Molecular origins of high viscosity in concentrated solutions of monoclonal antibodies.

IF 3.2 3区 生物学 Q2 BIOPHYSICS
Arjun Valiya Parambathu, David J Rosenman, Sandeep Yadav, Abraham M Lenhoff
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引用次数: 0

Abstract

Concentrated monoclonal antibody (mAb) solutions can allow subcutaneous administration of effective doses of the therapeutic, but for some mAbs this leads to anomalously high viscosities; mAb-mAb association, leading to formation of clusters or gels, is often the driver of such behavior. Statistical mechanical considerations suggest that such association is likely to be dominated by a single binding configuration. In this work we probe the possible molecular origins of this behavior using atomistic molecular simulations of a mAb known to display high viscosity at low salt concentrations. Orientational exploration identified a small number of high-affinity mAb-mAb configurations based on non-electrostatic contributions to the protein interactions, which reflect the geometric complementarity characteristic of biomolecular recognition. Consideration of electrostatic interactions, which account for most salt effects, adds several tens of kT of attraction to select configurations, although there are uncertainties in the electrostatic calculations using the Poisson-Boltzmann approach. The resulting overall attractive energies, greater than 40 kT, support the existence of a single attractive configuration strong enough to form a mAb network at high concentrations. Simulations with increased ionic strength or for small numbers of point mutations predict some but not all observed experimental trends. Independent molecular dynamics (MD) simulations for two select configurations showed partial agreement with the previous results. Overall, while the molecular origin of high viscosity is plausibly due to a single strongly bound configuration, unambiguous identification of this configuration is limited by the numerical accuracy of the underlying calculations.

单克隆抗体浓溶液中高粘度的分子起源。
浓缩单克隆抗体(mAb)溶液可以允许皮下给药有效剂量的治疗,但对于一些单克隆抗体,这导致异常高的粘度;单抗-单抗结合,导致簇或凝胶的形成,通常是这种行为的驱动因素。统计力学方面的考虑表明,这种联系很可能是由单一的结合结构主导的。在这项工作中,我们利用单抗在低盐浓度下显示高粘度的原子分子模拟来探索这种行为的可能分子起源。定向探索发现了少数基于非静电对蛋白质相互作用贡献的高亲和力单抗-单抗构型,这反映了生物分子识别的几何互补性特征。尽管使用泊松-玻尔兹曼方法进行静电计算存在不确定性,但考虑到大多数盐效应的静电相互作用,在选择构型时增加了几十kT的吸引力。所得的总吸引能大于40 kT,支持存在一个足够强的单一吸引构型,足以在高浓度下形成单抗网络。增加离子强度或少量点突变的模拟预测了一些但不是全部观察到的实验趋势。两种选择构型的独立分子动力学(MD)模拟结果与先前的结果部分一致。总的来说,虽然高粘度的分子起源似乎是由于单一的强束缚结构,但这种结构的明确识别受到基础计算的数值准确性的限制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biophysical journal
Biophysical journal 生物-生物物理
CiteScore
6.10
自引率
5.90%
发文量
3090
审稿时长
2 months
期刊介绍: BJ publishes original articles, letters, and perspectives on important problems in modern biophysics. The papers should be written so as to be of interest to a broad community of biophysicists. BJ welcomes experimental studies that employ quantitative physical approaches for the study of biological systems, including or spanning scales from molecule to whole organism. Experimental studies of a purely descriptive or phenomenological nature, with no theoretical or mechanistic underpinning, are not appropriate for publication in BJ. Theoretical studies should offer new insights into the understanding ofexperimental results or suggest new experimentally testable hypotheses. Articles reporting significant methodological or technological advances, which have potential to open new areas of biophysical investigation, are also suitable for publication in BJ. Papers describing improvements in accuracy or speed of existing methods or extra detail within methods described previously are not suitable for BJ.
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