**8. Radioimmunotherapy**

The first theory on the existence of proteins with specific binding capabilities to pathogenic organisms, thus acting as "magic bullet"', was postulated at the end of the 19th century by the german pathologist Paul Ehrlich (Enelich, 1906). He was the first to recognise antibodies for their ability to differentiate between normal cells and transformed malignant cells. He specifically introduced immunotherapy as a potential treatment modality for targeting and treating tumors. After it had been recognized in 1950 that proteins could be labeled with 131I without significantly altering their immunological specificity (Eisen & Keston, 1950), Pressman and Korngold tested the tumor-targeting potential of a 131I-labeled rabbit antiserum in rats bearing osteosarcoma and confirmed preferential antibody uptake in the tumor xenografts (Pressman & Korngold, 1953). The first clinical trial investigated the therapeutic efficacy of radiolabeled antibodies was performed in the 1950s by Beierwaltes, who treated fourteen patients with metastatic melanoma with 131I-labeled rabbit antibodies and reported a pathologically confirmed remission in one patient (Beierwaltes, 1974). In 1965, Gold and Freedman discovered carcinoembryonic antigen (CEA), the first well defined tumor-associated antigen. The purified polyclonal anti-CEA antibodies were shown to localize to CEA expressing tumors in vivo (Gold & Freedman, 1965). In the late 1970s, Goldenberg and colleagues successfully targeted colon cancer in patients using a polyclonal goat anti-CEA antiserum (Goldenberg et al., 1978). Nowadays, CEA has not only become one of the most extensively used tumor markers in clinical oncology, but also due to its pronounced expression in various carcinomas, it is one of the most targeted antigens in RIT. In 1975, Köhler and Milstein reformed the field of radioimmunotargeting as they introduced the hybridoma

technology, a method that made it possible to produce large quantities of monoclonal antibodies with high purity and reproducibility (Kohler & Milstein, 1975). Since then, numerous antigen-antibody systems have been established and several of the antibodies have been taken to clinical trials. Radioimmunotherapy is a method of selectively delivering radionuclides with toxic emissions to cancer cells, while reducing the dose to normal tissues. Using mAbs labeled with radionuclides has two major advantages over the application of mAbs conjugated with either drugs or toxins. Firstly, tumor cells not expressing the target antigen can still be sterilized by the so-called crossfire phenomenon, i.e., radiation energy emitted by radionuclides bound to antibodies targeting adjacent tumor cells. Secondly, radionuclides are not subject to multidrug resistance. Although promising, RIT has been less effective for solid tumors, in part because they are less radiosensitive. However, early micrometatasis of breast cancer have been demonstrated to be radiosensitive (Koppe et al., 2005). On the other hand, an advantage of RIT is that it can target small metastatic lesions that are undetected by conventional scanning and would otherwise remain untreated. In addition, RIT is able to target multiple metastases throughout the body in a single treatment.
