Targeted α-particle radiation using the radioisotope ²²⁵Ac is a promising form of therapy for various types of cancer. Historic obstacles to the use of ²²⁵Ac have been the difficulty in finding suitable chelators to stably attach it to targeting vehicles such as peptides and monoclonal antibodies, the low specific activities of the products, and the lack of cost-effective radiolabeling procedures. We initially solved the first problem with a procedure involving 2 chemical steps that has been used as a standard in preclinical and clinical studies. However, this procedure involves the loss of 90% of the input ²²⁵Ac. A more efficient, economical process is needed to facilitate the more widespread use of ²²⁵Ac. Methods: We conjugated representative antibodies with 2 forms of DOTA as well as other chelators as controls. We developed conditions to radiolabel these constructs in 1 chemical step and characterized their stability, immunoreactivity, biodistribution, and therapeutic efficacy in healthy and tumor-bearing mice. Results: DOTA–antibody constructs were labeled to a wide range of specific activities in 1 chemical step at 37°C. Radiochemical yields were approximately 10-fold higher, and specific activities were up to 30-fold higher than with the previous approach. The products retained immunoreactivity and were stable to serum challenge in vitro and in mice. Labeling kinetics of DOTA–antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through an N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs produced specific therapeutic responses in a mouse model of acute myeloid leukemia. Conclusion: We have characterized an efficient, 1-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with ²²⁵Ac at high specific activity. We propose that this technology greatly expands the possible clinical applications of ²²⁵Ac monoclonal antibodies.

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