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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/1/19 |
| _version_ | 1797543624419835904 |
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| author | Bradford A. Youngblood John Leung Rustom Falahati Jason Williams Julia Schanin Emily C. Brock Bhupinder Singh Alan T. Chang Jeremy A. O’Sullivan Robert P. Schleimer Nenad Tomasevic Christopher R. Bebbington Bruce S. Bochner |
| author_facet | Bradford A. Youngblood John Leung Rustom Falahati Jason Williams Julia Schanin Emily C. Brock Bhupinder Singh Alan T. Chang Jeremy A. O’Sullivan Robert P. Schleimer Nenad Tomasevic Christopher R. Bebbington Bruce S. Bochner |
| author_sort | Bradford A. Youngblood |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T13:48:16Z |
| format | Article |
| id | doaj.art-3a9df22d546640558f4cd6fc839dc654 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T13:48:16Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3a9df22d546640558f4cd6fc839dc6542023-11-21T02:24:30ZengMDPI AGCells2073-44092020-12-011011910.3390/cells10010019Discovery, Function, and Therapeutic Targeting of Siglec-8Bradford A. Youngblood0John Leung1Rustom Falahati2Jason Williams3Julia Schanin4Emily C. Brock5Bhupinder Singh6Alan T. Chang7Jeremy A. O’Sullivan8Robert P. Schleimer9Nenad Tomasevic10Christopher R. Bebbington11Bruce S. Bochner12Allakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USADivision of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAAllakos Inc., Redwood City, CA 94065, USAAllakos Inc., Redwood City, CA 94065, USADivision of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USASiglecs (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.https://www.mdpi.com/2073-4409/10/1/19Siglec-8mast cellseosinophilsmonoclonal antibodiesglycan ligandsAK002 |
| spellingShingle | Bradford A. Youngblood John Leung Rustom Falahati Jason Williams Julia Schanin Emily C. Brock Bhupinder Singh Alan T. Chang Jeremy A. O’Sullivan Robert P. Schleimer Nenad Tomasevic Christopher R. Bebbington Bruce S. Bochner Discovery, Function, and Therapeutic Targeting of Siglec-8 Cells Siglec-8 mast cells eosinophils monoclonal antibodies glycan ligands AK002 |
| 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 | Siglec-8 mast cells eosinophils monoclonal antibodies glycan ligands AK002 |
| url | https://www.mdpi.com/2073-4409/10/1/19 |
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