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Double-target chimeric antigen receptor targeting NKG2D ligand and CD19 as well as expression vector and application thereof

A technology of chimeric antigen receptors and expression vectors, applied in the field of tumor immunology drugs, can solve the problems of CD19 expression loss, antigen escape, tumor cell cancer recurrence, etc., achieve strong anti-tumor activity, avoid immune escape, and reduce the risk of recurrence Effect

Active Publication Date: 2020-04-10
华夏源细胞工程集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, although CD19CAR-T cells have achieved great success, as many as two-thirds of patients who receive CD19CAR-T cell therapy will experience loss of CD19 expression, resulting in antigen escape and continued growth of tumor cells. Cases showing cancer recurrence

Method used

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  • Double-target chimeric antigen receptor targeting NKG2D ligand and CD19 as well as expression vector and application thereof
  • Double-target chimeric antigen receptor targeting NKG2D ligand and CD19 as well as expression vector and application thereof
  • Double-target chimeric antigen receptor targeting NKG2D ligand and CD19 as well as expression vector and application thereof

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Embodiment 1

[0024] The embodiment of the present invention provides a dual-target chimeric antigen receptor targeting NKG2D ligand and CD19, such as figure 1 As shown, the dual-target chimeric antigen receptor includes: sequentially connected signal peptide (human CD8α signal peptide, CD8α leader), NKG2D extracellular region targeting NKG2D ligand (NKG2D ECD), connecting fragment (linker), Single-chain antibody targeting CD19 (CD19scFv), extended CD8α hinge region (human

[0025] CD8α hinge region, CD8α Hinge), transmembrane region (human CD8α transmembrane region, CD8α transmembrane), co-stimulatory factor and intracellular signal peptide (human CD3ζ intracellular signal peptide, CD3ζsignal), the nucleotide sequence of the signal peptide is as follows The nucleotide sequence of the NKG2D extracellular region targeting NKG2D ligand is shown in SEQ ID NO: 1 in the list, and the nucleotide sequence of the single-chain antibody targeting CD19 is shown in SEQ ID NO: 2 in the sequence listing ...

Embodiment 2

[0033] The present invention provides an expression vector, which includes the vector and the dual-target chimeric antigen receptor provided in Example 1. Specifically, the vector may be a lentiviral vector, a retroviral vector, an electrotransduction vector or a Sleeping Beauty transposon vector. In this embodiment, the vector is a lentiviral vector.

[0034] The following briefly introduces the preparation method of the expression vector, as follows:

[0035]Amplify and obtain the CART02 gene sequence by PCR (Polymerase Chain Reaction, polymerase chain reaction), add restriction site Xba I and restriction site EcoR I respectively at the two ends of CART02 gene sequence, obtain the thing to be digested, Carry out the double enzyme digestion reaction of Xba I and EcoR I with the lentiviral vector plasmid pCDH-EF1-MCS-T2A-copGFP, respectively, to obtain the enzyme-digested fragment containing CART02 and the enzyme-digested fragment containing pCDH-EF1-MCS-T2A-copGFP fragment....

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Abstract

The invention discloses a double-target chimeric antigen receptor targeting an NKG2D ligand and CD19 as well as an expression vector and an application thereof, which belong to the field of tumor immune drugs. The double-target chimeric antigen receptor comprises a signal peptide, a NKG2D extracellular region of a targeted NKG2D ligand, a connecting fragment, a single-chain antibody of the targeted CD19, a lengthened CD8 alpha hinge region, a transmembrane region, a costimulatory factor and an intracellular signal peptide which are connected in sequence; the double-target chimeric antigen receptor can be used for specifically identifying tumor cells expressed by two single targets, namely a targeted NKG2D ligand or a CD19 antigen; in addition, tumor cells co-expressed by the targeting NKG2D ligand and the CD19 antigen can be recognized, the double-target CAR-T has stronger anti-tumor activity, immune escape of positive tumor cells expressed by low-abundance antigen can be avoided, andthus the recurrence risk is reduced.

Description

technical field [0001] The present invention relates to the field of tumor immune drugs, in particular to a dual-target chimeric antigen receptor of NKG2D ligand and CD19, its expression vector and application. Background technique [0002] Malignant tumors are one of the diseases that seriously threaten human health. According to incomplete statistics, the annual incidence of malignant tumors in China has reached more than 4 million cases. In the past, most of them were middle-aged and elderly people, and gradually spread to young patients. This may be related to factors such as modern people's high life pressure, increased environmental pollution, and unhealthy living habits. [0003] Chimeric antigen receptor (CAR) technology is a cell therapy technology that has developed very rapidly in recent years. At present, although CD19CAR-T cells have achieved great success, as many as two-thirds of patients who receive CD19CAR-T cell therapy will experience loss of CD19 express...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62C12N15/867A61K39/00A61P35/00A61P35/02
CPCC07K16/2851C07K16/2803C07K14/70517C07K14/70578C07K14/7051C12N15/86A61K39/001112A61K39/001102A61P35/00A61P35/02C07K2317/622C07K2319/02C07K2319/03C07K2319/33C07K2319/74C12N2740/15043C12N2800/107A61K2039/5156A61K2039/804
Inventor 张坤
Owner 华夏源细胞工程集团股份有限公司
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