The Advantage of Antibody Cocktails for Targeted Alpha Therapy Depends on Specific Activity

Abstract

Nonuniform dose distributions among disseminated tumor cells can be a significant limiting factor in targeted α 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 α-particle emitters 211 At, 213 Bi, and 225 Ac. 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 α 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.

In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy

“…Heterogeneous distribution can influence the amount of ionizations traversing to the DNA of the cell causing irreparable DBS, as described by Pasternak et al (9). The advantage of increasing the MA of labelled antibodies by an antibody cocktail caused a more homogenous binding to the cells and increased the cell-killing ability of α-emitters [9]. …”

A preliminary study on treatment of human breast cancer xenografts with a cocktail of paclitaxel, doxorubicin, and 131I-anti-epithelial cell adhesion molecule (9C4)

“…It has been hypothesized that the mechanism behind this discrepancy is not solely due to differences in radiosensitivity but also due to widely varying degrees of antibody (Ab) binding to the tumor cells. [3][4][5][6] Identifying appropriate antigens to target remains a challenge in the development of immunotherapy agents. The epithelial cell adhesion molecule (EpCAM) is one possible target antigen that has been shown previously to be expressed significantly more on cancer cells than normal tissue.…”

“…It has been hypothesized that the mechanism behind this discrepancy is not solely due to differences in radiosensitivity but also due to widely varying degrees of antibody (Ab) binding to the tumor cells. [3456]…”

The Expression Profile and Textural Characteristics of C595-Reactive MUC1 in Pancreatic Ductal Adenocarcinoma for Targeted Radionuclide Therapy

“…The cellular heterogeneity of PDAC cells complicates the identification of an effective TRT target [5,6]. The expression of a receptor within and between individual PDAC cells can vary significantly and has been linked to the development of treatment resistance [7].…”