Steroid compounds as Treg modulators and uses thereof
Inventors
Littman, Dan R. • Huh, Jun R. • Fischbach, Michael
Assignees
Publication Number
US-12103946-B2
Publication Date
2024-10-01
Expiration Date
2039-10-08
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Abstract
Steroid compounds are disclosed that have a formula represented by the following: (I) and wherein R1, R2, R3a, R3b, R4a, R4b, R5, R6a, R6b, R7, R8, and n are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for promoting differentiation of T regulatory (Treg) lymphocytes, and for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, inflammatory conditions, autoimmune disorders, and graft-versus-host disease.
Core Innovation
The invention provides steroid compounds of formula I and related derivatives, which, when used in pharmaceutical compositions or administered as such, promote the differentiation of T regulatory (Treg) lymphocytes and/or suppress the function of pro-inflammatory Th17 cells. Specific compounds highlighted include derivatives such as 3-oxoLCA and isoalloLCA, as well as their salts, solvates, hydrates, prodrugs, and stereoisomers. These compounds can be employed in vitro, in vivo, or ex vivo to induce or enrich populations of Tregs from naive CD4+ T lymphocytes, either for direct therapeutic application or for adoptive transfer.
The problem addressed relates to the need for effective means to potentiate Treg differentiation and function, or to suppress Th17 cell function, in the context of controlling pathological immune responses. Tregs are known to regulate and inhibit excessive or uncontrolled immune responses, and deficits or dysfunctional Treg activity are implicated in autoimmune disorders, inflammatory diseases, and complications such as graft-versus-host disease (GVHD) after transplantation. The patent identifies that existing therapies either do not directly modulate adaptive immune cells or remain limited in efficacy regarding Treg expansion and functional modulation.
The invention demonstrates, through screening and in vitro and in vivo studies, that specific steroidal compounds—such as 3-oxoLCA which binds to RORγt to inhibit Th17 differentiation, and isoalloLCA which enhances Treg differentiation via mitochondrial ROS and CNS3-dependent FoxP3 acetylation—can modulate the activity and balance between Tregs and Th17 cells. This provides a chemical and biological basis for novel strategies in treating and managing diseases characterized by immune dysregulation, including use as therapeutics for autoimmune diseases, inflammatory conditions, and in transplant settings to mitigate rejection or GVHD.
Claims Coverage
The patent contains multiple independent claims, each directed to inventive features regarding the use of specific steroid compounds and their effects on Treg and Th17 cells.
Method for promoting differentiation of T regulatory lymphocytes and/or suppressing inflammatory Th17 cells using specified steroid compounds
A method comprises contacting naive CD4+ T lymphocytes with an effective amount of a compound having a defined steroid structure as specified by formula I or related structures. The key inventive feature is the direct use of these compounds to promote Treg differentiation and/or suppress Th17 cell function.
Use of iso-allo-lithocholic acid or allo-lithocholic acid for Treg differentiation
A method specifically uses iso-allo-lithocholic acid (isoalloLCA) or allo-lithocholic acid (alloLCA), contacting naive CD4+ T lymphocytes with an effective amount of these compounds to promote the differentiation of T regulatory (Treg) lymphocytes.
Use of 3-oxoLCA for T cell modulation
A method comprising the use of 3-oxoLCA, a specific steroid compound, for promoting differentiation of T regulatory lymphocytes and/or suppressing inflammatory Th17 cells, by contacting naive CD4+ T lymphocytes with an effective amount of 3-oxoLCA.
The inventive features of the independent claims center on the use of specific steroid compounds, particularly isoalloLCA, alloLCA, and 3-oxoLCA, to modulate Treg and Th17 differentiation via direct application to naive CD4+ T lymphocytes. The inventive aspects cover the compounds themselves, compositions thereof, and their use in methods for immune modulation.
Stated Advantages
The compounds and methods promote increased differentiation and function of T regulatory lymphocytes and/or suppress pro-inflammatory Th17 cells, thereby modulating immune responses effectively.
The invention enables prevention, treatment, or amelioration of autoimmune and inflammatory diseases, including those arising after organ or tissue transplantation, such as GVHD.
The compounds can be used to expand Treg populations both in vitro and in vivo, providing a means for improving the efficacy of Treg cell therapy.
The use of these compounds may lead to enhanced transplant retention and decrease the incidence of host immune response-mediated rejection.
Documented Applications
Treatment and prevention of autoimmune diseases, such as type 1 diabetes, multiple sclerosis (MS), rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, uveitis, and auto-immune gastritis.
Use in organ or tissue transplantation settings to treat or prevent graft-versus-host disease (GVHD) or rejection of transplants.
Promotion of Treg differentiation and/or activity in patients with excessive or uncontrolled immune responses and disorders with insufficient Treg responses.
Preparation and use of pharmaceutical compositions for the above indications, including oral, injectable, and transdermal formulations.
In vitro and ex vivo generation of Tregs for adoptive transfer to subjects in need thereof.
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