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

LAIR-1 agonism as a therapy for acute myeloid leukemia

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 6

LAIR-1 signaling restricts AML survival signaling pathways in vivo.

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LAIR-1 signaling restricts AML survival signaling pathways in vivo. (A) ...
(A) Model schematic (left) and MV4-11-luciferase growth (right) in CDX mice used for digital spatial imaging and target protein quantification. n = 6 mice per group. (B) Representative images of CDX mouse bones stained with DAPI (blue) and anti–human CD45 (red) used to quantify the number of MV4-11 cells in the indicated region of interest (ROI) (highlighted). ROI area is equal between samples. (C) Protein reads of human CD45, BCL-XL, or uncleaved PARP from bone or spleen harvested from CDX mice at day 22 after engraftment. Read counts are normalized to histone H3 and ribosomal protein S6. n = 3–11 quantified tissue regions across 2 isotype-treated or 2 NC525-treated mice. Data are shown as the mean ± SEM. P values determined by Student’s t test.