Despite impressive advances in combination chemoimmunotherapy, the majority of newly diagnosed patients with non-Hodgkin lymphomas (NHL) will relapse, and once this occurs only a minority can be cured with current treatments. The primary objective of this project is to develop and optimize an innovative strategy using high-dose radiolabeled monoclonal antibodies targeting the pan-hematopoietic antigen, CD45 in conjunction with autologous stem cell transplantation (ASCT) for patients with relapsed or refractory B or T-cell lymphomas. This approach possesses several advantages. It circumvents potential blocking of CD20 sites by rituximab, amplifies radiation exposure to sites of minimal disease, and allows treatment of CD20-negative lymphomas as well as CD20-expressing lymphomas with a safe, exportable, therapeutic radionuclide, [90]Y. Four Aims are proposed within the context of a phase I clinical trial designed to identify the maximally tolerated dose (MTD) of [90]Y-BC8 that can be delivered prior to ASCT. First, the optimal antibody protein dose of BCS will be determined to assure that a majority of patients achieve higher radiation exposures in tumor sites than in critical normal organs (Aim 1). Second, direct comparisons of the ability of CD45 and CD20 antibodies to target tumor sites will be obtained to confirm the benefit of this strategy in patients with B-NHL (Aim 2). Third, the critical dosimetry question regarding the ability of [111]In to predict [90]Y biodistribution will be addressed by means of [86]Y PET imaging (Aim 3). Following these dosimetry studies, all patients will be treated with [90]Y-BC8 in order to estimate the MTD of this therapy prior to ASCT (Aim 4). This comprehensive development plan should enable the successful evaluation of this innovative therapeutic strategy and achieve the long-term objectives of further establishing and augmenting the role of high dose radioimmunotherapy and ASCT in the treatment of relapsed NHL.