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Bidirectional activated costimulatory molecule acceptor and use thereof

A costimulatory signal, molecular technology, applied in the field of cell biology and immunology, which can solve the problems of lack of bystander function and inability to activate surrounding T cells

Pending Publication Date: 2019-07-05
SHANGHAI CELL THERAPY RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, no matter what kind of CAR-T cells, they can only provide stimulating signals to the modified T cells, lack the bystander function, and cannot activate surrounding T cells, resulting in a stronger cluster effect, causing a series of activation of T cell functions. cascade reaction

Method used

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  • Bidirectional activated costimulatory molecule acceptor and use thereof
  • Bidirectional activated costimulatory molecule acceptor and use thereof
  • Bidirectional activated costimulatory molecule acceptor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0336] Example 1-(1): 5 recombinant plasmids, pNB328-meso CAR G1, pNB328-meso G2 CAR, PS328b Construction of 137DCR1, PS328b 137DCR2 and PS328b 137DCR3

[0337] 1. Artificially synthesized 137DCR1 gene (SEQ ID NO:15), 137DCR2 gene (SEQ ID NO:16), 137DCR3 gene (SEQ ID NO:17), meso G1 CAR gene (SEQ ID NO:24) and meso G2 CAR gene (SEQ ID NO: 26), the schematic diagram of its structure is as follows: Figure 1A-1 , Figure 1B-1 , Figure 1 C-1, Figure 1E-1 and Figure 1F-1 shown. The 5 synthesized genes were respectively loaded into the PNB328 vector and the PS328b vector, between the EcoRI and SalI restriction sites,

[0338] The pNB328 vector contains elements such as the EF1α promoter and the PB transposon. For the construction of the pNB328 vector, please refer to Example 2 of WO2017054647A1. PS328b is an artificially synthesized sequence, synthesized by Shanghai Jierui Bioengineering Co., Ltd., and the sequence is shown in SEQ ID NO:27.

[0339] The constructed reco...

Embodiment 1-

[0344] Example 1-(3): 5 kinds of recombinant plasmids, namely pNB328-EGFR G1 CAR, pNB328-EGFR G2 CAR, PS328b Construction of 40DCR1, PS328b 40DCR2 and PS328b 40DCR3

[0345] 1. Artificially synthesized 40DCR1 gene (SEQ ID NO:65), 40DCR2 gene (SEQ ID NO:66), 40DCR3 gene (SEQ ID NO:67), EGFR G1CAR gene (SEQ ID NO:74) and EGFR G2 CAR gene (SEQ ID NO: 75), its structural schematic diagram is respectively as follows Figure 1A-3 , Figure 1B-3 , Figure 1C-3 , Figure 1F-3 and Figure 1D-3 shown. The 5 synthetic genes were respectively loaded into the pNB328 vector and the PS328b vector, between the EcoRI and SalI restriction sites,

[0346] The pNB328 vector contains elements such as the EF1α promoter and the PB transposon. For the construction of the pNB328 vector, please refer to Example 2 of WO2017054647A1. PS328b is an artificially synthesized sequence, synthesized by Shanghai Jierui Bioengineering Co., Ltd., and the sequence is shown in SEQ ID NO:27.

[0347] The c...

Embodiment 2-

[0348] Example 2-(1): Nine kinds of chimeric antigen receptor modified T cells, namely recombinant cells meso G1CAR, meso G2 CAR, meso G1 CAR-137DCR1, meso G1 CAR-137DCR2, meso G1 CAR-137DCR3, 137DCR1, Construction and Identification of 137DCR2, 137DCR3 and Mock T

[0349] (1) Construction of 9 kinds of recombinant cells

[0350] Peripheral blood mononuclear cells (PBMCs) were adhered and cultured for 2-4 hours, and the unattached suspension cells were naive T cells. Collect the suspended cells into a 15ml centrifuge tube, centrifuge at 1200rmp for 3min, discard the supernatant; add normal saline, centrifuge at 1200rmp for 3min, discard the normal saline, and repeat the steps of "adding normal saline, centrifuging at 1200rmp for 3min, discarding the normal saline" 3 times.

[0351] Take 8 1.5ml centrifuge tubes and add 5×10 6 The above-mentioned cells, numbered a, b, c, d, e, f, g, h, were centrifuged at 1200rmp for 3min, the supernatant was discarded, and the electrotr...

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Abstract

The invention belongs to the fields of cell biology and immunology, and relates to a bidirectional activated costimulatory molecule acceptor and use thereof, in particular to a bidirectional activatedcostimulatory molecule acceptor. The bidirectional activated costimulatory molecule acceptor sequentially comprises the following elements from the N terminal to the C terminal: selected signal peptide, a costimulatory signal molecule activated single-chain antibody, an extracellular hinge region, a transmembrane region and an intracellular costimulatory signal molecule. When the bidirectional activated costimulatory molecule acceptor and first generation CAR-T comprising the first signal jointly modify T cells, strong colony effect can be generated, and tumor cells can be killed. Besides, the bidirectional activating effect is only limited between the T cells in mutual contact, and cannot cause strong T cellular immunity so as to cause serious toxic and side effects like an activated antibody of injection costimulatory signal molecules.

Description

technical field [0001] The invention belongs to the field of cell biology and immunology, and relates to a bidirectionally activated co-stimulatory molecular receptor and the use of T cells modified by the receptor to treat malignant tumors. Background technique [0002] Adoptive cell therapy (ACT) is to reinfuse processed autologous or allogeneic immune cells (mainly autologous cells) to tumor patients to directly kill tumor cells, or to kill tumor cells by stimulating the body's immune response to achieve therapeutic purposes. Adoptive cell therapy for tumors is currently developing rapidly, and has achieved very good results in the clinical treatment of various malignant tumors (Nature.2016; Jun16; 534(7607):396-401); (Cell.2016Oct6; 167(2): 405-418.e13). Tumor immune cell therapy is considered to be one of the most promising means of treating malignant tumors. [0003] T cell activation requires the stimulation of two signals, namely two T cell activation related sign...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62C12N5/10A61P35/00
CPCC07K16/2878C07K16/2818C07K14/70517C07K14/70521C07K14/70578C12N5/0636C07K2317/622C07K2319/00C07K2319/02C07K2319/03C07K2319/33C07K2319/74C12N2510/00A61K39/4611A61K39/46447A61K39/464404A61K39/464468A61K2239/28A61K39/4631A61K2239/59A61P35/00C07K14/7051A61K48/005A61K38/00C07K16/3092C07K16/2863C07K2317/75A61K35/17
Inventor 钱其军金华君许慧敏刘祥箴李林芳王超
Owner SHANGHAI CELL THERAPY RES INST
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