The Journal of Clinical Investigation (Nov 2023)

LAIR-1 agonism as a therapy for acute myeloid leukemia

  • 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

Journal volume & issue
Vol. 133, no. 22

Abstract

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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.

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