ABSTRACT Radiolabeled monoclonal antibodies (mAbs) have long been pursued to improve outcomes for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) because neoplastic myeloid cells are exquisitely sensitive to ionizing radiation. Of particular interest are alpha-particle emitting radionuclides such as astatine-211 (211At) as they deliver a very high amount of radiation over just a few cell diameters. With this, they enable highly potent, precise, and efficient target cell kill with minimal off-target toxicity. Given its half-life of 7.2 hours, 211At is ideal for patient application. So far, alpha-emitters have been primarily used with mAbs against CD45 or CD33 for AML/MDS. However, broad display of these antigens on normal cells, including cells residing outside the bone marrow space, curtails the anti-tumor efficacy of this approach as it limits how much radiation can be safely delivered. Moreover, when used to augment HCT, CD45- and CD33-directed radioimmunotherapies (RITs) need to be given in conjunction with conditioning therapeutics, which by themselves may have little additional anti-leukemia activity but are necessary to ensure allogeneic hematopoietic stem cell (HSC) engraftment. Relative to RIT targeting CD45 or CD33, we hypothesize that 211At-based RIT targeting KIT (CD117), a receptor tyrosine kinase that is crucial for proliferation, survival, and differentiation of hematopoietic cells, will be a more precise approach to effectively treat AML/MDS that entails greatly reduced risks off-cancer cell toxicities and increased safety when used in the context of allogeneic HCT. Supporting this notion, 60-90% of patients with AML, and most patients with MDS, express CD117 on their neoplastic cells. Compared to CD45 or CD33, however, CD117 is expressed on a much more discrete set of normal cells, rendering it a highly suitable immunotherapeutic target to treat AML/MDS. What makes targeting CD117 particularly attractive for patients with AML or MDS – both disorders for which curative therapeutic strategies routinely include allogeneic HCT – is that anti-CD117 mAbs efficiently deplete endogenous HSCs and allow engraftment of allogeneic HSCs in immunodeficient mice. Combined with low-dose irradiation, anti-CD117 mAbs also provide effective conditioning and durable donor-derived HSC engraftment in immunocompetent animals. Thus, we envision 211At-CD117 RIT could be used with minimized or no need for additional conditioning therapeutics to enable allogeneic HCT. Here, we propose to conduct proof-of-principle studies to test the 2 core components of our hypothesis, namely effective leukemia cell eradiation and facilitation of allogeneic HSC engraftment, with 211At-CD117 RIT, using suitable immunodeficient and immunocompetent mouse models. Upon completion of the proposed research, it is our expectation that we will have gained critical insight into how 211At- labeled anti-CD117 mAbs can be best utilized to treat AML/MDS. Th...