MICA: Interleukin-21 in rheumatoid arthritis: exploring its therapeutic potential for the development of a novel targeted biologic therapy.

Lead Research Organisation: Queen Mary, University of London
Department Name: William Harvey Research Institute

Abstract

Rheumatoid arthritis (RA) is a chronic, autoimmune disease that affects ~1% of the population and an important cause of disability and premature mortality. The disease is driven by chronic inflammation of the joint synovial tissue in which there is accumulation of activated immune cells (macrophages, dendritic cells, T-cells, B-cells and plasma-cells).

The therapeutic benefit of B-cell depletion with anti-CD20 mAb in RA demonstrated that autoreactive B-cells play a crucial pathogenic role. Likewise, blockade of inflammatory cytokines (TNFa, IL-6) results in significant clinical response. However, ~30-40% of patients remain refractory to current therapies. Thus, the development of better therapies in this area of unmet need remains of critical importance particularly in "resistant" patients where the identification of additional/alternative inflammatory pathways may lead to novel therapeutics.

IL-21 is a potent pleiotropic cytokine involved in the activation/differentiation of many immune cell types including B and T cells but also stromal cells with the induction of metalloproteinases and inflammatory cytokines including TNFa. IL-21 is a member of the common cytokine receptor gamma chain-binding family and is mainly produced by activated T-cells including Th17 cells and TFh. TFh play a fundamental role in B cell activation and antibody production in secondary lymphoid organs and control humoral immune responses.

IL-21 has been associated with RA based on genetic studies and increased expression in RA patients; however its pathogenic function in RA joints and its potential as a therapeutic target have not been fully addressed. Blockade of IL-21 receptor (IL-21R) considerably ameliorates disease progression in animal models of RA indicating that modulation of the IL-21/IL-21R pathway is a promising therapeutic approach.

In support of this application we studied a large cohort of RA patients and demonstrated that i) the IL-21/IL-21R pathway is highly increased in a subset of RA patients presenting focal lesions called ectopic lymphoid structures (ELS) but not in patients with diffuse synovitis; ii) synovial IL-21 protein is expressed in strict association with a subset of TFh-like cells; iii) RA synovial fibroblasts, but not RA dermal fibroblasts, express high levels of IL-21R suggesting that IL-21 acts not only on infiltrating immune cells but also on resident synovial cells; iv) IL-21 and IL-21R expression is maintained for several weeks when RA synovial tissue is engrafted into immunodeficient (SCID) mice and support the production of human autoantibodies.

Thus, we ultimately aim to develop effective IL-21 targeting strategies in RA through the following 4 steps: Step 1) Identification of the cellular sources and targets of IL-21 within the joints of RA patients. Step 2) Analysis of IL-21 function on immune and stromal cells isolated from the RA joints in vitro and in vivo in the RA/SCID model. Step 3) Testing IL21/IL21R blocking reagents for human use (in preclinical development with the industrial partner) in the human RA/SCID model. Step 4) Evaluating IL-21 contribution to disease outcome and response to existing traditional and biological therapies in patients with early arthritis and in those treated with anti-TNFa or anti-IL-6R Biologics.

By addressing key aspects of IL-21 biology in RA this proposal will advance our knowledge of the role of IL-21 in chronic inflammation, B cell autoimmunity and ELS function with important implications for other autoimmune/chronic inflammatory diseases. Proof of concept studies of the effectiveness of human IL-21 blocking reagents on synovial inflammation and humoral autoimmunity in diseased tissue will advance the development of novel IL-21 therapeutics for the treatment of RA. Finally, the patient-based studies may enable better identification of key responders of IL-21 mediated arthritis and have a means of stratifying subjects in early clinical trials.

