肿瘤细胞治疗研究
英文原题：Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123.
这些结果支持CD123-NKCE的临床开发。
CD123是IL-3受体的α链，是急性髓系白血病（AML）治疗中一个有吸引力的靶点。然而，靶向CD123的细胞毒性抗体或T细胞衔接器在临床试验中疗效或安全性不足。我们发现，AML原始细胞上CD64（人IgG高亲和力受体）的表达在体外赋予其对anti-CD123抗体依赖性细胞毒性（ADCC）的耐药性。我们设计了一种三功能性NK 细胞衔接器（NKCE），靶向AML原始细胞上的CD123以及NK细胞上的NKp46和CD16a（CD123-NKCE）。CD123-NKCE对原代AML原始细胞具有强效抗肿瘤活性，且不受CD64表达影响，并且仅在存在AML细胞时诱导NK细胞活化和细胞因子分泌。其在小鼠CD123+肿瘤模型中的抗肿瘤活性超过基准的ADCC增强型抗体。在非人灵长类动物中，其具有延长的药效学效应，在较大剂量范围内耗竭CD123+细胞超过10天，且无毒性迹象，炎症细胞因子诱导极低。这些结果支持CD123-NKCE的临床开发。
CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro. We engineer a trifunctional natural killer cell engager (NKCE) that targets CD123 on AML blasts and NKp46 and CD16a on NK cells (CD123-NKCE). CD123-NKCE has potent antitumor activity against primary AML blasts regardless of CD64 expression and induces NK cell activation and cytokine secretion only in the presence of AML cells. Its antitumor activity in a mouse CD123 + tumor model exceeds that of the benchmark ADCC-enhanced antibody. In nonhuman primates, it had prolonged pharmacodynamic effects, depleting CD123 + cells for more than 10 days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE.
MEMBER ACCOUNT
登录成功会直接打开下一页。
