PhD student profiles

     
     
Felix Schumacher

Elizabeth Hull
Elizabeth studied for her PhD on the ISMB's Wellcome Trust 4-year Interdisciplinary PhD Programme, beginning in Autumn 2010

Project title
Antibody conjugates through disulfide bridging: Towards therapeutic and diagnostic applications

Principal investigator: Dr James Baker, Department of Chemistry, UCL
Co-investigators: Professor Kerry Chester, UCL Cancer Institute

   
Background
Before starting my PhD, I read Natural Sciences MSci at UCL, with a major in Organic chemistry and minor in Biomedical sciences. During this time I obtained a Wellcome Trust Biomedical Vacation Scholarship to work in the labs of Prof Helen Hailes and Prof Alethea Tabor for one summer on a collaborative research project investigating non-viral gene therapy systems. For my Master’s research I continued to work on a similar project in Prof Helen Hailes’ group. The Wellcome Trust PhD programme offered by the ISMB appealed as the perfect opportunity to continue to develop and expand my interdisciplinary research skills.  
 

Rotations
Rotation one (Supervisor: Dr J. R. Baker)
The development of new reagents for protein modification

Rotation two (Supervisor: Prof. B. A. Wallace)
Developing a fluorescence-based flux assay to study the function of sodium channels.

Rotation three (Supervisors: Prof. E. A. Shephard and Dr J. Santini)
Gut flora in FMO knockout mice

Through my first year rotations, I learnt key molecular biology research skills as well as further developing my synthetic skills in the chemistry lab. From these rotations I decided to stay in the lab of Dr James Baker, as I was very excited by the research and had early ideas of where I would like my PhD project to go.

 

PhD Project
My PhD project has a different focus to the research I carried out during my first year rotation in the group of Dr James Baker. I decided to focus my PhD on generating homogeneous antibody-protein conjugates via chemical modification, with the ultimate aim of producing conjugates for bispecific therapeutics and antibody-directed enzyme prodrug therapy (ADEPT). This project is in collaboration with Prof Kerry Chester (UCL Cancer Institute). In the Baker group, our chemical modification strategy is focused on the selective bridging of disulfide bonds. Consequently I designed and synthesised a series of disulfide bridging chemical linkers with the aim of generating homogeneous antibody-protein conjugates.

Such technology requires not only the synthesis of the appropriate reagent, but also the development of suitable conditions for successful protein conjugation. Through the collaboration of our groups, I have been able to work on all areas of my project, from synthesis to in vitro biological analysis and testing. Using our disulfide bridging strategy, we have now demonstrated an effective chemical platform for the construction of a diverse range of homogeneous bispecifics.

 

Research image

Figure: Strategy for the production of a homogeneous bispecific through disulfide bridging of two antibody fragments.

 

Publications and patent applications

Hull, E.A., Livanos, M., Miranda, E., Smith, M.E.B., Chester, K.A., and Baker, J.R. (2014) Homogeneous Bispecifics by Disulfide Bridging. Bioconjugate Chemistry.

Castañeda, L., Wright, Z. V. F., Marculescu, C., Tran, T. M., Chudasama, V., Maruani, A., Hull, E. A., Nunes, J. P. M., Fitzmaurice, R. J., Smith, M. E. B., Jones, L. H., Caddick, S., and Baker, J. R. (2013) A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones. Tetrahedron Lett. 54, 3493-3495.

 

 

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