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A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy
BACKGROUND: Strategies to reinvigorate exhausted T cells have achieved great efficacy in certain subpopulations of tumor patients. Blocking the antibodies that target programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 induces durable responses in Hodgkin’s lymphom...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990255/ https://www.ncbi.nlm.nih.gov/pubmed/33928230 http://dx.doi.org/10.1093/abt/tbaa022 |
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author | Kuang, Zhihui Li, Li Zhang, Pan Chen, Bingliang Wu, Min Ni, Haiqing Yi, Shuai Zou, Jia Liu, Junjian |
author_facet | Kuang, Zhihui Li, Li Zhang, Pan Chen, Bingliang Wu, Min Ni, Haiqing Yi, Shuai Zou, Jia Liu, Junjian |
author_sort | Kuang, Zhihui |
collection | PubMed |
description | BACKGROUND: Strategies to reinvigorate exhausted T cells have achieved great efficacy in certain subpopulations of tumor patients. Blocking the antibodies that target programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 induces durable responses in Hodgkin’s lymphoma, melanoma, renal and lung cancers. T cell immunoglobulin mucin-3 (TIM-3) is another well-defined inhibitory receptor that is expressed in terminally differentiated Th1/Tc1 cells, which produces interferon gamma and cytotoxic molecules. It is also significantly expressed on forkhead box P3+ regulatory T cells and innate immune cells such as dendritic cells and macrophages. METHODS: By immunizing BALB/c mice with recombinant TIM-3 and screening of 20 000 hybridoma clones, we selected a monoclonal TIM-3-blocking antibody (IBI104), which shows great efficacy in vitro and in vivo. RESULTS: IBI104 blocks phosphatidylserine interaction with TIM-3 but does not interfere with the interaction of TIM-3 with galectin-9 in ELISA assays. However, in vitro administration of IBI104 induces the potent internalization of TIM-3 in activated T cells to the extent that it will shut down the entire TIM-3 mediated signaling regardless of the ligands. IBI104 shows potent anti-tumor efficacy when combined with anti-PD1 in vivo. CONCLUSIONS: Our results suggest that IBI104 is a promising blocking antibody for TIM-3-mediated suppressive signaling and can serve as effective cancer immunotherapy, especially in combination with anti-PD1. |
format | Online Article Text |
id | pubmed-7990255 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-79902552021-04-28 A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy Kuang, Zhihui Li, Li Zhang, Pan Chen, Bingliang Wu, Min Ni, Haiqing Yi, Shuai Zou, Jia Liu, Junjian Antib Ther Research Article BACKGROUND: Strategies to reinvigorate exhausted T cells have achieved great efficacy in certain subpopulations of tumor patients. Blocking the antibodies that target programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 induces durable responses in Hodgkin’s lymphoma, melanoma, renal and lung cancers. T cell immunoglobulin mucin-3 (TIM-3) is another well-defined inhibitory receptor that is expressed in terminally differentiated Th1/Tc1 cells, which produces interferon gamma and cytotoxic molecules. It is also significantly expressed on forkhead box P3+ regulatory T cells and innate immune cells such as dendritic cells and macrophages. METHODS: By immunizing BALB/c mice with recombinant TIM-3 and screening of 20 000 hybridoma clones, we selected a monoclonal TIM-3-blocking antibody (IBI104), which shows great efficacy in vitro and in vivo. RESULTS: IBI104 blocks phosphatidylserine interaction with TIM-3 but does not interfere with the interaction of TIM-3 with galectin-9 in ELISA assays. However, in vitro administration of IBI104 induces the potent internalization of TIM-3 in activated T cells to the extent that it will shut down the entire TIM-3 mediated signaling regardless of the ligands. IBI104 shows potent anti-tumor efficacy when combined with anti-PD1 in vivo. CONCLUSIONS: Our results suggest that IBI104 is a promising blocking antibody for TIM-3-mediated suppressive signaling and can serve as effective cancer immunotherapy, especially in combination with anti-PD1. Oxford University Press 2020-11-09 /pmc/articles/PMC7990255/ /pubmed/33928230 http://dx.doi.org/10.1093/abt/tbaa022 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Research Article Kuang, Zhihui Li, Li Zhang, Pan Chen, Bingliang Wu, Min Ni, Haiqing Yi, Shuai Zou, Jia Liu, Junjian A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy |
title | A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy |
title_full | A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy |
title_fullStr | A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy |
title_full_unstemmed | A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy |
title_short | A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy |
title_sort | novel antibody targeting tim-3 resulting in receptor internalization for cancer immunotherapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990255/ https://www.ncbi.nlm.nih.gov/pubmed/33928230 http://dx.doi.org/10.1093/abt/tbaa022 |
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