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

Xin Liu; Yixiang Xu; Wei Xiong; Bingnan Yin; Yuqian Huang; Junjun Chu; Changsheng Xing; Chen Qian; Yang Du; Tianhao Duan; Helen Y Wang; Ningyan Zhang; John S Yu; Zhiqiang An; Rongfu Wang

doi:10.1136/jitc-2021-004035

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

J Immunother Cancer. 2022 Mar;10(3):e004035. doi: 10.1136/jitc-2021-004035.

Authors

Xin Liu^{1

2

3}, Yixiang Xu⁴, Wei Xiong⁴, Bingnan Yin^{1

2}, Yuqian Huang^{2

5}, Junjun Chu^{1

2}, Changsheng Xing^{1

2}, Chen Qian^{1

2}, Yang Du^{1

2}, Tianhao Duan^{1

2}, Helen Y Wang^{1

2}, Ningyan Zhang⁴, John S Yu⁶, Zhiqiang An⁷, Rongfu Wang^{8

2

3}

Affiliations

¹ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
² Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA.
³ Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas, USA.
⁴ Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁵ Xiangya School of Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
⁶ Neurosurgical Oncology in the Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷ Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA Zhiqiang.An@uth.tmc.edu rongfuwa@usc.edu.
⁸ Keck School of Medicine, University of Southern California, Los Angeles, California, USA Zhiqiang.An@uth.tmc.edu rongfuwa@usc.edu.

Abstract

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.

Keywords: antibody affinity; antibody specificity; immunotherapy; receptors, chimeric antigen.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies
Antigens, Neoplasm
Cell Line, Tumor
HLA-A2 Antigen
Humans
Immunotherapy
Male
Melanoma* / therapy
Mice
Peptides
Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen*
Triple Negative Breast Neoplasms*

Substances

Antibodies
Antigens, Neoplasm
HLA-A2 Antigen
Peptides
Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding