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Anti-DOTA chimeric antigen receptor-modified T cells and anti-tumor applications thereof

A chimeric antigen receptor and cell technology, applied in the field of T cells, can solve the problems of tumor evasion, high cost, labor and material resources, etc., and achieve good anti-tumor effect and strong adaptability

Inactive Publication Date: 2015-09-02
BIOMICS BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If every tumor-specific CAR-T cell is designed to treat every cancer patient, it will consume a lot of manpower and material resources, and the cost is expensive
Second, down-regulation or mutation of tumor antigens can cause tumors to escape CAR-T cell therapy
Third, the second-generation and third-generation CAR-T cells in the current preclinical and early clinical trials will produce a super-strong response to some normal tissues that express a small amount of tumor-associated antigens, and the excessive increase in a "waterfall" will cause damage to the immune system. exaggerated immune response in normal tissue

Method used

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  • Anti-DOTA chimeric antigen receptor-modified T cells and anti-tumor applications thereof
  • Anti-DOTA chimeric antigen receptor-modified T cells and anti-tumor applications thereof
  • Anti-DOTA chimeric antigen receptor-modified T cells and anti-tumor applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] An anti-DOTA (DOTA molecular structure such as figure 1 shown) chimeric antigen receptor (anti-DOTA-CAR). like figure 2 As shown, the anti-DOTA-CAR includes anti-DOTA antibody light chain variable domain (VL) and heavy chain variable domain (VH) to form the extracellular domain, the leader sequence is CD8α chain signal peptide, DOTA single chain antibody is linked to On a hinge of CD8, it is connected with the CD8 transmembrane domain (CD8TM), followed by the activation domain of the costimulatory molecule CD137 (4-1BB) and the CD3ζ domain of the immunoreceptor tyrosine activation motif peptide.

[0023] The above nucleic acid sequence encoding anti-DOTA-CAR (DOTA-CAR) was constructed into the lentiviral pLVX-IRES-GFP vector, and the lentivirus was packaged in the cells according to the operation manual of Clontech Company of the United States, and the purified lentivirus was infected with 293T After 3 days, the expression of green fluorescent (GFP) was observed unde...

Embodiment 2

[0025] Infect T cells with the anti-DOTA-CAR recombinant lentivirus prepared in Example 1 to prepare anti-DOTA-CAR modified T cells, and apply it to immunotherapy, such as Figure 5 As shown, it mainly includes two steps: 1) Targeting tumor cells in cancer patients with a tumor-specific antibody-conjugated DOTA molecule (TSA-DOTA); 2) T cells modified with anti-DOTA chimeric antigen receptor (CAR -T cells) surface anti-DOTA antibodies recognize the above TSA-DOTA, thereby activating CAR-T cells to kill cancer cells.

Embodiment 3

[0027] Infect T cells with the anti-DOTA-CAR recombinant lentivirus prepared in Example 1 to prepare anti-DOTA-CAR modified T cells, and apply it to immunotherapy, such as Figure 5 As shown, it mainly includes two steps: 1) targeting tumor cells in cancer patients with a tumor-specific ligand-conjugated DOTA molecule (TSA-DOTA); 2) T cells modified with anti-DOTA chimeric antigen receptor ( The anti-DOTA antibody on the surface of CAR-T cells) recognizes the above-mentioned TSA-DOTA, thereby activating CAR-T cells to kill cancer cells.

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Abstract

The present invention discloses anti-DOTA chimeric antigen receptor-modified T cells and anti-tumor applications thereof, wherein the anti-DOTA chimeric antigen receptor comprises an extracellular domain formed by an anti-DOTA antibody light chain variable domain (VL) and an anti-DOTA antibody heavy chain variable domain (VH), the leader sequence is CD8[alpha] chain signal peptide, the DOTA single chain antibody is coupled to a CD8 hinge, the obtained hinge is coupled with the CD8 transmembrane domain, and the obtained material is coupled with the activation domain and the immunologic receptor tyrosine activation motif peptide CD3[zeta] domain of the co-stimulatory molecule CD137 (4-1BB). According to the present invention, when tumor cells are bound to tumor-specific antibody-conjugated DOTA, the anti-DOTA chimeric antigen receptor-modified T cells of the present invention can specially recognize and kill the tumor cells.

Description

technical field [0001] The invention provides an anti-DOTA chimeric antigen receptor modified T cell and its application in anti-tumor. Background technique [0002] Chimeric Antigen Receptor (CAR)-modified T (CAR-T) cell therapy is a promising approach for cancer treatment. CAR-T cells eliminate cancer cells by recognizing tumor-associated antigens (Tumor-Associated Antigens, TAA) expressed on the surface of tumors. Many preclinical and early clinical trials have used the efficacy of CAR-T cells to treat hematopoietic malignancies and solid tumors in cancer patients with success. However, there are also some shortcomings, which limit the wide clinical application of CAT-T cells. First, CAR single-chain antibodies need to be directed against each tumor antigen because there is no universal antigen expressed on the surface of all types of cancer cells. Designing each tumor-specific CAR-T cell to treat each cancer patient will consume a lot of manpower and material resource...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N5/10C12N15/867A61K48/00A61P35/00
Inventor 仇建萍李铁军周宋峰袁建朱远源
Owner BIOMICS BIOTECH
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