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Cell comprising chimeric antigen receptor (CAR)

A technology of chimeric antigen receptors and cells, applied in the field of cells, can solve problems such as inability to work, fast suicide genes, and unclear immunotoxicity of suicide genes

Pending Publication Date: 2019-12-27
AUTOLUS LIMIED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Second, it is unclear whether suicide genes would contribute to some of the above-mentioned immunotoxicities: for example, by the time macrophage activation syndrome has been triggered, it may no longer require CAR T cells to perpetuate at all, and the suicide genes would no longer be effective. help
More acute cytokine release syndrome may occur too quickly for suicide genes to work

Method used

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  • Cell comprising chimeric antigen receptor (CAR)
  • Cell comprising chimeric antigen receptor (CAR)
  • Cell comprising chimeric antigen receptor (CAR)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0575] Example 1 - Functionality of the Rapa-Off Inhibition System

[0576] The tricistronic construct is expressed as a single transcript with the following structure:

[0577] SFGmR.V5_tag-CD22(2Ig)-CD19tm-RL-FRB-2A-FKBP12-L-CD148endo-2A-CAR

[0578] This self-cleaves at site 2A into a signaling inhibitory component containing FKBP12, a membrane-tethered component containing a transmembrane domain and an intracellular FRB domain, and an anti-CD19 second-generation CAR.

[0579] This construct was expressed in BW5 cells. SupT1 cells (CD19 negative) were engineered to be CD19 positive to give target negative and positive cell lines as similar as possible. Primary human T cells from 3 donors were transduced with two CAR constructs: (i) a "classical" anti-CD19 CAR; (ii) the tricistronic "repressible" CD19 CAR system described above. Non-transduced T cells and T cells transduced with different CAR constructs were challenged 1:1 with SupT1 cells or SupT1.CD19 cells in the pre...

Embodiment 2

[0582] Example 2 - Functionality of the Tet-ON suppression system

[0583] The tricistronic construct is expressed as a single transcript with the following structure:

[0584] SFG.TIP-L(16aa)-CD148endo-2A-V5-tag-CD22(2Ig)-CD19tm-RL-TetRB-2A-CAR

[0585] This self-cleaves at site 2A into a signaling inhibitory component containing TiP, a membrane-tethered component comprising a transmembrane domain and an intracellular TetRB domain, and an anti-CD19 second-generation CAR.

[0586] This construct was in BW5 cells, which were then challenged with wild-type SupT1 cells or SupT1 engineered to express CD19 using the method described in Example 1 in the presence or absence of tetracycline.

[0587] Such as Figure 5 and Figure 6 As shown in , in the "Tet-ON" inhibitory system in the presence of tetracycline, signaling inhibitory components diffuse freely in the cytoplasm and CAR-mediated signaling can occur. In the absence of tetracycline, the signaling inhibitory component d...

Embodiment 3

[0588] Example 3 - Functionality of the Rapa-Off Inhibition System with Anti-BCMA CAR

[0589] The tricistronic construct is expressed as a single transcript with the following structure:

[0590] SFGmR.V5_tag-CD22(2Ig)-TM-FRB-2A-FKBP12-CD148endo-2A-CAR

[0591] This self-cleaves at site 2A into a signaling inhibitory component containing FKBP12, a membrane-tethered component containing a transmembrane domain and an intracellular FRB domain, and a proliferation-inducing ligand (APRIL) with a BCMA-based natural ligand Anti-BCMA third-generation CAR with the antigen-binding site.

[0592] This construct was expressed in BW5 cells. SKOV3 cells were engineered to be BCMA positive for use as target cells. Primary human T cells from 2 donors were transduced with two CAR constructs: (i) the "classical" anti-BCMA CAR; (ii) the tricistronic "repressible" BCMA CAR system described above. Untransduced T cells and T cells transduced with different CAR constructs were challenged 8:1 ...

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Abstract

The present invention provides a cell which comprises; (i) a chimeric antigen receptor (CAR) which comprises an antigen binding domain and an intracellular signalling domain; (ii) a membrane tetheringcomponent (MTC) which comprises a first dimerization domain; and (Hi) a signal-dampening component (SDC) comprising a signal-dampening domain (SDD) and a second dimerization domain which specificallybinds the first dimerisation domain of the membrane-tethering component. Dimerisation between the MTC and SDC may be controllable with an agent, meaning that the agent can be used to control CAR-mediated cell signalling.

Description

[0001] field of invention [0002] The present invention relates to cells comprising a chimeric antigen receptor (CAR). [0003] Background of the invention [0004] Antigen-specific T cells have traditionally been generated by the selective expansion of peripheral blood T cells that are naturally specific for the target antigen. However, it is difficult and often impossible to select and expand large numbers of T cells specific for most cancer antigens. Gene therapy using integrating vectors offers a solution to this problem, as transgenic expression of chimeric antigen receptors (CARs) allows the generation of large numbers of T cells directed against any surface antigen by ex vivo viral vector transduction of large numbers of peripheral blood T-cells . [0005] Chimeric antigen receptors are proteins that transfer the specificity of monoclonal antibodies (mAbs) to the effector functions of T cells. Their usual form is a type I transmembrane domain protein in which the ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/725C07K14/705C12N5/0783A61K35/17C07K16/28A61K31/436
CPCA61K35/17C07K14/7051C07K14/70589C07K16/2803C12N5/0636A61K2039/505C07K2319/00C07K2319/03C07K14/70503C07K14/7056C07K14/70596C07K14/415A61K31/436A61K31/343A61K31/4025A61K39/395C07K2319/70C07K16/3084C07K14/70521
Inventor S.科多巴E.科卡拉基M.普勒S.托马斯S.奥诺哈
Owner AUTOLUS LIMIED
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