Radiotoxicity of systemically administered At-211-labeled human/mouse chimeric monoclonal antibody: A long-term survival study with histologic analysis

Purpose: The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide At-211 is of interest as an e ndoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of At-211-labeled chimeric 81C6 in patients, the long-ter m radiotoxicity of this radiopharmaceutical has been evaluated. Methods and Materials: Antibody labeling was performed using N-succinimidyl 3-[At-211]astato-benzoate. After an initial dose-finding experiment, a sec ond toxicity study was carried out at 4 dose levels in groups of 30 nonthyr oid blocked B6C3F(1) mice per group (15 males, 15 females). Male mice recei ved either saline or 15-81 kBq/g and females received either saline or 16-8 3 kBq/g of At-211-labeled antibody. Ten animals (5 males, 5 females) were f ollowed for 6 months and the remainder for 1 year. Results: The lethal dose in 10% of animals (LD10) for At-211-labeled chimer ic 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects-periv ascular fibrosis of the intraventricular septum of the heart, bone marrow s uppression, splenic white pulp atrophy, and spermatic maturational delay-ge nerally were confined to a few animals receiving the highest doses of label ed antibody. Conclusions: The LD10 of At-211-labeled chimeric 81C6 in this mouse strain was about half that of [At-211]astatide. These results establish the precli nical maximum tolerated dose of At-211-labeled chimeric 81C6 and define in the mouse the target organs for toxicity. These studies will be useful for determining starting doses for clinical studies with At-211-labeled chimeri c 81C6. (C) 1999 Elsevier Science Inc.