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 α-particles, β-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 β-particle emitters such as ¹³¹I, ¹⁷⁷Lu or ⁹⁰Y which have been commonly conjugated to the mAbs, due to their low linear energy transfer (LET=0.1-1.0keV/μm). Furthermore, since the β-particles have a 2-10mm 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 α-particle-emitters (e.g. ²²⁵Ac, ²¹³Bi, ²¹²Pb or ²¹¹At) or Auger electron-emitters (e.g. ¹¹¹In, ⁶⁷Ga, ¹²³I or ¹²⁵I) would increase the potency of RIT due to their high LET (50-230keV/μm and 4 to 26keV/μm, respectively). In addition, α-particles have a range in tissues of 28-100μm and Auger electrons are nanometer in range which greatly reduces or eliminates the cross-fire effect compared to β-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 α-particles or Auger electrons, and discuss the potential of these high LET forms of radiation to improve the outcome of cancer patients.