Communications Biology ( IF 5.2 ) Pub Date : 2022-08-18 , DOI: 10.1038/s42003-022-03787-x
Torleif Tollefsrud Gjølberg 1, 2, 3 , Rahel Frick 4 , Simone Mester 1, 2 , Stian Foss 1, 2 , Algirdas Grevys 1, 2 , Lene Støkken Høydahl 1, 5 , Øystein Kalsnes Jørstad 3 , Tilman Schlothauer 6 , Inger Sandlie 7 , Morten C Moe 3 , Jan Terje Andersen 1, 2
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Antibody-based therapeutics (ABTs) are used to treat a range of diseases. Most ABTs are either full-length IgG1 antibodies or fusions between for instance antigen (Ag)-binding receptor domains and the IgG1 Fc fragment. Interestingly, their plasma half-life varies considerably, which may relate to how they engage the neonatal Fc receptor (FcRn). As such, there is a need for an in-depth understanding of how different features of ABTs affect FcRn-binding and transport behavior. Here, we report on how FcRn-engagement of the IgG1 Fc fragment compare to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-α. The results reveal FcRn-dependent intracellular accumulation of the Fc, which is in line with shorter plasma half-life than that of full-length IgG1 in human FcRn-expressing mice. Receptor domain fusion to the Fc increases its half-life, but not to the extent of IgG1. This is mirrored by a reduced cellular recycling capacity of the Fc-fusions. In addition, binding of cognate Ag to ABTs show that complexes of similar size undergo cellular transport at different rates, which could be explained by the biophysical properties of each ABT. Thus, the study provides knowledge that should guide tailoring of ABTs regarding optimal cellular sorting and plasma half-life.
中文翻译:
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基于 IgG1 Fc 的疗法的生物物理差异与其细胞处理、与 FcRn 的相互作用和血浆半衰期有关
基于抗体的疗法 (ABT) 用于治疗一系列疾病。大多数 ABT 要么是全长 IgG1 抗体,要么是抗原 (Ag) 结合受体结构域和 IgG1 Fc 片段之间的融合体。有趣的是,它们的血浆半衰期差异很大,这可能与它们如何与新生儿 Fc 受体 (FcRn) 结合有关。因此,需要深入了解 ABT 的不同特征如何影响 FcRn 结合和转运行为。在这里,我们报告了 IgG1 Fc 片段的 FcRn 接合与临床相关 IgG 和受体结构域 Fc 融合物与 VEGF 或 TNF-α 结合的比较。结果揭示了 Fc 的 FcRn 依赖性细胞内积累,这与表达人 FcRn 的小鼠中的血浆半衰期短于全长 IgG1 的血浆半衰期一致。与 Fc 融合的受体结构域会增加其半衰期,但不会达到 IgG1 的程度。这反映在 Fc 融合体的细胞再循环能力降低。此外,同源 Ag 与 ABT 的结合表明,相似大小的复合物以不同的速率进行细胞转运,这可以通过每个 ABT 的生物物理特性来解释。因此,该研究提供的知识应指导 ABT 的最佳细胞分选和血浆半衰期的定制。