SBIR-STTR Award

Direct to Phase II

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.

Public Health Relevance Statement:
Narrative Patients diagnosed with MDS or AML have limited treatment options, resulting in unfavorable clinical outcomes. In this study, we will embark on the essential stages of manufacturing and toxicology testing to advance our promising novel antibody candidate one step closer to assessing its potential clinical benefits for these patients. Terms: <7S Gamma Globulin; AML - Acute Myeloid Leukemia; AML/MDS; Acute; Acute Myeloblastic Leukemia; Acute Myelocytic Leukemia; Acute Myelogenous Leukemia; Affinity; Antibodies; Apoptotic; Biomanufacturing; Blast Cell; Blood Precursor Cell; Blood Transfusion; Bone Marrow; Bone Marrow Reticuloendothelial System; CHO Cells; Cell Body; Cell Communication and Signaling; Cell Line; Cell Signaling; CellLine; Cells; Chemistry; Chinese Hamster Ovary Cell; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clonal Expansion; Co-culture; Cocultivation; Coculture; Coculture Techniques; Common Rat Strains; Data; Data Analyses; Data Analysis; Development; Diagnosis; Disease; Disorder; Domestic Rabbit; Dose; Drug Kinetics; Drugs; Dysmyelopoietic Syndromes; Elderly; Ensure; Exhibits; FLK2; FLT3; FLT3 gene; FMS-like tyrosine kinase 3; Face; Fms-Related Tyrosine Kinase 3; Frail Elderly; Frail Elders; Frail Older Adults; Frail Seniors; Funding; Genetic Alteration; Genetic Change; Genetic defect; HSC differentiation; HSC transplantation; Hematopoiesis; Hematopoietic Cellular Control Mechanisms; Hematopoietic Progenitor Cells; Hematopoietic Stem Cell Transplant; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; High Dose Chemotherapy; Human; Idiotype; IgG; Immunoglobulin G; Immunoglobulin Idiotypes; Immunosuppressants; Immunosuppressive Agents; Immunosuppressive drug; Immunosuppressive treatment; Induction of Apoptosis; Intracellular Communication and Signaling; Investments; Lead; Leukemic Cell; Leukemic progenitor and stem cell; Mediating; Medical; Medication; Mice; Mice Mammals; Modern Man; Murine; Mus; Mutation; Myelodysplastic Disease; Myelodysplastic Syndromes; Myelogenous; Myeloid; Nature; Neoplastic Colony-Forming Units; Neoplastic Stem Cells; Oncogenic; Oryctolagus cuniculus; Osteoblasts; Pathway interactions; Patients; Pb element; Pharmaceutical Preparations; Pharmacokinetics; Phase; Population; Process; Production; Proliferating; Rabbits; Rabbits Mammals; Rat; Rats Mammals; Rattus; Refractory Anemia with an Excess of Blasts; Refractory anaemia with excess blasts; Regimen; Relapse; Reporting; Research; Risk; STK-1 kinase; STK1; Sampling; Signal Transduction; Signal Transduction Systems; Signaling; Smoldering Leukemia; Source; Stem Cell Tyrosine Kinase 1; Strains Cell Lines; Survival Rate; System; Testing; Therapeutic; Time; Toxicity due to chemotherapy; Toxicology; Tumor Stem Cells; Unfavorable Clinical Outcome; Universities; Up-Regulation; Upregulation; Work; acute granulocytic leukemia; acute myeloid leukemia; acute myeloid leukemia/myelodysplastic syndrome; advanced age; antagonism; antagonist; biological signal transduction; blood cell formation; blood cell progenitor; blood progenitor; blood stem cell; blood-forming stem cell; cancer microenvironment; chemotherapy; chemotherapy toxicity; cultured cell line; curative intervention; curative therapeutic; curative therapy; curative treatments; data interpretation; developmental; drug/agent; efficacy study; elderly patient; faces; facial; falls; fetal liver kinase-2; fetal liver kinase-3; frail older adult; genome mutation; geriatric; heavy metal Pb; heavy metal lead; hematopoietic cell transplantation; hematopoietic cellular transplantation; hematopoietic progenitor; hematopoietic progenitor cell differentiation; hematopoietic progenitor cell transplantation; hematopoietic progenitor differentiation; hematopoietic stem cell differentiation; hematopoietic stem progenitor cell; hemopoietic progenitor; hemopoietic stem cell; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; improved; individual patient; inhibitor; innovate; innovation; innovative; jagged-1; jagged1 protein; leukemia; leukemic progenitor; leukemic stem cell; manufacture; manufacturing run; meeting; meetings; mouse model; murine model; myelodysplasia; new approaches; notch; notch protein; notch receptors; novel; novel approaches; novel strategies; novel strategy; older patient; pathway; postnatal; production run; progenitor cell based therapy; progenitor cell therapy; progenitor cell treatment; progenitor therapy; progenitor treatment; programs; senior citizen; side effect; standard of care; stem and progenitor cell therapy; stem cell based therapy; stem cell mediated therapy; stem cell therapeutics; stem cell therapy; stem cell treatment; stem cell-based therapeutic; stem cell-based treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; tumor microenvironment; tumor progenitor