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 3

LAIR-1 engagement eradicates primary and secondary AML in patient-derived xenograft models.

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LAIR-1 engagement eradicates primary and secondary AML in patient-derive...
(A) Schematic of the AML patient–derived xenograft (PDX) model and representative scatterplots of human (H) CD33+CD45+ leukemic cells in circulation at the indicated time after engraftment. Subgated population represents percent of parent. (B) Leukemic growth, as measured by the percentage of circulating HCD33+HCD45+ cells, in PDX mice engrafted with BM from donors with normal-karyotype AML (n = 4–5 mice per group), monocytic AML (n = 4–5 mice per group), acute myelomonocytic leukemia (AMML) (n = 4 mice per group), FLT3-ITD+ AML (n = 8 mice per group), or uncharacterized AML (n = 5 mice per group). Engrafted mice were treated with 5 mg/kg isotype control (gray) or NC525 (red). (C) Schematic of PDX secondary transplant model, where BM from PDX mice engrafted and treated as above was harvested and secondarily transplanted into naive recipient mice. Graphs show leukemic growth in secondary recipient mice after receiving BM from AMML PDX animals or normal-karyotype AML PDX animals that had been treated with 5 mg/kg isotype control (gray) or NC525 (red). n = 3 mice per group. P values calculated by 2-way ANOVA. Data are shown as the mean ± SEM.