Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784677542449381376 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8961179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT liuxin developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT xuyixiang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT xiongwei developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT yinbingnan developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT huangyuqian developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT chujunjun developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT xingchangsheng developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT qianchen developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT duyang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT duantianhao developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT wangheleny developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT zhangningyan developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT yujohns developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT anzhiqiang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT wangrongfu developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy |