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New approach could have ‘a major impact on antibody engineering’

13 October 2010

A rapid and reliable NMR spectroscopy method, developed by BBSRC-funded researchers at the University of Leicester in collaboration with scientists at UCB is providing valuable structural information about therapeutic antibodies and how they recognise their targets, an approach that could speed up the drug discovery and engineering process.

The modern field of drug discovery is increasingly focussed on 'rational' methods based on an understanding of molecular properties and principles, in contrast to a trial and error approach.

"These two Ph.D projects have really been a ‘win-win’ for science and for industry: we’ve learnt a lot about the basic biology of antibody-antigen interactions, as well as obtained tangible information for rational drug design."
Prof. Mark Carr, University of Leicester

Obtaining high resolution structural information for proteins and protein complexes now plays a major role in the design and optimisation of new therapeutic molecules, as well as providing companies with a significant advantage in terms of patent protection. But the process is typically rather long and involved.

Now, in a recent study, two BBSRC-industrial CASE students working with Professor Mark Carr at the University of Leicester have established a general approach for determining the structure of so-called scFv antibody fragments - the part of an antibody that binds to an antigen - bound to target proteins, which is rapid enough to provide valuable structural guidance to antibody engineering efforts.

The work was recently chosen as one of just 14 papers, from the many thousands published in the Journal of Biological Chemistry (JBC) over the past two years, judged to have exceptional potential for significant impact on drug discovery.

JBC compendium author Professor Adrian Whitty from Boston University, and former Director of Physical Biochemistry in the Department of Drug Discovery for Biogen Idec, said, "What struck me about this paper was not only the quality of the science, but also its potential to advance our capabilities in an area that I know to be of high interest and importance to the field of biopharmaceutical drug discovery."

Solving the structure of the scFv antibody fragment when bound to a target protein, IL-1B.

Solving the structure of the scFv antibody fragment when bound to a target protein, IL-1B. (Top) a ribbon structure of the complex and (bottom) and expanded view with the surface of IL-1B shown in grey with the backbones of the complementarity-determining regions of scFv shown as coloured loops.
Reproduced with permission from Wilkinson et al., Journal of Biological Chemistry (2009)

In the same paper, Prof. Carr and colleagues provided additional validation for the use of scFvs as surrogates for larger antibody fragments such as Fabs, a simplification that could also help to expedite antibody discovery and engineering.

With a successful partnership between his group and UCB that goes back over15 years, Prof. Carr is a strong supporter of the benefits of combining internationally competitive basic research, with synergistic industry-focussed and supported projects. "The work of these two BBSRC/UCB supported industrial CASE students is directly relevant to cutting edge drug design and development," says Prof. Carr.

He continues, "Catherine Hall's and Ian Wilkinson's research on scFvs and Fabs bound to target proteins has proven to be highly successful and informative and is already being applied to different systems to develop pharmaceutical products."

Since completing their PhDs, both Catherine and Ian have gone on to secure permanent positions in the pharmaceutical sector, which Prof. Carr believes is a result of the industry-relevant skills and knowledge they acquired.

"These two Ph.D projects have really been a 'win-win' for science and for industry: we've learnt a lot about the basic biology of antibody-antigen interactions, as well as obtained tangible information for rational drug design," says Prof. Carr. "The information obtained by our approach provides a clear competitive benefit in terms of the generation of IP around candidate drug molecules, as well as providing detailed structural insights into the fundamental biology that underpins our understanding of how candidate drug molecules work."

Further reading

  • Fundamental findings, pharmaceutical implications: drug discovery and design in JBC. Zagorski N; Whitty A; and Tonge P. (2010)
  • A high resolution NMR-based model for the structure of a ScFv-IL-1β complex: potential for NMR as a key tool in therapeutic antibody design and development. Wilkinson I, et al (2009) Journal of Biological Chemistry 284, 31928-31935

Next steps

  • The NMR-based approach developed is now being further refined to increase the detail of structural information obtained, to reduce the time required and to include other simplified antibody moieties. The approach is currently being successfully applied to another potential therapeutic antibody target and from our experience clearly has widespread applicability.

External contact

Professor Mark Carr, Department of Biochemistry, University of Leicester

tel: 0116 229 7075

Contact

Tracey Duncombe

tel: 01793 414695