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Discovery, Function, and Therapeutic Targeting of Siglec-8

Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cel...

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Autores principales: Youngblood, Bradford A., Leung, John, Falahati, Rustom, Williams, Jason, Schanin, Julia, Brock, Emily C., Singh, Bhupinder, Chang, Alan T., O’Sullivan, Jeremy A., Schleimer, Robert P., Tomasevic, Nenad, Bebbington, Christopher R., Bochner, Bruce S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823959/
https://www.ncbi.nlm.nih.gov/pubmed/33374255
http://dx.doi.org/10.3390/cells10010019
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author Youngblood, Bradford A.
Leung, John
Falahati, Rustom
Williams, Jason
Schanin, Julia
Brock, Emily C.
Singh, Bhupinder
Chang, Alan T.
O’Sullivan, Jeremy A.
Schleimer, Robert P.
Tomasevic, Nenad
Bebbington, Christopher R.
Bochner, Bruce S.
author_facet Youngblood, Bradford A.
Leung, John
Falahati, Rustom
Williams, Jason
Schanin, Julia
Brock, Emily C.
Singh, Bhupinder
Chang, Alan T.
O’Sullivan, Jeremy A.
Schleimer, Robert P.
Tomasevic, Nenad
Bebbington, Christopher R.
Bochner, Bruce S.
author_sort Youngblood, Bradford A.
collection PubMed
description Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.
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spelling pubmed-78239592021-01-24 Discovery, Function, and Therapeutic Targeting of Siglec-8 Youngblood, Bradford A. Leung, John Falahati, Rustom Williams, Jason Schanin, Julia Brock, Emily C. Singh, Bhupinder Chang, Alan T. O’Sullivan, Jeremy A. Schleimer, Robert P. Tomasevic, Nenad Bebbington, Christopher R. Bochner, Bruce S. Cells Review Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases. MDPI 2020-12-24 /pmc/articles/PMC7823959/ /pubmed/33374255 http://dx.doi.org/10.3390/cells10010019 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Youngblood, Bradford A.
Leung, John
Falahati, Rustom
Williams, Jason
Schanin, Julia
Brock, Emily C.
Singh, Bhupinder
Chang, Alan T.
O’Sullivan, Jeremy A.
Schleimer, Robert P.
Tomasevic, Nenad
Bebbington, Christopher R.
Bochner, Bruce S.
Discovery, Function, and Therapeutic Targeting of Siglec-8
title Discovery, Function, and Therapeutic Targeting of Siglec-8
title_full Discovery, Function, and Therapeutic Targeting of Siglec-8
title_fullStr Discovery, Function, and Therapeutic Targeting of Siglec-8
title_full_unstemmed Discovery, Function, and Therapeutic Targeting of Siglec-8
title_short Discovery, Function, and Therapeutic Targeting of Siglec-8
title_sort discovery, function, and therapeutic targeting of siglec-8
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823959/
https://www.ncbi.nlm.nih.gov/pubmed/33374255
http://dx.doi.org/10.3390/cells10010019
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