Neoleukin Therapeutics Inc., Seattle, WA, USA.
Neoleukin Therapeutics Inc., Seattle, WA, USA.
Curr Opin Chem Biol. 2020 Jun;56:119-128. doi: 10.1016/j.cbpa.2020.02.002. Epub 2020 May 1.
Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use naturally existing proteins as a starting point, and therefore, are intrinsically limited to small alterations of a protein's natural structure and function. Conversely, computational de novo protein design is free of such limitation, and can produce a virtually infinite number of novel protein sequences, folds, and functions. Recently, we used de novo protein engineering to create Neoleukin-2/15 (Neo-2/15), a protein mimetic of the function of both interleukin-2 (IL-2) and interleukin-15 (IL-15). To our knowledge, Neo-2/15 is the first de novo protein with immunotherapeutic activity, and in murine cancer models, it has demonstrated enhanced therapeutic potency and reduced toxicity compared to IL-2. De novo protein design is already showcasing its tremendous potential for driving the next wave of protein-based therapeutics that are explicitly engineered to treat disease.
工程蛋白正在彻底改变免疫疗法，但仍需要进一步发展来充分发挥其潜力。传统的蛋白质工程方法以天然存在的蛋白质为起点，因此本质上仅限于对蛋白质天然结构和功能的微小改变。相反，计算从头设计蛋白质不受这种限制，可以产生几乎无限数量的新型蛋白质序列、折叠和功能。最近，我们使用从头设计蛋白质工程来创建 Neoleukin-2/15（Neo-2/15），这是一种模拟白细胞介素-2（IL-2）和白细胞介素-15（IL-15）功能的蛋白质类似物。据我们所知，Neo-2/15 是第一个具有免疫治疗活性的从头设计蛋白，并且在小鼠癌症模型中，与 IL-2 相比，它显示出增强的治疗效力和降低的毒性。从头设计蛋白质已经展示了其巨大的潜力，可以推动下一波基于蛋白质的治疗药物的发展，这些药物是专门为治疗疾病而设计的。
