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LAIR-1 agonism as a therapy for acute myeloid leukemia
Rustin R. Lovewell, … , Dallas B. Flies, Tae Kon Kim
Rustin R. Lovewell, … , Dallas B. Flies, Tae Kon Kim
Published November 15, 2023
Citation Information: J Clin Invest. 2023;133(22):e169519. https://doi.org/10.1172/JCI169519.
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Research Article Oncology Article has an altmetric score of 200

LAIR-1 agonism as a therapy for acute myeloid leukemia

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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.

Authors

Rustin R. Lovewell, Junshik Hong, Subhadip Kundu, Carly M. Fielder, Qianni Hu, Kwang Woon Kim, Haley E. Ramsey, Agnieszka E. Gorska, Londa S. Fuller, Linjie Tian, Priyanka Kothari, Ana Paucarmayta, Emily F. Mason, Ingrid Meza, Yanira Manzanarez, Jason Bosiacki, Karla Maloveste, Ngan Mitchell, Emilia A. Barbu, Aaron Morawski, Sebastien Maloveste, Zac Cusumano, Shashank J. Patel, Michael R. Savona, Solomon Langermann, Han Myint, Dallas B. Flies, Tae Kon Kim

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Figure 5

NC525-mediated AML killing in vivo is dependent on LAIR-1 expression level.

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NC525-mediated AML killing in vivo is dependent on LAIR-1 expression lev...
(A) Schematic of the MV4-11–luciferase or THP-1–luciferase cell-derived xenograft (CDX) model of AML. (B) In vivo leukemic growth as measured by whole-body luminescence of MV4-11–luciferase cells (left) or THP-1–luciferase cells (right) in CDX mice treated with 10 mg/kg isotype control (gray) or NC525 (red). n = 8 mice per group. P values determined by 2-way ANOVA. (C and D) MV4-11 cell counts (C) or percent dead MV4-11 cells (D) in the blood, spleen, or BM of CDX mice treated with vehicle control (gray) or 10 μg/mL NC525 (red). (E) Total cell counts or mouse (M) CD45+ cell counts in the BM of CDX mice treated with vehicle control (gray) or 10 μg/mL NC525 (red). n = 9–10 mice per group. P values determined by Student’s t test. Data are shown as the mean ± SEM. (F) Representative histograms of LAIR-1 cell surface expression on the indicated cell lines. (G) Schematic of CDX model systems to test the inhibition of leukemic growth as a function of LAIR-1 expression. (H) Percent inhibition of MV4-11-LAIR-1–knockout (green), MV4-11-LAIR-1–wild-type (purple), or MV4-11-LAIR-1–overexpression cell growth in vivo (normalized to the mean of the respective isotype controls) after treatment with 10 mg/kg NC525 (left) and plotted against LAIR-1 geometric mean fluorescence intensity (gMFI) (right). (I) Percent inhibition of MV4-11 growth fit to a logarithmic regression curve of LAIR-1 expression. n = 9 mice per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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