Radioimmunotherapy (RIT) for treatment of
hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of
therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-
streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode
cane N,N',N",N'''-tetraacetic (
DOTA)-biotin.
Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the
PRIT approach provided high-contrast
tumor images with minimal blood-pool activity, whereas directly labeled anti-hCD45 Ab produced distinct
tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time.
Therapy experiments showed that (90)Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared with mice treated with conventional RIT using (90)Y-labeled anti-hCD45 Ab at 200 muCi. Because human
CD45 antigens are confined to xenograft
tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and
PRIT using an anti-murine (m)CD45 Ab where the target
antigen is present on normal hematopoietic tissues. After 24 h, 27.3% +/- 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using (131)I-A20-Ab compared with 40.0 +/- 5.4% ID/g for pretargeted (111)In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of
leukemia and may allow for the intensification of
therapy, while minimizing toxicities.