Anti-ICOSL New Antigen Receptor Domains Inhibit T Cell Proliferation and Reduce the Development of Inflammation in the Collagen-Induced Mouse Model of Rheumatoid Arthritis.

Ronan O’Dwyer,Jiquan Zhang,Deborah Luxenberg,Alfredo Darmanin-Sheehan,Emma Cummins,Matthew Whitters,Marina Kovaleva,Miguel F Carvalho,Caroline J Barelle,John Steven,Kenneth Saunders

doi:10.1155/2018/4089459

Abstract

Lymphocyte costimulation plays a central role in immunology, inflammation, and immunotherapy. The inducible T cell costimulator (ICOS) is expressed on T cells following peptide: MHC engagement with CD28 costimulation. The interaction of ICOS with its sole ligand, the inducible T cell costimulatory ligand (ICOSL; also known as B7-related protein-1), triggers a number of key activities of T cells including differentiation and cytokine production. Suppression of T cell activation can be achieved by blocking this interaction and has been shown to be an effective means of ameliorating disease in models of autoimmunity. In this study, we isolated specific anti-ICOSL new antigen receptor domains from a synthetic phage display library and demonstrated their ability to block the ICOS/ICOSL interaction and inhibit T cell proliferation. Anti-mouse ICOSL domains, considered here as surrogates for the use of anti-human ICOSL domains in patient therapy, were tested for efficacy in a collagen-induced mouse model of rheumatoid arthritis where they significantly decreased the inflammation of joints and delayed and reduced overall disease progression and severity.

Highlights

Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory joint disease affecting 0.5–1% of the global population and results in cartilage and bone damage as well as disability [1]
inducible T cell costimulatory ligand (ICOSL)-specific domains were isolated from a synthetic VNAR library using phage display technology
In an attempt to bias the selection of VNARs from the synthetic library that showed both receptor-ligand blocking and species cross-reactivity, a cell-based blocking assay as well as a cross-reactive selection campaign were introduced at an early stage of screening, with parallel selection and screening for mouse only or human only targets included

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory joint disease affecting 0.5–1% of the global population and results in cartilage and bone damage as well as disability [1]. The root cause of this debilitating disease is unknown; increased understanding of the underlying pathology has resulted in the development of a number of effective drugs, typically with one of three modes of action: (i) neutralising the effects of inflammatory cytokines, (ii) T cell costimulation blockade, or (iii) B cell depletion. Approved biologic-based treatments for RA include TNFα antagonists. Approved therapeutics include an antibody Fab′ fragment conjugated to a polyethylene glycol (PEG) (certolizumab pegol or Cimzia) [5,6,7] and a fifth biologic, etanercept or Enbrel, which comprises of a fusion protein of TNFRII and the Fc region of human IgG1 [8]. Targeting TNFα has been validated through proven therapeutic efficacy

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Conclusion