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首页> 外文期刊>Journal of pharmaceutical sciences. >Predicting Accelerated Aggregation Rates for Monoclonal Antibody Formulations, and Challenges for Low-Temperature Predictions
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Predicting Accelerated Aggregation Rates for Monoclonal Antibody Formulations, and Challenges for Low-Temperature Predictions

机译：预测单克隆抗体制剂的加速聚集速率，以及对低温预测的挑战

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摘要

Nonnative aggregation is a common degradation route for therapeutic proteins. Control of aggregate levels inherently requires control and/or prediction of aggregation rates at formulation conditions and storage temperatures of practical interest. Additionally, formulation screening often involves generation of accelerated stability data at one or more temperatures. A temperature-scanning approach for measuring nonnative aggregation rates as a function of temperature is proposed and evaluated here for a monoclonal antibody across different formulation conditions. Observed rate coefficients of aggregation (k_(obs)) were determined from isothermal kinetic studies for a range of pH and. salt conditions at several temperatures, corresponding to shelf lives spanning multiple orders of magnitude. Isothermal k_(obs) values were efficiently and quantitatively predicted by the temperature-scanning monomer loss (TSML) approach at accelerated conditions (half lives of the order 10~(-1)-10~2 h). At lower temperatures, non-Arrhenius behavior was apparent in some cases, and was semi-quantitatively described by nonlinear van't Hoff contributions to monomer unfolding free energies. Overall, the results demonstrate a novel strategy to quantitatively determine aggregation rates at time scales of industrial interest, based on k_(obs) values from TSML, which are sample- and time-sparing as compared with traditional isothermal approaches, and illustrate challenges for shelf-life prediction with non-Arrhenius kinetics
机译：非天然聚集是治疗性蛋白质的常见降解途径。聚集水平的控制固有地需要在实际感兴趣的配制条件和储存温度下控制和/或预测聚集速率。另外，制剂筛选通常涉及在一个或多个温度下产生加速稳定性数据。提出了一种用于测量作为温度函数的非天然聚集速率的温度扫描方法，并在此针对跨不同制剂条件的单克隆抗体进行了评估。观察到的聚集速率系数（k_（obs））是从等温动力学研究中确定的。在几个温度下的盐分条件，对应于跨越多个数量级的保质期。在加速条件下（半衰期为10〜（-1）-10〜2 h），通过温度扫描单体损失（TSML）方法有效地定量了等温k_（obs）值。在较低的温度下，在某些情况下会表现出非阿伦尼乌斯行为，并通过非线性范霍夫对单体展开自由能的贡献进行了半定量描述。总体而言，结果证明了一种新颖的策略，可基于TSML的k_（obs）值在工业关注的时间尺度上定量确定聚集率，与传统的等温方法相比，该值可节省样本和时间，并说明了货架面临的挑战非阿伦尼乌斯动力学的寿命预测

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