Abstract
1002
Objectives Nonuniform dose distributions, that result from lognormal activity distributions, can be a significant limiting factor in radioimmunotherapy (RIT). This study describes a method of formulating cocktails of radiolabeled antibodies (Ab), which can overcome the therapeutic limitation caused by lognormal distributions.
Methods Four fluorochrome-conjugated monoclonal Abs were added to culture medium (1:1:1:1 μg/mL). MDA-MB-231 human breast cancer cells were then treated with different concentrations of the Ab cocktail. The amount of each antibody, bound to each cell, was quantified with flow cytometry. A spreadsheet was created 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 (SF) of cells upon exposure to cocktails containing different permutations of the Abs.
Results Activity delivered to the least labeled cell can be increased by as much as 270% in quadruple Ab cocktails, relative to the best-performing single Ab. This was reflected in the SF decrease observed as the number of Abs in the cocktail increased. There was also a large difference (up to 16 logs) in the SF when a uniform Ab distribution was assumed and compared with the experimentally observed lognormal distribution.
Conclusions These findings demonstrate promise for improved therapeutic effectiveness of RIT with customized antibody cocktails. A near tripling of the minimum cellular absorbed dose by the cocktail can translate into a substantial increase in overall tumor cell killing. The quantitative comparisons between uniform and lognormal activity distributions highlight the hurdle that lognormal distribution of antigen expression represents. This methodology provides a foundation for the pre-treatment prediction of tumor cell survival when planning RIT treatments for a given patient.
Research Support NIH/NCI 5R25CA019536-32, UMDNJ Foundation Grant #PC85-12.