Pretargeted α emitting radioimmunotherapy using 213Bi 1,4,7,10-tetraazacyclododecane-N,N′,N",N′"-tetraacetic acid-biotin

Purpose: The use of an a emitter for radioimmuno-therapy has potential advantages compared with beta emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of short-lived alpha emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretar-geted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the alpha emitter, Bi-213-labeled biotin. Experimental Design: Biotinidase-resistant 7,10-tetra-azacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA)-bio-tin was radiolabeled with (205,206) Bi or (213) Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 mug) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored. Results: Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted. At therapeutically effective doses renal toxicity was observed. Conclusions: Bi-213-DOTA-biotin, directed by the Pre-target method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.