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Bispecific CD20-CD19-CAR and application thereof
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A scfv2, chimeric antigen receptor technology, applied in DNA/RNA fragments, recombinant DNA technology, specific peptides, etc., can solve the problems of easy recurrence, reduce recurrence rate, and reduce the immunogenicity of bispecific CAR-T
Active Publication Date: 2019-04-05
PERSONGEN BIOMEDICINESUZHOUCO
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However, the disadvantage of single-target therapy is that tumor cells are prone to relapse after down-regulating antigen expression. Therefore, the construction of bispecific CAR-T that can simultaneously target dual targets can reduce the escape of tumor cells and reduce the recurrence rate. In addition, if The antibody sequences in the bispecific CAR are all humanized sequences, which can further reduce the immunogenicity of the bispecific CAR-T
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[0176] The inventors used Fc antibody to detect the CAR positive rate of bispecific CD20-CD19-CAR-T cells, and the results were as follows figure 2 As shown, the positive rate of humanized CD19-CAR-T was 29.10%.
Embodiment 2
[0178] Cytotoxicity of humanized bispecific CD20-CD19-CAR-T cells against K562 cells overexpressing CD20 or CD19
[0179] The present inventors constructed K562 (K562-CD20) cells overexpressing CD20, K562 (K562-CD19) cells overexpressing CD19, K562 cells (K562-CD19-CD20) simultaneously expressing CD20 and CD19 as target cells, and evaluated the The in vitro killing function of specific CD20-CD19-CAR-T cells, the effect-to-target ratios were 0.5:1, 1:1, 5:1, and 10:1, respectively. K562 cells were negative target cells, and T cells were control effector cells.
[0180] The result is as image 3 As shown, compared with control T cells, CD20-CD19-CAR-T cells have significant specific killing effect on K562-CD20 cells, K562-CD19 cells, and K562-CD19-CD20 cells, while K562 cells ( CD20 negative) does not have specific killing, indicating that the constructed humanized bispecific CD20-CD19-CAR-T cells can produce specific cytotoxicity to K562 cells overexpressing CD20 or CD19 in v...
Embodiment 3
[0182] Cytotoxicity of humanized bispecific CD20-CD19-CAR-T cells against B-lymphoblastic leukemia cells (Nalm-6) and lymphoma cells (Raji) naturally expressing CD20 and CD19
[0183] The inventors used the constructed humanized bispecific CD20-CD19-CAR-T cells to conduct in vitro killing experiments on B lymphocytic leukemia (Nalm-6) and lymphoma (Raji) cells, and the effect-to-target ratios were 0.5:1, 1:1, 5:1, 10:1. T cells were control effector cells.
[0184] The result is as Figure 4 As shown, compared with the control T cells, CD20-CD19-CAR-T cells have a significant specific killing effect on Raji and Nalm-6, indicating that the humanized bispecific CD20-CD19-CAR-T we constructed The cells had significant cytotoxicity to both CD20-positive and CD19-positive Raji and Nalm-6 cells in vitro.
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Abstract
The invention provides building and application of a novel bispecific CD20-CD19-CAR carrier based on humanized CD20 antibodies and CD19 antibodies. Concretely, the invention provides an chimeric antigen receptor CAR; the CAR contains scFv targeting CD19 and scFv targeting CD20; the scFv targeting CD19 comprises a heavy chain variable region shown as SEQ ID No.:8 and a light-chain variable region shown as SEQ ID No.:9; the scFv targeting SD20 comprises a heavy chain variable region shown as SEQ ID No.:10 and a light chain variable region shown as SEQ ID No.:11. The CAR-T cells of the bispecificCD20-CD19-CAR carrier built by the method provided by the invention show very good in vitro killing effects.
Description
technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to the construction and application of a novel bispecific CD20-CD19-CAR carrier based on a humanized CD20 antibody and a CD19 antibody. Background technique [0002] In recent years, chimeric antigen receptorT cell (CAR-T) therapy, as a powerful new adoptive immunotherapy technology, has shown very effective therapeutic effects and has been used to treat a variety of solid and blood cancers, especially for CD19-CAR-T therapy for B-cell lymphocytic leukemia and lymphoma has shown very good therapeutic effects in clinical practice. In addition, CD20 is also an ideal target for B-cell tumors. However, the disadvantage of single-target therapy is that tumor cells are prone to relapse after down-regulating antigen expression. Therefore, the construction of bispecific CAR-T that can simultaneously target dual targets can reduce the escape of tumor cells and reduce the recurrence ...
Claims
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