A novel serum-based assay of functional IgG inhibitory activity is predictive of the clinical response to immunotherapy

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Hayfever affects 12 million people in UK and may ruin what for most of us is the best time of the year. Hayfever impairs concentration at work and may reduce performance in school exams. Many sufferers respond to antihistamines and nasal steroid sprays. There remains a hard core who may benefit from allergy vaccination (desensitisation injections). Discovered in UK 100 years ago, this treatment is highly effective but requires specialist supervision . We have developed in partnership with a company, ALK Abello, an alternative, effective and safer vaccine containing grass extract that is taken daily as a rapidly dissolving tablet under the tongue (GRAZAX). Based on our understanding of how vaccination works, we now wish to develop a test that measures ‘protective’ antibodies in the bloodstream that will allow us to predict those patients who are likely to respond best to desensitisation and to monitor the effects of treatment.

Technical Summary

Hayfever affects 12 million people in UK, of whom 4 million remain uncontrolled by medical therapy. For such individuals, subcutaneous allergen immunotherapy is effective and involves weekly then monthly injections of grass pollen extract, usually continued for 3-4 years. The subcutaneous route is associated with a small risk of systemic reactions and requires specialist supervision. The alternative sublingual route, using high dose allergen in liquid/tablet form under the tongue, is also effective and safe for home use. We are currently undertaking a definitive 5 year trial to address whether sublingual immunotherapy, like subcutaneous treatment, induces long-term remission after 3 years therapy.
Immunotherapy deviates B cell responses towards production of allergen-specific IgG, particularly IgG4, which has the potential to block IgE-mediated responses. Although IgG4 levels have historically shown poor correlations with treatment response, ?functional? assays reflecting antibody avidity/affinity could be more predictive of efficacy. Pollen-specific IgG4 induced by immunotherapy inhibits IgE-facilitated allergen presentation (IgE-FAP), possibly a rate-limiting process in Th2 cell-driven allergic responses at the low allergen concentrations encountered during the pollen season. We have replaced this complex technique with a simple flow cytometric assay (IgE-FAB) detecting allergen-IgE complex binding to B cells expressing CD23 (low affinity IgE receptor). Binding is inhibited by IgG within sera of immunotherapy-treated subjects. Remarkably, in a small double-blind withdrawal trial of immunotherapy, continuing clinical remission was associated with persistence of IgE-FAB inhibitory activity despite a marked reversal of absolute IgG4 concentrations. Thus our ?functional? assay is distinct from serum IgG as detected by ELISA. The detailed technical validation of this assay is now published (Dec 06).

We are now seeking validation of this assay as a biomarker in a wider context. Inhibitory activity for IgE-FAB will be measured in 2 recent large multi-centre immunotherapy trials in severe hayfever: (1) the UK Subcutaneous Immunotherapy study (n=410) - a one year double-blind placebo-controlled dose-response study, and (2) the International Sublingual Immunotherapy study (n=634) - an ongoing 5 year double-blind placebo-controlled study of sublingual grass allergen tablets, with the final 2 years comprising a double-blind withdrawal of therapy. Published results for year one confirm good efficacy.
These definitive studies will help determine whether simple immunoreactive IgG or ?functional? IgG are predictive biomarkers of the clinical response in individual patients. Moreover, we aim to provide the basis for a predictive assay to identify the responder population, when to discontinue therapy and to predict relapse after treatment discontinuation.

