Diaryl trehalose compounds and uses thereof
Inventors
Burkhart, David • ETTENGER, GEORGE • Evans, Jay • Ryter, Kendal T. • Smith, Alyson
Assignees
University of Montana Missoula
Publication Number
US-12319709-B2
Publication Date
2025-06-03
Expiration Date
2039-02-21
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Abstract
Disclosed herein are diaryl trehalose compounds and methods of use thereof, for example as vaccine adjuvants.
Core Innovation
The invention discloses a new class of diaryl trehalose (DAT) compounds, defined by specific chemical structures described in detail in the patent, and their pharmaceutically acceptable salts. These compounds are characterized by unique substitutions at particular trehalose positions, incorporating aryl or heteroaryl moieties with various substituents, and explicitly exclude previously known trehalose derivatives. The compounds are disclosed along with methods for their use, for example, as vaccine adjuvants or immunomodulators.
The problem addressed is the lack of effective adjuvants that induce Th17-mediated immune responses, which are important for protection against several bacterial and fungal pathogens and useful in cancer and autoimmune disease. Existing adjuvants for human use predominantly stimulate Th1 or Th2 responses, with only one Th17-inducing adjuvant (CAF01) known, which has not advanced beyond early clinical trials. There is a need for new adjuvants with improved efficacy and safety to enable the development of new vaccines and therapeutics.
The disclosed diaryl trehalose compounds are shown to strongly stimulate Th17-type immune responses, induce the production of cytokines such as IL-6, IL-1β, IL-23, and TNFα, and act as potent agonists of the Mincle receptor, which is associated with Th17 adjuvant activity. These compounds can be formulated in vaccine and adjuvant compositions, either alone or in combination with various antigens, to enhance immunogenicity and modulate immune responses, or used in monotherapy settings.
Claims Coverage
There are five core inventive features outlined in the independent claims.
Diaryl trehalose compound of formula (I)
A compound of formula (I) or a pharmaceutically acceptable salt thereof, defined such that: - The compound comprises two aryl or heteroaryl moieties attached to specific positions of trehalose via variable linkers and substituents. - The structural formula includes restrictions on possible substituents and explicitly excludes a comprehensive list of previously known compounds. - The compound may exist as stereoisomers, racemic or optically pure forms, and can be prepared as isotopically labeled versions.
Compound of formula (Ia) with specific alkyl substitutions
A compound of formula (Ia) as a subset of formula (I), or a salt thereof, where: - The aryl substituents on the trehalose have hydrogen, C1–C8 alkyl, and hydroxy groups. - At least one R3a and R5a is C1–C8 alkyl and at least one R3b and R5b is C1–C8 alkyl. - Specific variants where all R3a, R3b, R5a, and R5b are C1–C8 alkyl, including, but not limited to, isopropyl, tert-butyl, methyl or ethyl.
Compound of formula (Ib) with haloalkyl substituents
A compound of formula (Ib) as a subset of formula (I), or a salt thereof, where: - The aryl substituents on the trehalose include C1–C12 alkyl, hydroxy, C1–C12 alkoxy, or C1–C4 haloalkyl, among other defined allowed groups. - The C1–C4 haloalkyl is specifically defined as trifluoromethyl in one embodiment.
Adjuvant composition containing diaryl trehalose compound
An adjuvant composition comprising an effective amount of any of the compounds of claim 1 (covering all embodiments of formula (I)), or a pharmaceutically acceptable salt thereof.
Vaccine and methods of inducing or enhancing immunogenicity
A vaccine composition comprising: - (a) an antigen; and - (b) an adjuvant composition comprising an effective amount of one of the diaryl trehalose compounds or their salts. Additionally, the claims cover a method for inducing or enhancing immunogenicity of an antigen in a subject by administering to the subject such a vaccine composition. The claims further cover a method of modulating an immune response in a subject by administering to the subject an immunomodulatory composition comprising an effective amount of the diaryl trehalose compound or a pharmaceutically acceptable salt thereof.
The inventive features define novel diaryl trehalose compounds with specified chemical structures and substituents, detail their use in adjuvant and vaccine compositions, and cover methods for enhancing immunogenicity and modulating immune responses using these compounds.
Stated Advantages
The disclosed compounds represent a new class of Th17-inducing adjuvants, addressing the need for adjuvants that induce Th17-type immune responses for vaccines targeting bacterial and fungal pathogens, certain cancers, and autoimmune diseases.
The compounds are shown to potently stimulate cytokines associated with Th17 responses, such as IL-6, IL-1β, IL-23, and TNFα, and induce strong signaling through the Mincle receptor.
Some compounds, such as UM1024, display over 1000-fold increased potency (EC50) in cytokine induction compared to other compounds.
The adjuvant and vaccine compositions containing these compounds can enhance immunogenicity to a co-administered antigen and support the production of antigen-specific CD4+ and CD8+ Th17 cells.
Documented Applications
Use as vaccine adjuvants to enhance the immune response to antigens from microbial pathogens, bacteria, viruses, proteins, glycoproteins, lipoproteins, peptides, glycopeptides, lipopeptides, toxoids, carbohydrates, and tumor-specific antigens.
Use in treatment of cancer, either by modulating immune response or by directly inhibiting or reducing the growth or proliferation of cancer cells.
Use in the treatment and prevention of autoimmune disorders by modulating the immune response.
Use in methods for inducing or enhancing immunogenicity of an antigen in a subject, including incorporation into vaccine compositions for eliciting Th17-type immune responses.
Use as immunomodulatory agents for monotherapy to modulate the immune response in a subject.
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