Targeted alpha-therapy: past, present, future?

Abstract

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 alpha- and beta-particles. The alpha-particle has a short path length (50-80 microm) that is characterized by high linear energy transfer (100 keV microm(-1)). Actively targeted alpha-therapy potentially offers a more specific tumor cell killing action with less collateral damage to the surrounding normal tissues than beta-emitters. These properties make targeted alpha-therapy an appropriate therapy to eliminate minimal residual or micrometastatic disease. RIT using alpha-emitters such as (213)Bi, (211)At, (225)Ac, 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 alpha-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 alpha-therapy combined with integration into existing standards of care treatment regimens will determine the clinical utility of this modality.

Figure 1

Decay scheme for ¹⁴⁹Tb

Figure 2

Decay scheme for ²¹¹At

Figure 3

Decay scheme for ²¹²Pb and ²¹²Bi

Figure 4

Structures of DTPA, cyclic dianhydride of DTPA, CyDTPA, 1B4M-DTPA, and CHX-A” DTPA

Figure 5

Decay scheme for ²²⁵Ac and ²¹³Bi

Figure 6

Decay scheme for ²²³Ra

Figure 7

Structures of DOTA, and the bifunctional analogs C-DOTA, PA-DOTA, CHX-DOTA, lys-DOTA, and TCMC

Figure 8

Structures of the bifunctional chelating agent BF-HEHA