Radioimmunotherapy of Neoplastic Meningitis in Rats Using an α-Particle-emitting Immunoconjugate

Abstract

Because of their short range and high linear energy transfer, α-particles may be particularly effective in the treatment of neoplastic meningitis. Monoclonal antibody 81C6 was labeled with α-particle-emitting ²¹¹At using N-succinimidyl3-[²¹¹At]astatobenzoate, and the efficacy and toxicity of this immunoconjugate were evaluated in an athymic rat model. Animals were given injections via a chronic indwelling catheter with 5 × 10⁵ TE-671 human rhabdomyosarcoma cells and treated 8 days later with single intrathecal doses of either saline or 4–18 µCi of ²¹¹At-labeled specific 81C6 antibody or isotype-matched control ²¹¹At-labeled 45.6 antibody. In the first experiment, 4, 7, and 13 µCi ²¹¹At-labeled 81C6 produced statistically significant (P = 0.004-0.02) increases in median survival of 33, 29, and 51%, respectively, as compared with saline. Two of 10 animals receiving the 13-µCi dose lived for 6 months before being killed for histological analysis. In the second experiment, 12 µCi of ²¹¹At-labeled 45.6 did not increase median survival significantly relative to saline control, while 12 µCi of ²¹¹At-labeled 81C6 increased median survival by 113% (P < 0.005) and resulted in 33% apparent cures. Five of 10 animals receiving 18 µCi of ²¹¹At-labeled 81C6 survived until they were killed at 295 days. An additional study was performed in animals given intrathecal injections of 5 × 10⁶ TE-671 cells and given a single dose of 18 µCi of ²¹¹At-labeled 81C6 or ²¹¹At-labeled 45.6. At this higher cell number, significantly prolonged survival was still seen for specific antibody as compared with saline (P < 0.001) and control antibody (P < 0.05). These results suggest that treatment with ²¹¹At-labeled monoclonal antibodies may be a valuable approach for neoplastic meningitis.