Anti-CD20 monoclonal antibodies (MAb) radiolabeled with β-emitters can achieve remissions in 65-90% of non-Hodgkin lymphoma (NHL) patients failing conventional chemotherapy. However, most patients treated with these MAbs subsequently relapse. Hematopoietic cell transplantation (HCT) is an option for relapsed NHL patients, but this approach frequently fails because of disease recurrence. Intensifying the preparative regimen to reduce relapse has been limited by toxicities due to the non-specific nature of most agents. We have shown that patients whose tumors receive higher absorbed doses of radiation are less likely to recur after radioimmunotherapy (RIT). Despite successes, however, the toxicities are significant and not all NHL patients are cured using targeted RIT strategies combined with HCT. In addition, patients with CD20 negative NHL, such as T-cell NHL, do not benefit from targeted intensification of therapy directed at the CD20 antigen. Radiolabeled anti-CD45 MAbs have been highly effective as part of a conditioning regimen for HCT for relapsed myeloid diseases, but have not been tested in regimens for NHL even though >95% of NHL express the CD45 antigen. We have recently begun exploring 131I-anti-CD45 MAb to improve outcomes for relapsed NHL patients in the setting of HCT, but toxicity remains high and cure rates are suboptimal. Alpha emitters are an attractive alternative to the β-emitters in RIT due to the short path length and high cytotoxicity of α-emissions. The overall goal of this project is to overcome these limitations by delivering targeted anti-CD45 radiotherapy using an α-emitter, astatine-211 (211At), to sites of disease in dogs with spontaneous lymphoma. We predict that this effective treatment regimen will eradicate minimal residual disease (MRD) and decrease the risk of relapse after HCT with less toxicity. In Aim 1 we will define the optimal anti CD45 MAb protein dose for targeting CD45 in dogs with B- and T-cell NHL. We anticipate that the optimized anti-CD45 MAb dose will target the majority of targeted CD45 expressing cells while sparing normal tissues. In Aim 2 we will assess the efficacy and toxicities of 211At-labeled anti-CD45-MAb using the optimized protein dose determined in Aim 1 as consolidation therapy for canines in remission after prior anti-NHL chemotherapy. Although this approach will be expected to eliminate MRD and improve survival for dogs in remission, therapeutic doses of anti-CD45 RIT for relapsed NHL will likely require HCT as CD45 is expressed on most hematopoietic cells. Therefore, in Aim 3 we will investigate the feasibility, safety, and efficacy f 211At-labeled anti-CD45 MAb in escalating doses followed by autologous HCT in canines with NHL. Finally, in Aim 4 we will assess the relative merits of RIT with 211At-labeled anti-CD45 MAb and allogeneic HCT to cure NHL by further extending this approach to both DLA- identical and haploidentical dogs. We anticipate that the information from these studies will allow rapid translation of the optimized promising RIT strategy using 211At-anti-CD45 MAb into our clinical RIT HCT program for NHL.