ADDomer: Synthetic multiepitope display scaffold for next-generation therapeutics

Background: Infectious diseases continue to plague and decimate populations. To counter this threat, vaccination remains exceptionally powerful: small-pox is eradicated, measles, polio and tetanus contained. Nonetheless, severe threats challenge human health, notably from viruses (Zika, Dengue, Chikungunya) evolving new pathogenic strains. Originally confined to sub-Saharan habitats, these are emerging as a global threat, spread by the tiger mosquito increasingly present in the Northern hemisphere. Ideally, a vaccine will be safe, non-replicative, efficient, tuneable and easily produced at scale. Recombinant virus-like particles (VLPs) such as the ADDomer [1] we developed can address these requirements and hold enormous promise in the vaccine field.

The Project: ADDomer is a versatile, designer antigen-presenting platform originating from a single component of Adenovirus, the penton base protein [1]. Engineered penton base proteins spontaneously form exceptionally stable synthetic VLPs in vitro, highly soluble and safe as they contain no genetic material. ADDomer is uniquely suited to display on a single particle hundred and more copies of pathogenic epitopes inserted into flexible, variable loops on the surface. Recently, an international team of scientists including the Berger-Schaffitzel lab and Imophoron Ltd provided a compelling proof-of-concept of the first ADDomer-based vaccine candidate to combat Chikungunya infectious disease [1].

In the current project, we will combine biochemical, biophysical and structural means including high-resolution Cryo-EM, to develop ADDomer for a range of exciting applications. We have shown that peptide epitopes up to 200 amino acids can be efficiently displayed. Expanding our engineering approach, we will decorate ADDomer with novel functionalities, including insertion of small, folded proteins. Among others, we will insert albumin-binding protein and investigate whether we can decorate the resulting ADDomer particles with serum albumin and albumin receptor, which could be immensely valuable to shield future ADDomer-based therapeutics in the blood serum and improve pharmacokinetics. Using high-resolution Cryo-EM we will unlock ADDomer to structure-based design by determining structures. We will introduce structure-guided mutations to further enhance ADDomer stability and thermotolerance. ADDomer comprises an RGD motif mediating cell penetration. We will establish the capacity to penetrate a range of cell types and explore delivery of small biomolecules such as protein domains, DNA or RNA by ADDomer-mediated encapsulation. By using peptide “Velcro” approaches we will micro-engineer the ADDomer surface by epitoping, considerably expanding the scope of our design.

The PhD student will design, produce and purify ADDomer at Imophoron Ltd under the guidance of Frederic Garzoni (co-supervisor), experiencing life in a successful start-up [2]. Biochemical, biophysical and structural characterisation of ADDomers will be carried out at Uni Bristol in the laboratory of Christiane Berger-Schaffitzel (main supervisor), in collaboration with the team of Imre Berger (co-supervisor). Project planning and discussions will take place at regular meetings between the PhD student, Imophoron, and the Berger-Schaffitzel team.

The project will be associated with the new Max Planck Centre for Minimal Biology, a strategic priority uniting Uni Bristol and the Max Planck Gesellschaft, Germany. The project is fully funded for 4 years by the University of Bristol PhD Research Partnership Programme and starts 1st July 2020 latest. For more information and to apply for this position please contact: [Email Address Removed] and [Email Address Removed]. The deadline for applications is 15th January 2020.