Amunix, Inc., Mountain View, California, USA.
Nat Biotechnol. 2009 Dec;27(12):1186-90. doi: 10.1038/nbt.1588.
Increasing the in vivo residence times of protein therapeutics could decrease their dosing frequencies. We show that genetic fusion of an unstructured recombinant polypeptide of 864 amino acids, called XTEN, to a peptide or protein provides an apparently generic approach to extend plasma half-life. Allometric scaling suggests that a fusion of XTEN to the exenatide peptide should increase exenatide half-life in humans from 2.4 h to a projected time of 139 h. We confirmed the biological activity of the exenatide-XTEN fusion in mice. As extended stability might exacerbate undesirable side effects in some cases, we show that truncating the XTEN sequence can regulate plasma half-life. XTEN lacks hydrophobic amino acid residues that often contribute to immunogenicity and complicate manufacture. Based on data on XTEN fusions to exenatide, glucagon, GFP and human growth hormone, we expect that XTEN will enable dosing of otherwise rapidly cleared protein drugs at up to monthly intervals in humans.
增加蛋白质治疗药物的体内停留时间可以降低其给药频率。我们表明，将一种称为 XTEN 的 864 个氨基酸的无规重组多肽与肽或蛋白质进行基因融合，为延长血浆半衰期提供了一种通用的方法。比例缩放表明，XTEN 与 exenatide 肽的融合应该将 exenatide 的半衰期从 2.4 小时延长到预计的 139 小时。我们在小鼠中证实了 exenatide-XTEN 融合的生物学活性。由于延长稳定性在某些情况下可能会加剧不良副作用，我们表明截短 XTEN 序列可以调节血浆半衰期。XTEN 缺乏经常导致免疫原性并使制造复杂化的疏水性氨基酸残基。基于对 XTEN 与 exenatide、胰高血糖素、GFP 和人生长激素融合的数据，我们预计 XTEN 将使其他快速清除的蛋白质药物能够以每月一次的间隔在人类中给药。
