Department of Pharmaceutical Technology, Astellas Pharma Inc.
Faculty of Bioresources and Environmental Sciences, Ishikawa Prefectural University.
Biol Pharm Bull. 2022;45(9):1300-1305. doi: 10.1248/bpb.b22-00263.
Understanding a monoclonal antibody's (MAb) physicochemical properties early in drug discovery is important for determining developability. Viscosity is important because antibodies with high viscosity have limited administration routes. Predicting the viscosity of highly concentrated MAb solutions is therefore essential for assessing developability. Here, we measured the viscosity and diffusion interaction coefficient (k) of 3 MAbs under 15 different formulation conditions (pH and salt) and evaluated correlations between parameters. We also used a computational approach to identify the key factors underlying differences in concentration-dependent curves for viscosity among the MAbs and formulation conditions. Results showed that viscosity increased exponentially at high concentrations, and that this concentration-dependency could be predicted from k. Attempts to set viscosity criterion for use by subcutaneous (SC) and intramuscular (IM) administration suggested that solutions with k greater than -20 mL/g may be candidates. Computational analysis suggested that the presence of a large negative charge in the complementarity determining region (CDR) is a major factor underlying the difference in concentration-dependency among the three MAbs under different formulation conditions. Because it is possible to predict the administration form of antibody solutions, determination of k at the early discovery stage may be essential for effective antibody development.
在药物发现早期了解单克隆抗体 (MAb) 的物理化学性质对于确定其可开发性很重要。粘度很重要，因为高粘度的抗体具有有限的给药途径。因此，预测高浓度 MAb 溶液的粘度对于评估可开发性至关重要。在这里，我们在 15 种不同的配方条件（pH 值和盐）下测量了 3 种 MAb 的粘度和扩散相互作用系数 (k)，并评估了参数之间的相关性。我们还使用计算方法来确定导致 MAb 和配方条件之间粘度的浓度依赖性曲线差异的关键因素。结果表明，粘度在高浓度下呈指数增长，并且这种浓度依赖性可以从 k 预测。尝试为皮下（SC）和肌肉内（IM）给药设定粘度标准表明，k 值大于-20 mL/g 的溶液可能是候选溶液。计算分析表明，在不同配方条件下，CDR 中存在大量负电荷是三个 MAb 之间浓度依赖性差异的主要因素。由于可以预测抗体溶液的给药形式，因此在早期发现阶段确定 k 值对于有效的抗体开发可能至关重要。
