Award details

Elucidating the mechanisms of accelerated dissociation and allosteric processes in the antibody immunoglobulin E

Reference	BB/P000436/1
Principal Investigator / Supervisor	Professor James McDonnell
Co-Investigators / Co-Supervisors	Professor Brian Sutton
Institution	King's College London
Department	Randall Div of Cell and Molecular Biophy
Funding type	Research
Value (£)	292,546
Status	Completed
Type	Research Grant
Start date	01/08/2017
End date	31/07/2020
Duration	36 months

Abstract

Immunoglobulin E (IgE) is the central regulatory molecule of allergic reactions, which can result in a range of human diseases including asthma, allergic rhinitis, atopic dermatitis, urticaria and food allergies. We have previously characterized X-ray crystal structures of IgE, IgE/receptor complexes and IgE/anti-IgE complexes. We have demonstrated that IgE has an unusual conformational flexibility, which is important for receptor engagement and signalling. We have shown that IgE has an intrinsic potential for allostery, and this is utilized by its two natural cellular receptors. Its capacity for allostery gives some unusual properties to IgE, including allowing some ligands to cause the dissociation of IgE bound to its cellular receptors - a process we refer to as accelerated dissociation. This proposal seeks to elucidate the mechanisms of accelerated dissociation and other allosteric processes found in IgE. In this project, we will use NMR spectroscopy to define the structures and dynamics of IgE-Fc alone and in complex with a number of biologically important ligands, including its cellular receptors FceRI and CD23, and a therapeutic antibody used in the treatment of allergic disorders (Xolair). We will also employ real-time NMR experiments to derive atomic resolution kinetic information on ligand-induced allosteric changes. The NMR data will be integrated with data from high-resolution X-ray crystal structures, and detailed kinetic and thermodynamic data of ligand interactions, to derive atomistic, time-resolved mechanistic insights into IgE's structure and function. IgE's unique structural properties offer new potential mechanisms for interfering with its activities and will be used to inform the development of novel anti-IgE therapeutics. The translational aspects of this work will be taken forward in collaboration with UCB, our industrial collaborator on this project.

Summary

The incidence of allergic disease has increased alarmingly in recent decades, nowhere more so than in the UK, where rates are now among the highest in the world. These conditions range from mild hayfever to life-threatening severe asthma or anaphylaxis, and include allergic rhinitis, atopic dermatitis and food allergies. All of these conditions involve reactions to otherwise innocuous substances in the environment, and all involve a particular type of antibody known as IgE. We have studied this antibody over many years, and understand much about how it differs from other types of antibody such as the protective IgG antibodies. All antibodies play two important roles: they recognize and bind - usually, in the case of IgG - to foreign invaders such as bacteria or viruses using one part of the antibody molecule, and then bind via another part to "receptor" molecules on cells that become activated to destroy the foreign material. But IgE has the remarkable property of binding so tightly to the cells that once bound it almost never comes off within the lifetime of the cell. This means that when an allergen such as pollen, or peanut, or house dust mite, gets into the body (through airway, gut or skin) and binds to the IgE antibodies, they can activate the cells immediately to deliver a powerful, inflammatory response. The cells are effectively "sensitized" to react to the allergen. IgE can be targeted to alleviate allergic conditions, and an "anti-IgE" antibody therapy, called omalizumab (XolairTM), may be prescribed for certain patients with severe asthma. It works by binding to IgE molecules and blocking them from binding to the cell receptors, thus preventing sensitization; however, IgE already receptor-bound, the "pathogenic" IgE, is unaffected. It now appears that Xolair at extremely high levels, well above those reached therapeutically, can actually bind to receptor-bound IgE and actively remove it. This is a remarkable discovery, and one that would have profound implications for anti-allergy therapy if it could be understood and harnessed. We believe that the key to understanding this phenomenon lies in the unique flexibility of the IgE antibody. Our previous studies have revealed, quite unexpectedly, that the receptor-binding part of the IgE molecule can adopt several different shapes, and indeed can communicate signals from one part of the molecule to another through subtle changes in shape. This phenomenon - called allostery ("other shape") - is what we want to explore in detail using a technique that can probe these changes and this communication at the atomic level. If we can understand how binding to one part of the IgE molecule (which is accessible when IgE is bound on the cell) can release it at another site (where it binds to the receptor), then we can begin to develop a much more effective therapeutic agent for allergic disease. However, the benefits may go well beyond allergic disease. The molecular processes of health and disease ubiquitously involve interactions between different proteins, and many of these interactions, like the IgE/receptor interaction, are very tight. Targeting these protein/protein interactions is traditionally considered to be difficult, but an understanding of allostery could open up new possibilities for intervening in a range of diverse medical conditions. We are collaborating in this project with the pharmaceutical company UCB with whom we have been working for several years. They are providing protein materials for the analysis, and their interest in understanding the IgE/receptor system, publishing the results, and applying this knowledge to other protein/protein interactions will ensure the rapid dissemination and commercial translation of the results of this study.

Impact Summary

In addition to elucidating general principles of protein allostery, which we expect to be of broad academic interest (please see Academic Beneficiaries), our research will have practical applications that will inform drug development. Our work will be applied directly in our effort to develop novel anti-IgE therapeutics. For this part of the work, we expect our research will have impact in the commercial sector, will affect clinical approaches to how we treat allergic disorders, and will directly affect patients who suffer from allergic diseases. Given the large number of allergy sufferers in the UK and the enormous socioeconomic effects of allergic diseases, this research will therefore impact both the health and the wealth of the UK. On a broader scale, we expect our work will contribute to a changing protein structure-function paradigm and demonstrate novel ways of controlling protein-protein interactions through allosteric inhibitory mechanisms. Insights from our studies could have immensely broad applications for drug discovery. The opportunity to better understand the phenomenon of accelerated dissociation is very exciting: these studies could open up new classes of new protein targets, previously thought to be "undruggable", for therapeutic intervention.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Pharmaceuticals, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Industrial Partnership Award (IPA)

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search