A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells

Leukemia. 2021 Jun;35(6):1586-1596. doi: 10.1038/s41375-020-01065-5. Epub 2020 Oct 23.

Abstract

The low 5-year survival rate for patients with acute myeloid leukemia (AML), primarily caused due to disease relapse, emphasizes the need for better therapeutic strategies. Disease relapse is facilitated by leukemic stem cells (LSCs) that are resistant to standard chemotherapy and promote tumor growth. To target AML blasts and LSCs using natural killer (NK) cells, we have developed a trispecific killer engager (TriKETM) molecule containing a humanized anti-CD16 heavy chain camelid single-domain antibody (sdAb) that activates NK cells, an IL-15 molecule that drives NK-cell priming, expansion and survival, and a single-chain variable fragment (scFv) against human CLEC12A (CLEC12A TriKE). CLEC12A is a myeloid lineage antigen that is highly expressed by AML cells and LSCs, but not expressed by normal hematopoietic stem cells (HSCs), thus minimizing off-target toxicity. The CLEC12A TriKE induced robust NK-cell specific proliferation, enhanced NK-cell activation, and killing of both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Additionally, the CLEC12A TriKE was able to reduce tumor burden in preclinical mouse models. These findings highlight the clinical potential of the CLEC12A TriKE for the effective treatment of AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Female
  • GPI-Linked Proteins / immunology
  • Humans
  • Immunotherapy / methods*
  • Interleukin-15 / metabolism*
  • Killer Cells, Natural / immunology*
  • Lectins, C-Type / antagonists & inhibitors
  • Lectins, C-Type / immunology*
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Acute / therapy*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Prognosis
  • Receptors, IgG / immunology*
  • Receptors, Mitogen / antagonists & inhibitors
  • Receptors, Mitogen / immunology*
  • Single-Domain Antibodies / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • CLEC12A protein, human
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • IL15 protein, human
  • Interleukin-15
  • Lectins, C-Type
  • Receptors, IgG
  • Receptors, Mitogen
  • Single-Domain Antibodies