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Separation and characterization of subpopulations of biopharmaceuticals
Separation and characterization of subpopulations of biopharmaceuticals
The chemical changes that cause heterogeneity in protein therapeutics are well described and monitored during development and manufacturing. Many of these subpopulations were investigated regarding their impact on the therapeutic protein function. Adjustments in processes, formulation and protein engineering are applied to mitigate the number and quantity of protein variants. Yet, the root cause for the formation of protein subpopulations can not be controlled considering the manifold influences that lead to chemical changes. Therefore, it is important to know the impact of each variant on the stability of the protein drug. However, little is known about the impact of each subpopulation on protein stability, self-interaction, interaction with other variants or aggregation propensity. This thesis aims to separate, characterize and identify potential aggregation prone protein variants. If such variants are identified, further investigations are conducted to determine the influence of the variants on the stability of the therapeutic agent. With this work we aim to develop a tool kit of methods to gain knowledge about aggregation prone variants. A prerequisite for all methods is the maintenance of the intact protein variant in order to avoid any changes that might alter the protein behavior. Our tools include the separation and collection of individual subpopulations in their native state and analytical methods suitable for the limited quantities of sample. In the future, these applications and the knowledge gained from them can be used to remove or stabilize critical variants as a step towards protein therapeutics with increased stability and safety.
charge variants, hydrophobicity variants, protein aggregation, protein stability, FPLC
Meyer, Robina Mareike
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Meyer, Robina Mareike (2021): Separation and characterization of subpopulations of biopharmaceuticals. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The chemical changes that cause heterogeneity in protein therapeutics are well described and monitored during development and manufacturing. Many of these subpopulations were investigated regarding their impact on the therapeutic protein function. Adjustments in processes, formulation and protein engineering are applied to mitigate the number and quantity of protein variants. Yet, the root cause for the formation of protein subpopulations can not be controlled considering the manifold influences that lead to chemical changes. Therefore, it is important to know the impact of each variant on the stability of the protein drug. However, little is known about the impact of each subpopulation on protein stability, self-interaction, interaction with other variants or aggregation propensity. This thesis aims to separate, characterize and identify potential aggregation prone protein variants. If such variants are identified, further investigations are conducted to determine the influence of the variants on the stability of the therapeutic agent. With this work we aim to develop a tool kit of methods to gain knowledge about aggregation prone variants. A prerequisite for all methods is the maintenance of the intact protein variant in order to avoid any changes that might alter the protein behavior. Our tools include the separation and collection of individual subpopulations in their native state and analytical methods suitable for the limited quantities of sample. In the future, these applications and the knowledge gained from them can be used to remove or stabilize critical variants as a step towards protein therapeutics with increased stability and safety.