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Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy

BACKGROUND: The current therapeutic antibodies and chimeric antigen receptor (CAR) T cells are capable of recognizing surface antigens, but not of intracellular proteins, thus limiting the target coverage for drug development. To mimic the feature of T-cell receptor (TCR) that recognizes the complex...

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Autores principales: Liu, Xin, Xu, Yixiang, Xiong, Wei, Yin, Bingnan, Huang, Yuqian, Chu, Junjun, Xing, Changsheng, Qian, Chen, Du, Yang, Duan, Tianhao, Wang, Helen Y, Zhang, Ningyan, Yu, John S., An, Zhiqiang, Wang, Rongfu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961179/
https://www.ncbi.nlm.nih.gov/pubmed/35338087
http://dx.doi.org/10.1136/jitc-2021-004035
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author Liu, Xin
Xu, Yixiang
Xiong, Wei
Yin, Bingnan
Huang, Yuqian
Chu, Junjun
Xing, Changsheng
Qian, Chen
Du, Yang
Duan, Tianhao
Wang, Helen Y
Zhang, Ningyan
Yu, John S.
An, Zhiqiang
Wang, Rongfu
author_facet Liu, Xin
Xu, Yixiang
Xiong, Wei
Yin, Bingnan
Huang, Yuqian
Chu, Junjun
Xing, Changsheng
Qian, Chen
Du, Yang
Duan, Tianhao
Wang, Helen Y
Zhang, Ningyan
Yu, John S.
An, Zhiqiang
Wang, Rongfu
author_sort Liu, Xin
collection PubMed
description BACKGROUND: The current therapeutic antibodies and chimeric antigen receptor (CAR) T cells are capable of recognizing surface antigens, but not of intracellular proteins, thus limiting the target coverage for drug development. To mimic the feature of T-cell receptor (TCR) that recognizes the complex of major histocompatibility class I and peptide on the cell surface derived from the processed intracellular antigen, we used NY-ESO-1, a cancer-testis antigen, to develop a TCR-like fully human IgG1 antibody and its derivative, CAR-T cells, for cancer immunotherapy. METHODS: Human single-chain variable antibody fragment (scFv) phage library (~10(∧11)) was screened against HLA-A2/NY-ESO-1 (peptide 157–165) complex to obtain target-specific antibodies. The specificity and affinity of those antibodies were characterized by flow cytometry, ELISA, biolayer interferometry, and confocal imaging. The biological functions of CAR-T cells were evaluated against target tumor cells in vitro. In vivo antitumor activity was investigated in a triple-negative breast cancer (TNBC) model and primary melanoma tumor model in immunocompromised mice. RESULTS: Monoclonal antibody 2D2 identified from phage-displayed library specifically bound to NY-ESO-1(157-165) in the context of human leukocyte antigen HLA-A*02:01 but not to non-A2 or NY-ESO-1 negative cells. The second-generation CAR-T cells engineered from 2D2 specifically recognized and eliminated A2+/NY-ESO-1+tumor cells in vitro, inhibited tumor growth, and prolonged the overall survival of mice in TNBC and primary melanoma tumor model in vivo. CONCLUSIONS: This study showed the specificity of the antibody identified from human scFv phage library and demonstrated the potential antitumor activity by TCR-like CAR-T cells both in vitro and in vivo, warranting further preclinical and clinical evaluation of the TCR-like antibody in patients. The generation of TCR-like antibody and its CAR-T cells provides the state-of-the-art platform and proof-of-concept validation to broaden the scope of target antigen recognition and sheds light on the development of novel therapeutics for cancer immunotherapy.
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spelling pubmed-89611792022-04-11 Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy Liu, Xin Xu, Yixiang Xiong, Wei Yin, Bingnan Huang, Yuqian Chu, Junjun Xing, Changsheng Qian, Chen Du, Yang Duan, Tianhao Wang, Helen Y Zhang, Ningyan Yu, John S. An, Zhiqiang Wang, Rongfu J Immunother Cancer Immune Cell Therapies and Immune Cell Engineering BACKGROUND: The current therapeutic antibodies and chimeric antigen receptor (CAR) T cells are capable of recognizing surface antigens, but not of intracellular proteins, thus limiting the target coverage for drug development. To mimic the feature of T-cell receptor (TCR) that recognizes the complex of major histocompatibility class I and peptide on the cell surface derived from the processed intracellular antigen, we used NY-ESO-1, a cancer-testis antigen, to develop a TCR-like fully human IgG1 antibody and its derivative, CAR-T cells, for cancer immunotherapy. METHODS: Human single-chain variable antibody fragment (scFv) phage library (~10(∧11)) was screened against HLA-A2/NY-ESO-1 (peptide 157–165) complex to obtain target-specific antibodies. The specificity and affinity of those antibodies were characterized by flow cytometry, ELISA, biolayer interferometry, and confocal imaging. The biological functions of CAR-T cells were evaluated against target tumor cells in vitro. In vivo antitumor activity was investigated in a triple-negative breast cancer (TNBC) model and primary melanoma tumor model in immunocompromised mice. RESULTS: Monoclonal antibody 2D2 identified from phage-displayed library specifically bound to NY-ESO-1(157-165) in the context of human leukocyte antigen HLA-A*02:01 but not to non-A2 or NY-ESO-1 negative cells. The second-generation CAR-T cells engineered from 2D2 specifically recognized and eliminated A2+/NY-ESO-1+tumor cells in vitro, inhibited tumor growth, and prolonged the overall survival of mice in TNBC and primary melanoma tumor model in vivo. CONCLUSIONS: This study showed the specificity of the antibody identified from human scFv phage library and demonstrated the potential antitumor activity by TCR-like CAR-T cells both in vitro and in vivo, warranting further preclinical and clinical evaluation of the TCR-like antibody in patients. The generation of TCR-like antibody and its CAR-T cells provides the state-of-the-art platform and proof-of-concept validation to broaden the scope of target antigen recognition and sheds light on the development of novel therapeutics for cancer immunotherapy. BMJ Publishing Group 2022-03-25 /pmc/articles/PMC8961179/ /pubmed/35338087 http://dx.doi.org/10.1136/jitc-2021-004035 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Immune Cell Therapies and Immune Cell Engineering
Liu, Xin
Xu, Yixiang
Xiong, Wei
Yin, Bingnan
Huang, Yuqian
Chu, Junjun
Xing, Changsheng
Qian, Chen
Du, Yang
Duan, Tianhao
Wang, Helen Y
Zhang, Ningyan
Yu, John S.
An, Zhiqiang
Wang, Rongfu
Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy
title Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy
title_full Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy
title_fullStr Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy
title_full_unstemmed Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy
title_short Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy
title_sort development of a tcr-like antibody and chimeric antigen receptor against ny-eso-1/hla-a2 for cancer immunotherapy
topic Immune Cell Therapies and Immune Cell Engineering
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961179/
https://www.ncbi.nlm.nih.gov/pubmed/35338087
http://dx.doi.org/10.1136/jitc-2021-004035
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