Therapeutic Anti-Jagged1 Antibody Targeting Osteoblast-Related Myeloid Dysplasia to Overcome Standard of Care Resistance

Acute myeloid leukemia (AML) and myelodysplasia (MDS) are increasingly recognized as not only genetic but niche-dependent malignancies prompting the question of whether targeting signals from supporting stromal cells may provide a more stable target for therapy than emerging leukemic clones. Whereas standard of care and malignant cell targeted therapies fail to eliminate resistant clones or prevent the expansion of new ones, inhibition of oncogenic or tumor promoting signals from the stroma could overcome mutation dependance and clonal resistance and be an efficient approach to manage disease and prevent relapse. Here, we inhibited a potent, niche-driven tumorigenic pathway, constitutive activation of b-catenin/Jagged1 signaling in osteoblasts. This pathway is activated following hypermethylation of its regulators in MDS patients; is activated in approximately 40% of MDS and AML patients; its activation levels increase with disease severity and progression; correlate with MDS to AML transformation and del(5q)-associated myeloid malignancies and leads to MDS rapidly progressing to AML in mice. To examine the therapeutic potential of targeting this pathway we generated a human-mouse chimeric antibody that efficiently and specifically binds JAG1 (anti-JAG1) and inhibits Notch1 signaling. Administration of anti-JAG1 in leukemic mice with osteoblastic active b-catenin rescued anemia, thrombocytopenia, neutrophilia and lymphocytopenia, restored LT-HSCs (the leukemia initiating population), relieved myeloid differentiation block and eliminated blasts. Body weight increased and lethality was abrogated in treated mice. In contrast, chemotherapy at a dose simulating induction regimen used in humans, dramatically exacerbated anemia, thrombocytopenia and lymphocytopenia without decreasing blasts leading to increased lethality due to bone marrow failure. A lower chemotherapy dose induced a physiologically relevant response in wild type mice, but failed to improve hematopoiesis and myeloid differentiation block in leukemic mice and as a result AML progression and lethality was not affected. Emphasizing relevance to human disease, anti-JAG1 treatment of patient-derived samples with activated b-catenin in their osteoblasts, inhibited MDS and AML cell growth and survival and promoted myeloid and erythroid differentiation irrespective of disease category through its actions on osteoblasts. These findings suggest anti-JAG1 may provide a broad therapeutic approach that is effective in 1/3 of MDS and AML patients with cytogenetically distinct types of disease. The therapeutic potential of targeting the bone marrow stromal niche in hematological malignancies can be a treatment strategy that may evade relapse and overcome standard of care resistance and toxicity.

Ali:VOR Biopharma: Consultancy, Patents & Royalties: December 31, 2023, Research Funding; Actinium Pharmaceuticals: Research Funding. Adams:AvantGen Inc: Current Employment. Corper:AvantGen Inc: Current Employment. Woods:AvantGen: Current Employment. Fan:AvantGen Inc: Current Employment. Raza:Taiho: Consultancy; Epizyme: Consultancy.