Exploring, Understanding and Intervening in IgE-dependent Mechanisms in Allergic Disease and Asthma

Lead Research Organisation: King's College London
Department Name: Randall Div of Cell and Molecular Biophy

Abstract

The incidence of allergic disease, and asthma in particular, has increased alarmingly in the UK and there is an urgent need for new therapies. Antibodies of a type known as immunoglobulin E (IgE) are crucially involved in the allergic response, and individuals susceptible to allergies have high IgE levels. These IgE antibodies recognise allergens that enter the airways (e.g. grass pollen), the gut (food allergens) or the skin (contact allergies), and then trigger allergic reactions. We know, from the success of an anti-IgE treatment, that removal of IgE relieves allergic symptoms. But anti-IgE, itself an antibody, is very expensive, requires administration in the clinic, and is licensed only for severe asthma. By understanding how the body produces IgE, and the way IgE activates allergic reactions, we expect to discover new ways to inhibit IgE, and develop compounds that are cheaper, more widely applicable to different allergic conditions, and easier to administer.

The cells in the body that make antibodies, B-cells, switch in response to certain signals from producing beneficial, protective antibodies to producing IgE; our aim is to understand and prevent this switch. We have discovered that switching can occur in the nose rather than, as previously thought, only in lymph nodes, and now, using nasal tissue available from a surgical procedure (to clear nasal passages) developed at Guy?s Hospital, we can study the process in detail. We shall use an ultra-high resolution microscope (the first of its kind in the UK) to study events within the B-cell nucleus as the genes for IgE are switched on, and then study the survival and proliferation of these IgE-producing cells. This work will undoubtedly identify new targets for intervention.

We have also discovered that ?superantigens?, bacterial molecules that trigger antibody production, are present in asthmatic patients? airways. We believe that these superantigens may promote IgE production, in the lung or nose, and will study how they interact with IgE ? opening up a new approach to allergy treatment. We will also investigate the claim that certain IgE molecules are more active than others in triggering allergy. We have already determined the molecular structure of IgE and found that it changes its shape when it triggers an allergic reaction. We can now test compounds that prevent this change in shape, collaborating with the pharmaceutical industry to develop small-molecule inhibitors that overcome the limitations of anti-IgE.

Technical Summary

The IgE antibody is a central element in the allergic response and the aetiology of asthma. Our proposed research is predicated on the existing evidence that IgE is an effective therapeutic target. The options include suppression of IgE synthesis and the interactions of IgE with its receptors, with allergens and with superantigens. We plan to address the following questions:
1. Since we know that heavy-chain chain switching to IgE occurs locally in the target organs of allergy, we need next to complement our biochemical studies on regulation of switching to IgE by imaging of the genes and associated proteins. Cell biological investigations of this kind have been limited by the resolution of commercial confocal microscopes, but a new instrument constructed here gives an unprecedented improvement in resolution, thus bringing it into the required range.
2. Thanks to a new surgical technique of turbinectomy developed at Guy?s Hospital by our collaborator, we can now explore the mechanisms by which the B-cells in the nasal mucosa are driven to synthesise and secrete IgE. We will also isolate single plasma cells secreting IgE antibodies directed against aeroallergens and S. aureus superantigens, clone and express their light-chain and epsilon heavy-chain genes and prepare recombinant IgE antibodies for structural studies.
3. We have discovered that bacterial superantigens are involved in the pathogenesis of allergic disease. We will explore the details of allergen- and superantigen-IgE interactions by X-ray crystallography (cf. our earlier X-ray structures of IgE and superantigen-antibody complexes).
4. We wish to uncover the structural basis for mast cell signalling triggered by monomeric murine IgE in the absence of antigen (with the collaboration of two groups in the US), and to survey our recombinant human IgEs for similar activity. The outcome will throw light on the relevance of ?highly cytokinergic? IgE to the pathogenesis of allergy.
5. We plan to develop a new generation of inhibitors to target the conformational change that the IgE molecule undergoes upon interaction with its high-affinity receptor, FceRI. We shall investigate the mechanism of action of peptide and other inhibitors, and anti-IgE Fabs, by structural and biophysical methods to ascertain whether they affect the conformational change. These results will provide a basis for design of inhibitors through collaboration with the pharmaceutical industry.

