小柯机器人

法国艾克斯-马赛大学Eric Vivier等合作发现，以CD123为靶点的三功能NKp46-CD16a-NK细胞组合可控制急性髓系白血病（AML）。该研究成果发表在2023年1月12日出版的《自然-生物技术》上。

研究表明，CD64（人IgG的高亲和力受体）在AML原始细胞上的表达在体外可中和抗CD123抗体依赖性细胞毒性（ADCC）。研究人员设计了一种三功能自然杀伤细胞接合器（NKCE），以AML原始细胞上的CD123和NK细胞上的NKp46和CD16a（CD123-NKCE）为靶点。无论CD64表达如何，CD123-NKCE对原发性AML原始细胞都产生有效的抗肿瘤活性，并且仅在存在AML细胞的情况下诱导NK细胞活化和细胞因子分泌。它在小鼠CD123⁺肿瘤模型中的抗肿瘤活性超过了ADCC增强抗体的基准。在非人灵长类动物中，它具有延长的药效学作用，消除CD123⁺细胞超过10天，也没产生毒性，并且在大剂量使用范围内诱导出的炎症细胞因子非常低。这些结果为CD123-NKCE的临床开发提供了支持。

据了解，CD123是IL-3受体的α链，是急性髓系白血病的潜在治疗靶点。然而，靶向CD123的细胞毒性抗体或改造T细胞在临床试验中的存在有效性或安全性缺陷。

附：英文原文

Title: Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

Author: Gauthier, Laurent, Virone-Oddos, Angela, Beninga, Jochen, Rossi, Benjamin, Nicolazzi, Cline, Amara, Cline, Blanchard-Alvarez, Audrey, Gourdin, Nicolas, Courta, Jacqueline, Basset, Alexandra, Agnel, Magali, Guillot, Franceline, Grondin, Gwendoline, Bonnevaux, Hlne, Bauchet, Anne-Laure, Morel, Ariane, Morel, Yannis, Chiron, Marielle, Vivier, Eric

Issue&Volume: 2023-01-12

Abstract: 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 10days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE.

DOI: 10.1038/s41587-022-01626-2

Source: https://www.nature.com/articles/s41587-022-01626-2

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