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High-Level Production of -Particle–Emitting ²¹¹At and Preparation of ²¹¹At-Labeled Antibodies for Clinical Use

Departments of Radiology and Pathology, Duke University Medical Center, Durham, North Carolina

In vitro and in vivo studies in human glioma models suggest that the antitenascin monoclonal antibody 81C6 labeled with the 7.2-h–half-life -particle emitter ²¹¹At might be a valuable endoradiotherapeutic agent for the treatment of brain tumors. The purpose of this study was to develop methods for the production of high levels of ²¹¹At and the radiosynthesis of clinically useful amounts of ²¹¹At-labeled human/mouse chimeric 81C6 antibody. Methods: ²¹¹At was produced through the ²⁰⁹Bi(, 2n)²¹¹At reaction using an internal target system and purified by a dry distillation process. Antibody labeling was accomplished by first synthesizing N-succinimidyl 3-[²¹¹At]astatobenzoate from the corresponding tri-n-butyl tin precursor and reacting it with the antibody in pH 8.5 borate buffer. Quality control procedures consisted of methanol precipitation, size-exclusion high-performance liquid chromatography (HPLC), and pyrogen and sterility assays, as well as determination of the immunoreactive fraction by a rapid procedure using a recombinant tenascin fragment coupled to magnetic beads. Results: A total of 16 antibody labeling runs were performed. Using beam currents of 50–60 µA -particles and irradiation times of 1.5–4.5 h, the mean ²¹¹At production yield was 27.75 ± 2.59 MBq/µA.h, and the maximum level of ²¹¹At produced was 6.59 GBq after a 4-h irradiation at 55 µA. The decay-corrected distillation yield was 67% ± 16%. The yield for the coupling of the ²¹¹At-labeled active ester to the antibody was 76% ± 8%. The fraction of ²¹¹At activity that eluted with a retention time corresponding to intact IgG on HPLC was 96.0% ± 2.5%. All preparations had a pyrogen level of <0.125 EU/mL and were determined to be sterile. The mean immunoreactive fraction for these 16 preparations was 83.3% ± 5.3%. Radiolysis did not interfere with labeling chemistry or the quality of the labeled antibody product. Conclusion: These results show that it is feasible to produce clinically relevant activities of ²¹¹At-labeled antibodies and have permitted the initiation of a phase I trial of ²¹¹At-labeled chimeric 81C6 administered directly into the tumor resection cavities of brain tumor patients.

Key Words: radioimmunotherapy • ²¹¹At • -particles • monoclonal antibodies

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