Publications

10 25 50
 
Description Asthma UK Consultation on Basic Asthma Research Strategy
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description Asthma UK Consultation on Basic Asthma Research Strategy
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description Asthma UK Research Grants Committee
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Asthma UK Research Strategy
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Asthma UK Foundation Grant
Amount £31,240 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description Asthma UK Project Grant
Amount £125,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 01/2008
 
Description Asthma UK Project Grant
Amount £143,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 01/2008
 
Description Asthma UK Project Grant
Amount £200,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 10/2011
 
Description BBSRC CASE Award
Amount £167,235 (GBP)
Funding ID BB/K501815/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2016
 
Description BBSRC CASE award
Amount £167,235 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2013 
End 12/2017
 
Description BBSRC Project Grant
Amount £400,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2013 
End 12/2016
 
Description BBSRC Project Grant
Amount £468,367 (GBP)
Funding ID BB/K006142/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2012 
End 10/2015
 
Description BBSRC Project Grant
Amount £458,250 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2011 
End 12/2013
 
Description Biomedical Research Centre, Programme Grant
Amount £500,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Comprehensive Biomedical Research Centre, Guy's and St Thomas
Sector Public
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description CRUK Project Grant
Amount £205,428 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description Capital Investment Award
Amount £1,687,570 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2008 
End 06/2013
 
Description Guy's and St. Thomas' Charity/Novartis Clinical Trial
Amount £300,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 01/2009 
End 01/2011
 
Description Guy's and St. Thomas' Charity/Novartis Clinical Trial
Amount £300,000 (GBP)
Organisation Guy’s & St Thomas’ Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description Guy's and St. Thomas's Trust Charity, Project Grant
Amount £261,554 (GBP)
Organisation Guy’s & St Thomas’ Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description Heptagon Fund
Amount £26,000 (GBP)
Organisation Heptagon Fund 
Sector Private
Country United Kingdom
Start 10/2006 
End 09/2007
 
Description Industrial collaboration
Amount £164,139 (GBP)
Organisation UCB Pharma 
Sector Private
Country United Kingdom
Start 02/2018 
End 02/2019
 
Description King's Health Partners Research Grant (Ramadani)
Amount £80,754 (GBP)
Organisation King’s Health Partners 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 06/2018
 
Description London Law Fellowship
Amount £120,000 (GBP)
Organisation London Law Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 01/2012
 
Description MRC CASE Studentship
Amount £62,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description MRC CASE Studentship
Amount £28,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description MRC CASE Studentship
Amount £60,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 10/2011 
End 09/2014
 
Description MRC CASE Studentship
Amount £28,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 10/2011 
End 09/2014
 
Description MRC Collaborative Award/Novartis
Amount £62,318 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description MRC Collaborative Award/Novartis
Amount £31,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 10/2010 
End 09/2013
 
Description MRC Programme Grant
Amount £1,840,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2011 
End 12/2016
 
Description MRC Programme Grant
Amount £2,323,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 09/2011
 
Description MRC Project
Amount £64,281 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 01/2019
 
Description MRC/EPSRC Project Grant
Amount £670,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2007 
End 01/2011
 
Description MRC/GSK Programme Grant
Amount £2,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 01/2016
 
Description MRC/GSK Programme Grant
Amount £2,000,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 01/2012 
End 01/2016
 
Description NIHR Biomedical Research Centre
Amount £66,378 (GBP)
Organisation National Institute for Health Research 
Department NIHR Comprehensive Biomedical Research Centre, Guy's and St Thomas
Sector Public
Country United Kingdom
Start 07/2012 
End 12/2013
 
Description NIHR Biomedical Research Centre Fellowship
Amount £188,422 (GBP)
Organisation National Institute for Health Research 
Department NIHR Comprehensive Biomedical Research Centre, Guy's and St Thomas
Sector Public
Country United Kingdom
Start 01/2009 
End 01/2012
 
Description PhD funded by Taiwan Government Scholarship
Amount £60,000 (GBP)
Organisation Government of Taiwan 
Sector Public
Country Taiwan, Province of China
Start 10/2009 
End 09/2012
 
Description PhD studentship funded by MRC/Asthma UK Centre
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description PhD studentship funded by MRC/Asthma UK Centre
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description PhD studentship funded by MRC/Asthma UK Centre
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description Translational Research Award
Amount £98,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2008 
End 04/2009
 
Description UCB Industrial Collaboration
Amount £858,000 (GBP)
Organisation UCB Pharma 
Sector Private
Country United Kingdom
Start 01/2009 
End 12/2012
 
Description UCB Industrial Collabration
Amount £152,756 (GBP)
Organisation UCB Pharma 
Department UCB Celltech
Sector Private
Country United Kingdom
Start 01/2013 
End 12/2013
 
Description VIP Award
Amount £49,956 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2008 
End 01/2010
 
Description Wellcome Trust Project Grant
Amount £362,269 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 01/2013
 
Title Bioinformatics tools for identification of FISH probes 
Description A new tool for identifying sequences for use in generating FISH probes; here used for the analysis of spatial and temporal events involved in class switching to IgE in human B cells by confocal microscopy. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Exploitation of this technology is in progress; yet to be published. 
 
Title Cell lines producing recombinant IgE 
Description Improved cell lines producing IgE antibodies 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact Ongoing trials of IgE for cancer immunotherapy 
 
Title Flow cytometric assay for phagocytic/cytotoxic activity 
Description Three colour flow cytometric assay to distinguish phagocytic activity from cytotoxic activity in ADCC in tumour cells. 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact The method has revealed the mechanism of IgE antibody dependent tumour cell killing, and has led to the initiation of clinical trials. 
 
Title Fluorescently labelled IgE biosensors 
Description Fluorescently labelled versions of IgE-Fc that are sensitive to conformational changes in the IgE molecule. Valuable for screening for small molecules that influence the structure of IgE and that might therefore be leads for IgE inhibitors. 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact Currently under investigation within our group; publications in preparation; potential IgE small molecule inhibitors. 
 
Title High resolution IgE-Fc structure 
Description Crystal structure of IgE-Fc determined at high resolution (1.9 Angstroms); valuable for anti-IgE drug discovery; PDB code 2WQR 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact This structure has enabled in silico and rational design of anti-IgE inhibitors, which are currently being evaluated. 
URL http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=2WQR
 
Title IgE expression system 
Description Novel antibody expression vectors for producing chimeric human antibodies of any isotype. 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact Has been used to produce chimeric IgE antibodies for anti-cancer immunotherapy. 
 
Title IgE inhibitors 
Description Small molecule inhibitors of the IgE/receptor interaction. 
Type Of Material Biological samples 
Provided To Others? No  
Impact Basis for a drug discovery programme; collaboration with industrial partner. 
 
Title IgE-Fc crystal structure 
Description Crystal structure of IgE-Fc. Coordinates deposited in the Protein Data Bank code 2wqr. 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact This structure of IgE-Fc revealed the molecule to be acutely bent, and this led to understanding that allosteric approaches to inhibiting IgE activity might be possible. 
URL http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=2WQR
 
Title IgE-producing cell line 
Description Improved cell lines producing various IgE antibodies for immunotherapy of cancer (ovarian and breast). 
Type Of Material Antibody 
Year Produced 2007 
Provided To Others? Yes  
Impact On-going trials of IgE for cancer immunotherapy 
 
Title IgG4 blocking antibodies 
Description Allergen-specific IgG4 blocking antibodies for amelioration of allergic response. 
Type Of Material Antibody 
Provided To Others? No  
Impact Gained MRC Programme Grant and Fellowship (London Law & NIHR BRC) support to develop these antibodies in a therapeutic context. 
 
Title Mouse model for allergy and cancer immunotherapy 
Description Transgenic mouse model for intervention in allergic disease and for immunotherpy for cancer. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact On-going development programme for small molecule inhibitors of IgE/receptor interactions in allergy, and on-going trials of IgE in cancer immunotherapy. 
 
