Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model.
OBJECTIVE
The aim of the study was to establish and refine a preclinical model to alpha-immunoradiotherapy of ovarian cancer.


METHODS
At-211 was produced by cyclotron irradiation of a bismuth-209 target and isolated using a novel dry distillation procedure. Monoclonal antibodies were radiohalogenated with the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate and characterized in terms of radiochemical yield and in vitro binding properties. In vitro OVCAR-3 cells were irradiated using an external Cobalt-60 beam, as reference, or At-211-albumin and labeled antibody. Growth assays were used to establish cell survival. A Monte Carlo program was developed to simulate the energy imparted and the track length distribution. Nude mice were used for studies of WBC depression, with various activities of Tc-99m antibodies, as reference, and At-211 antibodies. In efficacy studies, OVCAR-3 cells were inoculated i.p., and animals were treated 2 weeks later. The animals were either dissected 6 weeks later or followed-up for long-term survival.


RESULTS
A rapid distillation procedure, as well as a rapid and high-yield, single-pot labeling procedure, was achieved. From growth inhibition data, the relative biological effectiveness of the alpha-emission for OVCAR-3 cells was estimated to be approximately 5, which is in the same range as found in vivo for hematological toxicity. At-211 MOv18 was found to effectively inhibit the development of tumors and ascites, also resulting in long-term survival without significant toxic effect.


CONCLUSIONS
Use of the short-range, high-linear energy transfer alpha-emitter At-211 conjugated to a surface epitope-recognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001246:Astatine / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002986:Clinical Trials as Topic; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007554:Isotopes / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009010:Monte Carlo Method; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D013997:Time Factors; D014018:Tissue Distribution; D014298:Trimethyltin Compounds / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D001565:Benzoates; D007554:Isotopes; D014298:Trimethyltin Compounds; C061345:N-succinimidyl 3-(trimethylstannyl)benzoate; D001246:Astatine