Radioimmunotherapy of breast cancer metastases with α-particle emitter ²²⁵Ac: Comparing efficacy with ²¹³Bi and ⁹⁰Y

α-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. α-Particle emitter ²¹³Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of ²²⁵Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T_1/2 = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the α-particle emitter ²²⁵Ac, parent of ²¹³Bi, in a mouse model of breast cancer metastases. Asingle administration of ²²⁵Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in ∼67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with ²²⁵Ac-7.16.4 is significantly more effective than ²¹³Bi-7.16.4 (120 μCi; median survival, 61 days; P = 0.001) and ⁹⁰Y-7.16.4 (120 μCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that ²²⁵Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from ²¹³Bi and 2.4 Gy from ⁹⁰Y. Biodistribution studies revealed that ²²⁵Ac daughters, ²²¹Fr and ²¹³Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest ²²⁵Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients.