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Switchable chimeric antigen receptor-engineered human natural killer cells

A technology of chimeric antigen receptor and natural killing, applied in the direction of genetically modified cells, receptor/cell surface antigen/cell surface determinant, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc. It can solve the problems of irreversible elimination of CAR-T cells, low anti-tumor activity, transient CAR expression, etc.

Pending Publication Date: 2022-02-08
RGT UNIV OF CALIFORNIA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The second challenge is the difficulty in scaling up the rate at which CAR cells are manufactured to meet the needs of patients
However, the kill switch does not provide control over T cell activation and expansion and leads to irreversible elimination of potentially therapeutic CAR-T cells
RNA-based systems lead only to transient CAR expression, lower antitumor activity and fail to capture fully dynamic and titratable on / off activity 9,10

Method used

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  • Switchable chimeric antigen receptor-engineered human natural killer cells
  • Switchable chimeric antigen receptor-engineered human natural killer cells
  • Switchable chimeric antigen receptor-engineered human natural killer cells

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[0089] NK cells expressing sCAR: Since the sCAR system had previously only been tested in T cells, an initial proof-of-concept test was performed on an anti-CD19 sCAR expressed in NK92 cells. NK92 is an NK cell line previously used to test novel NK cell-CAR constructs 19 . Here, sCAR was reengineered to contain the CAR4 NK cell signaling described above that mediates activation of signaling pathways within NK cells and improves NK-CAR antitumor activity compared to CAR-T cell constructs expressed in NK cells transduction domain 19 . Demonstrated anti-CD19 switch and anti-FZD7 switch mediate specific killing of CD19 + Raji B-cell lymphoblastic leukemia (model of hematological malignancies) or FZD7 + Efficacy of MA148 ovarian cancer cell line (solid tumor model) ( Figure 2A-2B ). For the anti-CD19 switch, specificity of killing was only demonstrated when the anti-CD19 switch was presented using CD19-deficient Raji cells and CD19-negative K562 cells ( Figure 2A and data ...

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Abstract

Engineered natural killer cells with a switchable chimeric antigen receptor, methods of manufacture, pharmaceutical compositions, and methods of use in treating cancer and viral infection are disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 822,389, filed March 22, 2019, which is incorporated herein by reference. technical field [0003] The present invention relates to engineered immunotherapy. Background technique [0004] Existing CAR-engineered T-cell (CAR-T)-based therapies represent one of the most successful immunotherapy approaches developed in recent years. Most CAR-T cell therapies have been used clinically to treat hematologic malignancies by targeting the B-cell-specific antigen CD19. However, this approach is not without limitations due to several intrinsic properties of T cells, including alloreactivity that limits their use strictly to autologous patients and side effects caused by uncontrolled proliferation or uncontrolled release of cytokines. NK cells, on the other hand, function as allogeneic cytotoxic effector cells that are not necessarily based ...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61P35/02C07K16/28C07K16/30
CPCA61P35/02C07K16/30C07K2319/03C07K14/7051C07K2317/55C07K2317/622C07K16/2803A61K2039/505A61K38/00A61K2239/59C12N5/0646A61K2239/48A61K39/4613A61K39/4631A61K2239/23A61K39/464412A61K39/464429C07K14/705C07K16/2863C07K14/7056A61P35/00A61P31/12C12N2510/00
Inventor D·S·考夫曼X-H·李E·拉博达T·杨
Owner RGT UNIV OF CALIFORNIA