Technical Summary

Our developmental plan follows 4 steps

Step 1 Identification of IL-21 producing/target cells in RA
We will employ confocal microscopy on RA synovial tissues and FACS on isolated RA synovial cells to identify IL-21 and IL-21R+ cells in in association with specific markers for Th1 (IFNg,T-bet, CXCR3), Th2 (IL-4/GATA-3), Th17 (IL-17A/F, Rorgt, CCR6) and TFh (CXCR5, ICOS, PD-1) cells. Additionally, IL-21R expression will be investigated on synovial B cells subsets and CD8+ T cells.

Step 2 Functional role of IL-21 in inflammation, autoimmunity and tissue damage
We will define the functional role of IL-21:
in vitro: i) on human IL-21R+ RA synovial fibroblasts assessing the capacity of IL-21 to induce cytokines and MMPs (mRNA and protein) and ii) on synovial B cell activation, including B cell differentiation (FACS), AID/circular transcripts (rt-PCR) and class-switched antibodies (ELISA).
in vivo: in the RA/SCID chimera by analysing IL-21-induced activation of pro-inflammatory pathways such as ELS function, B cell autoreactivity, production of inflammatory cytokines and stromal cell activation.

Step 3 Pre-clinical development of IL-21 blocking agents
We will directly contribute to the development of pre-clinical IL-21 therapeutics by testing their efficacy in vivo in the HuRA-SCID chimera on i) synovial inflammation and ELS; ii) B/T cell function; iii) autoantibody production and iv) stromal cell activation.

Step 4 IL-21 in disease outcome and response to treatment in RA: a roadmap to patient stratification
We will assess IL-21 and related pathways as biomarkers of disease evolution and response to treatment in prospective clinical studies in the MRC Pathobiology of Early Arthritis Cohort and in RA patients treated with IL6-R and TNFa biologics.

Emerging data will be applied to clinical trial design based on IL-21 target validation, role in synovial immunopathology, development of IL-21 blocking reagents and stratification of patients for treatment

Planned Impact

The project will have a significant impact both on basic research and applied translational science.

1. Impact on basic research and knowledge acquisition within and beyond the field of RA and rheumatology.

At the basic science level a better understanding of IL-21 in key inflammatory immune mechanisms in a complex disease such as RA will broadly benefit the scientific community with considerable advance in knowledge not only in the specific field of RA but with significant repercussion on other autoimmune diseases, particularly those characterized by ELS, both within the rheumatology field (i.e. Sjogren's syndrome, lupus) and beyond with applications in numerous other medical conditions including: inflammatory bowel diseases, multiple sclerosis, as well as potentially on hematological malignancies.

2. Impact on translational and clinical research.

- Shifting therapeutic paradigms within the RA field. Demonstration of functionality in ELS at synovial tissue level will provide supporting evidence to target IL-21 therapeutically in RA. Furthermore, the opportunity to dissect the molecular functions in sophisticated in vitro and in vivo models (SCID/RA chimeric model) using human tissues will provide invaluable data for the translational relevance of this important cytokine pathway to the disease and may lead to potential biomarkers that could be used to help identify anti-IL-21 responding patients.
Additionally, this project aims to transform the notion of "blind" clinical trial to that of biopsy-guided, pathology driven patient stratification. In this regard, IL-21 seems an ideal candidate as it is clear that IL-21 expression is linked to the formation of ELS in the synovium, which occurs in ~40-50% of RA patients. Thus, a better comprehension of IL-21 function in diseased tissue subtypes will provide a stronger understanding on how to stratify subjects for IL-21 based therapies. In addition, the evaluation of IL-21 expression in disease evolution in deeply phenotyped early arthritis patients [Pathobiology of Early Arthritis Cohort (PEAC) http://www.peac-mrc.mds.qmul.ac.uk/] and following treatment with current biologics (IL6-R and TNFa) may identify novel biomarkers of disease prognosis and/or response to anti-IL-21 therapy.

