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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-03-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004035.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823863297269563392 |
|---|---|
| author | Xin Liu Yang Du Ningyan Zhang Zhiqiang An Wei Xiong Yixiang Xu Bingnan Yin Yuqian Huang Junjun Chu Changsheng Xing Chen Qian Tianhao Duan Helen Y Wang John S. Yu Rongfu Wang |
| author_facet | Xin Liu Yang Du Ningyan Zhang Zhiqiang An Wei Xiong Yixiang Xu Bingnan Yin Yuqian Huang Junjun Chu Changsheng Xing Chen Qian Tianhao Duan Helen Y Wang John S. Yu Rongfu Wang |
| author_sort | Xin Liu |
| collection | DOAJ |
| 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-1157-165 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 | Article |
| id | doaj-art-b9b7739a886e47e9a7dc197a9738abbe |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b9b7739a886e47e9a7dc197a9738abbe2025-02-09T12:10:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004035Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapyXin Liu0Yang Du1Ningyan Zhang2Zhiqiang An3Wei Xiong4Yixiang Xu5Bingnan Yin6Yuqian Huang7Junjun Chu8Changsheng Xing9Chen Qian10Tianhao Duan11Helen Y Wang12John S. Yu13Rongfu Wang144 China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China2 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, China2 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USAUniversity Hospitals Cleveland Medical Center, Cleveland, Ohio, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USACenter for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USANeurosurgical Oncology in the Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USAKeck School of Medicine, University of Southern California, Los Angeles, California, USABackground 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-1157-165 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.https://jitc.bmj.com/content/10/3/e004035.full |
| spellingShingle | Xin Liu Yang Du Ningyan Zhang Zhiqiang An Wei Xiong Yixiang Xu Bingnan Yin Yuqian Huang Junjun Chu Changsheng Xing Chen Qian Tianhao Duan Helen Y Wang John S. Yu Rongfu Wang Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy Journal for ImmunoTherapy of Cancer |
| 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 |
| url | https://jitc.bmj.com/content/10/3/e004035.full |
| work_keys_str_mv | AT xinliu developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT yangdu developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT ningyanzhang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT zhiqiangan developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT weixiong developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT yixiangxu developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT bingnanyin developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT yuqianhuang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT junjunchu developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT changshengxing developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT chenqian developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT tianhaoduan developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT helenywang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT johnsyu developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy AT rongfuwang developmentofatcrlikeantibodyandchimericantigenreceptoragainstnyeso1hlaa2forcancerimmunotherapy |