Three of the authors receiving their award. From left: Dr Daniel Higazi, Dr Matthew Edgeworth, Dr Paul Varley (Vice President for Science and Collaborations, MedImmune Ltd) and Dr Jonathan Phillips
A recent paper by JJ Phillips has earned a Publication of the Year award from MedImmune.
The paper is Global and Local Conformation of Human IgG Antibody Variants Rationalizes Loss of Thermodynamic Stability by Dr Matthew Edgeworth (University of Warwick and MedImmune Ltd), Dr Jonathan Phillips (Department of Chemical Engineering and Biotechnology, University of Cambridge), Dr David Lowe (Senior Director, MedImmune Ltd), Dr Alistair Kippen (Director, MedImmune Ltd), Dr Daniel Higazi (Senior Scientist, MedImmune Ltd) and Prof. James Scrivens (University of Warwick). It was published in the Angewandte Chemie International Edition, 54: 15156–15159. doi:10.1002/anie.201507223
Five of the top ten selling drugs in the world are monoclonal antibodies and a sixth contains the Fc (fragment crystallisable) region of an antibody fused to a receptor protein. Therefore, this Fc region of an antibody is clearly a major component of the current and future generations of highly effective drugs. The Fc component governs properties such as the half-life of the drug in the body, which can be engineered to extend up to 29 days. As it does not contribute to the primary drug activity, such as binding to a virus or cancer cell, molecular engineering efforts focused on the Fc region can be recycled and incorporated into many different drugs. However, this can lead to drugs having reduced stability – a critical attribute to developing a successful drug.
The recent paper by JJ Phillips (CEB) in collaboration with The University of Warwick and MedImmune described the instability associated with antibody Fc engineering. Mass spectrometry techniques (native ion mobility and hydrogen/deuterium-exchange) were used to determine the structural basis for the thermodynamic instability. This was ultimately shown to be a co-operative effect and localised to a small ectopic site in the antibody. This site can now be targeted by molecular engineering efforts to increase drug stability.
The insight and relevance into a critical aspect of biopharmaceutical development have earned this work a Publication of the Year award from MedImmune.