Abstract Patients diagnosed with myelodysplastic syndrome (MDS) face a challenging treatment landscape, with limited options consisting mainly of blood transfusions and hypomethylating agents. This therapeutic regimen has remained stagnant for the past two decades. Adding to the complexity, a significant concern is that approximately one-third of MDS patients progress to acute myeloid leukemia (AML), a condition that, while relatively rare (with around 20,000 cases per year), becomes more prevalent among the elderly population. The sole curative therapy for medically fit patients with AML remains high-dose induction chemotherapy followed by hematopoietic stem cell therapy. Unfortunately, this approach has not significantly improved the overall 5-year survival rates, which have stagnated at 29.5%. For medically unfit or frail elderly patients, the outlook is even more dismal, with a 5-year survival rate plummeting to 7.3% and a median survival time of just 7.3 months. Recent advancements in targeted therapies have provided some hope, specifically for subsets of AML patients harboring specific mutations (e.g., Flt3, IDH, and Bcl2). Medications like Midostaurine, enasidenib, and Venetoclax have been approved for those who cannot undergo high-dose chemotherapy. However, these therapies are associated with a high relapse rate due to the genetically unstable nature of AML, resulting in only marginal improvements in median survival compared to low-dose chemotherapy or hypomethylation inhibitors. Moreover, they come with their own set of adverse side effects. Consequently, there is an urgent and unmet medical need for innovative approaches to treat both MDS and AML. Our research has identified a promising lead antibody candidate that specifically targets Jagged-1, thereby blocking a critical oncogenic pathway originating from the stable bone marrow stromal compartment in the leukemic stem cell (LSC) tumor microenvironment (TME). This pathway promotes the proliferation and survival of LSCs. The lead antibody disrupts the interaction between upregulated Jagged-1 on osteoblasts and Notch-1 expressed on LSCs, leading to the inhibition of leukemic blast proliferation, induction of apoptosis, and reversal of myeloid block in a mouse model of this pathway. It has also displayed antiproliferative and pro-apoptotic effects on MDS or AML blast cells in co-cultures involving osteoblasts and blast cells from individual patients whose osteoblasts exhibit elevated activated Jagged-1. In this Direct to Phase II proposal, we outline our plan to conduct preliminary IND-enabling studies, encompassing cell line development, early chemistry, manufacturing, and controls (CMC) activities, as well as preliminary toxicology studies, aiming to advance our program closer to clinical proof-of-concept studies.