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A kind of T cell receptor that recognizes sage1 antigen and the nucleic acid encoding the receptor

A cell receptor and encoding technology, applied in the field of TCR, can solve problems such as normal cell damage

Active Publication Date: 2021-10-19
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For the treatment of the above diseases, methods such as chemotherapy and radiotherapy can be used, but all of them will cause damage to their own normal cells

Method used

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  • A kind of T cell receptor that recognizes sage1 antigen and the nucleic acid encoding the receptor
  • A kind of T cell receptor that recognizes sage1 antigen and the nucleic acid encoding the receptor
  • A kind of T cell receptor that recognizes sage1 antigen and the nucleic acid encoding the receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1 Cloning of SAGE1-specific T cells

[0138] Peripheral blood lymphocytes (PBL) from healthy volunteers with genotype HLA-A2402 were stimulated with a synthetic short peptide (Beijing Saibaisheng Gene Technology Co., Ltd.) VFSTVPPAFI (SEQ ID NO.9, named PX149 in the present invention). The short peptide was annealed with biotin-labeled HLA-A*2402 to prepare pHLA monomers. These monomers were combined with PE-labeled streptavidin (BD Company) to form PE-labeled tetramers, and the tetramers and anti-CD8-APC double-positive cells were sorted. Sorted cells were expanded and subjected to secondary sorting as described above, followed by monoclonal culture by limiting dilution.

[0139] Due to the long time-consuming process of the entire experiment, many influencing factors, and the complexity of the experiment, the performance of the cells cannot be predicted at all. Even after layers of screening and strict testing, the success rate of obtaining the corresponding ...

Embodiment 2

[0142] Example 2 Construction of the TCR gene and vector for obtaining SAGE1-specific T cell clones

[0143] with Quick-RNA TM MiniPrep (ZYMO research) extracted the total RNA of the VFSTVPPAFI-specific and HLA-A2402-restricted T cell clones screened in Example 1. The cDNA was synthesized using clontech's SMART RACE cDNA amplification kit, and the primers used were designed at the C-terminal conserved region of the human TCR gene. The sequence was cloned into T vector (TAKARA) for sequencing. After sequencing, the sequence structures of the α-chain and β-chain of the TCR expressed by the double-positive clone are as follows: Figure 1a-Figure 1f and Figure 2a-Figure 2f as shown, Figure 1a , Figure 1b , Figure 1c and Figure 1d They are the amino acid sequence of TCRα chain variable domain, the nucleotide sequence of TCRα chain variable domain, the amino acid sequence of TCRα chain and the nucleotide sequence of TCRα chain; Figure 2a , Figure 2b , Figure 2c and...

Embodiment 3

[0153] Example 3 Expression, refolding and purification of SAGE1 antigen short peptide-specific soluble TCR

[0154] In order to obtain a soluble TCR molecule, the α and β chains of the TCR molecule of the present invention may only include their variable domains and part of the constant domains respectively, and a cysteine ​​residue is introduced into the constant domains of the α and β chains respectively To form an artificial interchain disulfide bond, the positions of the introduced cysteine ​​residues are Thr48 of TRAC*01 exon 1 and Ser57 of TRBC2*01 exon 1; the amino acid sequence and nucleotides of the α chain sequence as Figure 4a and Figure 4b As shown, the amino acid sequence and nucleotide sequence of its β chain are as follows Figure 5a and Figure 5b The introduced cysteine ​​residues are shown in bold and underlined letters. By the standard method described in > (Molecular Cloning a Laboratory Manual) (third edition, Sambrook and Russell), the target gene ...

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Abstract

The present invention provides a T cell receptor (TCR) capable of specifically binding to the short peptide VFSTVPPAFI derived from the SAGE1 antigen. The antigen short peptide VFSTVPPAFI can form a complex with HLA A2402 and be presented on the cell surface together. The present invention also provides the nucleic acid molecule encoding the TCR and the vector comprising the nucleic acid molecule. In addition, the present invention also provides cells transduced with the TCR of the present invention.

Description

technical field [0001] The present invention relates to TCRs capable of recognizing short peptides derived from SAGE1 antigens. The present invention also relates to SAGE1-specific T cells obtained by transducing the above TCRs, and their use in preventing and treating SAGE1-related diseases. Background technique [0002] As an endogenous tumor antigen, SAGE1 is degraded into small molecular polypeptides after being generated in cells, and combines with MHC (major histocompatibility complex) molecules to form a complex, which is presented to the cell surface. Studies have shown that VFSTVPPAFI is a short peptide derived from SAGE1. SAGE1 antigen is expressed in tumor tissues such as melanoma, bladder cancer, liver cancer, epidermoid carcinoma, non-small cell lung cancer and squamous cell carcinoma, but not in most normal tissues except testis (Martelange V1, De Smet C, De Plaen E, Lurquin C, Boon T. Cancer Res. 2000; 60(14): 3848-55; Atanackovic D, et al., Cancer Biol Ther....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/725C12N15/12C12N15/867C12N5/10A61K38/17A61P35/00A61P37/02
CPCA61K35/17A61K38/00C07K14/7051C12N15/86C12N2740/15043
Inventor 李懿陈安安
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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