Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease

Charles P Semba,1 Thomas R Gadek2 1Vascular and Interventional Radiology, Stanford University School of Medicine, Stanford, CA, USA; 2Ophthalma Logic Consulting, Park City, UT, USA Abstract: Dry eye disease (DED) is a multifactorial disorder of the ocular surface characterized by symptoms of disco...

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Autores principales: Semba CP, Gadek TR
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Publicado: Dove Medical Press 2016
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spelling oai:doaj.org-article:d5b2ba6793c64d6094fdf2f58bec45112021-12-02T00:23:17ZDevelopment of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease1177-5483https://doaj.org/article/d5b2ba6793c64d6094fdf2f58bec45112016-06-01T00:00:00Zhttps://www.dovepress.com/development-of-lifitegrast-a-novel-t-cell-inhibitor-for-the-treatment--peer-reviewed-article-OPTHhttps://doaj.org/toc/1177-5483Charles P Semba,1 Thomas R Gadek2 1Vascular and Interventional Radiology, Stanford University School of Medicine, Stanford, CA, USA; 2Ophthalma Logic Consulting, Park City, UT, USA Abstract: Dry eye disease (DED) is a multifactorial disorder of the ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation that affects an estimated 20 million patients in the US alone. DED is associated with localized inflammation of the ocular surface and periocular tissues leading to homing and activation of T cells, cytokine release, and development of hyperosmolar tears. This inflammatory milieu results in symptoms of eye dryness and discomfort. Homing of T cells to the ocular surface is influenced by the binding of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2), a cell surface adhesion protein, to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54), which is expressed on inflamed ocular/periocular epithelium and vascular endothelium. LFA-1/ICAM-1 binding within the immunologic synapse enables both T-cell activation and cytokine release. Lifitegrast is a novel T-cell integrin antagonist that is designed to mimic the binding epitope of ICAM-1. It serves as a molecular decoy to block the binding of LFA-1/ICAM-1 and inhibits the downstream inflammatory process. In vitro studies have demonstrated that lifitegrast inhibits T-cell adhesion to ICAM-1-expressing cells and inhibits secretion of pro-inflammatory cytokines including interferon gamma, tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6, all of which are known to be associated with DED. Lifitegrast has the potential to be the first pharmaceutical product approved in the US indicated for the treatment of both symptoms and signs of DED. Clinical trials involving over 2,500 adult DED patients have demonstrated that topically administered lifitegrast 5.0% ophthalmic solution can rapidly reduce the symptoms of eye dryness and decrease ocular surface staining with an acceptable long-term safety profile. The purpose of this review is to highlight the developmental story – from bench top to bedside – behind the scientific rationale, engineering, and clinical experience of lifitegrast for the treatment of DED. Keywords: LFA-1, ICAM-1, ocular surface disease, inflammation, drug developmentSemba CPGadek TRDove Medical Pressarticlelifitegrastdry eye diseaseintegrin antagonistLFA-1ICAM-1inflammationOphthalmologyRE1-994ENClinical Ophthalmology, Vol 2016, Iss Issue 1, Pp 1083-1094 (2016)
institution DOAJ
collection DOAJ
language EN
topic lifitegrast
dry eye disease
integrin antagonist
LFA-1
ICAM-1
inflammation
Ophthalmology
RE1-994
spellingShingle lifitegrast
dry eye disease
integrin antagonist
LFA-1
ICAM-1
inflammation
Ophthalmology
RE1-994
Semba CP
Gadek TR
Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease
description Charles P Semba,1 Thomas R Gadek2 1Vascular and Interventional Radiology, Stanford University School of Medicine, Stanford, CA, USA; 2Ophthalma Logic Consulting, Park City, UT, USA Abstract: Dry eye disease (DED) is a multifactorial disorder of the ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation that affects an estimated 20 million patients in the US alone. DED is associated with localized inflammation of the ocular surface and periocular tissues leading to homing and activation of T cells, cytokine release, and development of hyperosmolar tears. This inflammatory milieu results in symptoms of eye dryness and discomfort. Homing of T cells to the ocular surface is influenced by the binding of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2), a cell surface adhesion protein, to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54), which is expressed on inflamed ocular/periocular epithelium and vascular endothelium. LFA-1/ICAM-1 binding within the immunologic synapse enables both T-cell activation and cytokine release. Lifitegrast is a novel T-cell integrin antagonist that is designed to mimic the binding epitope of ICAM-1. It serves as a molecular decoy to block the binding of LFA-1/ICAM-1 and inhibits the downstream inflammatory process. In vitro studies have demonstrated that lifitegrast inhibits T-cell adhesion to ICAM-1-expressing cells and inhibits secretion of pro-inflammatory cytokines including interferon gamma, tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6, all of which are known to be associated with DED. Lifitegrast has the potential to be the first pharmaceutical product approved in the US indicated for the treatment of both symptoms and signs of DED. Clinical trials involving over 2,500 adult DED patients have demonstrated that topically administered lifitegrast 5.0% ophthalmic solution can rapidly reduce the symptoms of eye dryness and decrease ocular surface staining with an acceptable long-term safety profile. The purpose of this review is to highlight the developmental story – from bench top to bedside – behind the scientific rationale, engineering, and clinical experience of lifitegrast for the treatment of DED. Keywords: LFA-1, ICAM-1, ocular surface disease, inflammation, drug development
format article
author Semba CP
Gadek TR
author_facet Semba CP
Gadek TR
author_sort Semba CP
title Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease
title_short Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease
title_full Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease
title_fullStr Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease
title_full_unstemmed Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease
title_sort development of lifitegrast: a novel t-cell inhibitor for the treatment of dry eye disease
publisher Dove Medical Press
publishDate 2016
url https://doaj.org/article/d5b2ba6793c64d6094fdf2f58bec4511
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