Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
BioDrugs. 2013 Apr;27(2):159-66. doi: 10.1007/s40259-013-0013-x.
Fibroblast growth factor 21 (FGF21) has potent effects on normalizing glucose, lipid, and energy homeostasis, and represents an attractive novel therapy for type 2 diabetes mellitus and obesity. Approaches to improve the pharmacokinetic properties of FGF21, such as conjugation with polyethylene glycol, have been explored for therapeutic development. However, not only is there room for further pharmacokinetic improvements, additional re-engineering approaches to improve the potency and stability of FGF21 have not been reported. Here, we describe a novel approach to modify and improve the function of FGF21 by altering its C-terminal βKlotho interaction domain.
We first identified Avimer proteins that are capable of binding βKlotho. Then we explored replacing the C-terminal βKlotho interaction domain of FGF21 with a βKlotho-binding Avimer protein.
Such a βKlotho-binding Avimer protein was able to fully complement the C-terminal domain function of FGF21. The resulting FGF21-Avimer fusion is functionally indistinguishable from wild type FGF21, and more tolerant of C-terminal modification.
These results demonstrate a viable strategy to modulate the affinity, potency, and engineering of FGF21, paving the way for further improvements of FGF21 as a therapeutic.
成纤维细胞生长因子 21（FGF21）具有调节葡萄糖、脂质和能量稳态的强大作用，是治疗 2 型糖尿病和肥胖症的一种有吸引力的新型疗法。为了改善 FGF21 的药代动力学特性，如与聚乙二醇偶联，已经探索了多种方法用于治疗开发。然而，不仅有进一步改善药代动力学的空间，而且还没有报道其他工程改造方法来提高 FGF21 的效力和稳定性。在这里，我们描述了一种通过改变其 C 末端 βKlotho 相互作用结构域来修饰和改善 FGF21 功能的新方法。
我们首先鉴定了能够与 βKlotho 结合的 Avimer 蛋白。然后，我们探索了用βKlotho 结合的 Avimer 蛋白替代 FGF21 的 C 末端 βKlotho 相互作用结构域。
这种 βKlotho 结合的 Avimer 蛋白能够完全补充 FGF21 的 C 末端结构域功能。所得的 FGF21-Avimer 融合蛋白在功能上与野生型 FGF21 没有区别，并且对 C 末端修饰的耐受性更高。
这些结果表明了一种可行的策略，可以调节 FGF21 的亲和力、效力和工程改造，为进一步改善 FGF21 作为治疗药物铺平了道路。