Title Rapid antibody expression system 
Description Mouse or human V region sequences are incorporated into a complete human antibody of any isotype for rapid expression. 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact Patent applications in US and UK are under consideration 
 
Title Rat model for immunotherapy of cancer 
Description Generated rat MOV18 monocloncal antibody to folate binding protein; WAG rat cell line that expresses human folate binding protein; application to tracking pharmacokinetics of IgE antibody. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Too early - experiments in progress. 
 
Title Structure of IgE-Fc and receptor complex 
Description X-ray crystal structure at high resolution of IgE-Fc (PDB code 2wqr), and also the structure of the complex with receptor. 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact The structural data reveal conformational changes that can be targetted in the design of an allosteric inhibitor of the IgE/receptor interaction. A drug discovery programme is in progress, both in-house and as an industrial collaboration. 
URL http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=2WQR
 
Title TIRF microscope 
Description TIRF microscopy set up to study lipid bilayers incorpotating membrane proteins, in order to study co-crosslinking of these membrane proteins; will be used to study mIgE and CD23 and CD21. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Too early - experiments in progress. 
 
Title Transgenic mouse model for allergy and cancer 
Description Transgenic mouse model for intervention in allergic disease and immunotherapy of cancer. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact On-going development programme for small molecule inhibitors of IgE/receptor interactions in allergy, and on-going trials of IgE in cancer immunotherapy. 
 
Title VH gene sequences 
Description Sequences of VH genes associated with IgE antibodies from allergic patients. 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact These sequences contribute to understanding the repertoire of IgE antibodies in allergic patients, from which the allergen or superantigenic causative agent may be identified. Other expected outcomes are: understanding receptor revision and other DNA recombination events involved in IgE class switching; the structural basis of cytokinergic activity. 
 
Description Dr. David Dombrowicz 
Organisation Pasteur Institute, Paris
Country France 
Sector Academic/University 
PI Contribution Material and labour and expertise in IgE, CD23 and FceRI.
Collaborator Contribution Transgenic mouse model of allergy and cancer.
Impact Publications; proof of concept for inhibition of IgE/FceRI for treatment of allergy, and also for monoclonal antibodies in immunotherapy of cancer; development of an animal models.
 
Description Dr. David Dombrowicz 
Organisation Pasteur Institute, Paris
Country France 
Sector Academic/University 
PI Contribution Expertise in IgE and receptor interactions; functional assays; provision of IgE and other materials for the in vivo studies.
Collaborator Contribution Transgenic mouse models for allergic disease and cancer, and provision of mast cell lines.
Impact Publications; demonstration of proof of principle for small molecule inhibition of IgE/FceRI interaction for therapeutic intervention in allergic disease, and for recombinant IgE immunotherapy in cancer.
 
Description Dr. Gary Felsenfeld 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Expertise in molecular biology; assays for gene regulation and synthesis of IgE.
Collaborator Contribution Expertise in chromatin structure and function, and gene regulation mechanisms; hosting visits from KCL scientists, and post-doctoral worker at NIH.
Impact Publications; demonstration that changes in chromatin structure at the IgE locus are responsible for class switching; demonstration of isotype-specific differences in DNA methylation patterns at the IgG and IgE loci.
 
Description Dr. James Spicer 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in recombinant IgE design and production; functional assays and biophysical characterisation of IgE.
Collaborator Contribution Expertise in translational research in cancer
Impact On-going trials of recombinant IgE and IgG antibodies in cancer.
Start Year 2009
 
Description Dr. Pooja Takhar 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Design of experiments to investigate receptor revision and other DNA recombination events involved in isotype switching to IgE. Allergen-specific IgE Fabs derived from this work will be studied by X-ray crystallography.
Collaborator Contribution Expertise in B cell cloning and local IgE synthesis assays
Impact NIHR Fellowship gained.
Start Year 2009
 
