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A chimeric antigen receptor based on targeting gd2 and its application

A chimeric antigen receptor and antigen technology, applied in the field of tumor cell immunotherapy, can solve the problems of increasing the difficulty of re-treatment, unable to exist in the body for a long time, and difficult to accurately enter the tumor tissue, etc., and achieve strong immune response and high safety. sexual effect

Active Publication Date: 2021-08-20
BEIJING MEIKANG JIMIAN BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] GD2 is widely expressed in tumors such as neuroblastoma and melanoma, and is expressed in a low amount and limitedly in normal tissues. It is an ideal tumor antigen for immunotherapy. At present, it is relatively mature in the immunotherapy of neuroblastoma Antibody therapy targeting GD2 has achieved initial clinical success. However, the problem with antibody therapy is that it is difficult for the antibody to enter the tumor tissue or the tiny residual tumor site accurately after the antibody is injected. After the antibody is administered, it cannot exist in the body for a long time, and the anti-GD2 antibody is a human-mouse chimeric antibody structure, which will inevitably make the human body resistant to it and increase the difficulty of retreatment

Method used

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  • A chimeric antigen receptor based on targeting gd2 and its application
  • A chimeric antigen receptor based on targeting gd2 and its application
  • A chimeric antigen receptor based on targeting gd2 and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: Construction of Chimeric Antigen Receptor (I)

[0071] (1) Synthesize Secretory signal peptide, GD2 antigen binding domain, CD28 extracellular and transmembrane domain, CD28 intracellular signaling domain and 4-1BB signaling domain, CD3ζ signaling domain, 2A sequence through whole gene synthesis and caspase 9 domains, such as figure 1 As shown, namely Secretory-GD2scFv-CD28-4-1BB-CD3ζ-2A-FBKP.Casp9;

[0072] The amino acid sequence of the chimeric antigen receptor, SEQ ID NO.12, is as follows:

[0073] MLLLVTSLLLCELPHPAFLLIPQVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYNSAFMSRLTISKDNSKNTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSSGSTSGSGKPGSSEGSTKGEIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPARFSGSGYGTEFTFTISSVQSEDFAVYFCQQDYSSFGQGTKLEIKAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSASGGGGSGGGGSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGGGGSGGGGSGGGGSRVKFSRSADAPAYQQGQNQL...

Embodiment 2

[0074]Example 2: Construction of Chimeric Antigen Receptor (II)

[0075] (1) Synthesize Secretory signal peptide, GD2 antigen binding domain, CD28 extracellular and transmembrane domain, CD28 signaling domain and 4-1BB signaling domain, CD3ζ signaling domain, 2A sequence and cysteine ​​domain through whole gene synthesis Caspase 9 domain, namely Secretory-GD2scFv-CD28-4-1BB-CD3ζ-2A-FBKP.Casp9;

[0076] The amino acid sequence of the chimeric antigen receptor, SEQ ID NO.13, is as follows:

[0077] MLLLVTSLLLCELPEVQLVQSGAEVEKPGASVKISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRATLTVDKSTSTAYMHLKSLRSEDTAVYYCVSGMEYWGQGTSVTVSSGSTSGSGKPGSSEGSTKGDVVMTQTPLSLPVTPGEPASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELKAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSASGGGGSGGGGSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGGGGSGGGGSGGGGSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPR...

Embodiment 3

[0078] Example 3: Construction of Chimeric Antigen Receptor (III)

[0079] (1) Synthesize Secretory signal peptide, GD2 antigen binding domain, CD28 extracellular and transmembrane domain, CD28 signaling domain and 4-1BB signaling domain, CD3ζ signaling domain, 2A sequence and cysteine ​​domain through whole gene synthesis Caspase 9 domain, namely Secretory-GD2scFv-CD28-4-1BB-CD3ζ-2A-FBKP.Casp9;

[0080] The amino acid sequence of the chimeric antigen receptor, SEQ ID NO.14, is as follows:

[0081] MLLLVTSLLLCELPAFLLIPEVKLVESGGGLVLPGDSLRLSCATSEFTFTDYYMTWVRQPPRKALEWLGFIRNRANGYTTEYNPSVKGRFTISRDNSQSILYLQMNTLRTEDSATYYCARVSNWAFDYWGQGTTLTVSSGSTSGSGKPGSSEGSTKGDVVMTQTPLSLPVSLGDQASISCRSSQSLLKNNGNTFLHWYLQKSGQSPKLLIYKVSNRLSGVPDRFSGSGSGTYFTLKISRVEAEDLGVYFCSQSTHIPYTFGGGTKLEIKAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSASGGGGSGGGGSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGGGGSGGGGSGGGGSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDK...

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Abstract

The present invention relates to a chimeric antigen receptor based on targeting GD2, the chimeric antigen receptor comprises an antigen binding domain, a transmembrane domain, a co-stimulatory signaling domain, a CD3ζ signaling domain and a self-destruct structure domains in series; wherein, the antigen-binding domain binds to a tumor surface antigen, the tumor surface antigen is GD2, the antigen-binding domain is a single-chain antibody against the tumor surface antigen GD2, and the self-destruct domain is Caspase 9 domain. The chimeric antigen receptor of the present invention is actually applied to patients with stage IV neuroblastoma expressing the tumor-specific target GD2, which has smaller clinical side effects and higher safety, can effectively shrink solid tumor foci, and is more effective in patients. The presence of GD2-CART was detected in the body for a long time, effectively prolonging the overall survival rate of patients.

Description

technical field [0001] The present invention relates to the field of tumor cell immunotherapy, in particular to a chimeric antigen receptor targeting GD2 and its application, specifically chimeric antigen receptor T (CAR-T) based on tumor-specific GD2 Construction method of cell technology and its application in anti-tumor therapy. Background technique [0002] With the development of tumor immunology theory and clinical technology, chimeric antigen receptor T-cell immunotherapy (CAR-T) has become one of the most promising tumor immunotherapy. Generally, a chimeric antigen receptor CAR consists of a tumor-associated antigen-binding region, an extracellular hinge region, a transmembrane region, and an intracellular signal transduction region. Usually, CAR contains the single chain fragment variable (single chain fragment variable, scFv) region of the antibody or the binding domain specific to the tumor associated antigen (tumor associated antigen, TAA), which communicates wi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00C12N15/867C12N5/10A61K35/17A61P35/00
CPCA61P35/00C12N5/0636C12N15/86C07K14/7051C07K14/70517C07K14/70521C07K14/70578C07K16/3084C07K2317/622C07K2319/00C07K2319/02C07K2319/03C07K2319/33C07K2319/74C07K2319/95C12N2740/15043C12N2510/00C12N2800/107A61K39/4611A61K2239/38A61K39/4631A61K39/464471A61K2239/31A61K2039/505C07K2317/24C12N2740/16043C07K2317/73A61K38/00C07K2317/76C07K2319/30C12N7/00C12N9/6472C12N2740/15021C12Y304/22062
Inventor 李昱琛
Owner BEIJING MEIKANG JIMIAN BIOTECH CO LTD