90Y-labeled antibody uptake by human tumor xenografts and the effect of systemic administration of EDTA.

Abstract

A human tumor xenograft model was used to compare the tumor and normal tissue uptake of a tumor-associated monoclonal antibody radiolabeled with 125I or 90Y. Nude mice bearing SC xenografts of the human colon adenocarcinoma, HT29, were injected with a mixture of 125I- and 90Y-DTPA-labeled AUA1 monoclonal antibody, which recognizes an antigen expressed on the surface of the tumor cells. In addition, the effect of systemic ethylenediaminetetraacetic acid (EDTA) administration on 90Y-labeled antibody clearance, tumor uptake of antibody and bone accumulation of 90Y was studied in a nude mouse model of intraperitoneal cancer. Both the absolute amount (%id.g-1) and the tumor:normal tissue ratios were superior for the 90Y-labeled antibody, compared with the iodinated antibody, with the notable exception of bone. These results suggest that 90Y is a preferable isotope to iodine for radioimmunotherapy of solid masses, but that myelotoxicity, due to bone uptake of released 90Y, will limit the radiation dose which can be given when DTPA is used to chelate the 90Y. The 90Y-labeled antibody showed similar serum stability in vitro in the presence or absence of EDTA after incubation for up to 48 h. In vivo, urine excretion of 90Y was significantly enhanced in mice receiving daily injections of 20 mg EDTA for 3 days, commencing 2 h after intraperitoneal antibody administration, compared with control mice. There was no significant difference in the tumor uptake of 90Y-labeled antibody in EDTA-treated and control mice at any time-point up to 9 days postinjection. However, the bone levels of 90Y were significantly reduced in EDTA-treated mice at all times from 1 to 9 days. Based on these results, it should be possible to increase the amount of 90Y-labeled antibody administered, by chelating the released 90Y with systemic EDTA to facilitate its excretion, without compromising tumor uptake of radiolabeled antibody.