Autologous hematopoietic stem cell transplant (autoHSCT) is a highly effective treatment for multiple autoimmune diseases. AutoHSCT can induce long-term remission (up to 15 years) with 70-80% progression free survival in patients with relapsed refractory and secondary progressive MS subtypes (Muraro 2017). Likewise, patients with systemic scleroderma achieved 74% event-free survival at 72 months following autoHSCT (Sullivan, 2018). These results are achieved by eradication of autoreactive immune cells and re-establishment of a self-tolerant immune system. However, only a small fraction of eligible patients elect to undergo autoHSCT, in part due to complications associated with current conditioning. To address these issues, we are developing antibody drug conjugates (ADCs) targeting CD45, a target expressed throughout the hematopoietic system to enable simultaneous myelo- and lympho-depletion prior to autologous transplant in autoimmune diseases. To model this strategy, we created an anti-mouse CD45-ADC that achieved full myeloablation with single dose administration in mice. Following CD45-ADC administration, transplantation of whole bone marrow (BMT) cells enabled full donor chimerism in a congenic model. We are evaluating this CD45-ADC in the murine experimental autoimmune encephalomyelitis (EAE) and sclerodermatous Graft-vs-Host-Disease (scGVHD) models of autoimmune disease. In EAE, conditioning with irradiation (9 Gy) followed by congenic transplant resulted in transient amelioration of disease. The impact of CD45-ADC conditioning and BMT on disease in these models will be presented. This novel approach for conditioning prior to autoHSCT could increase the number of autoimmune patients eligible for transplant and significantly reduce the side effects associated with current conditioning protocols.