Improved Targeting Strategies

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We have demonstrated the feasibility and effectiveness of treating patients with relapsed leukemia and lymphoma with myeloablative doses of radiolabeled anti-CD20 and anti-CD45 monoclonal antibodies followed by autologous or allogeneic stem cell transplantation. Response rates to this therapy are high and many patients are cured. Despite these encouraging results, relapses still occur frequently and toxicities are substantial. In this Project we will investigate novel strategies to further improve the efficacy and diminish the toxicity of radioimmunotherapy by augmenting the amount of radioactivity delivered to tumor cells (by pretargeting with tetravalent fusion proteins) and by removing the proportion of radioisotope that fails to bind to tumor and remains in the bloodstream perfusing normal organs (by pretargeting or extracorporeal antibody adsorption). In Aim 1, we will evaluate the feasibility, safety, and toxicity of administering anti-CD20 lF5(scFv)4-streptavidin and anti-CD45 BC8(scFv)4-streptavidin fusion proteins to primates and will compare and contrast the pharmacokinetics and tissue penetration of the fusion proteins with those of directly radiolabeled anti-CD20 (1F5) and anti-CD45 (BC8) antibodies. In Aim 2, we will compare the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD20 1F5 (scFv)4-streptavidin and anti-CD45 BC8(scFv)4-streptavidin fusion proteins with the biodistributions and dosimetries of directly radiolabeled anti-CD20 1F5 and anti-CD45 BC8 Abs, respectively. In Aim 3 we will assess the impact of extracorporeal adsorption of circulating, radiolabeled anti-B cell and anti-myeloid radiolabeled antibodies on the pharmacokinetics, biodistribution and dosimetry of these radioimmunoconjugates in macaques. In Aim 4, we will generate and validate Master Cell Banks for the anti-CD20 lF5(scFv)4-streptavidin and the anti-CD45 BC8(scFv)4-streptavidin fusion proteins and produce, purify and characterize sufficient fusion protein under current good manufacturing practice (cGMP) conditions to conduct Phase I & II clinical trials in Projects 1 and 3. We hypothesize that pretargeting and EC AT will improve the delivery of radiation to tumor sites compared to normal tissues, thereby allowing us to escalate the tumor dose while maintaining well-defined, tolerable upper limits on the dose to critical normal organs. Based on the results of these studies, human clinical trials of pretargeting (and possibly ECAT) are planned in collaboration with Projects 1 and 3.