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Specific chimeric antigen receptor T cells targeting CD19 and preparation and clinical application thereof

A chimeric antigen receptor and specific technology, applied in the field of biomedicine for tumor immunotherapy, can solve problems such as fever or neurotoxic side effects

Pending Publication Date: 2019-09-24
NANJING KAEDI BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, so far, CAR-T products targeting CD19 generally have side effects of fever or neurotoxicity caused by cytokine release syndrome, which brings great challenges to the wide clinical use and clinical treatment of this product

Method used

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  • Specific chimeric antigen receptor T cells targeting CD19 and preparation and clinical application thereof
  • Specific chimeric antigen receptor T cells targeting CD19 and preparation and clinical application thereof
  • Specific chimeric antigen receptor T cells targeting CD19 and preparation and clinical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] Preparation of expression plasmids targeting CD19-specific chimeric antigen receptors

[0153] Step 1) Determination of the amino acid sequence of the specific chimeric antigen receptor targeting CD19

[0154] First, the full-length amino acid sequence (as shown in SEQ ID No.1) and the full-length Nucleotide sequence (as shown in SEQ ID No.2).

[0155] Second, construct a specific chimeric antigen receptor targeting CD19.

[0156] details as follows:

[0157]The amino acid sequence of the CD19-specific CAR molecule: from the amino terminal to the carboxyl terminal, consists of the amino acid sequence of the guide peptide (as shown in SEQ ID No.3), the amino acid sequence of the anti-human CD19 single-chain antibody (as shown in SEQ ID No.4, shown), the amino acid sequence of human CD8 hinge region (as shown in SEQ ID No.8), the amino acid sequence of human CD8 transmembrane region (as shown in SEQ ID No.9), the amino acid sequence of human 4-1BB intracellular domain ...

Embodiment 2

[0186] Example 2 Preparation of expression plasmids targeting specific chimeric antigen receptors targeting CD19

[0187] In addition to step 1, the anti-human CD19 single-chain antibody sequence (as shown in SEQ ID No.5) in the amino acid sequence of the targeting CD19-specific CAR molecule, the amino acid sequence of the human CD3ζ domain is shown in SEQ ID No.13, The nucleotide sequence encoding the anti-human CD19 single-chain antibody sequence (as shown in SEQ ID No.16) in the nucleotide sequence of the CD19-specific CAR molecule,

[0188] and step 2) construction and identification of a plasmid expressing a specific CAR molecule targeting CD19

[0189] The nucleotide sequence of the specific CAR molecule targeting CD19 was synthesized from the whole gene, and connected to the lentiviral vector lentiGuide-Puro (Addgene, figure 1 ), constructing the full-length CAR sequence expression frame stage of a single coding frame, using the EFS promoter (SEQ ID No.26 in the sequen...

Embodiment 3

[0190] Example 3 Preparation of expression plasmids targeting specific chimeric antigen receptors targeting CD19

[0191] In addition to step 1, the anti-human CD19 single-chain antibody sequence (as shown in SEQ ID No.6) in the amino acid sequence of the targeting CD19-specific CAR molecule, the nucleotide sequence of the targeting CD19-specific CAR molecule encodes anti-human The nucleotide sequence of the CD19 single-chain antibody sequence (shown in SEQ ID No.17, the rest are the same as in Example 1.

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Abstract

The invention relates to specific chimeric antigen receptor T cells targeting CD19, and a preparation method and clinical application thereof. The present invention constructs a specific chimeric antigen receptor targeting CD19 and immune response cells modified by the chimeric antigen receptor based on a targeted human CD19 single-chain antibody sequence. The novel modified immune response cells can effectively target and attack a plurality of tumor cells, especially tumor cells with positive CD19 expressiion, and can be used to prepare a preparation for the treatment of tumors. The method for preparing the modified immune response cells targeting CD19 is simple, and the obtained modified immune response cells targeting CD19 have a high killing rate on tumor cells. Clinical verification shows that: after a million-grade low-dose back transfusion, patients with recurrent and refractory advanced CD19-positive lymphoma get a significant clinical symptom relief after two weeks of treatment, almost complete relief curative effect is obtained on the 77th day, and no fever caused by cytokine release syndrome and any neurotoxic side effect occur.

Description

technical field [0001] The invention belongs to the technical field of biomedicine for tumor immunotherapy, and relates to specific chimeric antigen receptor T cells. Background technique [0002] With the rapid development of biotechnology, immune cell therapy has become the fourth largest therapy in the field of cancer treatment. [0003] Cancer immunotherapy mainly includes adoptive cell therapy, immunomodulators, tumor vaccines, and immune checkpoint blockade therapy. Among them, in the field of cell therapy, chimeric antigen receptor-modified immune cells (especially Chimeric Antigen Receptor T-Cell, CAR-T) therapy has undoubtedly become a star that research institutions and pharmaceutical companies are vying for. [0004] Immunotherapy represented by CAR-T (Chimeric Antigen Receptor T-Cell, Chimeric Antigen Receptor T-Cell) is based on the principle of modifying chimeric antigen receptors on T cells extracted from patients themselves through genetic engineering. Form...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K19/00C12N15/62C12N15/867C12N5/10A61K39/00A61P35/00A61P31/00A61P37/02A61P29/00A61P37/06A61P39/06
CPCC07K16/2803C07K14/70517C07K14/70578C07K14/7051C12N15/86C12N5/0636A61K39/001112A61P35/00A61P31/00A61P37/02A61P29/00A61P37/06A61P39/06C07K2317/622C07K2319/00C07K2319/33C07K2319/74C07K2319/03C07K2319/02C12N2800/107C12N2740/15043C12N2510/00A61K2039/5156
Inventor 代红久李艳云
Owner NANJING KAEDI BIOTECH INC
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