Developing a novel pipeline to determine monoclonal antibody solution structures and stabilities in bioprocessing conditions
Prof S J Perkins. Department of Structural and Molecular Biology, Univerisity College London
Prof P A Dalby. Department of Biochemical Engineering, University College London
Dr Tibor Nagy and Dr Jonathan Haigh, Fujifilm Diosynth Biotechnologies
BACKGROUND: Monoclonal human IgG1 and IgG4 antibodies have become important therapeutics in the biotechnology industry. Primarily engineered for efficacy against specific targets, antibodies are highly susceptible to aggregation in downstream bioprocess environments, particularly as antibody concentrations increase up to their final high product concentrations. This issue represents a major challenge for the biotechnology industry where aggregates can seriously compromise safety. An analysis of the physical parameters that initiate protein aggregation would allow the design of more robust lead candidates that aggregate less. We have developed new methods for this problem using high throughput synchrotron X-ray scattering and analytical ultracentrifugation to determine atomistic solution structures for IgG antibodies (Rayner et al, 2015). We have also improved our methods by the incorporation of advanced structural modelling methods for scattering data in the CCP-SAS project via molecular dynamics simulations (Perkins et al., 2016). We are thus ideally poised to undertake this timely project.
- By studying the solution conformations of human monoclonal IgG antibodies as a function of physical parameters, we will show how the antibody conformation relates to its aggregation propensity.
- Using new atomistic modelling methods, we will determine antibody structures for correlation with experimental conditions.
- We will extend this work to carefully-selected other monoclonal antibodies.
Rayner, L. E., Hui, G. K., Gor, J., Heenan, R. K., Dalby, P. A. & Perkins S. J. (2015). The solution structures of two human IgG1 antibodies show conformational stability and accommodate their C1q and FcγR ligands. J. Biol. Chem. 290, 8420-8438. Pubmed 25659433.
Perkins, S. J., Wright, D. W., Zhang, H., Brookes, E. H., Chen, J., Irving, T. C., Krueger, S., Barlow, D. J., Edler, K. J., Scott, D. J., Terrill, N. J., King, S. M., Butler, P. D. & Curtis, J. E. (2016) Atomistic modelling of scattering data in the Collaborative Computational Project for Small Angle Scattering (CCP-SAS). J. Appl. Crystall. In press.
Final molecular modelling results for human IgA1 antibody from molecular dynamics (Hui et al., 2015). The protein mainchain is shown as a yellow ribbon. The structure was taken from the median of the 112 models in the best-fit cluster. The O-glycans in the hinge and the N-glycans in the Fc region and tailpiece respectively are shown as green sticks. See Perkins et al. (2016)
This multidisciplinary project would suit a candidate with a Biochemistry, Biochemical Engineering, Physics, or Computational Science degree who is keen to learn about the physical biochemistry of proteins in solution and their molecular modelling in an industrial and manufacturing context. The successful applicant would spend 3 months at Fujifilm. Applicants will need to satisfy UK residence eligibility.
Applicants must hold, or be expected to achieve, a first or high upper second-class undergraduate honours degree or equivalent (for example BA, BSc, MSci) or a Masters degree in a relevant subject. Interested applicants are encouraged to contact Prof. Perkins (firstname.lastname@example.org) in advance of the deadline, 20th January 2017 at 5pm.
To apply you will need to send the following documents in a single email to: LIDo.Admissions@ucl.ac.uk. All documents must be submitted in unprotected PDF format.
- Completed Application Form (Sections A and B) including details of two Academic References
- The disability and ethnic origin monitoring form
- Official Final Transcripts from Completed Programmes of Study
- Official Interim Transcripts from On-going Programmes of Study
- English Language Qualification (if required, please see below)
- Academic CV
- Copy of Passport