Differences in human IgG1 and IgG4 S228P monoclonal antibodies viscosity and self-interactions: Experimental assessment and computational predictions of domain interactions.
Differences in human IgG1 and IgG4 S228P monoclonal antibodies viscosity and self-interactions: Experimental assessment and computational predictions of domain interactions.
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DOI：
10.1080/19420862.2021.1991256
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发表时间：
2021-01
期刊：
影响因子：
5.3
通讯作者：
Trout BL
中科院分区：
文献类型：
--
作者：
Lai PK;Ghag G;Yu Y;Juan V;Fayadat-Dilman L;Trout BL
人/人源化IgG 4抗体相对于IgG 1抗体具有降低的效应子功能，这对于某些治疗目的是期望的。然而，IgG 4抗体的可开发性和生物物理特性尚未得到很好的理解。这项工作的重点是头对头比较的关键生物物理特性，如自我相互作用和粘度，为14人/人源化，嵌合IgG 1和IgG 4 S228 P单克隆抗体对，含有相同的可变区。实验测量显示，IgG 4 S228 P抗体在20 mM乙酸钠（pH 5.5）中具有与IgG 1抗体相似或更高的自身相互作用和粘度。我们报告的序列和结构的驱动程序增加的粘度和自我相互作用的IgG 4 S228 P抗体中检测到的实验数据和计算模型的组合。此外，我们应用并扩展了先前建立的IgG 1抗体的计算模型，以预测每个抗体对的自相互作用和粘度行为，从而深入了解这两种同种型的结构特征和差异。有趣的是，我们观察到IgG 4 S228 P交换变体，其中CH 3结构域交换为IgG 1结构域，显示出降低的自我相互作用行为。这些结构域交换的IgG 4 S228 P分子也显示出来自实验和粗粒度模拟的降低的粘度。我们还观察到，实验扩散相互作用参数（kD）值与计算扩散率预测的IgG 1和IgG 4 S228 P同种型具有很高的相关性。缩略语：，恒定区Hamaker常数;，可变区Hamaker常数; CDR，互补决定区; CG，粗粒模型; CH 1，恒定重链1; CH 2恒定重链2; CH 3恒定重链3; chgCH 3 CH 3区上的有效电荷; CL恒定轻链; cP，厘泊; DLS，动态光散射; Fab，抗原结合片段; Fc，可结晶片段; Fv，可变域;（r）径向分布函数;重链的H1 CDR 1;重链的H2 CDR 2;重链的H3 CDR 3; HVI，高粘度指数; IgG 1亚类的IgG 1人免疫球蛋白; IgG 4亚类的IgG 4人免疫球蛋白; kD，扩散相互作用参数;轻链的L1 CDR 1;轻链的L2 CDR 2;轻链的L3 CDR 3; mAb，单克隆抗体; MD，分子动力学; PPI蛋白质-蛋白质相互作用; SCM，空间电荷图; UP-SEC，超高效分子排阻色谱法; VH，重链可变区; VL，轻链可变区
Human/humanized IgG4 antibodies have reduced effector function relative to IgG1 antibodies, which is desirable for certain therapeutic purposes. However, the developability and biophysical properties for IgG4 antibodies are not well understood. This work focuses on the head-to-head comparison of key biophysical properties, such as self-interaction and viscosity, for 14 human/humanized, and chimeric IgG1 and IgG4 S228P monoclonal antibody pairs that contain the identical variable regions. Experimental measurements showed that the IgG4 S228P antibodies have similar or higher self-interaction and viscosity than that of IgG1 antibodies in 20 mM sodium acetate, pH 5.5. We report sequence and structural drivers for the increased viscosity and self-interaction detected in IgG4 S228P antibodies through a combination of experimental data and computational models. Further, we applied and extended a previously established computational model for IgG1 antibodies to predict the self-interaction and viscosity behavior for each antibody pair, providing insight into the structural characteristics and differences of these two isotypes. Interestingly, we observed that the IgG4 S228P swapped variants, where the CH3 domain was swapped for that of an IgG1, showed reduced self-interaction behavior. These domain swapped IgG4 S228P molecules also showed reduced viscosity from experiment and coarse-grained simulations. We also observed that experimental diffusion interaction parameter (kD) values have a high correlation with computational diffusivity prediction for both IgG1 and IgG4 S228P isotypes. Abbreviations: , constant region Hamaker constant; , variable region Hamaker constant; CDRs, Complementarity-determining regions; CG, Coarse-grained model; CH1, Constant heavy chain 1; CH2 Constant heavy chain 2; CH3 Constant heavy chain 3; chgCH3 Effective charge on the CH3 region; CL Constant light chain; cP, Centipoise; DLS, Dynamic light scattering; Fab, Fragment antigen-binding; Fc, Fragment crystallizable; Fv, Variable domaing; (r) Radial distribution function; H1 CDR1 of Heavy Chain; H2 CDR2 of Heavy Chain; H3 CDR3 of Heavy Chain; HVI, High viscosity index; IgG1 human immunoglobulin of IgG1 subclass; IgG4 human immunoglobulin of IgG4 subclass; kD, Diffusion interaction parameter; L1 CDR1 of Light Chain; L2 CDR2 of Light Chain; L3 CDR3 of Light Chain; mAb, Monoclonal antibody; MD, Molecular dynamics; PPI Protein–protein interactions; SCM, Spatial charge map; UP-SEC, Ultra-high-performance size-exclusion chromatography; VH, Variable domain of Heavy Chain; VL, Variable domain of Light Chain
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影响因子：
2.4
作者：
Heads, James T.;Lamb, Richard;Lawson, Alastair D. G.
通讯作者：
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影响因子：
5.3
作者：
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5.3
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通讯作者：
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