Radioimmunotherapy (RAIT) is, in principle, an attractive modality for cancer treatment. However, many uncertainties remain concerning the optimal implementation of this modality, and it is becoming increasingly apparent that the processing of antibodies after antigen binding must be considered when designing effective antibody conjugates for immunotherapy. This is especially important for radioiodinated monoclonal antibodies (MAbs), because catabolism of radioiodinated MAbs followed by diffusion of the catabolites out of the target cells leads to a relatively short residence time of the isotope at the tumor site. The overall objective of this research proposal is to develop a simple and efficient method to introduce a residualizing form of radioiodine label into MAbs for application in radioimmunotherapy, and to compare targeting and therapeutic efficacy of the residualizing radioiodine to those of conventional iodine and radiometal (90Y for therapy or 111In for imaging). Specifically, we will begin by seeking to find an alternative conjugation chemistry which will retain the benefits of the DLT methodology used in our work thus far (i.e., ability to be trapped inside cells, no aggregation of MAb-conjugates, improved targeting and therapy), yet will afford an increased yield of a higher specific activity product. Secondly, we will incorporate an analysis of the use of the fragments into the study. This is now appropriate since fragments allow improved tumor penetration into tumors, and the recent work of Behr, et al., has shown that elevated kidney toxicity, which has resulted in the past from the use of the radiolabeled MAb fragments, can be reduced using cationic amino acids and their derivatives. In addition to these laboratory studies, a pilot clinical targeting study is planned. Our previous studies have shown a marked advantage in the animal model in the use of residualizing labels (yttrium and iodo-DLT) for targeting and therapy of non-small cell carcinoma of the lung. This proposed clinical study will evaluate whether these results can be translated to the clinical management of non-small lung cancer, which is a major goal of the National Cancer Plan. Our working hypothesis is that enhanced tumor targeting and therapeutic efficacy with both rapidly internalizing and slowly internalizing MAbs may be obtained by using optimized conjugates, prepared with residualizing radioisotopes.
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