Thermal and pH stress dictate distinct mechanisms of monoclonal antibody aggregation.

Autor: Meng HK; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Pang KT; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore; School of Chemistry, Chemical Engineering, and Biotechnology, Nanyang Technology University, Singapore., Wan C; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Zheng ZY; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Beiying Q; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Yang Y; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Zhang W; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Ho YS; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Walsh I; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. Electronic address: ian_walsh@bti.a-star.edu.sg., Chia S; Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. Electronic address: sean_chia@bti.a-star.edu.sg.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Dec; Vol. 282 (Pt 2), pp. 136601. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1016/j.ijbiomac.2024.136601
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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