Alpha-particle radioimmunotherapy with astatine-211 and bismuth-213

Abstract

Radioimmunotherapy (RIT) with β-emitting radionuclides is an established part of the treatment of some haematological malignancies. Over the past two decades, new αemitters with a short half-life have also emerged and started to be considered for use in RIT [1], as Cherel and colleagues, of the Department of Cancerology, University of Nantes, INSERM U601, France, have pointed out. The specific properties of α-particles (i.e., a shorter path length than β-particles and a high linear energy transfer) offer new clinical opportunities, complementary to those afforded by β-RIT. However, the development of α-RIT is still in the preclinical stage, for several reasons: the radiolabelling methods need to be optimized to ensure in vivo stability of the radiopharmaceuticals; some radionuclides have complex decay schemes with daughters emitting further αparticles whose toxicity needs to be investigated; and the administration modalities need to be improved to allow the delivery of high doses to tumour targets. Furthermore, a comprehensive analysis of the specific events occurring at cell and tissue level in response to α-irradiation is needed to establish the best therapeutic associations, both with other treatments for residual disease and with consolidation treatments. Zalutsky et al., in a paper on α-RIT with astatine-211labelled monoclonal antibodies (At-mAbs), highlight, as a particularly attractive feature of the therapy, the ability to select radionuclides and targeting vehicles best suited to the specific clinical application [2]. They remark on the growing interest in the possibility of using combinations of monoclonal antibodies (mAbs) specifically reactive to receptors and antigens expressed in tumour cells to ensure selective delivery of α-emitting radiohalogen At to malignant cell populations, but point out that this concept is proving slow to reach the clinic. Zalutsky notes that one of the major obstacles has been the short supply of the radionuclides (in turn due to the limited availability of accelerators with the medium-energy α-particle beams needed to produce At through bombardment of natural bismuth metal targets). Clinically useful amounts of At can be obtained by utilizing incident α-beams of 28– 29 MeV. Unfortunately, however, there are few cyclotrons worldwide equipped with beams of this type. Other obstacles include the need for suitable radiochemistry methods operant at high activity levels and a lack of data on the toxicity of α-particle emitters in humans. Finally, the development of mAbs is struggling to keep up with needs. Despite these difficulties, this is a very active field of research. A number of vehicles have now been developed, targeting various tumours. Let us look at some recent examples. The powerful synergy between mAbs and radionuclide technologies was recently underlined by Martin Brechbiel of the Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, NCI, NIH, MD, USA. mAbs have become a viable strategy for the delivery of RIT to tumour cells, either to augment the antitumour action of the native antibodies or simply to exploit their action as targeting vectors [3]. Rational selection of radionuclide Eur J Nucl Med Mol Imaging (2008) 35:1729–1733 DOI 10.1007/s00259-008-0856-4