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Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response
The natural killer group 2 member D (NKG2D) receptor is a C-type lectin-like activating receptor mainly expressed by cytotoxic immune cells including NK, CD8(+) T, γδ T and NKT cells and in some pathological conditions by a subset of CD4(+) T cells. It binds a variety of ligands (NKG2DL) whose expre...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781768/ https://www.ncbi.nlm.nih.gov/pubmed/33457075 http://dx.doi.org/10.1080/2162402X.2020.1854529 |
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author | Raynaud, Adeline Desrumeaux, Klervi Vidard, Laurent Termine, Elise Baty, Daniel Chames, Patrick Vigne, Emmanuelle Kerfelec, Brigitte |
author_facet | Raynaud, Adeline Desrumeaux, Klervi Vidard, Laurent Termine, Elise Baty, Daniel Chames, Patrick Vigne, Emmanuelle Kerfelec, Brigitte |
author_sort | Raynaud, Adeline |
collection | PubMed |
description | The natural killer group 2 member D (NKG2D) receptor is a C-type lectin-like activating receptor mainly expressed by cytotoxic immune cells including NK, CD8(+) T, γδ T and NKT cells and in some pathological conditions by a subset of CD4(+) T cells. It binds a variety of ligands (NKG2DL) whose expressions is finely regulated by stress-related conditions. The NKG2DL/NKG2D axis plays a central and complex role in the regulation of immune responses against diverse cellular threats such as oncogene-mediated transformations or infections. We generated a panel of seven highly specific anti-human NKG2D single-domain antibodies targeting various epitopes. These single-domain antibodies were integrated into bivalent and bispecific antibodies using a versatile plug-and-play Fab-like format. Depending on the context, these Fab-like antibodies exhibited activating or inhibitory effects on the immune response mediated by the NKG2DL/NKG2D axis. In solution, the bivalent anti-NKG2D antibodies that compete with NKG2DL potently blocked the activation of NK cells seeded on immobilized MICA, thus constituting antagonizing candidates. Bispecific anti-NKG2DxHER2 antibodies that concomitantly engage HER2 on tumor cells and NKG2D on NK cells elicited cytotoxicity of unstimulated NK in a tumor-specific manner, regardless of their apparent affinities and epitopes. Importantly, the bispecific antibodies that do not compete with ligands binding retained their full cytotoxic activity in the presence of ligands, a valuable property to circumvent immunosuppressive effects induced by soluble ligands in the microenvironment. |
format | Online Article Text |
id | pubmed-7781768 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-77817682021-01-14 Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response Raynaud, Adeline Desrumeaux, Klervi Vidard, Laurent Termine, Elise Baty, Daniel Chames, Patrick Vigne, Emmanuelle Kerfelec, Brigitte Oncoimmunology Original Research The natural killer group 2 member D (NKG2D) receptor is a C-type lectin-like activating receptor mainly expressed by cytotoxic immune cells including NK, CD8(+) T, γδ T and NKT cells and in some pathological conditions by a subset of CD4(+) T cells. It binds a variety of ligands (NKG2DL) whose expressions is finely regulated by stress-related conditions. The NKG2DL/NKG2D axis plays a central and complex role in the regulation of immune responses against diverse cellular threats such as oncogene-mediated transformations or infections. We generated a panel of seven highly specific anti-human NKG2D single-domain antibodies targeting various epitopes. These single-domain antibodies were integrated into bivalent and bispecific antibodies using a versatile plug-and-play Fab-like format. Depending on the context, these Fab-like antibodies exhibited activating or inhibitory effects on the immune response mediated by the NKG2DL/NKG2D axis. In solution, the bivalent anti-NKG2D antibodies that compete with NKG2DL potently blocked the activation of NK cells seeded on immobilized MICA, thus constituting antagonizing candidates. Bispecific anti-NKG2DxHER2 antibodies that concomitantly engage HER2 on tumor cells and NKG2D on NK cells elicited cytotoxicity of unstimulated NK in a tumor-specific manner, regardless of their apparent affinities and epitopes. Importantly, the bispecific antibodies that do not compete with ligands binding retained their full cytotoxic activity in the presence of ligands, a valuable property to circumvent immunosuppressive effects induced by soluble ligands in the microenvironment. Taylor & Francis 2020-12-29 /pmc/articles/PMC7781768/ /pubmed/33457075 http://dx.doi.org/10.1080/2162402X.2020.1854529 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Raynaud, Adeline Desrumeaux, Klervi Vidard, Laurent Termine, Elise Baty, Daniel Chames, Patrick Vigne, Emmanuelle Kerfelec, Brigitte Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response |
title | Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response |
title_full | Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response |
title_fullStr | Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response |
title_full_unstemmed | Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response |
title_short | Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response |
title_sort | anti-nkg2d single domain-based antibodies for the modulation of anti-tumor immune response |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781768/ https://www.ncbi.nlm.nih.gov/pubmed/33457075 http://dx.doi.org/10.1080/2162402X.2020.1854529 |
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