Saluja Atul, Badkar Advait V, Zeng David L, Kalonia Devendra S
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
J Pharm Sci. 2007 Dec;96(12):3181-95. doi: 10.1002/jps.20970.
The purpose of this work was to investigate if physical stability of a model monoclonal antibody (IgG(2)), as determined by extent of aggregation, was related to rheology of its solutions. Storage stability of the model protein was assessed at 25 degrees C and 37 degrees C for three months in solutions ranging from pH 4.0 to 9.0 and ionic strengths of 4 mM and 300 mM. The rheology of IgG(2) solutions has been characterized at 25 degrees C in our previous work and correlation of solution storage modulus (G') with protein-protein interactions established. The extent of aggregation was consistent with solution rheology as understood in terms of changes in G' with protein concentration. Thermodynamic stability of native IgG(2) conformation increased with increasing pH. The correlation between rheology and aggregation was also assessed at increased ionic strengths. The decrease in aggregation was consistent with change in solution rheology profile at pH 7.4 and 9.0. The results provide evidence of a relationship between solution rheology and extent of aggregation for the model protein studied. The implications of this relationship for formulation and physical stability assessment in high concentration protein solutions are discussed.
这项工作的目的是研究一种模型单克隆抗体（IgG(2)）的物理稳定性（通过聚集程度来确定）是否与其溶液的流变学相关。在25℃和37℃下，于pH值为4.0至9.0、离子强度为4 mM和300 mM的溶液中对模型蛋白的储存稳定性进行了为期三个月的评估。在我们之前的工作中，已对IgG(2)溶液在25℃下的流变学进行了表征，并建立了溶液储能模量（G'）与蛋白质 - 蛋白质相互作用之间的相关性。聚集程度与溶液流变学一致，这可从G'随蛋白质浓度的变化来理解。天然IgG(2)构象的热力学稳定性随pH值升高而增加。在离子强度增加时，也评估了流变学与聚集之间的相关性。聚集的减少与pH值为7.4和9.0时溶液流变学曲线的变化一致。结果为所研究的模型蛋白的溶液流变学与聚集程度之间的关系提供了证据。讨论了这种关系对高浓度蛋白质溶液的配方设计和物理稳定性评估的意义。
