Radioimmunotherapy of cancer with high linear energy transfer (LET) radiation delivered by radionuclides emitting α-particles or Auger electrons

Radioimmunotherapy (RIT) aims to selectively deliver radionuclides emitting alpha-particles, beta-particles or Auger electrons to tumors by conjugation to monoclonal antibodies (mAbs) that recognize tumor-associated antigens/receptors. The approach has been most successful for treatment of non-Hodgkin's B-cell lymphoma but challenges have been encountered in extending these promising results to the treatment of solid malignancies. These challenges include the low potency of beta-particle emitters such as I-131, Lu-177 or Y-90 which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET = 0.1-1.0 keV/mu m). Furthermore, since the beta-particles have a 2-10 mm range, there has been dose-limiting non-specific toxicity to hematopoietic stem cells in the bone marrow (BM) due to the cross-fire effect. Conjugation of mAbs to alpha-particle-emitters (e.g. Ac-225, Bi-213, Pb-212 or At-211) At) or Auger electron -emitters (e.g. In-111, Ga-67, I-123 or I-125) would increase the potency of RIT due to their high LET (50-230 keV/mu m and 4 to 26 keV/mu m, respectively). In addition, alpha-particles have a range in tissues of 28-100 mu m and Auger electrons are nanometer in range which greatly reduces or eliminates the cross-fire effect compared to beta-particles, potentially reducing their non-specific toxicity to the BM. In this review, we describe the results of preclinical and clinical studies of RIT of cancer using radioimmunoconjugates emitting alpha-particles or Auger electrons, and discuss the potential of these high LET forms of radiation to improve the outcome of cancer patients. (C) 2015 Elsevier B.V. All rights reserved.