The use of rational design at the DNA level to aid in the discovery of potential biotherapeutics is one of the ways in which Oxford Genetics is leveraging its proprietary SnapFast™ platform. Examples of this include the engineering of highly potent promoters for improving protein expression and the identification of monoclonal antibodies (mAbs) with high affinities to challenging targets.
A limiting factor in the development of effective expression systems is the availability of promoter elements with high activity in different cell types. Many of the strong promoters currently in use have highly variable levels of transcription in different cellular contexts and show little or no expression in many cell or tissues. This restricts their utility in genetic screens, as well as the production of recombinant protein production or virus for gene therapy.
Oxford Genetics overcomes these limits through an automated high throughput promoter design, library generation and screening platform. The algorithms which drive this have been continually refined through real life biology and now allow the rapid identification of highly effective promoters, as well as other enhancer elements.
The creation of high affinity antibodies to important biomolecules for therapeutic use is a challenging task. Dozens of therapeutic mAbs are now commercially available, with hundreds more in clinical trials. The early use of hybridomas to create mAbs typically leads to low affinity and therefore an improvement in this is often required to get into the clinic. The next approach for antibody discovery was phage display, which was later joined by bacterial and yeast cell surface display. However, all three of these are non-mammalian and thus suffer from suboptimal expression of the recombinant antibody, such as lacking posttranslational modifications that are required for antibody function.
Oxford Genetics is currently building a novel mammalian cell display system to overcome these issues and engineer the next generation of mAbs with high affinity against difficult biological targets, such as membrane spanning proteins, by displaying these in their native configuration. This optimized approach will decrease the scale of the screen, but increase both the efficiency and accuracy by maximizing its discriminatory power.