一种工程化的人源 Fc 结构域，可作为 pH 翻转开关，实现超长循环半衰期。
An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
机构信息
Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.
Department of Applied Chemistry, Kookmin University, Seoul, Republic of Korea.
出版信息
Nat Commun. 2019 Nov 6;10(1):5031. doi: 10.1038/s41467-019-13108-2.
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.
抗体的药代动力学特性在很大程度上取决于 IgG 片段结晶（Fc）结构域与人类新生 Fc 受体（hFcRn）之间 pH 依赖性的结合。通过与 hFcRn 更有利的 pH 依赖性结合赋予更长循环半衰期的工程化 Fc 结构域具有重要的治疗意义。在这里，我们开发了一种 pH 翻转开关 Fc 变体，其中包含 L309D/Q311H/N434S（DHS）取代，与天然 IgG1 和广泛使用的半衰期延长变体相比，无论是在常规 hFcRn 转基因小鼠还是在新的基因敲入小鼠品系中，都表现出明显改善的药代动力学特性。这些小鼠品系专门设计用于重现与人类抗体在循环中持续存在相关的所有关键过程，即：（i）hFcRn 的生理表达，（ii）hFcγRs 对抗体清除的影响，以及（iii）内源性 IgG 的竞争。DHS-IgG 保留了完整的效应功能，这对于清除靶标致病细胞很重要，同时也具有良好的可开发性。
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