Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model

Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with beta-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. alpha-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to beta-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used Bi-213 in mice with human leukemia xenografts. Results demonstrated excellent localization of Bi-213-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5% +/- 1.1% of the injected dose of Bi-213 was delivered per gram of tumor. alpha-imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after Bi-213-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a beta-emitting radionuclide (Y-90) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of Bi-213-DOTA-biotingiven 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 mu Ci of Bi-213- or Y-90-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for more than 100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an alpha-emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia. (Blood. 2011;118(3):703-711)