Methods of treating disease by metabolic control of T-cell differentiation
Inventors
Assignees
Publication Number
US-11241455-B2
Publication Date
2022-02-08
Expiration Date
2037-01-12
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Abstract
Provided herein are methods for treating an individual for a disease (e.g., an autoimmune disease or a cancer) using an active agent which affects metabolism of α-ketoglutarate (α-KG) and/or 2-hydroxyglutarate (2-HG) in differentiating T cells. In some embodiments, a Got1 inhibitor is used to generate a population of T cells enriched in peripheral regulatory T (iTreg) cells, which population enriched in iTreg cells may find use in treating an autoimmune disease. In some embodiments, a TCA cycle-associated metabolite, or a derivative thereof, is used to generate a population of T cells in enriched in IL-17- and IL-17F-producing CD4 T (TH17) cells, which population enriched in TH17 cells may find use in treating a cancer.
Core Innovation
Provided herein are methods for treating an individual for a disease, such as an autoimmune disease or cancer, by using an active agent that affects metabolism of α-ketoglutarate (α-KG) and/or 2-hydroxyglutarate (2-HG) in differentiating helper T cells. The active agent can be used to manipulate the balance between IL-17- and IL-17F-producing CD4 T (TH17) cells and peripheral regulatory T (iTreg) cells. Specifically, a Got1 inhibitor is used to generate a population enriched in iTreg cells, beneficial for treating autoimmune diseases. Conversely, a tricarboxylic acid (TCA) cycle-associated metabolite or its derivative can be used to enrich TH17 cells, which may be useful in treating cancers.
The problem addressed is the need to control the differentiation balance between pathogenic TH17 cells and regulatory iTreg cells, which is dysregulated in autoimmune diseases and cancers. TH17 cells have a dual role, contributing to host defense as well as pathogenic roles in autoimmune diseases. Regulatory T cells restrict TH17 function to maintain balance. Current treatments lack methods for precise metabolic control of this differentiation to treat diseases effectively.
This disclosure solves the problem by targeting metabolic pathways involving α-KG and 2-HG in differentiating T cells, using agents such as Got1 inhibitors or TCA cycle-associated metabolites to modulate the TH17/iTreg ratio. The methods include direct administration of the agents or ex vivo manipulation of T cells to generate enriched populations, which can then be administered therapeutically. This metabolic approach offers a novel strategy for immune balance reprogramming in disease treatment.
Claims Coverage
The patent contains multiple independent claims focusing on methods of treating autoimmune disease or cancer and methods of preparing T cell populations using metabolic agents. Three main inventive features are identified based on the independent claims presented.
Use of Got1 inhibitors to treat autoimmune diseases by enriching iTreg cells
Administering a therapeutically effective amount of a Got1 inhibitor selected from aminooxy-acetic acid (AOA), L-cycloserine, L-2-amino-4-methoxy-trans-but-3-enoic acid, 2-aminobut-3-enoic acid, and ethyl hydrazinoacetate to increase the ratio of peripheral regulatory T (iTreg) cells to IL-17- and IL-17F-producing helper T (TH17) cells, thereby treating autoimmune disease.
Use of TCA cycle-associated metabolites to treat cancer by enriching TH17 cells
Administering a therapeutically effective amount of a TCA cycle-associated metabolite, or derivative thereof, selected from 2-hydroxyglutarate (2-HG) and α-ketoglutarate (α-KG) to reduce the ratio of iTreg to TH17 cells and enrich for IL-17- and IL-17F-producing TH17 cells, thereby treating cancer.
Methods of preparing enriched T cell populations in vitro for treatment
Contacting populations of differentiating T cells with a Got1 inhibitor or a TCA cycle-associated metabolite/derivative to promote differentiation into iTreg or TH17 cells respectively, generating populations enriched for these cells compared to a reference population, followed by administering these enriched populations to an individual needing treatment for autoimmune disease or cancer.
The claims cover therapeutic methods of treating autoimmune diseases with Got1 inhibitors to increase iTreg cells, treating cancers with TCA cycle metabolites to enrich TH17 cells, and preparing populations of T cells ex vivo enriched for iTreg or TH17 cells by modulating α-KG/2-HG metabolism for therapeutic use.
Stated Advantages
Selective targeting of the glutamate metabolic pathway to shift the TH17/iTreg balance enables treatment of TH17-mediated autoimmune diseases.
Modulating metabolism of α-KG and 2-HG provides control over T-cell fate decisions affecting disease pathology.
Ex vivo manipulation of T cells to enrich desired T-cell subsets allows for tailored cell-based immunotherapies.
In vivo use of Got1 inhibitors demonstrated therapeutic efficacy in a mouse model of multiple sclerosis by promoting recovery.
Documented Applications
Treatment of autoimmune diseases characterized by pathological levels or activity of TH17 cells, including but not limited to acute disseminated encephalomyelitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, and other specified autoimmune disorders.
Treatment of cancers by enriching TH17 cells capable of tumor-associated antigen recognition, including hematological malignancies like leukemias and lymphomas and various solid tumors such as carcinomas, sarcomas, and melanomas.
Ex vivo preparation of T cell populations enriched for iTreg or TH17 cells for adoptive immunotherapy use in autoimmune disease or cancer patients respectively.
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