肿瘤细胞治疗研究
英文原题：Efbalropendekin Alfa enhances human natural killer cell cytotoxicity against tumor cell lines in vitro.
这些数据表明，XmAb24306在体外增强人NK细胞的直接细胞毒性和ADCC介导的细胞毒性。
IL-15 通过增强自然杀伤（NK）细胞的功能成熟而显示出临床前活性。包括 IL-15 在内的大多数细胞因子的潜在抗癌活性的临床评价，一直受限于耐受性低和体内清除快。Efbalropendekin Alfa（XmAb24306）是一种可溶性 IL15/IL15 受体 α 异二聚体复合物，与半衰期延长的 Fc 结构域融合（IL15/IL15Rα-Fc），经工程改造引入突变以降低 IL-15 对 CD122 的亲和力。亲和力降低导致效力下降，从而在食蟹猴中产生延长的药效学应答。我们表明，在体外，经 XmAb24306 处理的人 NK 细胞对多种肿瘤细胞系表现出增强的细胞毒性。经 XmAb24306 处理的 NK 细胞还表现出对 3D 结直肠癌球体杀伤的增强。Daratumumab（dara）是一种靶向 CD38 的单克隆抗体（mAb），可导致多发性骨髓瘤（MM）细胞和 NK 细胞的抗体依赖性细胞介导的细胞毒性（ADCC）。加入 XmAb24306 可在体外增强 dara 介导的 NK 细胞对多种 MM 细胞系的 ADCC。由于 NK 细胞表达 CD38，XmAb24306 会增加 dara 介导的 NK 细胞自相残杀，但总体上不会对针对一种 MM 细胞系的 ADCC 活性产生负面影响，可能是由于存活细胞的 NK 细胞活性增强。这些数据表明，XmAb24306 在体外增强人 NK 细胞的直接细胞毒性和 ADCC 介导的细胞毒性。
IL-15 has shown preclinical activity by enhancing the functional maturation of natural killer (NK) cells. Clinical evaluation of the potential anticancer activity of most cytokines, including IL-15, has been limited by low tolerability and rapid in vivo clearance. Efbalropendekin Alfa (XmAb24306) is a soluble IL15/IL15-receptor alpha heterodimer complex fused to a half-life extended Fc domain (IL15/IL15Rα-Fc), engineered with mutations to reduce IL-15 affinity for CD122. Reduced affinity drives lower potency, leading to prolonged pharmacodynamic response in cynomolgus monkeys. We show that in vitro , human NK cells treated with XmAb24306 demonstrate enhanced cytotoxicity against various tumor cell lines. XmAb24306-treated NK cells also exhibit enhanced killing of 3D colorectal cancer spheroids. Daratumumab (dara), a monoclonal antibody (mAb) that targets CD38 results in antibody-dependent cellular cytotoxicity (ADCC) of both multiple myeloma (MM) cells and NK cells. Addition of XmAb24306 increases dara-mediated NK cell ADCC against various MM cell lines in vitro . Because NK cells express CD38, XmAb24306 increases dara-mediated NK cell fratricide, but overall does not negatively impact the ADCC activity against a MM cell line likely due to increased NK cell activity of the surviving cells. These data show that XmAb24306 increases direct and ADCC-mediated human NK cell cytotoxicity in vitro .
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