(MRC CASE) Laser interferometry for interfacial biosensoring of antibody therapeutics

Monoclonal antibody (mAb) therapeutics, designed and bioengineered for individual patients or groups of them, are fast evolving into a major treatment to cancers. Subcutaneous administration of formulated mAb solutions is currently a preferred approach. Further development into self-administration through an automated injection system could realize more attractive benefits. For a typical injection of 5-10 ml, the concentration of mAb must be in the range of 5-10% or even higher. Thus, understanding how to stabilize therapeutic mAbs under relatively high mAb concentrations represents a major bottleneck to biotherapeutic formulation. A number of techniques have been utilised to examine mAb stability, but they offer indirect information about mAb interactions and their capabilities become limited at high mAb concentrations.
This MRC-AstraZeneca sponsored PhD project aims to develop dual polarisation interferometry (DPI) as a novel tool to examine how bioengineered mAbs interact under different solution conditions, leading to efficient assessment of key parameters that mediate molecular interactions. In a typical DPI measurement, mAb solutions are pumped through dual microfluidic channels sitting on top of a set of waveguide slabs. Injection of a beam of laser across the waveguide setup causes optical interferences associated with the different refractive indices. The peaks of the interference patterns shift as mAb adsorbs onto the surface of the microfluidic channels from which the amount and thickness of the adsorbed layer can be resolved as a function of time. The structural Information together with the globular dimensions of Fab, Fc and the whole mAb allows us to infer the structural conformations mAb molecules adopt and modes of interaction between them. As it takes only 1 ms to complete a run, DPI can follow dynamic build-up of the adsorbed mAb layer from seconds to minutes, providing accurate information about how mAb-mAb interact under different sequence modification, mAb concentration, pH and ionic strength and more importantly, adjuvants such as short peptide amphiphiles and surfactants that could help mediate mAb-mAb interactions, thereby offering useful guidance to product formulation. The microfluidic system requires a small sample volume, saves highly expensive mAb samples and allows an efficient search of conditions affecting mAb stability. Neutron reflection and scattering experiments which offer structural information in better resolution could be planned on the basis of the DPI studies. The combined studies could not only help develop DPI as a benchtop tool for screening mAb stability but also offer valuable insight to product formulation.

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.