- Broader impact on translational and clinical science through the development of IL-21 blocking agents for clinical use. MedImmune is a biopharmaceutical company and world player in antibody therapeutics with significant expertise in the development of novel therapeutics in autoimmune diseases. IL-21 blockade is highly ranked in the translational pipeline. The opportunity to develop unique reagents in partnership with MedImmune could enable the acceleration of the development programme to bring targeted IL-21 therapies for clinical use not only in patients with RA, but also in other autoimmune conditions in which IL-21 is emerging as a critical pathogenic player.

3- Commercial impact on the public and private sector.

A defined development programme described in this application coupled with the formation of a strong Academic Industry partnership will maximise the opportunity of success by translating novel scientific and clinical observation into commercially valuable assets such as diagnostic or therapeutic agents. The equitable Head of Terms agreed between QMUL and MedImmune will also ensure that economic benefits will profit both private and public partners.

4- Impact on patient health.

The ultimate beneficiaries of this research it is hoped will be patients with RA. Although the time-scale for the direct impact on patient health of IL-21 blocking agents in RA is likely to be long-term, the definition of biomarkers of disease evolution and clinical response to current treatments in RA and the role of IL-21 in this context would provide more immediate impact on RA patients through biopsy-based stratification allowing higher response rates to available therapies.

Publications

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Bombardieri M (2017) Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. in Nature reviews. Rheumatology

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Corsiero E (2016) NETosis as Source of Autoantigens in Rheumatoid Arthritis. in Frontiers in immunology

 
Title Tate Exchange Programme (Jun 2019) 
Description Exhibition to demonstrate the 'Effect of Arthritis on Movement and Art' Gloves will be used to restrict movement and simulate the effects of arthritis Ultrasound machines will show delegates the inside of their joints Art from patients with arthritis (including Renoir ) will be displayed The role of research in the development of new medicines and the alleviation of symptoms will be highlighted 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2019 
Impact Too early 
URL https://www.tate.org.uk/visit/tate-modern/tate-exchange
 
Description Arthritis Research UK and NIHR sponsored Experimental Musculoskeletal Medicine Conference - to explore the alignment and opportunities to maximise, improve and add to the UK musculoskeletal experimental medicine investment in order to accelerate the translation of innovations for the benefit of patients, the public and the healthcare system
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Influence on Industry drug development policy: Stratified Medicine for RA
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Joint Translation Research Collaboration meeting 25th March 2019
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description TRC Strategy Review /Objectives Setting
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://www.nihr.ac.uk/life-sciences-industry/access-to-expertise-and-collaborations/collaborations-...
 
Description VERSUS ARTHRITIS ANNUAL FELLOWS' MEETING 2019 (14-15March 2019)- Chair of a main session & ran 'meet the expert' session
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL https://www.versusarthritis.org/research/research-funding-and-policy/fellowships-and-career-support/...
 
Description Versus Arthritis senior stakeholder meeting
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Arthritis Research UK Clinical lecturer in experimental medicine and rheumatology
Amount £565,973 (GBP)
Funding ID 21890 
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 01/2023
 
Description NIHR Clinical Lectureship
Amount £310,937 (GBP)
Organisation Health Education England 
Sector Public
Country United Kingdom
Start 01/2019 
End 01/2023
 
Title EMR Biobank 
Description EMR biobank containing over 800 synovial biopsies supports multiple projects and each research project adds to the samples and information available Synovial biopsies are linked to tight clinical databases including ultrasound synovitis assessments 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact Supports academic and industry collaborations 
URL https://directory.biobankinguk.org/Profile/Biobank/GBR-1-254
 
Title Human RA/SCID mouse transplantation model 
Description Human RA/SCID mouse transplantation model 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Supports multiple RA research projects 
 
Description MedImmune / AZ: MRC/MICA Targeting IL-21 in specific synovial tissue pathotypes 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution Analysis of synovial samples
Collaborator Contribution Financial support
Impact Work ongoing
Start Year 2013
 
