Construction of Switch Modules for CAR‑T Cell Treatment Using a Site-Specific Conjugation System

Chimeric antigen receptor T-cell (CAR-T cell) therapy has become a promising treatment option for B-cell hematological tumors. However, few optional target antigens and disease relapse due to loss of target antigens limit the broad clinical applicability of CAR-T cells. Here, we conjugated an antibo...

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Bibliographic Details
Published in:Bioconjugate chemistry 2024-05, Vol.35 (5), p.604-615
Main Authors: Abudureheman, Tuersunayi, Zhou, Hang, Yang, Li-Ting, Huang, Xiu-Song, Jing, Jun-Jie, Duan, Cai-Wen, Chen, Kai-Ming
Format: Article
Language:English
Subjects:
Animals
Antigens
Antigens, CD19 - immunology
Aptamers
CD19 antigen
CD4 antigen
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Chimeric antigen receptors
Conjugation
Cytotoxicity
ErbB-2 protein
Fusion protein
Health services
Humans
Immunotherapy, Adoptive - methods
Lymphocytes
Lymphocytes B
Lymphocytes T
Mice
Modules
Receptor, ErbB-2 - immunology
Receptors, Chimeric Antigen - immunology
Safety
Tumor cells
Tumors
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Summary:Chimeric antigen receptor T-cell (CAR-T cell) therapy has become a promising treatment option for B-cell hematological tumors. However, few optional target antigens and disease relapse due to loss of target antigens limit the broad clinical applicability of CAR-T cells. Here, we conjugated an antibody (Ab) fusion protein, consisting of an Ab domain and a SpyCatcher domain, with the FITC-SpyTag (FITC-ST) peptide to form a bispecific safety switch module using a site-specific conjugation system. We applied the safety switch module to target CD19, PDL1, or Her2-expressing tumor cells by constructing FMC63 (anti-CD19), antiPDL1, or ZHER (anti-Her2)-FITC-ST, respectively. Those switch modules significantly improved the cytotoxic effects of anti-FITC CAR-T cells on tumor cells. Additionally, we obtained the purified CD8+ T cells by optimizing a shorter version of the CD8-binding aptamer to generate anti-FITC CD8-CAR-T cells, which combined with the CD4-FITC-ST switch module (anti-CD4) to eliminate the CD4-positive tumor cells in vitro and in vivo. Overall, we established a novel safety switch module by site-specific conjugation to enhance the antitumor function of universal CAR-T cells, thereby expanding the application scope of CAR-T therapy and improving its safety and efficacy.
ISSN:1043-1802
1520-4812
1520-4812
DOI:10.1021/acs.bioconjchem.4c00050