These results extend previous evidence that antibody conjugates with emitters of low-energy electrons can be effective therapeutic agents for micrometastatic cancer.
Assuntos
Imunoconjugados/uso terapêutico , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Radioimunoterapia , Animais , Antígenos CD20/imunologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Elétrons , Feminino , Antígenos HLA-DR/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Radioisótopos de Índio/uso terapêutico , Injeções Subcutâneas , Radioisótopos do Iodo/uso terapêutico , Masculino , Camundongos , Camundongos SCID , Doses de Radiação , Taxa de Sobrevida , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Antibodies (Abs) conjugated to 177Lu, a relatively low-energy beta-particle emitter, were evaluated in vitro for their cytotoxic activity and in vivo for their therapeutic activity against disseminated B-cell lymphoma xenografts in SCID mice. 177Lu was compared with other beta-particle emitters ((131)I and 90Y), and also with emitters of low-energy electrons (LEEs, meaning Auger and conversion electrons of < 50 keV). The Abs used reacted with CD20, CD74 or HLA-DR, and the target cell was the Raji B lymphoma. Like the other beta-particle emitters, 177Lu was a potent and specific toxic agent in vitro, when conjugated to Abs recognizing high-density antigens. It appeared to be slightly less potent than (131)I per decay, but this difference was relatively small, and would not be a major factor in the selection of the optimal radionuclide for clinical use. The nonspecific toxicity from 177Lu was less than from 90Y, but 177Lu still produced greater nonspecific toxicity in vitro than LEE emitters. The maximum tolerated dose (MTD) of 177Lu-anti-CD74 in SCID mice was 1.81 MBq (49 microCi)/mouse. When this dose was administered on day 5 after tumor inoculation, significant protection was obtained, but considerably less than the protection obtained in previous experiments with LEE emitters (111)In and 67Ga. In conclusion, 177Lu has advantages over other available beta-particle emitters as a therapeutic agent, but its efficacy in the treatment of micrometastases seems to be less than that of LEE emitters, due to greater nonspecific toxicity. This conclusion, however, may not apply to therapy of macroscopic tumors.
Assuntos
Anticorpos/uso terapêutico , Sobrevivência Celular/efeitos da radiação , Lutécio/uso terapêutico , Linfoma de Células B/radioterapia , Radioimunoterapia/métodos , Radioisótopos/uso terapêutico , Animais , Carga Corporal (Radioterapia) , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Metástase Linfática , Linfoma de Células B/diagnóstico , Camundongos , Camundongos SCID , Doses de Radiação , Radiometria , Compostos Radiofarmacêuticos/uso terapêutico , Eficiência Biológica Relativa , Análise de Sobrevida , Resultado do TratamentoRESUMO
A (213)Bi-labeled antibody to CD74 was evaluated as a therapeutic agent for B-cell lymphoma. The alpha-particle emission, with a half-life of 46 min, is appropriate for therapy of micrometastases. The labeled Ab retained full immunoreactivity, and was potent at single-cell kill of the Raji B-lymphoma cell line. Approximately 30 decays of cell-bound (213)Bi was required for a cell kill of 99%, and dosimetry calculations suggested that the cGy dose delivered was sufficient to produce the level of toxicity observed. A non-reactive control Ab, labeled similarly, also produced toxicity, due to decays occurring in the medium, but was approximately 3-fold less potent than the reactive Ab. In a SCID mouse xenograft micrometastatic model, Ab injection at day 2 or day 5 after tumor inoculation resulted in strong, specific suppression of tumor growth, with some apparent cures.