Project Summary/Abstract This NCI Diversity Supplement application outlines the research and career development plans for Stephen Persaud, M.D., Ph.D, who is preparing for a career as an academic physician-scientist. Dr. Persaud completed his M.D. and PhD in immunology in 2015 at Washington University School of Medicine, then completed his residency in Clinical Pathology in 2018 at Barnes-Jewish Hospital as part of the Physician Scientist Training Program. During his residency elective time, he began his postdoctoral research in the lab of John DiPersio, M.D., Ph.D, Chief of the Oncology Division in the Department of Medicine at Washington University School of Medicine. Dr. DiPersio is an expert in allogeneic hematopoietic stem cell transplantation (allo-HSCT), normal and malignant hematopoiesis, and cellular immunotherapy, and has an outstanding track record of training successful physician-scientists. The scientific resources and environment provided by the DiPersio lab and Washington University School of Medicine, combined with the mentoring, educational, and training plans described herein, will propel Dr. Persaud’s career forward by enhancing the growth of his independent research program and his competitiveness for extramural funding. The long-term goal of the proposed research is to optimize minimally toxic, antibody-based HSCT conditioning regimens for the therapy of acute myeloid leukemia (AML). Led by Dr. Persaud, the DiPersio lab published the first study showing that CD45- or cKit-targeted antibody-drug conjugates (ADCs) combined with Janus kinase 1/2 (JAK1/2) inhibitors enabled fully MHC-mismatched HSCT in mice, with myeloid donor chimerism ≥99%. Notably, unlike conditioning with irradiation, ADC-based conditioning did not promote graft-versus-host disease (GvHD). Finally, JAK1/2 inhibitors plus CD45-ADC balanced GvHD with GvL activity in a delayed donor lymphocyte infusion lymphoma model, with evidence of direct ADC-mediated antitumor efficacy. By enabling allogeneic engraftment and GvL effects while mitigating GvHD and systemic toxicities, our novel regimen provides the ideal blend of activities for the immediate post-transplant period in the treatment of AML. We will build on this body of work with two Specific Aims. In Aim 1, we will develop and characterize fully myeloablative CD45 and cKit ADCs and evaluate their antileukemic efficacy and impact on GvHD and GvL responses. In Aim 2, we will develop toxic payload-free, antibody-based conditioning methods by combining anti-cKit and anti-CD47 targeting with JAK1/2 inhibition, which we hypothesize will simultaneously condition for allo-HSCT and eliminate leukemia cells. Collectively, these studies will adapt antibody-based conditioning strategies for the purpose of treating hematologic malignancies, achieving maximal antileukemia benefit with minimal injury to the host.