Departments of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pediatric Hematology, Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
Oncoimmunology. 2021 Mar 11;10(1):1893500. doi: 10.1080/2162402X.2021.1893500.
The role of T cells in controlling human cancers is well known. Their success requires continued persistence in vivo and efficient trafficking to tumor sites, requirements shared by other effectors such as Natural Killer (NK) cells. To date, cytokine IL2 remains the only clinically approved cytokine therapy available to expand, maintain, and activate these effector lymphoid cells, but toxicities can be severe. Cytokine IL15 offers similar T cell proliferation and activation properties, but without the unwanted side-effects seen with IL2. Several IL15-cytokine fusion proteins have been developed to improve their in vivo function, typically exploiting the IL15Rα to complex with IL15, to extend serum half-life and increase affinity for IL15β receptor on immune cells. Here we describe a novel IL15 complex incorporating the full-length IL15Rα to complex with wild type IL15 to form spontaneous trimers of dimers (6 IL15 + 6 IL15Rα) during co-expression, resulting in a substantial increase in serum half-life and enhancement of in vivo cytokine effect on IgG or T cell engaging antibody-dependent cell-mediated cytotoxicities, when compared to alternative strategies.
T 细胞在控制人类癌症方面的作用是众所周知的。它们的成功需要在体内持续存在并有效地运送到肿瘤部位，这是其他效应器（如自然杀伤 (NK) 细胞）所共有的要求。迄今为止，细胞因子 IL2 仍然是唯一经临床批准可用于扩增、维持和激活这些效应淋巴样细胞的细胞因子治疗方法，但毒性可能很严重。细胞因子 IL15 提供了类似的 T 细胞增殖和激活特性，但没有 IL2 所见的不良副作用。已经开发了几种 IL15-细胞因子融合蛋白来改善它们的体内功能，通常利用 IL15Rα 与 IL15 结合，以延长血清半衰期并增加对免疫细胞上 IL15β 受体的亲和力。在这里，我们描述了一种新型的 IL15 复合物，该复合物包含全长的 IL15Rα，与野生型 IL15 结合形成二聚体的自发三聚体（6 个 IL15+6 个 IL15Rα），在共表达时，与替代策略相比，血清半衰期显著延长，并增强了 IgG 或 T 细胞结合抗体依赖性细胞介导的细胞毒性的体内细胞因子效应。
