期刊
JOURNAL OF NUCLEAR MEDICINE
卷 55, 期 12, 页码 2012-2019出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.114.141580
关键词
radioimmunotherapy; targeted alpha therapy; antibody cocktails; isolated tumor cells; disseminated tumor cells; flow cytometry; Monte Carlo; radionuclide; specific activity; alpha particle
资金
- NIH/NCI grant [5R25CA019536-32]
- New Jersey Health Care Foundation grant [PC85-12]
- New Jersey Commission on Cancer Research [DFHS13PPCO17]
- NATIONAL CANCER INSTITUTE [R25CA019536] Funding Source: NIH RePORTER
Nonuniform dose distributions among disseminated tumor cells can be a significant limiting factor in targeted a therapy. This study examines how cocktails of radiolabeled antibodies can be formulated to overcome this limitation. Methods: Cultured MDA-MB-231 human breast cancer cells were treated with different concentrations of a cocktail of 4 fluorochrome-conjugated monoclonal antibodies. The amount of each antibody bound to each cell was quantified using flow cytometry. A spreadsheet was developed to arm the antibodies with any desired radionuclide and specific activity, calculate the absorbed dose to each cell, and perform a Monte Carlo simulation of the surviving fraction of cells after exposure to cocktails of different antibody combinations. Simulations were performed for the alpha-particle emitters At-211, Bi-213, and Ac-225. Results: Activity delivered to the least labeled cell can be increased by 200%-400% with antibody cocktails, relative to the best-performing single antibody. Specific activity determined whether a cocktail or a single antibody achieved greater cell killing. With certain specific activities, cocktails outperformed single antibodies by a factor of up to 244. There was a profound difference (<= 16 logs) in the surviving fraction when a uniform antibody distribution was assumed and compared with the experimentally observed nonuniform distribution. Conclusion: These findings suggest that targeted a therapy can be improved with customized radiolabeled antibody cocktails. Depending on the antibody combination and specific activity of the radiolabeled antibodies, cocktails can provide a substantial advantage in tumor cell killing. The methodology used in this analysis provides a foundation for pretreatment prediction of tumor cell survival in the context of personalized cancer therapy.
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