Description Dr. Rajat Varma 
Organisation National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Country United States 
Sector Public 
PI Contribution Proteins for developing artifical bilayer TIRF microscopy to study protein:protein interactions in the membrane
Collaborator Contribution EXpertise in artificial bilayer technique
Impact Paper in preparation; TIRF microscope set up at King's; combination of molecular biology and physics.
Start Year 2009
 
Description MRC & Asthma UK Centre in Allergic Mechanisms of Asthma 
Organisation King's College London
Department MRC & Asthma UK Centre in Allergic Mechanisms of Asthma
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of expertise in molecular, cellular and structural biology across a range of projects.
Collaborator Contribution Provision of studentships; support of the Protein Production Facility; network of collaborators for provision of clinical materials from allergic and asthmatic patients.
Impact Many publications and outputs described in the other sections.
Start Year 2006
 
Description Novartis 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution Expertise in IgE and clinical trial facilities and patients.
Collaborator Contribution Provision of anti-IgE and manpower to conduct the experiments
Impact A clinical trial has been initiated as a result of the collaboration; additional funding was obtained from other sources; understanding of role of IgE in non-atopic asthma
Start Year 2009
 
Description Philippe Gevaert 
Organisation University of Ghent
Country Belgium 
Sector Academic/University 
PI Contribution Complementary molecular biological assays
Collaborator Contribution Provision of materials and assays
Impact Materials generated; posters and talks at meetings; manuscripts in preparation.
Start Year 2009
 
Description Professor Chris Corrigan 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Experitse in IgE regulation and function; molecular biology expertise and assays.
Collaborator Contribution Provision of clinical materials (bronchial biopsies).
Impact Publications; clinical trial of anti-IgE in non-atopic asthma in progress; demonstrating that IgE plays a role in non-atopic asthma; potential for more effective treatment of this condition.
 
Description Professor Claus Bachert 
Organisation University of Ghent
Country Belgium 
Sector Academic/University 
PI Contribution Expertise and materials related to IgE regulation and function; functional assays.
Collaborator Contribution Provision of clinical material (nasal polyps and turbinates) and manpower for experimental work at King's.
Impact Demonstration of receptor revision and isotype switching to IgE in nasal polyps; the demonstration of local IgE switching and production, and the role of bacterial superantigens in the pathogenesis of nasal polyps, will inform future therapeutic intervention.
Start Year 2006
 
Description Professor Erika Jensen-Jarolim 
Organisation Medical University of Vienna
Country Austria 
Sector Academic/University 
PI Contribution Expertise in IgE function; recombinant DNA technology; materials and facilities for the functional studies, all of which were performed at King's.
Collaborator Contribution Two students from the Vienna lab worked at King's on functional studies of chimeric monocloncal IgEs against ovarian and breast cancer.
Impact Several publications; further funding from BRC and CRUK; a clinical trial of a monoclonal IgE (in progress); studentships from BRC.
Start Year 2007
 
Description Professor Gideon Lack 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular biology to study peanut allergen-specific IgE response
Collaborator Contribution Provision of clinical material
Impact None yet. Collaboration is multidisciplinary: molecular biology and clinical medicine (paediatric allergy). Gained funding for new MRC Programme Grant (2011-2016).
Start Year 2010
 
Description Professor Michihiro Hide 
Organisation Hiroshima University
Department Department of Dermatology
Country Japan 
Sector Academic/University 
PI Contribution B cell confocal microscopy
Collaborator Contribution Cell lines and personnel to carry out confocal microscopy
Impact Paper published (see list)
Start Year 2010
 
Description Professor Peter Hawarth 
Organisation Southampton General Hospital
Department Department of Immunology
Country United Kingdom 
Sector Hospitals 
PI Contribution Molecular biology for study of IgE VH regions sequences in atopic and non-atopic asthma.
Collaborator Contribution Clinical samples
Impact Multi-disciplinary: molecular biology and clinical medicine
Start Year 2009
 
Description Professor Robert Aalberse 
Organisation Sanguine Research
Country Spain 
Sector Private 
PI Contribution X-ray crystallographic analysis of IgG4 and Fc region.
Collaborator Contribution Provision of purified IgG4 and IgG4-Fc for structural analysis
Impact Crystal structure of human IgG4 determined
Start Year 2009
 
