ADVANTAGE OF RESIDUALIZING RADIOLABELS FOR AN INTERNALIZING ANTIBODY AGAINST THE B-CELL LYMPHOMA ANTIGEN, CD22

LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiola beled, has a high sensitivity for detecting B-cell, non-Hodgkin's lymp homa (NHL), as well as an antitumor efficacy in therapeutic applicatio ns. The aim of this study was to determine whether intracellularly ret ained radiolabels have an advantage in the diagnosis and therapy of ly mphoma with LL2. In vitro studies showed that iodinated LL2 is intrace llularly catabolized, with a rapid release of the radioiodine from the cell. In contrast, residualizing radiolabels, such as radioactive met als, are retained intracellularly for substantially longer. In vivo st udies were performed using LL2-labeled with radioiodine by a non-resid ualizing (chloramine-T) or a residualizing method (dilactitol-tyramine , DLT), or with a radioactive metal (In-111). The biodistribution of a mixture of I-125 (non-residualizing chloramine-T compared to residual izing DLT), In-111-labeled LL2 murine IgG2a or its fragments [F(ab')(2 ), Fab'], as well as its humanized, CDR-grafted form, was studied in n ude mice bearing the RL human B-cell NHL cell line. Radiation doses we re calculated from the biodistribution data according to the Medical I nternational Radiation Dose scheme to assess the potential advantage f or therapeutic applications. At all assay times, tumor uptake was high er with the residualizing labels (i.e., In-111 and DLT-I-125) than wit h the non-residualizing iodine label. For example, tumor/blood ratios of In-111-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non -residualizing iodinated IgG on days 3, 7 and 14, respectively. Simila r results were obtained for DLT-labeled IgG and fragments with residua lized radiolabels. Tumor/organ ratios also were higher with residualiz ing labels. No significant differences in tumor, blood and organ uptak e were observed between murine and humanized LL2. The conventionally i odinated anti-CD20 antibody, 1F5, had tumor uptake values comparable t o those of iodinated LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies such as LL2, labeling with intracellularly retained isotope s has an advantage over released ones, which justifies further clinica l trials with residualizing In-111-labeled LL2 for diagnosis, and resi dualizing I-131 and Y-90 labels for therapy.