Abstract
Biopharmaceuticals generally describe drugs synthesized by biotechnology rather than chemistry, and are normally macromolecules such as proteins (vaccines, antibodies, hormones) or nucleic acids (RNA, DNA), but could also include synthetic biology ambitions such as designed therapeutic microorganisms.
AstaZeneca has an experimental protein crystallography research group at each of its three research sites (Sweden, USA and UK). These groups support small molecule drug design for local projects as their main focus. AstraZeneca acquired MedImmune in 2007 as a strategic boost of its biopharmaceutical capability. Currently, there is no experimental structure capability within MedImmune.
A question arose whether the current structural support facility could address MedImmune projects with business impact. This chapter illustrates two cases where structural support provided unique information that could be incorporated into the patenting strategy in a timely fashion. These are structures of antibody-antigen complexes, which provide definitive epitope characterization. The structure of two interleukins, IL-17A and IL-15 are presented in complex with neutralizing antibodies that have been subjected to in-vitro affinity maturation. For the IL-17A antibody, the affinity maturation optimization process resulted in seven amino changes increasing affinity 6-fold and activity 30-fold. For the IL-15 antibody, there were nine amino acid changes with affinity increasing 228-fold and activity increasing a staggering 40,000-fold. We were intrigued to see whether the structures would help explain this, as well as providing the definitive epitopes.
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Acknowledgements
Many contributors enabled this work. Mark Abbott, Rick Davies, Maurice Needham, Melanie Snow, Caroline Langham, Wendy Barker, Adid Aziz, Sarah Dawson, and Malcolm Anderson at AstraZeneca prepared and characterized reagents; Fraser Welsch, Trevor Wilkinson, Tris Vaugan, Gerald Beste, Sarah Bishop, Bojana Popovich, Gareth Rees, Matthew Sleeman, Caroline Russel, David Lowe, Franco Ferraro, Debbie Patterson, Catriona Buchanon, Donna Finch and Phillip Mallinder at MedImmune Cambridge isolated and characterized the antibodies; Stefan Gerhardt and David Hargreaves at AstraZeneca did the crystallography; Steven Coales, Yoshitomo Hamura, and Steven Tuske at ExSAR provided additional epitope mapping by H/D exchange MS.
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Pauptit, R. (2015). Crystallography and Biopharmaceuticals. In: Scapin, G., Patel, D., Arnold, E. (eds) Multifaceted Roles of Crystallography in Modern Drug Discovery. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9719-1_4
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DOI: https://doi.org/10.1007/978-94-017-9719-1_4
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