Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
复制标题
出版商更正：一种工程化的人类 Fc 结构域，其行为类似于 pH 切换开关，可实现超长的循环持久性。
DOI：
10.1038/s41467-019-13458-x
复制
发表时间：
2019
影响因子：
16.6
通讯作者：
Tess
中科院分区：
文献类型：
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作者：
Lee,Chang-Han;Kang,TaeHyun;Godon,Ophélie;Watanabe,Makiko;Delidakis,George;Gillis,CaitlinM;Sterlin,Delphine;Hardy,David;Cogné,Michel;Macdonald,LynnE;Murphy,AndrewJ;Tu,Naxin;Lee,Jiwon;McDaniel,JonathanR;Makowski,Emily;Tess
抗体的药代动力学特性很大程度上取决于 IgG 片段可结晶 (Fc) 结构域与人新生儿 Fc 受体 (hFcRn) 的 pH 依赖性结合。工程化的 Fc 结构域凭借与 hFcRn 更有利的 pH 依赖性结合而赋予更长的循环半衰期，因此具有巨大的治疗意义。在这里，我们开发了一种包含 L309D/Q311H/N434S (DHS) 取代的 pH 切换开关 Fc 变体，与天然 IgG1 和广泛使用的半衰期延长变体相比，其在传统 hFcRn 转基因小鼠和新的敲入小鼠品系中均表现出显着改善的药代动力学。专门设计用于概括与人抗体在循环中持久性相关的所有关键过程，即：（i）hFcRn 的生理表达，（ii）hFcγR 对抗体清除的影响以及（iii）竞争性内源 IgG 的作用。 DHS-IgG保留了完整的效应功能，这对于清除靶病原细胞很重要，并且具有良好的可开发性。
The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.