Description Role of IL-27 in regulating TFh 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution We entered a formal collaboration to conduct experiments in Cardiff University with a novel model of inducible ectopic lymphoid neogenesis that we previously developed via adenoviral-delivery in murine submandibular glands through retrograde cannulation of the excretory duct.
Collaborator Contribution Our collaborator is making available IL-27Ra KO mice to run the cannulation model
Impact The collaboration has just been formally set up, further details will be included in the next report period
Start Year 2016
 
Description IL21 Operational 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Regular communication through meetings/presentations for the research team, department and Institute.
Year(s) Of Engagement Activity 2015,2016
 
Description MSK TRC Springboard 2020 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Chaired by Prof C Pitzalis To develop innovative strategies that will increase MSK research across various specialities including preliminary talks and overarching workstream meetings for discussions around future development and projects.
Year(s) Of Engagement Activity 2020
 
Description Precision Medicine UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact NOCRI joined UK leaders in the research, development and commercialisation of precision medicine for a one-day event this week designed to encourage new partnerships and highlight new opportunities in the field. The Precision Medicine UK: Collaboration Nation event at De Vere Holborn Bars, London, on 9 December was organised on behalf of the Stratified Medicine Innovation Platform by Innovate UK,, National Institute for Health Research, Cancer Research UK,Medical Research Council, Invest Northern Ireland, Health and Care Research Wales and the Knowledge Transfer Network, with the NIHR Office for Clinical Research Infrastructure (NOCRI) coordinating the NIHR's involvement. The day formed part of a programme to make the UK a world leader in precision medicine and provided real-world examples of the discovery and development of precision medicine solutions, through talks, panel discussions, workshops and exhibitions with the opportunity to arrange one-to-one partnering meetings. Precision medicine is an emerging approach to the treatment and diagnosis of disease that takes into account variations in a patient's genes, environment and lifestyle. It aims to better target treatments to an individual's circumstances to improve outcomes for patients. Representatives from across the NIHR were involved in the day and presented on a range of projects and funding programmes. Professor Bryan Williams of NIHR UCLH Biomedical Research Centre joined the first panel of the day which highlighted UK investments in the invention and evaluation phase of research. Professor Williams' highlighted key NIHR's investments in this space and provided examples of exciting precision medicine projects from UCLH BRC. In addition, a number of NIHR precision medicine projects were presented during the disease area specific showcase sessions. This included Professor Costantino Pitzalis who presented the THERAPIST study on behalf of the NIHR Translational Research Partnership, Professor Simon Mead's who presented a project at NIHR Queen's Square Biomedical Research Unit on the "dementia chip" and Professor Tariq Sadiq's who presented on Capacity Building and Delivery of Precision Medicine in Sexual Health, through NIHR Funding. Mark Samuels, Managing Director of NOCRI, also chaired a discussion panel themed 'Enabling Collaboration', which highlighted the value of collaborative working between companies, academics, charities and patients. The event saw the launch by the chief executive of Innovate UK, Dr Ruth McKernan, of a new map of the precision medicine landscape. A whole range of organisations, including charities, health bodies and devolved administrations are coordinating their work under the umbrella of Innovate UK's Stratified Medicine Innovation Platform, with NOCRI representing the NIHR.
Year(s) Of Engagement Activity 2015
 
Description Tate Exchange "Creating without constraint. Arthritis and art" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Participated in "IDEAS IN MOTION: BORDERS, BODIES, AND THE UNIVERSE WITH QUEEN MARY UNIVERSITY OF LONDON
11-16 JUNE 2019" with a workshop on:

Creating without Constraint: Arthritis and Art
Members of the public were invited to to experience an interactive workshop exploring the relationship between impaired mobility and artistic expression. Our researchers will guide you in a 'journey' inside the joints with activities simulating the restriction of movement. The display will include the work of Renoir and Pickering, two artists who lived with arthritis, to explore how art can overcome disability. Also, emerging painter Rebecca Ivatts will give a talk about her collaboration with Pickering.
Year(s) Of Engagement Activity 2019
URL https://www.tate.org.uk/whats-on/tate-modern/tate-exchange/workshop/ideas-motion-borders-bodies-and-...