期刊
JOURNAL OF NUCLEAR MEDICINE
卷 49, 期 9, 页码 1537-1545出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.107.049833
关键词
astatination; At-211; radioimmunotherapy
资金
- Swedish Cancer Society [3548]
- Swedish Research Council [K2007-53X-20321-01-3]
- King Gustaf V Jubilee Clinic Cancer Research Foundation in Gothenburg, Sweden
At-211-labeled tumor-specific antibodies have long been considered for the treatment of disseminated cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. Methods: The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. Results: The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0 +/- 0.06 (mean +/- SD), 0.44 +/- 0.06, and 0.29 +/- 0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. Conclusion: The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
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