INTERMOLECULAR INTERACTIONS AND RHEOLOGICAL PROPERTIES IN MONOCLONAL ANTIBODY SOLUTIONS

Abstract

The success of a monoclonal antibody drug product is predicated on the manufacturability and stability of the concentrated therapeutic protein solution. A key factor in facilitating the processing, packaging and administration of monoclonal antibodies is the formulation design. The development of an optimal formulation maintains the conformational and colloidal stability of the protein, and ensures the viscosity of the solution is minimised. Formulation design is dependent on reliable measurements of nanoscale protein properties and interactions which can be related to macroscopic bulk solution behaviour. Analytical techniques to better facilitate formulation design, especially in relation to solution viscosity, are needed. The aim of this thesis is to develop methods to measure parameters which bridge our understanding of protein-protein interactions to bulk solution properties. The grounding of these experimental techniques in theoretical models of molecular properties and solution structure is an objective of this project. The use of differential viscometry to measure the Huggins coefficient is evaluated as a method for the optimisation of protein solution viscosity. The relationship of high protein concentration solution viscosity to protein-protein interactions is explored by measuring viscosity using a microfluidic rheometer and comparing it with results from static and dynamic light scattering experiments. Correlations between dilute solution parameters and the viscosity of concentrated mAb solutions are evaluated. The applicability of models relating the electrophoretic mobility experimentally determined with electrophoretic light scattering to monoclonal antibody net charge is examined. The contributions in this thesis widen the scope of analytical testing of monoclonal antibodies to complement therapeutic protein formulation development.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	James Warwicker (Supervisor) & Robin Curtis (Supervisor)