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Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy
Despite over 20 years of clinical use, IL-2 has not fulfilled expectations as a safe and effective form of tumour immunotherapy. Expression of the high affinity IL-2Rα chain on regulatory T cells mitigates the anti-tumour immune response and its expression on vascular endothelium is responsible for...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036003/ https://www.ncbi.nlm.nih.gov/pubmed/27650575 http://dx.doi.org/10.1038/ncomms12878 |
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author | Ghasemi, Reza Lazear, Eric Wang, Xiaoli Arefanian, Saeed Zheleznyak, Alexander Carreno, Beatriz M. Higashikubo, Ryuji Gelman, Andrew E. Kreisel, Daniel Fremont, Daved H. Krupnick, Alexander Sasha |
author_facet | Ghasemi, Reza Lazear, Eric Wang, Xiaoli Arefanian, Saeed Zheleznyak, Alexander Carreno, Beatriz M. Higashikubo, Ryuji Gelman, Andrew E. Kreisel, Daniel Fremont, Daved H. Krupnick, Alexander Sasha |
author_sort | Ghasemi, Reza |
collection | PubMed |
description | Despite over 20 years of clinical use, IL-2 has not fulfilled expectations as a safe and effective form of tumour immunotherapy. Expression of the high affinity IL-2Rα chain on regulatory T cells mitigates the anti-tumour immune response and its expression on vascular endothelium is responsible for life threatening complications such as diffuse capillary leak and pulmonary oedema. Here we describe the development of a recombinant fusion protein comprised of a cowpox virus encoded NKG2D binding protein (OMCP) and a mutated form of IL-2 with poor affinity for IL-2Rα. This fusion protein (OMCP-mutIL-2) potently and selectively activates IL-2 signalling only on NKG2D-bearing cells, such as natural killer (NK) cells, without broadly activating IL-2Rα-bearing cells. OMCP-mutIL-2 provides superior tumour control in several mouse models of malignancy and is not limited by mouse strain-specific variability of NK function. In addition, OMCP-mutIL-2 lacks the toxicity and vascular complications associated with parental wild-type IL-2. |
format | Online Article Text |
id | pubmed-5036003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50360032016-10-04 Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy Ghasemi, Reza Lazear, Eric Wang, Xiaoli Arefanian, Saeed Zheleznyak, Alexander Carreno, Beatriz M. Higashikubo, Ryuji Gelman, Andrew E. Kreisel, Daniel Fremont, Daved H. Krupnick, Alexander Sasha Nat Commun Article Despite over 20 years of clinical use, IL-2 has not fulfilled expectations as a safe and effective form of tumour immunotherapy. Expression of the high affinity IL-2Rα chain on regulatory T cells mitigates the anti-tumour immune response and its expression on vascular endothelium is responsible for life threatening complications such as diffuse capillary leak and pulmonary oedema. Here we describe the development of a recombinant fusion protein comprised of a cowpox virus encoded NKG2D binding protein (OMCP) and a mutated form of IL-2 with poor affinity for IL-2Rα. This fusion protein (OMCP-mutIL-2) potently and selectively activates IL-2 signalling only on NKG2D-bearing cells, such as natural killer (NK) cells, without broadly activating IL-2Rα-bearing cells. OMCP-mutIL-2 provides superior tumour control in several mouse models of malignancy and is not limited by mouse strain-specific variability of NK function. In addition, OMCP-mutIL-2 lacks the toxicity and vascular complications associated with parental wild-type IL-2. Nature Publishing Group 2016-09-21 /pmc/articles/PMC5036003/ /pubmed/27650575 http://dx.doi.org/10.1038/ncomms12878 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Ghasemi, Reza Lazear, Eric Wang, Xiaoli Arefanian, Saeed Zheleznyak, Alexander Carreno, Beatriz M. Higashikubo, Ryuji Gelman, Andrew E. Kreisel, Daniel Fremont, Daved H. Krupnick, Alexander Sasha Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy |
title | Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy |
title_full | Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy |
title_fullStr | Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy |
title_full_unstemmed | Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy |
title_short | Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy |
title_sort | selective targeting of il-2 to nkg2d bearing cells for improved immunotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036003/ https://www.ncbi.nlm.nih.gov/pubmed/27650575 http://dx.doi.org/10.1038/ncomms12878 |
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