**11.9 Improving the internalization of the radiolabeled mAb**

One significant factor that influences the absorbed radiation dose to the tumor is the fate of the radiolabel after internalization of the radiolabeled mAb into the tumor cells. In case of internalisation, the radionuclides will come closer to the critical radiation target, i.e. nuclear DNA. Internalization of the antibody depends on various factors including the antibody, the targeted antigen and the tumor cells. On the other hand, internalisation might be disadvantageous, if it leads to quick degradation of the targeting agent followed by diffusion and elimination of the radionuclide (Boswell et al., 2007). Most antibodies including those that target antigens located on the surface of the tumor cells such as anti-CEA antibodies, are eventually catabolized. Intracellular degradation of the targeting agent can be prevented by e.g. dextranation (Bue et al., 2000). Radiolabeling of antibodies with 90Y or 177Lu is performed by linking these radionuclides to chelators (DTPA or DOTA) which are chemical moieties that complex free metal ions. These chelators are conjugated to the antibodies and subsequently to the radiolabel. After catabolization of mAbs labeled with 90Y- or 177Lu-DTPA/-DOTA, the catabolic products are conjugated to, in most cases, lysine (e.g. 90Y- or 177Lu-DOTA-lysine). Whereas radioiodinated tyrosine is excreted by the cell, the 90Y- or 177Lu-DTPA/DOTA-lysine metabolites are trapped within the lysosomes, thereby increasing the tumor retention time of these radiolabels (Koppe et al., 2005). Cellular excretion can also be limited if the radionuclides are of metal type, e.g. indium or yttrium, and this is due to intracellular retention of metal containing catabolic products (Press et al., 1996).
