Chimeric antigen receptor based on GD2 and application thereof

A technology of chimeric antigen receptors and antigens, which is applied in the field of tumor cell immunotherapy, can solve problems such as difficult to accurately enter tumor tissue, cannot exist in the body for a long time, and increases the difficulty of retreatment, achieving good results and safety. Immunity-stimulating effect, reducing the risk of storms

Active Publication Date: 2018-12-07
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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  • Chimeric antigen receptor based on GD2 and application thereof
  • Chimeric antigen receptor based on GD2 and application thereof
  • Chimeric antigen receptor based on GD2 and application thereof

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 invention relates to a chimeric antigen receptor based on GD2. The chimeric antigen receptor is characterized by being prepared from an antigen combined structural domain, a transmembrane structural domain, a costimulatory signal transduction structural domain, a CD3 zeta signal transduction structural domain and a self-destroying structural domain which are connected in series, wherein the antigen combined structural domain is combined with a surface antigen of a tumor, the surface antigen of the tumor is GD2, the antigen combined structural domain is a single chain antibody for the surface antigen of the tumor GD2, and the self-destroying structural domain is a caspase 9 structural domain. The chimeric antigen receptor is actually applied to a patient suffered from phase IV neuroblastoma expressing a specific target point GD2 of the tumor, is smaller in clinical side effect and higher in safety, can reduce the solid tumor foci effectively, and improves the whole survival rate ofthe patient effectively as presence of GD2-CART can be monitored in the body of the patient for a long time.

Description

technical field [0001] The present invention relates to the field of tumor cell immunotherapy, in particular to a GD2-based chimeric antigen receptor and its application, specifically the chimeric antigen receptor T (CAR-T) cell technology based on tumor-specific target GD2 The construction method 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 communi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C12N15/867C12N5/10A61K35/17A61P35/00
CPCA61P35/00A61K35/17C12N5/0636C12N15/86C07K14/7051C07K14/70517C07K14/70521C07K14/70578C07K16/3084C07K2317/622C07K2319/00C07K2319/02C07K2319/03C07K2319/33C07K2319/74C07K2319/95C12N2740/15043C12N2510/00C12N2800/107A61K2039/505C07K2317/24C12N2740/16043A61K39/001171A61K2039/5156A61K2039/5158C07K2317/73A61K38/00C07K2317/76C07K2319/30C12N7/00C12N9/6472C12N2740/15021C12Y304/22062
Inventor 李昱琛
Owner BEIJING MEIKANG JIMIAN BIOTECH CO LTD
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