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EGFRvIII specific chimeric antigen receptors for cancer immunotherapy

A specific, immune cell technology, applied in the direction of targeting specific cell fusion, NGF-receptor/TNF-receptor superfamily, derived from mammalian medical raw materials, etc., can solve the problem of antigen markers that cannot be expanded, etc. question

Inactive Publication Date: 2017-08-18
ALLOGENE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the particular combination of signaling, transmembrane and co-stimulatory domains used for CD19ScFv is rather antigen-specific and cannot be extended to arbitrary antigenic markers

Method used

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  • EGFRvIII specific chimeric antigen receptors for cancer immunotherapy
  • EGFRvIII specific chimeric antigen receptors for cancer immunotherapy
  • EGFRvIII specific chimeric antigen receptors for cancer immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0797] Example 1: Proliferation of TCRα-inactivated cells expressing EGFRvIII-CAR.

[0798] A heterodimeric TALE-nuclease targeting two 17-bp long sequences (termed half-targets) separated by a 15-bp spacer within the T cell receptor alpha constant chain region (TRAC) gene was designed and generated. Each half-target is recognized by repeats of the half-TALE-nucleases listed in Table 10.

[0799] Table 10: TAL nucleases targeting the TCRα gene

[0800]

[0801] Each TALE-nuclease construct was subcloned in a mammalian expression vector under the control of the T7 promoter using restriction enzyme digestion. mRNA encoding the TALE-nuclease cleaved TRAC genomic sequence was synthesized from a plasmid carrying the coding sequence downstream of the T7 promoter.

[0802] Purified T cells pre-activated for 72 hours with anti-CD3 / CD28-coated beads were transfected with each of the 2 mRNAs encoding the two half-TRAC_T01 TALE-nucleases. Forty-eight hours after transfection, differe...

Embodiment 2

[0807] Example 2: EGFRvIII CAR-T

[0808] Development of engineered CAR T cells targeting epidermal growth factor receptor variant III (EGFRvIII) for the treatment of glioblastoma.

[0809] EGFRvIII is the most common EGFR mutant and consists of an in-frame deletion of exons 2-7. This deletion results in a truncated extracellular ligand-binding domain and allows constitutive activation of the protein in a ligand-independent manner. EGFRvIII expression has been shown to enhance tumorigenicity, promote cell motility, and confer resistance to radiation and chemotherapy. EGFRvIII has been reported to be expressed in 24-67% of glioblastomas, but not in any normal tissues, making it an attractive target for immunotherapy with CAR T cells ( figure 1 ).

[0810] 1. EGFRvIII CAR:

[0811] 1.1. Constructs

[0812] Four EGFRvIII CARs were designed ( figure 2 and image 3 ) and prepared using different scfvs as previously described in documents US2010 / 0105136 and US2010 / 0105136 A1...

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Abstract

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from an EGFRvIII monoclonal antibody, conferring specific immunity against EGFRvIII positive cells. The TCR KO engineered immune cells endowed with such CARs are particularly suited for treating lung cancer, anal cancers and glioblastoma multiforme.

Description

[0001] field of invention [0002] The present invention relates to Chimeric Antigen Receptors (CARs), which are recombinant chimeric proteins capable of redirecting immune cell specificity and reactivity to EGFRvIII, which is expressed in human tumors including glioblastoma, glial Cell surface glycoprotein found on tumors, non-small cell lung cancer, ovarian cancer and prostate cancer. When expressed in T cells or NK cells, the CAR according to the present invention is particularly suitable for the treatment of malignant cells bearing the EGFRvIII antigen. The resulting engineered immune cells display high levels of specificity for malignant cells, conferring safety and efficacy to immunotherapy. [0003] Background of the invention [0004] Adoptive immunotherapy, which involves the transfer of autologous antigen-specific T cells generated ex vivo, is a promising strategy for the treatment of viral infections and cancer. T cells for adoptive immunotherapy can be generated b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C12N15/62C12N5/10A61K35/17A61P35/00
CPCC07K14/7051C07K14/70578C07K16/2863C07K2319/33C07K2317/622C07K2317/73C07K2319/03A61K39/4611A61K39/464404A61K39/4631A61K2239/47G01N2333/71A61P35/00A61K48/00A61K35/17C07K14/70517C07K2317/24C07K2317/53C07K2317/56
Inventor C·施弗-曼纽伊
Owner ALLOGENE THERAPEUTICS INC
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