Description Professor Sebastian Johnston 
Organisation Imperial College London
Department Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular biology for studying viral exacerbation of asthma
Collaborator Contribution Provision of mouse models and clinical materials
Impact None yet. Multidisciplinary: molecular biology and clinical medicine.
Start Year 2010
 
Description Professor Stephen Durham 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in analysing antibody V gene sequences, antibody expression, purification and characterisation; access to facilities.
Collaborator Contribution Access to patient samples, biopsies etc.
Impact See publication list. Main outcome is the understanding that isotype switching to IgE and production of IgE occurs locally in peripheral tissue. This has major implications for therapeutic intervention in allergic rhinitis and asthma, and also the treatment of non-atopic asthma, since IgE plays a role. Studies of the protective role of IgG4 antibodies in immunotherapy will inform future treatment protocols for this approach.
 
Description Professor Toshi Kawakami 
Organisation Los Angeles Institute of Allergy and Clinical Immunology
Country United States 
Sector Academic/University 
PI Contribution Provision of cDNA of potentially cytokinergic IgE for analysis.
Collaborator Contribution Expertise in analysis of cytokinergic IgE; sequence data.
Impact Demonstration that human IgE can exert cytokinergic activity; this has profound implications for the pathogenesis of allergic disease and asthma in particular.
Start Year 2007
 
Description UCB Collaboration 
Organisation UCB Pharma
Country United Kingdom 
Sector Private 
PI Contribution Provision of reagents for assay and development of a small molecule inhibitor.
Collaborator Contribution Experience of structure based small molecule drug discovery.
Impact Work in progress; confidential.
Start Year 2009
 
Title Anti-IgE antibodies 
Description Antibody-derived biologic that inhibits binding of IgE to its receptors on effector cells. 
IP Reference WO2017/211928 A1 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact Understanding of the mechanism of action of anti-IgE antibodies in general and the possibilities for allosteric inhibition.
 
Title Expression system for antibodies 
Description Set of optimised expression vectors for the production of whole human antibodies. 
IP Reference WO2009150426 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact Expression system used for production of human antibodies in various applications supporting projects relating to the use of IgE in cancer therapy, and also studies of cytokinergic IgE.
 
Title IgE anti-HMW-MAA antibody patent 
Description Antibody capable of binding high molecular weight melanoma associated antigen and also to Fc-epsilon receptor, with application to cancer therapy. 
IP Reference WO2013050725 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact Too early to report.
 
Title IgE antibodies against melanoma antigen 
Description Production of IgE monoclonal antibody against a melanoma-associated antigen 
IP Reference Insufficient Information 
Protection Patent application published
Year Protection Granted
Licensed No
Impact Too early to report.
 
Description Asthma UK Website for World Asthma Day 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/parliamentarians
Results and Impact Report of our asthma research to develop a novel therapy was highlighted on the website and in publicity material distributed in association with World Asthma Day, 2009.

Raised profile of the need for more research funding and clinical provision for asthma.
Year(s) Of Engagement Activity 2009,2011
 
Description Atlas Project 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Interview about X-ray crystallography, crystallisation and structure analysis; reference to our work on antibodies in allergy and asthma.
Year(s) Of Engagement Activity 2018
 
Description Atlas Project Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presentation of crystallisation process of various substances from sea water to salivary fluid. Encouraged people to think about natural variation of environmental and medically relevant substances.
Year(s) Of Engagement Activity 2018
 
Description BBC Radio 4 Programme 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Contributed to a BBC Radio Programme on Asthma provision and asthma research: Our Lives in Our Hands - Asthma, Living on a Knife Edge.

Raised profile of the life-threatening aspect of asthma and allergic disease, and of the widespread nature of asthma.
Year(s) Of Engagement Activity 2006
 
Description BBC TV Programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Contribution to BBC TV Series on History of Science

Led to further media interest, interviews etc.
Year(s) Of Engagement Activity 2011
 
Description Bush House, King's College London, The Science and Art of Mirror Symmetry. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Hands-on activity to explore symmetry in tiling patterns, mirror symmetry and aperiodic symmetry. Included one-hour lecture (repeated). All-day event in public accessible space. Sparked discussion about pattern, structure, molecular structure and the work with antibodies in allergy and asthma in which we are engaged.
Year(s) Of Engagement Activity 2018
 
Description MRC Centenary Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Engaged very large number of the public over several hours and generated considerable interest.

