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 goal is to improve the outcome of stem cell transplantation for acute leukemia with 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 leukemia 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. This study employs pretargeting which consists of a multi-step process to dissociate the slow distribution phase of the antibody molecule from the administration of the therapeutic radioisotope. First, a non-radioactive streptavidin (SA)-antibody complex which binds to the target antigen is administered. After accumulation of the antibody in the target organ, a vitamin (biotin)-containing clearing agent is injected. Finally, a biotin-containing radioactive construct with high affinity for the SA-antibody 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 seem promising.
The specific aims of these studies in non-human primates are: To evaluate the feasibility, safety, and toxicity of administering radioiodine-labeled anti-CD45 fusion proteins, BC8(scFv)4SA, to nonhuman primates and to compare and contrast the pharmacokinetics and tissue penetration of the fusion proteins with those of directly radiolabeled anti-CD45 (BC8) antibodies. To compare the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD45 BC8(scFv)4SA fusion proteins in macaques with the biodistributions and dosimetries of directly radiolabeled anti-CD45 BC8 Abs. During the current period we have conducted one study, involving two M. fascicularis animals. The study was performed to determine the pharmacokinetic properties of the BC8(scFv)4SA. A higher dose was used than in our prior experiments to optimize delivery to target sites. The animals tolerated the infusions without evidence of toxicity. Data collected are currently being analyzed.
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