源自新型高亲和力抗 CLL-1 单克隆抗体并显示显著抗 AML 效应的 CAR-T 细胞

CAR T cells targeting CLL-1 have shown antileukemia efficacy in patients with acute myeloid leukemia (AML).

However, CLL-1 low/- 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 low/- AML.