Vaccine adjuvants based on TLR receptor ligands
Inventors
Bazin-Lee, Helene • