Cancer radioimmunotherapy with alpha-emitting nuclides

Abstract

In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

Targeted α-particle radiotherapy with 211At-labeled monoclonal antibodies

“…Of the more than 100 known α-particle emitting radionuclides, three have received the most attention for radioimmunotherapy -213 Bi, 211 At and 225 Ac with half lives of 46 min, 7.2 h and 10 days, respectively [1,8,9]. The half life of 213 Bi is so short that it is problematic from a logistical perspective, both in terms of labeling chemistry and patient management.…”

“…Given the short tissue range of α-particles, it would seem counterintuitive to combine them with monoclonal antibodies (mAbs) which diffuse through tissue very slowly, drastically limiting delivery of the radionuclide to the majority of tumor cells. Nonetheless, mAbs have been the most widely evaluated molecular carrier for targeted α-particle therapy and the results to date have been encouraging [7][8][9]. This apparent disconnect is due to the fact that in general, α-emitter radioimmunotherapy is generally pursued in settings in which rapid exposure of the tumor to the labeled mAb can be achieved, for example, by targeting tumors of the blood such as leukemia or those amenable to intracavitary delivery such as ovarian carcinoma.…”

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides 213Bi and 211At

“…While there are a large number of biological agents to choose from, making the choice of an appropriate cancer-targeting agent to carry highly cytotoxic, short half-lived, α-emitting radionuclides is not easy. For systemic delivery, intact monoclonal antibodies (mAbs) and their F(ab′) 2 fragments are questionable for carrying 213 Bi or 211 At due to their inherent properties (6)(7)(8) and unfavorable tumor-targeting pharmacokinetics. Smaller mAb fragments, engineered proteins and peptides are also unfavorable due to their propensity to localize in kidney, although a number of studies to decrease localization have been published (9)(10)(11)(12)(13).…”

“…Smaller mAb fragments, engineered proteins and peptides are also unfavorable due to their propensity to localize in kidney, although a number of studies to decrease localization have been published (9)(10)(11)(12)(13). As an alternative, we have been investigating the use of two different 2-step approachs 2 for targeting 213 Bi and 211 At to cancer cells in vivo termed "pretargeting". In one form of the 2-step pretargeting approach (14,15), monoclonal antibodies (mAbs) are conjugated with a biotin derivative and that conjugate is injected to target the cancer cells.…”

213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe

“…As few as four a-particles traversing the nucleus are sufficient to irreversibly damage a cell (2). The use of a-emitter immunoconjugates is promising in the therapy of minimal residual disease as well as in the elimination of disseminated single tumor cells (3). Successful clinical trials have been done with 213 Bi-HuM195 conjugates targeting CD33 in the treatment of myeloid leukemia as well as with 211 At-antitenascin in malignant glioma with intralesional application after resection of the primary tumor (4,5).…”