Chimeric autoantibody receptor (CAAR) that binds autoantibodies targeting the central nervous system in neurological autoimmune disease

A technology for autoimmune diseases and autoantibodies, applied in nervous system diseases, allergic diseases, antibody medical components, etc., can solve problems such as lack of experimental support, reduce the risk of infection or sepsis, and reduce toxic immune side effects , the effect of reducing the risk of clinical recurrence

Pending Publication Date: 2022-02-01
德国神经退行性疾病中心 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no experimental support is provided for this embodiment, and effector T cells are excluded from the use of such constructs

Method used

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  • Chimeric autoantibody receptor (CAAR) that binds autoantibodies targeting the central nervous system in neurological autoimmune disease
  • Chimeric autoantibody receptor (CAAR) that binds autoantibodies targeting the central nervous system in neurological autoimmune disease
  • Chimeric autoantibody receptor (CAAR) that binds autoantibodies targeting the central nervous system in neurological autoimmune disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0321] Example 1: Generation of NMDAR-CAAR constructs and corresponding CAAR-T cells

[0322] A schematic outline of the method of the present invention is as figure 1 shown.

[0323] In order to demonstrate a practical non-limiting embodiment of the invention, the inventors created several CAAR-T constructs ( figure 2 ). These constructs are based on the backbone of the CAR vector ( figure 2 B). The domain of the NMDA receptor has been localized in the CAR vector, replacing the conventional antibody fragment usually contained in the CAR vector.

[0324] To this end, various combinations of immune-relevant extracellular NMDA receptor domains were cloned into CAR constructs ( figure 2 A). Such as figure 2 Shown in A, the amino-terminal domain (ATD) and domains S1 and S2 of the NR1 subunit of the NMDA receptor were used in place of the typical antigen-binding antibody fragment of the CAR construct, resulting in a chimeric autoantibody receptor (CAAR) Constructs in wh...

Embodiment 2

[0328] Example 2: Activation of CAAR-T cells by clustered anti-NMDAR NR1 antibodies

[0329] For this, ELISA plates were coated with human NMDAR antibodies and then incubated with CAAR-T cells or control T cells. Activation of CAAR-T cells results in the release of interferon-γ, which is measured in the supernatant.

[0330] image 3 It was shown that strong release of interferon-γ was clearly visible only when NMDAR antibodies (003-102, 008-218) bound to CAAR-T cells (left column in the figure). No significant amounts of interferon-γ were detected in samples on ELISA plates coated with control antibodies (mGo, 113-115), or in samples incubated with NMDAR antibodies and control T cells (right column in the figure).

Embodiment 3

[0331] Example 3: Activation of CAAR-T cells by NMDAR NR1 antibody presented on the surface of HEK or K562 cells

[0332] To this end, the inventors employed a previously established human cell model producing NMDA receptor antibodies. In this model, HEK293 cells express a human monoclonal NMDA receptor antibody localized to their cell membrane. The sequence of a human NMDA receptor antibody was previously determined (Kreye et al., 2016).

[0333] Figure 4showed that, similar to the assay described in Example 2, strong activation of CAAR T cells was observed only in samples subjected to co-culture with target cells for 48h (upper panel) or 24h (lower panel) (left column in the figure) is evident, corresponding to a large release of interferon-γ, but could not be observed in samples co-cultured with HEK wild-type cells or co-cultured with control T cells (right column in the figure).

[0334] Figure 5 showed that co-culture of CAAR T cells at a ratio of 1:1 with K562 cell...

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Abstract

The invention relates to a chimeric autoantibody receptor (CAAR) that enables targeting of an immune cell to autoantibody producing B cells. The CAAR comprises an autoantigen or fragment thereof that is bound by autoantibodies associated with a neurological autoimmune disease primarily targeting the central nervous system. The invention relates to a nucleic acid molecule encoding a chimeric autoantibody receptor (CAAR), the nucleic acid molecule comprising a sequence encoding an autoantigen or fragment thereof that is bound by autoantibodies associated with a neurological autoimmune disease primarily targeting the central nervous system, a sequence encoding a transmembrane domain, and a sequence encoding an intracellular signaling domain. In one embodiment, the autoantigen encoded by the nucleic acid sequence comprises or consists of an N- methyl-D-aspartate receptor (NMDAR), or one or more NMDAR fragments. The invention further relates to the chimeric autoantibody receptor (CAAR) protein of the invention, a vector comprising a nucleic acid molecule encoding a chimeric autoantibody receptor (CAAR) of the invention, a genetically modified immune cell comprising the nucleic acid molecule encoding the CAAR and the use of the immune cell in the treatment or prevention of a neurological autoimmune disease primarily targeting the central nervous system, such as an autoimmune encephalopathy or encephalomyelopathy, preferably anti-NMDAR encephalitis.

Description

technical field [0001] The present invention relates to the field of targeted cell therapy using chimeric autoantibody receptors and the treatment of neurological autoimmune diseases. [0002] The present invention relates to chimeric autoantibody receptors (CAARs) capable of targeting immune cells to autoantibody-producing B cells. The CAAR comprises an autoantigen or fragment thereof that binds an autoantibody associated with a neuroautoimmune disease primarily targeting the central nervous system. The present invention relates to a nucleic acid molecule encoding a chimeric autoantibody receptor (CAAR), comprising: a sequence encoding an autoantigen or a fragment thereof that binds to a neural autoimmunity primarily targeting the central nervous system A disease-associated autoantibody; a sequence encoding a transmembrane domain; and a sequence encoding an intracellular signaling domain. [0003] In one embodiment, the self-antigen encoded by said nucleic acid sequence com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/62C07K19/00C12N15/867C12N5/10A61K39/00A61P25/00A61P25/28A61P37/02
CPCC07K14/7051C07K16/286C12N15/86C12N5/0636A61K39/001111A61P25/00A61P25/28A61P37/02C07K2319/03C07K2319/33C07K2319/02C12N2740/15043C12N2740/00043C12N2510/00A61K2039/5158A61K2039/505C07K2319/00A61K35/17C07K14/70571C07K14/4713C07K2317/21A61K2039/572C07K14/70517A61K35/15A61K31/506
Inventor 哈拉尔德·普吕斯S·莫姆森·赖因克伊南·埃德斯
Owner 德国神经退行性疾病中心
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