This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our main goal is to improve the outcome of bone marrow (stem cell) transplantation for patients with leukemia or lymphoma by delivering supplemental radiation to target tissues using radiolabeled antibodies. The improvement of targeting methods may allow the delivery of larger doses of radioactivity from antibody to diseased cells and blood-forming organs, while delivering lower radiation doses to non-target organs, this may result in higher cure rates and fewer treatment-related toxicities. We are investigating a new technique called pretargeting which consists of a multi-step process to separate the slow distribution phase of the antibody molecule from the administration of the therapeutic radiation (radionuclide). First, a non-radioactive streptavidin(SA)-antibody or fusion protein (FP) complex capable of binding with the target antigen is administered. After maximal accumulation of the antibody/FP in the target organ, a biotin-containing clearing agent is injected. Biotin and SA have high affinity for each other, allowing the clearing agent to removes unbound antibody/FP from the bloodstream. Finally, a biotin-containing radioactive moiety with high affinity for the SA-antibody/FP complex is administered. Because of their small size, unbound molecules of radioactive reagent are rapidly cleared from the blood and excreted in the urine. This system has resulted in superior delivery of radiation to target versus nontarget organs in preclinical and clinical studies of radioimmunotherapy for solid tumors. Mouse studies using this technique with anti-CD45 antibodies also support the efficacy of this approach. Studies performed during this reporting period have demonstrated the safety of infusing each reagent in the three-step pretargeting process into nonhuman primates. Additional studies have documented the effectiveness of the pretargeting approach in improving the ratio of radiation delivered to target sites relative to non-target normal organs. Further investigations are ongoing to establish the optimal doses and time intervals for each step in the pretargeting process.
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