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Auto/allo-immune defense receptors for the selective targeting of activated pathogenic t cells and nk cells

a technology of auto-immune defense and alloimmune defense, which is applied in the field of immunology, cell biology, molecular biology, medicine, can solve the problems of limiting the therapeutic benefit, and achieve the effect of avoiding allo-immune reactions and convenient us

Pending Publication Date: 2022-01-06
BAYLOR COLLEGE OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes how to modify cells to make them suitable for use in treatment without causing rejection by the host. Specifically, the cells are modified to express a chimeric receptor that targets specific compounds present on activated T cells. This receptor can be introduced into cells using a variety of methods, such as retroviral infection or electroporation. The modified cells can then be delivered to the individual to inhibit the rejection response and promote T-cell activation. This approach allows for the use of third-party-derived therapeutic cells without the need for patient-specific production every time. Overall, this technology provides a way to prevent rejection of allogeneic cells and tissues and promote immune tolerance.

Problems solved by technology

Although some steps may be taken to reduce the reactivity of allogeneic cells in the recipient individual, such cells would still be targeted by the immune system of the recipient (primarily T- and NK-cells), which would recognize them as foreign leading to rejection and limiting therapeutic benefit.

Method used

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  • Auto/allo-immune defense receptors for the selective targeting of activated pathogenic t cells and nk cells
  • Auto/allo-immune defense receptors for the selective targeting of activated pathogenic t cells and nk cells
  • Auto/allo-immune defense receptors for the selective targeting of activated pathogenic t cells and nk cells

Examples

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example 1

Auto / Allo-Immune Defense Receptors for the Selective Targeting of Pathogenic T Cells

[0140]Disclosed herein is a novel approach to specifically target pathogenic T cells using auto / allo-immune defense receptors (ADRs) expressed on normal T cells. ADR-expressing T cells find and eliminate only activated T cells and spare resting non-pathogenic naïve and memory T cells, which constitute the majority of circulating lymphocytes

[0141]The concept of the ADR-mediated targeting is based on the observation that within 24 h of activation, T cells transiently upregulate costimulatory genes 4-1BB, OX40, and / or CD40L on their cell surface. The expression of 4-1BB, OX40, and / or CD40L is only maintained when the T-cells are actively cytotoxic and is gradually downregulated within 4-5 days, when TCR signaling has stopped. Notably, activated CD8+ T cells showed higher magnitude of 4-1BB expression whereas CD4+ T cells preferentially expressed OX40 and / or CD40L. Apart from activated T cells, ADR ligan...

example 2

Auto / Allo-Immune Defense Receptors for the Selective Targeting of NK Cells

[0146]The ADRs demonstrate a specific cytotoxic activity against NK cells, a key cell population mediating rapid rejection of HLAlow or HLA-mismatched cells.

[0147]NK cells are capable of recognizing HLA-mismatched cells or cells with low HLA expression, as a part of the anti-tumor and anti-viral immune surveillance. Adoptive transfer of allogeneic cells into immunoreplete patients would thus result in NK-cell activation and rejection of the HLA-mismatched cells. Here, it is shown that co-culture of T cells expressing 4-1BB- and OX40-specific auto / allo-immune defense receptors (ADRs) leads to elimination of NK cells and thus would offset the NK cell-mediated host rejection of ADR-armed allogeneic T cells. Therefore, ADRs do not only inhibit the alloreactive T-cell response but also suppress NK cell mediated rejection, further supporting the application of ADRs to enhance the persistence and activity of “off-the...

example 3

ADR-Expressing T Cells Eliminate Target Cells

[0148]ADRs can be expressed on cell surface of immune cells and promote cytotoxicity against respective targets. FIG. 1A illustrates one example of a schematic of ADR (a label such as GFP is optional). The expression of ADR on the surface of T cells was confirmed (FIG. 1B) and the cells were expanded commensurate with controls (FIG. 1C). (FIG. 1D) The ADR-expressing T cells were cytotoxicity against target cells expressing corresponding ADR ligands (FIG. 1D). FIG. 1E demonstrates expansion of wild-type vs 4-1BB KO T cells expressing 4-1BB ADR and their cytotoxicity against 4-1BB+ targets. Knocking out the ADR ligand on T cells can further enhance expansion and cytotoxicity, and co-expression of ADR and its ligand on T cells is not required for ADR-T cell expansion or function (FIG. 1E).

[0149]Selective expression of ADR ligands on activated T cells enables their selective elimination by ADR T cells. Expression of ADR ligands on resting vs ...

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Abstract

Embodiments of the disclosure concern engineered auto / allo-immune defense receptor (ADR)-expressing T cells that selectively target activated T cells, including pathogenic T cells, to incapacitate them. The chimeric receptors comprise moieties for targeting 4-1BB, OX40, and CD40L, for example, whose expression is indicative of activated T cells. In particular embodiments, there are methods of preventing or treating conditions associated with activated T cells using adoptive T-cell transfer of cells encoding the ADRs.

Description

[0001]This application is a continuation of U.S. Non-Provisional application Ser. No. 17 / 049,561 filed Oct. 21, 2020 which is a national phase application under 35 U.S.C. § 371 that claims priority to International Application No. PCT / US2019 / 029163 filed Apr. 25, 2019, which claims priority to U.S. Provisional Patent Application 62 / 662,817, filed Apr. 26, 2018, all of which are incorporated by reference herein in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under P50 CA126752 awarded by National Institutes of Health and the National Cancer Institute. The government has certain rights in the invention.INCORPORATION OF SEQUENCE LISTING[0003]The instant application contains a Sequence Listing, named “Seq_Listing.txt” (18,804 bytes), created Feb. 26, 2021, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.TECHNICAL FIELD[0004]Embodiments of...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/17A61P37/06C07K14/705
CPCA61K35/17A61P37/06C07K2319/30C07K14/70578C07K14/70575A61K48/00C07K14/70596C07K2319/03C07K14/7051C07K2319/33C12N15/62C07K14/705A61K39/464471A61K39/4631A61K39/4611A61K39/46434A61K2239/48A61K2239/26C12N5/0636A61K39/4621A61K2239/38C07K16/2875C12N2510/00C07K2319/02A61K48/005C07K16/2878A61K39/0011A61K2039/5158A61K2039/5156
Inventor MAMONKIN, MAKSIMBRENNER, MALCOLM K.MO, FEIYAN
Owner BAYLOR COLLEGE OF MEDICINE
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