Department of Translational Medicine Oncology, Genentech Inc., South San Francisco, CA, United States.
Department of Pathology, Genentech Inc., South San Francisco, CA, United States.
Front Immunol. 2024 Mar 7;15:1341804. doi: 10.3389/fimmu.2024.1341804. eCollection 2024.
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 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 , 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 . 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 .
白细胞介素-15（IL-15）通过增强自然杀伤（NK）细胞的功能成熟，显示出临床前活性。大多数细胞因子（包括 IL-15）的临床评估受到低耐受性和快速清除的限制。Efbalropendekin Alfa（XmAb24306）是一种可溶性白细胞介素-15/白细胞介素-15 受体α异二聚体复合物，与半衰期延长的 Fc 结构域（IL15/IL15Rα-Fc）融合，通过突变工程设计降低了 IL-15 与 CD122 的亲和力。亲和力降低导致效力降低，从而在食蟹猴中延长了药效反应。我们表明，用 XmAb24306 处理的人类 NK 细胞对各种肿瘤细胞系表现出增强的细胞毒性。XmAb24306 处理的 NK 细胞也表现出对 3D 结直肠癌细胞球体的增强杀伤作用。达雷木单抗（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毒性（ADCC）。添加 XmAb24306 可增加达雷木单抗介导的对各种 MM 细胞系的 NK 细胞 ADCC。因为 NK 细胞表达 CD38，XmAb24306 增加了达雷木单抗介导的 NK 细胞自噬，但总体上不会对 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 细胞活性增加。这些数据表明，XmAb24306 可增加直接和 ADCC 介导的人类 NK 细胞细胞毒性。
