Armstrong Georgina Bethany, Burley Glenn A, Lewis William, Rattray Zahra
Drug Substance Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NFX, U.K.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, U.K.
Mol Pharm. 2024 Dec 2;21(12):6423-6432. doi: 10.1021/acs.molpharmaceut.4c01010. Epub 2024 Nov 7.
Early-phase manufacturability assessment of high-concentration therapeutic monoclonal antibodies (mAbs) involves screening of process-related risks impacting their translation into the clinic. Manufacturing a mAb at scale relies on cost-effective and robust approaches to derisk manufacturability parameters, such as viscosity, conformational stability, aggregation, and process-related impurities. Using a panel of model anti-IL-8 IgG1 mutants, we investigate upstream and downstream processability, phase behavior, and process-related impurities. We correlate trends in the biophysical properties of mAbs with their cell growth, expression, filtration flux, solubility, and post-translational modifications. We find significant trends in increased relative free light chain expression with heavy chain mutants and detect a requirement for adjusted operation pH for cation exchange polishing steps with charge-altering variants. Moreover, trends between phase stability and high-concentration viscosity were observed. We also investigated unique correlations between increased glycosylation and biophysical behavior. Further in-depth analysis and modeling are required to elucidate the impact of the mAb sequence on the metabolism of the expression system, solubility limits, and alternative gelation models as future directions.
高浓度治疗性单克隆抗体（mAb）的早期可制造性评估涉及筛选影响其临床转化的工艺相关风险。大规模生产单克隆抗体依赖于具有成本效益且稳健的方法来降低可制造性参数的风险，如粘度、构象稳定性、聚集以及与工艺相关的杂质。使用一组抗IL-8 IgG1模型突变体，我们研究了上下游加工性能、相行为以及与工艺相关的杂质。我们将单克隆抗体的生物物理性质趋势与其细胞生长、表达、过滤通量、溶解度和翻译后修饰相关联。我们发现重链突变体导致相对游离轻链表达增加的显著趋势，并检测到对于电荷改变变体的阳离子交换纯化步骤需要调整操作pH值。此外，观察到了相稳定性和高浓度粘度之间的趋势。我们还研究了糖基化增加与生物物理行为之间的独特相关性。作为未来的方向，需要进一步深入分析和建模以阐明单克隆抗体序列对表达系统代谢、溶解度极限和替代凝胶化模型的影响。
