Unverdorben Felix, Richter Fabian, Hutt Meike, Seifert Oliver, Malinge Pauline, Fischer Nicolas, Kontermann Roland E
a Institute of Cell Biology and Immunology; University of Stuttgart ; Allmandring 31; 70569 ; Stuttgart ; Germany.
b Novimmune; 14 chemin des Aulx; 1228 Plan-les-Ouates ; Geneva ; Switzerland.
MAbs. 2016;8(1):120-8. doi: 10.1080/19420862.2015.1113360.
Fusion to an IgG Fc region is an established strategy to extend the half-life of therapeutic proteins. Most Fc fusion proteins, however, do not achieve the long half-life of IgGs. Based on findings that scFv-Fc fusion proteins exhibit a shorter half-life than the corresponding IgG molecules, we performed a comparative study of different antibody-derived Fc fusion proteins. We could confirm that fusion of single-chain Fv (scFv) and single-chain diabody (scDb) molecules to an Fc region yields in fusion proteins with substantially extended half-lives compared with the single-chain versions. However, even fusion proteins with a size similar to that of IgG, e.g., scDb-Fc, did not have a half-life as long as an IgG molecule. Binding to the neonatal Fc receptor (FcRn) under acidic and neutral conditions was similar for IgG and all Fc fusion proteins. However, we observed differences between IgG and the Fc fusion proteins for dissociation of FcRn-bound proteins induced by shifting from acidic to neutral pH, reflecting the physiological release mechanism, further supporting a contribution of the kinetics of pH-dependent release from FcRn to the pharmacokinetic properties of IgG and Fc fusion proteins.
与IgG Fc区域融合是一种已确立的延长治疗性蛋白质半衰期的策略。然而，大多数Fc融合蛋白并未达到IgG那样长的半衰期。基于单链抗体片段- Fc（scFv-Fc）融合蛋白的半衰期比相应IgG分子短的发现，我们对不同抗体衍生的Fc融合蛋白进行了比较研究。我们可以证实，与单链形式相比，将单链Fv（scFv）和单链双特异性抗体（scDb）分子与Fc区域融合可产生半衰期显著延长的融合蛋白。然而，即使是大小与IgG相似的融合蛋白，例如scDb-Fc，其半衰期也不如IgG分子长。在酸性和中性条件下，IgG和所有Fc融合蛋白与新生儿Fc受体（FcRn）的结合相似。然而，我们观察到，从酸性pH转变为中性pH诱导的FcRn结合蛋白解离过程中，IgG和Fc融合蛋白之间存在差异，这反映了生理释放机制，进一步支持了从FcRn进行pH依赖性释放的动力学对IgG和Fc融合蛋白药代动力学特性的贡献。
