Therapeutic monoclonal antibodies comprise the largest class of biopharmaceuticals on the market. Antibody therapeutics are generally administered intravenously and subcutaneously. Subcutaneous administration is volume limited so antibody concentrations in excess of 100 mg/ml are required for adequate drug potency. This requirement can pose a myriad of problems to the manufacture, storage and administration of antibody therapeutics; at high protein concentrations intermolecular distances between molecules mean that attractive protein-protein interactions can start to dominate. Attractive protein-protein interactions have been linked to undesirable solution behaviour such as opalescence and liquid-liquid phase separation. The overall aim of this project is to study the behaviour of high concentration antibody solutions with a focus on their behaviour as they undergo phase separation. The central goal is to demonstrate the link between protein-protein interactions and highly concentrated protein behaviour. Correlations between dilute solution measurements of protein-protein interactions and concentrated solution properties are explored and compared using interaction models. The complicated behaviour of antibody solutions at high protein concentrations which is often referred to as reversible self-association and leads to the formation of oligomers is discussed in terms of protein-protein interactions. Finally, the use of protein-protein interactions as characterised by the second osmotic virial coefficient and the relationship to liquid-liquid phase separation is explored. The contributions in this thesis provide an initial investigation that suggests some monoclonal antibody solutions exhibit universal behaviour.
- liquid-liquid phase separation
- monoclonal antibodies
- phase diagrams
- protein-protein interactions
- critical behaviour
Molecular Interactions of Monoclonal Antibodies and the Relationship to Liquid-Liquid Phase Separation
Sibanda, N. (Author). 31 Dec 2021
Student thesis: Phd