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

Abstract

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 (T1/2 = 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. ©2009 American Association for Cancer Research.