LAIR-1 agonism as a therapy for acute myeloid leukemia.

Autor: Lovewell RR; NextCure Inc., Beltsville, Maryland, USA., Hong J; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Seoul National University Hospital and.; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea., Kundu S; NextCure Inc., Beltsville, Maryland, USA., Fielder CM; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Hu Q; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Kim KW; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Ramsey HE; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Gorska AE; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Fuller LS; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Tian L; NextCure Inc., Beltsville, Maryland, USA., Kothari P; NextCure Inc., Beltsville, Maryland, USA., Paucarmayta A; NextCure Inc., Beltsville, Maryland, USA., Mason EF; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center., Meza I; NextCure Inc., Beltsville, Maryland, USA., Manzanarez Y; NextCure Inc., Beltsville, Maryland, USA., Bosiacki J; NextCure Inc., Beltsville, Maryland, USA., Maloveste K; NextCure Inc., Beltsville, Maryland, USA., Mitchell N; NextCure Inc., Beltsville, Maryland, USA., Barbu EA; NextCure Inc., Beltsville, Maryland, USA., Morawski A; NextCure Inc., Beltsville, Maryland, USA., Maloveste S; NextCure Inc., Beltsville, Maryland, USA., Cusumano Z; NextCure Inc., Beltsville, Maryland, USA., Patel SJ; NextCure Inc., Beltsville, Maryland, USA., Savona MR; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Vanderbilt Center for Immunobiology.; Vanderbilt-Ingram Cancer Center, and.; Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA., Langermann S; NextCure Inc., Beltsville, Maryland, USA., Myint H; NextCure Inc., Beltsville, Maryland, USA., Flies DB; NextCure Inc., Beltsville, Maryland, USA., Kim TK; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center.; Vanderbilt Center for Immunobiology.; Vanderbilt-Ingram Cancer Center, and.; Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.; Veterans Affairs Tennessee Valley Healthcare, Nashville, Tennessee, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2023 Nov 15; Vol. 133 (22). Date of Electronic Publication: 2023 Nov 15.
DOI: 10.1172/JCI169519
Abstrakt: 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.
Databáze: MEDLINE