Objectives Controlled immune responses rely on integrated crosstalk between cells and their microenvironment. We investigated whether targeting proinflammatory signals from the extracellular matrix that persist during pathological inflammation provides a viable strategy to treat rheumatoid arthritis (RA).
Methods Monoclonal antibodies recognising the fibrinogen-like globe (FBG) of tenascin-C were generated by phage display. Clones that neutralised FBG activation of toll-like receptor 4 (TLR4), without impacting pathogenic TLR4 activation, were epitope mapped by crystallography. Antibodies stained synovial biopsies of patients at different stages of RA development. Antibody efficacy in preventing RA synovial cell cytokine release, and in modulating collagen-induced arthritis in rats, was assessed.
Results Tenascin-C is expressed early in the development of RA, even before disease diagnosis, with higher levels in the joints of people with synovitis who eventually developed RA than in people whose synovitis spontaneously resolved. Anti-FBG antibodies inhibited cytokine release by RA synovial cells and prevented disease progression and tissue destruction during collagen-induced arthritis.
Conclusions Early changes in the synovial microenvironment contribute to RA progression; blocking proinflammatory signals from the matrix can ameliorate experimental arthritis. These data highlight a new drug class that could offer early, disease-specific immune modulation in RA, without engendering global immune suppression.
- extracellular matrix
- monoclonal antibodies
- rheumatoid arthritis
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Handling editor Josef S Smolen
Contributors All authors made substantial contributions to the conception or design of this study, or to the generation, analysis and/or interpretation of data, and agree to be accountable for the integrity of the work herein. All authors reviewed the manuscript and approved the submitted version. No person who fulfils the criteria for authorship has been excluded as an author.
Funding This work was supported by grants from Nascient Ltd (SRA, AJC, FC and JLM), Arthritis Research UK Fellowships (20003: AS and KSM) and (18547: AF), and an Arthritis Research UK programme grant (19791: CDB). This work was also supported by the Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (20298). BDM was supported by the SGC and by the Kennedy Trust for Rheumatology Research. This report includes independent research supported by the National Institute for Health Research/Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust.
Disclaimer The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. KR, IS, AF and CDB were supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre.
Competing interests MRD, PS, KP, AK-V and JLM are employed by IONTAS. EC and PH are employed by Nascient. KSM is a founder and director of Nascient Ltd. AF has received research funding from Roche and Pfizer. KR has received research funding from Abbvie and Pfizer and honoraria/consultancy fees from Lilly, BMS, UCB, Pfizer, Janssen and Roche Chugai. JLM is currently funded by Roche Holding AG. BDM was partly supported by the SGC, which is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute (OGI-055), Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck KGaA, Darmstadt, Germany, MSD, Novartis Pharma AG, Ontario Ministry of Research, Innovation and Science (MRIS), Pfizer, Sao Paulo Research Foundation – FAPESP, Takeda and Wellcome (106169/ZZ14/Z).
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional unpublished data for this study.
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