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Viscosities and Protein Interactions of Bispecific Antibodies and Their Monospecific Mixtures
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-29 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00706 Mahlet A. Woldeyes 1 , Lilian L. Josephson 1 , Danielle L. Leiske 2 , William J. Galush 2 , Christopher J. Roberts 1 , Eric M. Furst 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-29 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00706 Mahlet A. Woldeyes 1 , Lilian L. Josephson 1 , Danielle L. Leiske 2 , William J. Galush 2 , Christopher J. Roberts 1 , Eric M. Furst 1
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Solution viscosities (η) and protein–protein interactions (PPI) of three monoclonal antibodies (mAb-A, mAb-B, mAb-C), two bispecific antibodies (BsAb-A/B, BsAb-A/C), and two 1:1 binary mixtures (mAb-A + mAb-B and mAb-A + mAb-C) were measured. mAb-A and mAb-C have similar isoelectric point (pI) values but significantly different η versus protein concentration (c2) profiles. The viscosity of the mAb-A + mAb-C mixture followed an Arrhenius mixing rule and was identical to viscosity of the bispecific BsAb-A/C. In contrast, mAb-A and mAb-B had similar η versus c2 profiles, but the Arrhenius mixing rule failed to predict the higher viscosities of their mixtures. The viscosity of the bispecific BsAb-A/B followed the 1:1 mAb-A + mAb-B mixture at all concentrations. The nature of the interactions for mAb-A, mAb-B, the BsAb-A/B bispecific, and the 1:1 mAb-A + mAb-B mixture were characterized by static and dynamic light scattering (SLS and DLS). mAb-A and mAb-B exhibited net-attractive and -repulsive electrostatic interactions, respectively. The bispecific antibody (BsAb-A/B) had short-ranged attractive interactions, suggesting that the increase in viscosity for this molecule and the mAb-A + mAb-B mixture was due to cross-interactions between Fab regions. At high and low ionic strengths and protein concentrations, the Rayleigh scattering profile, the collective diffusion coefficient, and viscosity for the mixture closely followed that for the bispecific antibody. These results highlight the possible anomalous viscosity increases of bispecific antibodies constructed from relatively low-viscosity mAbs but demonstrates a potentially fruitful approach of using mAb mixtures to predict the viscosity of candidate bispecific constructs.
中文翻译：
双特异性抗体及其单特异性混合物的粘度和蛋白质相互作用
三种单克隆抗体（mAb-A，mAb-B，mAb-C），两种双特异性抗体（BsAb-A / B，BsAb-A / C）的溶液粘度（η）和蛋白质-蛋白质相互作用（PPI）测量了1：1的二元混合物（mAb-A + mAb-B和mAb-A + mAb-C）。mAb-A和mAb-C具有相似的等电点（pI）值，但η与蛋白质浓度（c 2）曲线存在显着差异。mAb-A + mAb-C混合物的粘度遵循Arrhenius混合规则，与双特异性BsAb-A / C的粘度相同。相反，mAb-A和mAb-B的η与c 2相似曲线，但Arrhenius混合规则无法预测其混合物的更高粘度。在所有浓度下，双特异性BsAb-A / B的粘度均遵循1：1 mAb-A + mAb-B混合物。mAb-A，mAb-B，BsAb-A / B双特异性抗体和1：1 mAb-A + mAb-B混合物的相互作用性质通过静态和动态光散射（SLS和DLS）来表征。mAb-A和mAb-B分别表现出净吸引和排斥静电相互作用。双特异性抗体（BsAb-A / B）具有短距离吸引相互作用，表明该分子和mAb-A + mAb-B混合物的粘度增加是由于Fab区之间的交叉相互作用。在高和低离子强度和蛋白质浓度下，瑞利散射曲线，集体扩散系数，混合物的粘度和粘度紧随双特异性抗体的粘度。这些结果突显了由相对较低粘度的mAb构建的双特异性抗体可能异常粘度增加，但证明了使用mAb混合物预测候选双特异性构建体粘度的潜在成果。
更新日期：2018-08-29
中文翻译：
双特异性抗体及其单特异性混合物的粘度和蛋白质相互作用
三种单克隆抗体（mAb-A，mAb-B，mAb-C），两种双特异性抗体（BsAb-A / B，BsAb-A / C）的溶液粘度（η）和蛋白质-蛋白质相互作用（PPI）测量了1：1的二元混合物（mAb-A + mAb-B和mAb-A + mAb-C）。mAb-A和mAb-C具有相似的等电点（pI）值，但η与蛋白质浓度（c 2）曲线存在显着差异。mAb-A + mAb-C混合物的粘度遵循Arrhenius混合规则，与双特异性BsAb-A / C的粘度相同。相反，mAb-A和mAb-B的η与c 2相似曲线，但Arrhenius混合规则无法预测其混合物的更高粘度。在所有浓度下，双特异性BsAb-A / B的粘度均遵循1：1 mAb-A + mAb-B混合物。mAb-A，mAb-B，BsAb-A / B双特异性抗体和1：1 mAb-A + mAb-B混合物的相互作用性质通过静态和动态光散射（SLS和DLS）来表征。mAb-A和mAb-B分别表现出净吸引和排斥静电相互作用。双特异性抗体（BsAb-A / B）具有短距离吸引相互作用，表明该分子和mAb-A + mAb-B混合物的粘度增加是由于Fab区之间的交叉相互作用。在高和低离子强度和蛋白质浓度下，瑞利散射曲线，集体扩散系数，混合物的粘度和粘度紧随双特异性抗体的粘度。这些结果突显了由相对较低粘度的mAb构建的双特异性抗体可能异常粘度增加，但证明了使用mAb混合物预测候选双特异性构建体粘度的潜在成果。
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