Protein-Protein Interactions of Highly Concentrated Monoclonal Antibody Solutions via Static Light Scattering and Influence on the Viscosity
Protein-Protein Interactions of Highly Concentrated Monoclonal Antibody Solutions via Static Light Scattering and Influence on the Viscosity
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DOI：
10.1021/acs.jpcb.8b09527
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发表时间：
2019-01-31
影响因子：
3.3
通讯作者：
Johnston, Keith P.
中科院分区：
文献类型：
--
作者：
Hung, Jessica J.;Dear, Barton J.;Johnston, Keith P.
设计和配制mAb以使高浓度下的吸引力相互作用最小化的能力对于蛋白质加工、稳定性和施用是重要的，特别是在皮下递送中，其中高粘度通常具有挑战性。通过静态光散射（SLS）测定低浓度至高浓度的IgG 1和IgG 4单克隆抗体（mAb）的蛋白质-蛋白质相互作用（PPI）强度，并用于了解粘度数据。使用NaCl和五种有机离子共溶质调谐PPI。PPI强度通过从SLS数据确定的归一化结构因子S（0）/S（0）（Hs）和Kirkwood-Buff积分G（22）/G（22），（Hs）（HS =硬球）以及通过与（1）球形Yukawa势和（2）相互作用硬球（IHS）模型拟合来量化，该模型根据假设的低聚物描述吸引力。IHS模型比球形Yukawa势更能描述强相互作用体系（单克隆抗体和/或共溶质）的散射行为。对于PPI的每个描述符，在高浓度（200 mg/mL）下的粘度与给定mAb在低浓度（20 mg/mL）和高浓度（200 mg/mL）下评价的相互作用强度之间获得线性相关性。然而，IHS模型中唯一的参数是（M-低聚物/单体+二聚体），表明自缔合（除了有吸引力的PPI的直接影响之外）对粘度的重要性。
The ability to design and formulate mAbs to minimize attractive interactions at high concentrations is important for protein processing, stability, and administration, particularly in subcutaneous delivery, where high viscosities are often challenging. The strength of protein-protein interactions (PPIs) of an IgG1 and IgG4 monoclonal antibody (mAb) from low to high concentration was determined by static light scattering (SLS) and used to understand viscosity data. The PPI were tuned using NaCl and five organic ionic co-solutes. The PPI strength was quantified by the normalized structure factor S(0)/S(0)(Hs) and Kirkwood-Buff integral G(22)/G(22),(Hs) (HS = hard sphere) determined from the SLS data and also by fits with (1) a spherical Yukawa potential and (2) an interacting hard sphere (IHS) model, which describes attraction in terms of hypothetical oligomers. The IHS model was better able to capture the scattering behavior of the more strongly interacting systems (mAb and/or co-solute) than the spherical Yukawa potential. For each descriptor of PPI, linear correlations were obtained between the viscosity at high concentration (200 mg/mL) and the interaction strengths evaluated both at low (20 mg/mL) and high concentrations (200 mg/mL) for a given mAb. However, the only parameter that (M-ollgomer/Mmonomer+dimer) from the IHS model, indicating the importance of self-association (in addition to the direct influence of the attractive PPI) on the viscosity.