In vivo selection of bioprocessable biopharmaceuticals

Biopharmaceuticals (or biologics) are medicines that are made from biological materials, most usually proteins. The UK is a prominent stakeholder in this sector, which is growing in importance as biologics are often more specific to their target in the body and have fewer side effects. The development and production of biologics is, however, a labour and time intensive process. Many promising therapeutic proteins are never commercialised due to problems with self-association (aggregation). Failure of these 'candidate' therapeutics at a late stage of development is expensive to both industry and society as these therapies are usually indicated for serious life-threatening or life-limiting conditions. The aim of this project is to assess the ability of a screen developed by the applicants to identify candidate therapeutics at an early stage of development that are inherently resistant to aggregation. This would reduce the cost of development and reduce the failure rate of promising therapies for serious diseases.

The project is a collaboration between academics at the University of Leeds and stakeholders in biopharmaceutical production (MedImmune) and their biophysical characterisation (Avacta Group Plc). The objectives of this feasibility award application are:
1. To test whether an in vivo screen that reports on the aggregation of proteins/peptides in the periplasm of E. coli can be used (a) to predict bioprocessibility of candidate sequences of diverse protein platforms directly after affinity panning (b) to facilitate re-design of a previously identified candidate with high target affinity but poor biophysical properties and (c) to optimise formulation by quantifying the effects of excipients added to the bacterial growth medium.
2. To miniaturize and automate the screen to allow higher throughput in a 48-well format.
Development of a screen that obviates the need to purify candidates and identifies failures early would reduce the time and cost of biologic development increasing the competitiveness of the industrial biotechnology sector in the UK.

As described in proposal submitted to TSB