Preliminary clinical trials have demonstrated that Iodine-131-conjugated anti-CD20 (B1) monoclonal antibodies can achieve remissions in 75-95 percent of lymphoma patients failing conventional chemotherapy. However, at least half of these patients subsequently suffer recurrent disease. The objective of this project is to optimize I-131-anti-CD20 antibody treatment utilizing two-step and three-step streptavidin-biotin pretargeting amplification strategies to improve the efficacy and decrease the toxicity of conventional radioimmunotherapy (RAIT). The investigators will compare and contrast the pharmacokinetics, tumor localization, and tumor-to-normal organ ratios of absorbed radiation obtained by targeting human B cell lymphoma xenografts in nude mice with either conventional I-131-labeled-CD20 antibody prepared by the IodoGen method or """"""""pretargeted"""""""" CD20 antibody. Two basic pretargeting strategies will be compared, namely, 1) streptavidin-conjugated anti-CD20 antibody followed by I-131-labeled-""""""""biotinidase-resistant"""""""" biotin constructs and 2) biotinylated CD20 antibody followed by streptavidin (sAv) amplification and then I-131-biotin. They will explore the lymphoma response rates, disease-free survival, and overall survival of tumor-bearing mice treated with either conventional RAIT or with optimized two-and three-step pretargeting protocols. They will compare the relative merits of several genetically engineered sAv mutant constructs with those of native sAv for pretargeting protocols. They will compare conventional RAIT (I-131-anti-CD20), and optimized stAv-biotin pretargeting using intact anti-CD20 MAbs to pretargeting with genetically engineered, dimeric anti-CD20 scFv-streptavidin constructs. They hypothesize that the pretargeting strategies defined in this application will improve the tumor-to-normal organ ratios of absorbed radiation currently achievable with radioimmunotherapy, allowing improvement in response rates and response durations with less toxicity than is currently feasible. They anticipate that this pretargeting approach will eliminate the necessity of administering myeloablative doses of I-131-anti-CD20 antibodies with hematopoietic stem cell rescue to achieve maximal response rates and survival rates. Rapid translation of the results of these preclinical experiments into active clinical radioimmunotherapy program for human non-Hodgkin's lymphomas is anticipated.
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