Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life.
Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life.
复制标题
抗体可变序列对细胞转运和血浆半衰期具有明显的影响。
DOI：
10.1016/j.isci.2022.103746
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发表时间：
2022-02-18
期刊：
影响因子：
5.8
通讯作者：
Andersen JT
中科院分区：
文献类型：
--
作者：
Grevys A;Frick R;Mester S;Flem-Karlsen K;Nilsen J;Foss S;Sand KMK;Emrich T;Fischer JAA;Greiff V;Sandlie I;Schlothauer T;Andersen JT
单克隆IgG抗体是增长最快的一类生物制剂，但其在人体中的血浆半衰期存在很大差异。因此，为了设计具有有利的药代动力学的IgG抗体，鉴定这种差异的决定因素至关重要。在这里，我们证明了IgG抗体的可变区序列极大地影响细胞摄取和随后的再循环，并从内皮细胞的细胞内降解救援。当可变序列被同源抗原掩蔽时，它会影响它们的转运行为和与新生儿Fc受体（FcRn）的结合，后者是IgG血浆半衰期的关键调节因子。此外，我们显示了如何在可变结构域的电荷补丁的差异调制的结合和运输性能和短的血浆半衰期，由于不利的电荷补丁，可以部分地克服Fc-工程改进FcRn结合。IgG可变区序列极大地影响细胞摄取和再循环可变区电荷斑影响FcRn结合和转运同源抗原的存在调节细胞转运和FcRn结合用于改善FcRn结合的Fc工程可以克服不利的电荷斑生物科学;免疫学;生物物理学
Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells. When the variable sequences are masked by the cognate antigen, it influences both their transport behavior and binding to the neonatal Fc receptor (FcRn), a key regulator of IgG plasma half-life. Furthermore, we show how charge patch differences in the variable domains modulate both binding and transport properties and that a short plasma half-life, due to unfavorable charge patches, may partly be overcome by Fc-engineering for improved FcRn binding. IgG variable region sequences greatly affect cellular uptake and recycling Variable region charge patches affect FcRn binding and transport The presence of cognate antigen modulates cellular transport and FcRn binding Fc-engineering for improved FcRn binding can overcome unfavorable charge patches Biological sciences; Immunology; Biophysics
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影响因子：
4.8
作者：
Chaparro-Riggers, Javier;Liang, Hong;Rajpal, Arvind
通讯作者：
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影响因子：
5.3
作者：
Bonvin, Pauline;Venet, Sophie;Fischer, Nicolas
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影响因子：
15.8
作者：
Gaudinski MR;Coates EE;Houser KV;Chen GL;Yamshchikov G;Saunders JG;Holman LA;Gordon I;Plummer S;Hendel CS;Conan-Cibotti M;Lorenzo MG;Sitar S;Carlton K;Laurencot C;Bailer RT;Narpala S;McDermott AB;Namboodiri AM;Pandey JP;Schwartz RM;Hu Z;Koup RA;Capparelli E;Graham BS;Mascola JR;Ledgerwood JE;VRC 606 Study Team
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影响因子：
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作者：
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通讯作者：
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