Publications

10 25 50

publication icon
Pree I (2010) Inhibition of CD23-dependent facilitated allergen binding to B cells following vaccination with genetically modified hypoallergenic Bet v 1 molecules. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

publication icon
Radulovic S (2008) Grass pollen immunotherapy induces Foxp3-expressing CD4+ CD25+ cells in the nasal mucosa. in The Journal of allergy and clinical immunology

publication icon
Renand A (2018) Synchronous immune alterations mirror clinical response during allergen immunotherapy. in The Journal of allergy and clinical immunology

 
Guideline Title EAACI guideline on Allergen Immunotherapy for allergic rhinitis 2018
Description Included in EAACI guideline on Allergen Immunotherapy for allergic rhinitis 2018
Geographic Reach Europe 
Policy Influence Type Citation in clinical guidelines
Impact Prolonged remission of hayfever following grass pollen immunotherapy requires a minimum of 3 years treatment
 
Description New registration for hay fever vaccine in USA 2013
Geographic Reach North America 
Policy Influence Type Citation in other policy documents
Impact Sublingual tablet immunotherapy is an effective, safer alternative to subcutaneous immunotherapy that induces long-term disease remission. The tablet approach is now widespread in Europe and is being successfully extended to other allergies (housedust mite) and internationally (ragweed allergy in USA and Japanese Cedar pollen allergy). The work is quoted in guidelines internationally and regulatory bodies now recognise the disease-modifying potential of immunotherapy and its ability to induce long-term remission.
URL http://www.fda.gov/BiologicsBloodVaccines/Allergenics/ucm393162
 
Description Immne Tolerance Network
Amount $211,393 (USD)
Funding ID FY15ITN086, A3 
Organisation National Institute of Allergy and Infectious Diseases (NIAID) 
Sector Public
Country United States
Start 02/2015 
End 01/2016
 
Description Immune Tolerance Network Clinical Trial Application (Single Centre award)
Amount £3,800,000 (GBP)
Funding ID ITN049D 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 04/2011 
End 03/2016
 
Description Investigator initiated grant:Regeneron Pharmaceuticals Inc
Amount £497,124 (GBP)
Funding ID REGN1908/1909 
Organisation Regeneron Pharmaceuticals, Inc. 
Sector Private
Country United States
Start 08/2014 
End 08/2015
 
Description Investigator initiated project grant: Merck
Amount £55,782 (GBP)
Organisation Merck 
Sector Private
Country Germany
Start 12/2013 
End 05/2014
 
Description Investigator-initiated project grant: Biotech Tools
Amount £54,468 (GBP)
Organisation BioTech Tools 
Sector Private
Country Belgium
Start 11/2013 
End 12/2014
 
Description Investigator-led collaboration with ALK Denmark, a manufacturer of allergy vaccines
Amount £330,000 (GBP)
Organisation ALK-Abelló A/S 
Sector Private
Country Denmark
Start 04/2014 
End 03/2017
 
Title Assay of binding of allergen-IgE complexes to B cells and its inhibition by IgG-containing serum 
Description A bioassay for measuring functional activity of IgG-containing serum obtained pre/post immunotherapy. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Method published in J Immunol methods Potential assay for predicting clinical response to allergen immunotherapy 
 
Description Bio-assay of serum pre/post recombinant birch immunotherapy 
Organisation Medical University of Vienna
Department Laboratory for Allergy Research Vienna
Country Austria 
Sector Academic/University 
PI Contribution Principle Investigator for this project. Laboratory experimental analyses and data analysis Samples supplied Profesor Rudolf Valenta
Collaborator Contribution Joint collaboration resulting in publication:
Impact Joint collaboration resulting in publication Pree I, Shamji MH, Kimber I, Valenta R, Durham SR, Niederberger V. Inhibition of CD23-dependent facilitated allergen binding to B cells following vaccination with genetically modified hypoallergenic Bet v 1 molecules. Clin Exp Allergy 2010;40:1346-52.PMID: 20604801 Further Joint publication : Marth K, Breyer I, Focke-Tejkl M, Blatt K, Shamji M, Layhadi J, Gieras A, Swoboda I, Zafred D?, Keller, Valent P, Durham S Valenta R. A non-allergenic birch pollen allergy vaccine consisting of hepatitis PreS-fused Bet v 1 peptides focuses blocking IgG towards IgE epitopes and shifts immune responses to a tolerogenic and Th1 phenotype. Journal of Immunology 2012 (favourably reviewed in final revision)
Start Year 2008
 
