Successful therapy of human cancer with monoclonal antibodies (mAbs) has not yet been achieved, but remains a possibility. Our previous experiments demonstrated that, for most Abs reacting with cell surface antigens, binding is predominantly irreversible, and bound Ab is gradually internalized and degraded, with a half-life of approximately one day. We have also shown that, depending on the radioisotope used to label the Ab, the isotope may be either rapidly excreted from the cell after degradation (example: conventional 125I), or retained for prolonged periods (examples: 111 In or iodinated dilactitol-tyramine, DLT). These results suggest that the processing of a particular isotope after Ab catabolism is a critical factor. Iodinated molecules such as disaccharide derivatives are known to be trapped within lysosomes after catabolism of the protein to which they were linked. It seems likely that the use such """"""""residualizing"""""""" radiolabels can increase the radiation dose delivered from SAbs deposited within tumors, and the major purpose of this proposal is to evaluate this possibility. Labeled Abs will be injected into nude mice bearing human tumor xenografts, to determine whether they produce better tumor/non-tumor localization ratios and better immunotherapy results. These approaches should maximize the toxic effect of radiolabeled Abs at the tumor site, while minimizing their toxicity to normal tissues, and therefore will aid in the thorough evaluation of the potential of radioimmunotherapy. In addition to the DLT label, which was developed previously, we will also evaluate the 125 I-DTAF label. This label appears to be strongly retained within some but not all cell lines. The advantage of this label is that the configation efficiency is considerably higher that with DLT conjugation, and the specific activity approaches that obtained with conventional iodination. Widespread use of """"""""residualizing"""""""" labels will require not only proof of improved efficacy (relative to a conventional label), but also development of simple and efficient conjugation methods.
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