Targeted α-therapy: past, present, future?

Monoclonal antibodies have become a viable strategy for the delivery of therapeutic, particle emitting radionuclides specifically to tumor cells to either augment anti-tumor action of the native antibodies or to solely take advantage of their action as targeting vectors. Proper and rational selection of radionuclide and antibody combinations is critical to making radioimmunotherapy (RIT) a standard therapeutic modality due to the fundamental and significant differences in the emission of either α- and β-particles. The α-particle has a short path length (50–80 µm) that is characterized by high linear energy transfer (100 keV µm⁻¹). Actively targeted α-therapy potentially offers a more specific tumor cell killing action with less collateral damage to the surrounding normal tissues than β-emitters. These properties make targeted α-therapy an appropriate therapy to eliminate minimal residual or micrometastatic disease. RIT using α-emitters such as ²¹³Bi, ²¹¹At, ²²⁵Ac, and others has demonstrated significant activity in both in vitro and in vivo model systems. Limited numbers of clinical trials have progressed to demonstrate safety, feasibility, and therapeutic activity of targeted α-therapy, despite having to traverse complex obstacles. Further advances may require more potent isotopes, additional sources and more efficient means of isotope production. Refinements in chelation and/or radiolabeling chemistry combined with rational improvements of isotope delivery, targeting vectors, molecular targets, and identification of appropriate clinical applications remain as active areas of research. Ultimately, randomized trials comparing targeted α-therapy combined with integration into existing standards of care treatment regimens will determine the clinical utility of this modality.