Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis.
OBJECTIVE
The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide 211At is of interest as an endoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of 211At-labeled chimeric 81C6 in patients, the long-term radiotoxicity of this radiopharmaceutical has been evaluated.


METHODS
Antibody labeling was performed using N-succinimidyl 3-[211At]astato-benzoate. After an initial dose-finding experiment, a second toxicity study was carried out at 4 dose levels in groups of 30 nonthyroid blocked B6C3F1 mice per group (15 males, 15 females). Male mice received either saline or 15-81 kBq/g and females received either saline or 16-83 kBq/g of 211At-labeled antibody. Ten animals (5 males, 5 females) were followed for 6 months and the remainder for 1 year.


RESULTS
The lethal dose in 10% of animals (LD10) for 211At-labeled chimeric 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects--perivascular fibrosis of the intraventricular septum of the heart, bone marrow suppression, splenic white pulp atrophy, and spermatic maturational delay--generally were confined to a few animals receiving the highest doses of labeled antibody.


CONCLUSIONS
The LD10 of 211At-labeled chimeric 81C6 in this mouse strain was about half that of [211At]astatide. These results establish the preclinical maximum tolerated dose of 211At-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 211At-labeled chimeric 81C6.
McLendon
R E
RE
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Archer
G E
GE
Larsen
R H
RH
Akabani
G
G
Bigner
D D
DD
Zalutsky
M R
MR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001246:Astatine / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000922:Immunotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009928:Organ Specificity; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000627:therapeutic use*; D012737:Sex Factors
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D000922:Immunotoxins; D019275:Radiopharmaceuticals; D001246:Astatine