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ARTICLES: Robert M. Sharkey and David M. Goldenberg Targeted Therapy of Cancer: New Prospects for Antibodies and Immunoconjugates CA Cancer J Clin 2006; 56: 226-243 [Abstract] [Full text] [PDF]

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Targeted cancer therapy with ultra-short range Auger electron emitting isotopes

Tom C. Karagiannis   (19 September 2006)

Targeted cancer therapy with ultra-short range Auger electron emitting isotopes 19 September 2006
Tom C. Karagiannis, Research Officer and Educator Peter MacCallum Cancer Centre and The University of Melbourne, Victoria, Australia Send letter to journal: Re: Targeted cancer therapy with ultra-short range Auger electron emitting isotopes tom.karagiannis{at}petermac.org Tom C. Karagiannis	As Sharkey and Goldenberg highlight in their article (1), the long-heralded potential of targeted therapy with anticancer antibodies is finally being realized. Being part of a very small, but committed group of researchers, investigating Auger electron emitters, it was particularly encouraging to note the discussion of this unique class of isotopes in the context of radioimmunotherapy. Given that specialists outside the field generally have very limited knowledge of these isotopes, I thought that it may be appropriate to somewhat expand the discussion of Auger electron emitting isotopes for interested readers. In the early 1920s, Pierre Auger discovered the process of transition of electrons between orbital shells and the consequent ejection of low energy electrons (2), and it was later discovered that Auger electrons are also emitted by radioisotopes that decay by electron capture or internal conversion. For example, the prototype Auger emitter [125]I emits an average of 21 low energy electrons per decay (3). In regards to targeted cancer therapy, the important feature is that the majority of these electrons traverse only molecular ranges (1-20 nanometres) in biological tissues (3). The intense and highly localized DNA damage induced by [125]I was highlighted by a seminal study by Martin and Haseltine in which it was shown that the vast majority of the radiochemical damage occurs within 15-20 angstroms (4-5 nucleotides) from the site of [125]I-decay (4). Numerous other studies using DNA precursors to incorporate [125]I into DNA or DNA binding ligands to localize the isotope in close proximity to DNA have demonstrated the intense DNA damage and cytotoxicity induced by DNA-associated [125]I-decay. In contrast, [125]I is much less efficient (by a factor of approximately 8-10 compared to DNA incorporated isotope) at inducing cytotoxic effects when the isotope is localized on the cell membrane or is confined in the cytoplasm (5). Therefore, realizing the full potential of Auger emitters in radioimmunotherapy requires more sophisticated approaches than simply radiolabelling internalizing anticancer antibodies. Strategies which involve targeting not only to cancer cells but also to the DNA of those cells would be the most appropriate. Dual, receptor and DNA, targeting systems could for example, involve packaging DNA ligands labeled with an Auger electron emitter into liposomes or nanoparticles which can be conjugated to a tumor-specific antibody in such a way, that once the antibody is internalized into cancer cells, the DNA binding drug is released allowing localization of the isotope in close proximity to the DNA. As pointed out by Sharkey and Goldenberg (1), one of the main advantages of radioimmunotherapy over other antibody-based therapies is the ability to kill cancer cells by the bystander or crossfire effect—i.e. killing cells that are not directly labeled with isotope. The crossfire effect, which may circumvent the problems associated with heterogeneous antigen expression and poor penetration of antibodies in tumors, is mainly applicable to beta-emitters which can penetrate up to a few millimeters but also applies to alpha-emitters which have effective ranges of a few cell diameters (micrometer range). By considering our discussion of Auger emitters thus far, it would be reasonable to assume that homogeneous expression of cell-surface receptors is a minimal requirement for successful radioimmunotherapy with these ultra-short range isotopes. However, this dogma was broken by a landmark study by Kassis and colleagues in which it was demonstrated that [125]I induces bystander effects in vivo (6). This adds another dimension to the clinical potential of Auger electron emitting isotopes. With respect to selection of appropriate Auger emitters for targeted cancer therapy, Sharkey and Goldenberg mention [67]Ga, [111]In and [125]I (1). The metal isotopes have an appropriate half-life for radioimmunotherapy (about 3 days for both [67]Ga and [111]In); however, they require more elaborate conjugation chemistry than iodine isotopes. On the other hand, although the direct iodination of tyrosine residues in proteins is a simple and well-characterized reaction, there are issues with the stability of iodinated antibodies in vivo, probably due to the iodophenol group which is analogous to that in endogenous thyroid hormones. Therefore, by using an intermediate iodinated ligand (preferably a DNA binding molecule), both the therapeutic potency and in vivo stability may be improved simultaneously. Nevertheless, the long half-life of [125]I (60 days) is incompatible with antibody pharmacokinetics and imposes severe limitations from a radiation protection standpoint. Therefore, there is interest in the potential therapeutic use of [123]I, which has a much shorter half-life (13.2 hours). Although [123]I is a weaker Auger electron emitter than [125]I, molecular studies suggest only a modest reduction in the DNA breakage efficiency of DNA-associated [123]I compared to [125]I (7). Given the slow clearance of antibodies from the blood, the short-lived [123]I isotope may potentially be more suited to treating cancers of the blood and for clearing metastatic cells in the circulation. Furthermore, targeted [123]I could be appropriate for treating cancers that are amenable to intralesional injection such as malignant gliomas. Ironically, [124]I, which was mainly considered as an unwanted contaminant in the preparation of [123]I in the early reports, is emerging as a useful isotope for both therapy and imaging. This isotope has an appropriate half-life (4 days) and emission profile (positrons and Auger electrons are emitted along with the high energy gamma rays) for both radioimmuno–detection and therapy (8). Although [124]I is already being widely investigated for PET imaging, it is anticipated that as the isotope becomes more widely available, investigation of its therapeutic efficacy due to the Auger emissions will become a priority. Indeed, the growing availability of [124]I has injected further excitement regarding the potential clinical use of Auger electron emitting isotopes. Finally, I would like to reiterate the comments made by Sharkey and Goldenberg (1) that antibody-based pharmaceuticals will continue to grow as the next generation of cancer therapies, and that major improvements are anticipated with the identification of additional cancer-specific targets. Unfortunately, as raised by Sharkey and Goldenberg (1), the cost of these new “biological” therapies, is a significant issue. Indeed, the price of antibody therapy is also staggering in Australia, rendering the pharmaceuticals out of reach for the average paying patient. The prime example is trastuzumab (Herceptin), for which the yearly cost per patient is in the order of $US50,000. The Australian Government has a scheme for funding Herceptin for patients with advanced HER-2 positive breast cancer and, following an intense campaign by the mainstream media and public advocacy in the past year, the antibody has been fast-tracked for approval for subsidization under the Australian Pharmaceutical Benefits scheme, for women with early HER-2 positive breast cancer. Although economic factors are beyond my scope, (like for most others) my hope is that every cancer patient that can benefit from emerging antibody-based therapies has the ability to access the pharmaceuticals. 1. Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin 2006;56(4):226-43. 2. Auger P. Sur les rayons ß secondaires praduit dans un gaz par des rayons X. Comp Rend 1925;180:65-8. 3. Charlton DE, Booz J. A Monte Carlo treatment of the decay of 125I. Radiat Res 1981;87(1):10-23. 4. Martin RF, Haseltine WA. Range of radiochemical damage to DNA with decay of iodine-125. Science 1981;213(4510):896-8. 5. Faraggi M, Gardin I, Stievenart JL, Bok BD, Le Guludec D. Comparison of cellular and conventional dosimetry in assessing self-dose and cross-dose delivered to the cell nucleus by electron emissions of 99mTC, 123I, 111In, 67Ga and 201T1. Eur J Nucl Med 1998;25(3):205-14. 6. Xue LY, Butler NJ, Makrigiorgos GM, Adelstein SJ, Kassis AI. Bystander effect produced by radiolabeled tumor cells in vivo. Proc Natl Acad Sci U S A 2002;99(21):13765-70. 7. Lobachevsky PN, Martin RF. DNA breakage by decay of Auger electron emitters: experiments with 123I-iodoHoechst 33258 and plasmid DNA. Radiat Res 2005;164(6):766-73. 8. Stepanek J, Larsson B, Weinreich R. Auger-electron spectra of radionuclides for therapy and diagnostics. Acta Oncol 1996;35(7):863-8.