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Engineered regulatory t cell

An engineered, intracellular domain technology that can be used in animal cells, vertebrate cells, genetically modified cells, etc., and can solve problems related to high IL-2 dependence

Pending Publication Date: 2021-06-15
KINGS COLLEGE LONDON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the engineered Tregs of the present invention solve the problems associated with the high IL-2 dependence of adoptively transferred Tregs without the need to administer exogenous IL-2 but by providing potent IL-2 signaling in an antigen-specific manner

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0454] Example 1 - Production of anti-HLA.A2 IL2R CAR-Treg

[0455] CD4 + CD25 高 CD127 低 cells and activated with anti-CD3 / CD28 beads. Three days after activation, use HLA.A2-CAR (such as figure 2 indicated) and lentiviral transduction of GFP reporter gene Treg. After polyclonal activation, the cellular expansion of total Tregs showed no significant difference between non-transduced or transduced Tregs ( image 3 ).

Embodiment 2

[0456] Example 2 - Anti-HLA.A2 Quantification of transduction efficiency of IL2R constructs over time

[0457] GFP expression on untransduced Tregs and Tregs transduced with CAR constructs was analyzed at different time points after cell activation.

[0458] The frequency of GFP+ cells was analyzed to assess the transduction efficiency and expression persistence of the different constructs during Treg expansion. Tregs containing dCAR, CD28z, Construct 1, Construct 2, and Construct 3 showed similar expression frequencies after transduction. The percentage of GFP+ cells in the whole Treg was maintained during polyclonal cell expansion ( Figure 4 ).

Embodiment 3

[0459] Example 3 - Quantification of Cell Surface Expression of Anti-HLA.A2 IL2R CAR Constructs on Transduced Tregs

[0460] Membrane expression of the CAR constructs on non-transduced and transduced Tregs was analyzed by PE-conjugated HLA-A*0201 / CINGVCWTV dextroform (Immudex, Copenhagen, Denmark). The frequency of Treg expressing CAR protein on the cell surface among all constructs (HLA-A2 dextromorph + )resemblance( Figure 5 ).

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Abstract

The present invention provides an engineered regulatory T cell (Treg) comprising a chimeric antigen receptor (CAR) for use in induction of tolerance to a transplant; treating and / or preventing graft-versus-host disease (GvHD), an autoimmune or allergic disease; to promote tissue repair and / or tissue regeneration; or to ameliorate chronic inflammation secondary to metabolic disorders; wherein the CAR comprises an endodomain which comprises a STAT association motif and a JAK1- and / or a JAK2-binding motif.

Description

technical field [0001] The present invention relates to engineered regulatory T cells and therapeutic uses of such cells. In particular, the invention relates to engineered regulatory T cells that are less sensitive to microenvironments with limited IL-2 availability. Background technique [0002] Regulatory T cells (Treg) are immune cells with suppressive functions that control cytopathic immune responses and are critical for maintaining immune tolerance. The suppressive properties of Tregs can be used therapeutically, eg, to ameliorate and / or prevent immune-mediated organ damage in inflammatory diseases, autoimmune diseases and transplantation. Treg immunotherapy usually involves the isolation, culture, and expansion of Tregs, which are then infused into patients. As part of this process, Tregs can be incubated with cytokines, drugs, other cells or antigens to improve Treg viability and function and / or to confer enhanced reactivity to Tregs against specific antigens. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/0783C07K14/705
CPCC12N5/0637C12N2510/00C07K2319/03C07K2319/33C07K2319/70C07K14/7051C07K14/7155C12N2501/51C07K2317/622C07K16/2833A61P37/06A61K39/4631A61K39/4611A61K39/464419A61K39/4621C07K14/70521A61K48/00C07K2319/02C07K2319/30
Inventor M·马丁内斯-洛德拉A·桑切斯-富尤G·隆巴尔迪
Owner KINGS COLLEGE LONDON