Recent advances in the development and utilization of therapeutic monoclonal antibodies (mAbs) have demonstrated promising potential in treating a diverse range of illnesses, including cancers, autoimmune diseases, cardiovascular diseases, and transplant rejections. It is essential to maintain the stability of mAb drugs during their manufacturing, storage, transportation, and administration to ensure their functionality. During these processes, mAbs may become adsorbed on various surfaces such as glass, polystyrene, or silicon oil. Interfacial adsorption of mAb could lead to denaturation, deformation, or aggregation, causing the loss of bio-activity or triggering immune responses. To address this issue, non-ionic surfactants, such as the Tween and Pluronic families, are commonly used as co-formulators in antibody drugs to stabilize, solubilize, and emulsify the mAbs. In this project, a series of techniques including Spectroscopic Ellipsometry (SE), Quartz Crystal Microbalance with Dissipation (QCM-D) and Neutron Reflection were employed to reveal the interfacial interaction of mAb and non-ionic surfactant. Firstly, the properties and interactions of the monoclonal antibody COE-3 were analyzed meticulously, focusing particularly on its stability when interacting with non-ionic agents at the PDMS/water interface. This interfacial model mimics the lubricant film functioning in pre-filled syringes. The results 14 illustrated that COE-3 is prone to deformation and forms a dense layer on the PDMS surface, though this is significantly reduced by the introduction of the non-ionic agent Tween 80, thereby preserving the antibody's efficacy and stability. Furthermore, the study shed light on the complex interfacial structures of COE-3 and its Fab and Fc fragments at varying pH levels. A notable divergence in the adsorption characteristics between COE-3 and Fc at pH 8 compared to pH 5.5 was recorded, with the Fab fragment displaying consistent adsorption patterns across different pH environments. The research highlighted the significant impacts on the adsorption dynamics and structural integrity of COE-3, primarily due to protonation and deprotonation processes in the Fc fragment residues, leading to novel multilayered formation in an alkaline setup. Lastly, the investigation delved into the effects of Pluronic copolymers on lipid bilayer structures, exploring their cytotoxicity and potential disruptions to the membrane. It was determined that Pluronic variants exhibit varying degrees of cytotoxicity and membrane interaction capabilities, with F-68 showing minimal cytotoxicity and L-31 displaying negligible interaction with the lipid bilayer. This comprehensive study paves the path for developing adaptable Pluronic formulations in protein drugs, enhancing the understanding of potential synergistic or antagonistic effects when combining different Pluronic copolymers, hence fostering further advances in drug formulation and delivery.
Date of Award | 1 Aug 2023 |
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Original language | English |
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Awarding Institution | - The University of Manchester
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Supervisor | Jian Lu (Supervisor) & Thomas Waigh (Supervisor) |
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- antibody
- adsorption
- interface
- surfactant
- neutron reflection
Interfacial interaction of monoclonal antibody and non-ionic surfactants
Shen, K. (Author). 1 Aug 2023
Student thesis: Phd