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CAR EXPRESSION VECTOR AND CAR-EXPRESSING T CELLS

Foreign code F160008803
File No. (S2014-1580-N0)
Posted date Aug 4, 2016
Country WIPO
International application number 2015JP005080
International publication number WO 2016056228
Date of international filing Oct 6, 2015
Date of international publication Apr 14, 2016
Priority data
  • P2014-208200 (Oct 9, 2014) JP
Title CAR EXPRESSION VECTOR AND CAR-EXPRESSING T CELLS
Abstract The present invention addresses the problem of providing chimeric antigen receptor (CAR)-expressing T cells that express a CAR and also express a T cell immunological function promoting factor, and that have a strong immunity-inducing effect and high antitumor activity. The present invention also addresses the problem of providing a CAR expression vector for producing such CAR-expressing T cells. This CAR expression vector contains a nucleic acid that codes for a CAR, and a nucleic acid that codes for a T cell immunological function promoting factor, wherein the nucleic acid that codes for the T cell immunological function promoting factor comprises either: the nucleic acid that codes for interleukin-7 and the nucleic acid that codes for CCL19; a nucleic acid that codes for a dominant-negative mutant of SHP-1; or a nucleic acid that codes for a dominant-negative mutant of SHP-2. CAR-expressing T cells into which said CAR expression vector has been introduced are produced.
Outline of related art and contending technology BACKGROUND ART
Chimeric antigen receptors (Chimeric Antigen Receptor: hereinafter, also referred to as' CAR ') is, the cell surface of cancer cells and single-chain antibody that recognizes an antigen, T cells induces the activation of the signaling region fuzed to the artificial chimeric protein. As shown in Fig. 1, does not have a tumour-reactive T cells normal peripheral blood (peripheral blood T lymphocytes) to by introducing a gene encoding CAR, CAR T cells capable of expressing CAR expression (hereinafter, simply referred to as' CAR-T cells' also referred to as) and producing a large number of possible. Such CAR-T cell is a tumor has reactivity, major histocompatibility complex (MHC) without depending on the interaction of cancer cells and guided to the injury.
Administration of the cells by cancer immunotherapy CAR-T, more specifically, T cells were harvested from the patient, such T cells by introducing a gene encoding CAR is amplified, again introduced into the patient therapy (see non-patent document 1) is, worldwide clinical trials has progressed, such as a malignant tumor such as lymphoma or leukemia hematopoietic shows efficacy in a result is obtained.
In recent years, various CAR-T cell studies have been performed. For example, an antigen-binding region and the transmembrane region CD19 cell co-stimulatory signal region 4-1BB, consisting of a nucleic acid encoding CAR CD3 ζ signal region comprising a modified human T cells a pharmaceutical composition comprising autologous (see Patent Document 1) or, 1 binds to the cell one or more cancer of the tagged protein of the formulation is administered to a subject simultaneously or separately, the tagged proteins bound to the, cancer cell death-inducing 1 one or more therapeutic effective anti tagukimera T (AT-CAR) antigen receptor (see Patent Document 2) expression and cell population, the antigen-binding domain of the human antibody 139, an extracellular hinge domain, a transmembrane domain cells, a cellular signaling domain and an intracellular T, encoding a chimeric antigen receptor (see Patent Document 3) cells containing the nucleic acid or, a nucleic acid sequence encoding a chimeric antigen-receptors or a cell that contains a, the chimeric antigen receptor antigen-binding domain, a transmembrane domain cells, co-stimulatory signal transfer region, and, comprises the amino acid sequence SEQ ID NO:24 CD3 ζ signaling domain (see Patent Document 4) or a cell containing, on the cell surface CD19 expression and possesses specific chimeric receptor, the chimeric receptor of the effector function of immune cells for intracellular signaling domain, a transmembrane domain and at least one cell 1 1 and at least one extracellular domain, the extracellular domain containing receptor CD19, genetically engineered cells produced CD19 (see Patent Document 5) specific T and, the intracellular domain as glucocorticoid induced tumor necrosis factor receptor (GITR) an intracellular domain of the chimeric antigen receptor has been introduced a nucleic acid encoding a chimeric antigen receptor expressing cell line (see Patent Document 6) is proposed.
However, the survival of cells in vivo CAR-T efficiency is low, or induced by an endogenous CAR-T T cell activation and tumor cells is insufficient and a problem in that local accumulation at the, a tumor having cancer cells immune evasion mechanism PD-1 PD-L1/signal via the second immunosuppressive microenvironment and cancer TGF-β in or secreted immunosuppressive factors such as IL-10 CAR-T cell activity by inhibiting the problem with past technology has not been solved. Therefore, sufficient treatment effect is not species and cancer cases exist, for more effective CAR-T cells, and cells for making such CAR-T has been desired in the preparation of the expression vector.
Scope of claims (In Japanese)[請求項1]
キメラ抗原受容体(CAR)をコードする核酸及びT細胞の免疫機能促進因子をコードする核酸を含有するCAR発現ベクターであって、前記免疫機能促進因子をコードする核酸が、インターロイキン7をコードする核酸及びCCL19をコードする核酸、SHP-1に対するドミナントネガティブ変異体をコードする核酸、又はSHP-2に対するドミナントネガティブ変異体をコードする核酸であることを特徴とするCAR発現ベクター。
[請求項2]
免疫機能促進因子をコードする核酸が、インターロイキン7をコードする核酸及びCCL19をコードする核酸であることを特徴とする請求項1記載のCAR発現ベクター。
[請求項3]
CARをコードする核酸とT細胞の免疫機能促進因子とをコードする核酸が、自己切断型ペプチドをコードする配列を介して連結されていることを特徴とする請求項2記載のCAR発現ベクター。
[請求項4]
インターロイキン7をコードする核酸とCCL19とをコードする核酸が、自己切断型ペプチドをコードする配列を介して連結されていることを特徴とする請求項2又は3記載のCAR発現ベクター。
[請求項5]
CARをコードする核酸が、FITC又はCD20を認識する一本鎖抗体のポリペプチドをコードする核酸を含有することを特徴とする請求項1~4のいずれか記載のCAR発現ベクター。
[請求項6]
CARをコードする核酸が、CD8の細胞膜貫通領域のポリペプチドをコードする核酸を含有することを特徴とする請求項1~5のいずれか記載のCAR発現ベクター。
[請求項7]
CARをコードする核酸が、CD28の細胞内領域、4-1BBの細胞内領域、及びCD3ζの細胞内領域のポリペプチドをコードする核酸を含有することを特徴とする請求項1~6のいずれか記載のCAR発現ベクター。
[請求項8]
以下の(a)又は(b)に示すベクターを導入したCAR発現T細胞。
(a)請求項1~7のいずれか記載のCAR発現ベクター;
(b)CARをコードする核酸及びインターロイキン7をコードする核酸を含有するCAR発現ベクターと、CARをコードする核酸及びCCL19をコードする核酸を含有するCAR発現ベクター;
[請求項9]
請求項8記載のCAR発現T細胞と薬学的に許容される添加剤とを含有する抗がん剤。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • YAMAGUCHI UNIVERSITY
  • Inventor
  • TAMADA, Koji
  • SAKODA, Yukimi
  • ADACHI, Keishi
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG

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