Schools visits following discussion at event with teachers.
Year(s) Of Engagement Activity 2013
 
Description MRC Centre Public Engagement Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 100 people attended raising the profile of asthma research

Enhanced awareness of need for long-term basic research
Year(s) Of Engagement Activity 2012
 
Description Newspaper and radio interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Articles and interviews concerning the trials of IgE in the immunotherapy of cancer

Raised awareness of this approach with the public and assisted in gaining funding.
Year(s) Of Engagement Activity 2007,2008,2009,2013
 
Description Newspaper and radio interviews 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Articles and interviews concerning the trials of IgE in the immunotherapy of cancer

Raised awareness of this approach with the public and assisted in gaining funding.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Presentations at Asthma UK events 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Presented my research on IgE and the development of novel therapeutics to fundraisers, supporters and patients at events organised by Asthma UK.

Raises profile of asthma research nationally. Assisted the charity in attracting new donors and raising funds for asthma research.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Royal Society Summer Science Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Hands-on activity involving tiling patterns to present principles of symmetry, crystallography and structure analysis. Discussion of antibody structure, antibody recognition and allergic disease including asthma.
Year(s) Of Engagement Activity 2017
 
Description School Visit to KCL (The Grey Coat Hospital School) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Visit to labs; tour of other facilities relevant to our work in allergy and asthma; talks; time for free discussion.
Year(s) Of Engagement Activity 2017
 
Description Seminar on novel asthma/allergy therapy development 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presented at several activities organised by Asthma UK aimed at their fundraisers, other supporters and of course including patients.

Raied profiule for our work, and the role of structural biology in the drug discovery process. Enhanced the ability of the charity to engage new donors and raise funds for asthma research.
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Seminars on development of IgE inhibitors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Various talks to companies, under confidentiality agreements (UCB Celltech, UK; AstraZeneca, Sweden; Pfizer, UK & USA)

We successfully negotiated an agreement with a company for collaborative development of IgE inhibitors.
Year(s) Of Engagement Activity 2007,2008,2009
 
Description Seminars on development of IgE inhibitors for anti-allergy therapy 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Discussions under confidentiality agreements, with various companies, recently UCB-Celltech (UK), AstraZeneca (Sweden) and Pfizer (UK and USA).

Negotiations concluded with one UK-based company; unable to provide further details at present.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Sixth Form talks on Asthma, Allergy and Drug Design 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Most recently to St. Paul's School, London.

Positive feedback from teachers about pupils' university choices and career plans. This talk led to initiation of a project to bring sixth formers into King's to carry out an experiemtnal project involving molecular and structural biology. First run in 2009, the scheme was a great success and will be repeated annually.
Year(s) Of Engagement Activity 2008,2009,2010,2014
 
Description Sixth Form talks on Asthma, Allergy and Drug Design 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Talks to Sixth Forms, most recently at Magdalen College School, Oxford, and St. Paul's School, London.

Very positive feedback from school staff about pupils' future subject choices at university and career plans. Led to collaborative project with St. Paul's School sixth form; students spend day in lab at King's.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Telephone interviews with journalists 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Telephone interviews with journalists about our IgE work and development of new drugs. Press releases accompanied recent publication in J. Biol. Chem. Reports in the Times, Daily Telegraph, Daily Mail, London Metro, NHS Web pages.

Raises profile of our work nationally, and of the need for research into allergy and asthma generally.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Telephone interviews with newspapers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Various interviews leading to pieices in newspapers: Times, Daily Telegraph, Sunday Times, Daily Mail, London Metro, NHS Web pages. (Earlier years: breakfast TV appearance and Radio 4 programme "Leading Edge")

Raised national public profile of allergy research generally.
Year(s) Of Engagement Activity 2007,2008