Pretargeting radioinimunotherapy of a murine model of adult T-cell leukemia with the α-emitting radionuclide, bismuth 213

We used a pretargeting technique to treat a nonobese diabetic/severe combined immunodeficient murine model of human adult T-cell leukemia with an anti-Tac antibody-streptavidin (HAT-SA) conjugate, which recognizes CD25, followed by bismuth 213 (Bi-213)-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)biotin. In the 3-step pretargeting radioimmunotherapy protocol, HAT-SA (140 or 400 mug) was administered intravenously (i.v.) to bind to the interleukin 2 receptor alpha (IL-2Ralpha; CD25)-expressing tumor cells. After 24 hours, 100 mug of a synthetic clearing agent was administered i.v. to remove unbound circulating HAT-SA conjugate from the circulation. Four hours later, Bi-213-DOTA-biotin was administered i.v. for therapy. Tumor growth was significantly inhibited in 3 trials by using 250 muCi (9.25 MBq) of Bi-213-DOTA-biotin with a pretargeting technique as monitored by serum levels of soluble IL-2Ralpha and/or human beta-2-microglobulin (P<.05, t test) and by survival of tumor-bearing mice in the treatment groups (P<.02, log rank test) as compared with the control groups. No prolongation of survival was observed with a nonspecific antibody-SA conjugate or in the absence of the radionuclide. Additionally, no prolongation of survival resulted from administration of Bi-213 directly linked to intact HAT. Furthermore, there was no prolongation of survival when the beta-emitting radionuclide yttrium 90 instead of the alpha-emitting radionuclide Bi-213 was used. The pretargeting approach with Bi-213 inhibited tumor growth more effectively than did immunotherapy with unmodified HAT. The best results were obtained with combination therapy that involved Bi-213-DOTA-biotin with a pretargeting technique supplemented by 4 weekly doses of HAT. The findings of this study support the use of this combination approach in a clinical trial in patients with IL-2Ralpha-expressing leukemias.