Meng, H. K., Pang, K. T., Wan, C., Zheng, Z. Y., Beiying, Q., Yang, Y., Zhang, W., Ho, Y. S., Walsh, I., & Chia, S. (2024). Thermal and pH stress dictate distinct mechanisms of monoclonal antibody aggregation. International Journal of Biological Macromolecules, 282, 136601. https://doi.org/10.1016/j.ijbiomac.2024.136601
Abstract:
Protein aggregation is a significant challenge in the development of monoclonal antibodies (mAbs), which can be exacerbated by stress conditions encountered along its production pipeline. In this study, we examine how thermal and pH stress conditions influence mAb aggregation mechanisms. We observe a complex interplay between these factors that significantly affects mAb stability, particularly under combined stress conditions. The mAb aggregates formed also varied distinctly in size and properties depending on the pH and thermal conditions, suggesting differences in their underlying mechanisms. Using a combination of experimental methods and kinetic modelling, we found that acidic pH conditions primarily promoted aggregation via the mAb unfolding step, while higher temperature conditions facilitated the formation of larger aggregates via monomer-independent cluster-cluster aggregation steps. These insights underscore the importance of extrinsic stress conditions in determining mAb aggregation propensity, and potentially provides a quantitative framework to holistically assess this across various accelerated stress conditions for the development of stable biologics.
License type:
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the Ministry of Health - Open Fund-Young Individual Research Grant (OF-YIRG)
Grant Reference no. : MOH-001132-00
This research / project is supported by the Agency for Science, Technology, and Research (A*STAR) - A*STAR Start Up Fund
Grant Reference no. :