title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Radiation Research, Department of Radiology, New Jersey Medical School Cancer Center, Rutgers, State University of New Jersey, Newark, New Jersey; and.
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Pasternack
authors.affiliation: Division of Radiation Research, Department of Radiology, New Jersey Medical School Cancer Center, Rutgers, State University of New Jersey, Newark, New Jersey; and.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Domogauer
authors.affiliation: Division of Radiation Research, Department of Radiology, New Jersey Medical School Cancer Center, Rutgers, State University of New Jersey, Newark, New Jersey; and.
authors.forename: Alisha
authors.initials: A
authors.lastname: Khullar
authors.affiliation: Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: John M
authors.initials: JM
authors.lastname: Akudugu
authors.affiliation: Division of Radiation Research, Department of Radiology, New Jersey Medical School Cancer Center, Rutgers, State University of New Jersey, Newark, New Jersey; and rhowell@rutgers.edu.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Howell
mesh_terms: D000186:Actinium; D000465:Algorithms; D000512:Alpha Particles / Q000627:therapeutic use*; D000906:Antibodies / Q000378:metabolism / Q000627:therapeutic use*; D001246:Astatine; D001729:Bismuth; D001943:Breast Neoplasms / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004338:Drug Combinations; D005260:Female; D006801:Humans; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D004338:Drug Combinations; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D000186:Actinium; D001729:Bismuth; D001246:Astatine
keywords: Monte Carlo; alpha particle; antibody cocktails; disseminated tumor cells; flow cytometry; isolated tumor cells; radioimmunotherapy; radionuclide; specific activity; targeted alpha therapy