1. LAIR-1 agonism as a therapy for acute myeloid leukemia.
- Author
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Lovewell RR, Hong J, Kundu S, Fielder CM, Hu Q, Kim KW, Ramsey HE, Gorska AE, Fuller LS, Tian L, Kothari P, Paucarmayta A, Mason EF, Meza I, Manzanarez Y, Bosiacki J, Maloveste K, Mitchell N, Barbu EA, Morawski A, Maloveste S, Cusumano Z, Patel SJ, Savona MR, Langermann S, Myint H, Flies DB, and Kim TK
- Subjects
- Animals, Humans, Hematopoietic Stem Cells metabolism, Signal Transduction, Disease Models, Animal, Neoplastic Stem Cells metabolism, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism
- Abstract
Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. NC525 also significantly improved the activity of azacitidine and venetoclax to establish LAIR-1 targeting as a therapeutic strategy for AML that may synergize with standard-of-care therapies.
- Published
- 2023
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