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<p>CAR T cells targeting CLL-1 have shown antileukemia efficacy in patients with acute myeloid leukemia (AML). However, CLL-1<sup>low/−</sup> AML cells are present in some patients, suggesting that the development of CAR T cells with high sensitivity is necessary to eradicate all AML clones in these patients. Here, we identified CAR T cells derived from a novel, high-affinity anti-CLL-1 monoclonal antibody (mAb) that exhibited a significant anti-AML effect in vivo. We generated 13 new mAbs against CLL-1 and established CAR T cells from them. Of these, CAR T cells derived from mAb 2–23, which demonstrated greater affinity for CLL-1 than M26, the anti-CLL-1 mAb used in many previous studies, exhibited significant potential for cytokine production and cytotoxicity when co-cultured with AML cells. Treatment with 2–23 CAR T cells eradicated AML cells and significantly prolonged survival in AML xenograft models. Additionally, treatment with revumenib, a menin inhibitor, increased CLL-1 expression in AML cells harboring mixed-lineage leukemia (MLL) fusion genes or the NPM1 mutation, making them more susceptible to 2–23 CAR T cell-mediated cytotoxicity in vitro. These findings suggest that the clinical efficacy of CAR T cells derived from the novel, high-affinity anti-CLL-1 mAb 2–23 should be tested in patients with CLL-1-positive AML and also that combining 2–23 CAR T cells with revumenib may benefit some patients with CLL-1<sup>low/−</sup> AML.</p>

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CAR T cells derived from a novel, high-affinity anti-CLL-1 monoclonal antibody exhibit a significant anti-AML effect

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Shuhei Kida,
  • Makiko Suga,
  • Yuta Yamaguchi,
  • Shunya Ikeda,
  • Yosuke Kogue,
  • Ryuhei Kawamoto,
  • Kumi Shibata,
  • Kazuhito Tsutsumi,
  • Hiraku Murakami,
  • Emiko Mizuta,
  • Yo Mizutani,
  • Naoki Hosen

摘要

CAR T cells targeting CLL-1 have shown antileukemia efficacy in patients with acute myeloid leukemia (AML). However, CLL-1low/− AML cells are present in some patients, suggesting that the development of CAR T cells with high sensitivity is necessary to eradicate all AML clones in these patients. Here, we identified CAR T cells derived from a novel, high-affinity anti-CLL-1 monoclonal antibody (mAb) that exhibited a significant anti-AML effect in vivo. We generated 13 new mAbs against CLL-1 and established CAR T cells from them. Of these, CAR T cells derived from mAb 2–23, which demonstrated greater affinity for CLL-1 than M26, the anti-CLL-1 mAb used in many previous studies, exhibited significant potential for cytokine production and cytotoxicity when co-cultured with AML cells. Treatment with 2–23 CAR T cells eradicated AML cells and significantly prolonged survival in AML xenograft models. Additionally, treatment with revumenib, a menin inhibitor, increased CLL-1 expression in AML cells harboring mixed-lineage leukemia (MLL) fusion genes or the NPM1 mutation, making them more susceptible to 2–23 CAR T cell-mediated cytotoxicity in vitro. These findings suggest that the clinical efficacy of CAR T cells derived from the novel, high-affinity anti-CLL-1 mAb 2–23 should be tested in patients with CLL-1-positive AML and also that combining 2–23 CAR T cells with revumenib may benefit some patients with CLL-1low/− AML.