Description IgG modulation of IgE-associated risk for wheeze in high risk (mite sensitised) children: a potential predictive bioassay 
Organisation Telethon Kids Institute
Country Australia 
Sector Academic/University 
PI Contribution Principle Investigator for this project. Laboratory experimental analyses and data analysis Samples supplied Profesor Patrik Holt
Collaborator Contribution We look forward to a joint publication
Impact We look forward to a joint publication
Start Year 2010
 
Description Inhibition of IgE-facilitated allergen binding following mix grass pollen specific sublingual immunotherapy 
Organisation Stallergenes Group
Country Global 
Sector Private 
PI Contribution Principle Investigator for this project. Laboratory experimental analyses and data analysis Samples supplied Stallergenes SA
Collaborator Contribution All laboratory analyses will be perfomed by research team. We look forward to a joint publication
Impact We look forward to a joint publication
Start Year 2010
 
Description Inhibition of IgE-facilitated allergen binding following ragweed allergen immunotherapy with and without omalizumab therapy 
Organisation Creighton University
Department Division of Allergy & Immunology
Country United States 
Sector Academic/University 
PI Contribution Principle Investigator for this project. Laboratory experimental analyses and data analysis Samples supplied Profesor Thomas Casale
Collaborator Contribution Joint collaboration resulting in publication in journal of Allergy Clin Immunol 2008
Impact Joint collaboration resulting in publication in journal of Allergy Clin Immunol 2008 PMID: 17631952
Start Year 2006
 
Description Time course of serum inhibitory activity for facilitated allergen-IgE binding during bee venom immunotherapy in children. 
Organisation Medical University of Graz
Department Department of Paediatrics, Respiratory and Allergic Disease Division
Country Austria 
Sector Academic/University 
PI Contribution Principle Investigator for this project. Laboratory experimental analyses and data analysis Samples supplied Dr Eva-Maria Varga
Collaborator Contribution Joint collaboration resulting in publication in journal of Clinical and Experimental Allergy 2009
Impact Joint collaboration resulting in publicationTime course of serum inhibitory activity for facilitated allergen-IgE binding during bee venom immunotherapy in children. Varga EM, Francis JN, Zach MS, Klunker S, Aberer W, Durham SR. Clin Exp Allergy. 2009;39:1353-7. PMID: 19538349. Further recent joint publication on line: Varga EM, Kausar F, Aberer W, Zach M, Eber E, Durham SR, Shamji MH.Tolerant beekeepers display venom-specific functional IgG(4) antibodies in the absence of specific IgE. J Allergy Clin Immunol. 2012. doi:pii: S0091-6749(12)01452-2. 10.1016/j.jaci.2012.08.037. [Epub ahead of print] PMID: 23063581
Start Year 2008
 
Description BBC Radio broadcast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact BBC radio broadcast to highlight importance of insect venom anaphylaxis, diagnosis and its treatment with immunotherapy
Year(s) Of Engagement Activity 2015
 
Description Public workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Wellcome-funded public engagement at King's Mall, Hammersmith Shopping Centre. 'Heart and Lung Convenience Store'. 10-15 participants engaged on hayfever its importance, diagnosis and management with skin prick testing demonstration with active participation of attendees.
Year(s) Of Engagement Activity 2014,2015
URL https://www1.imperial.ac.uk/nhli/public_engagement/the_curious_act/the_heart_and_lung_convenience_st...
 
Description Television interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Broadcast on 6 O clock national television news

Enquiries from members of public
Year(s) Of Engagement Activity 2009
 
Description Television interview 'Trust me I'm a Doctor' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Broadcast nationally on a popular health programme on ITV Channel 4

Positive feedback from the ITV Presenter, patients in clinic and reserach participants
http://www.bbc.co.uk/programmes/p01dgd9c/features/allergies.24.10.13
Year(s) Of Engagement Activity 2013
URL http://www.bbc.co.uk/programmes/p01dgd9c/features/allergies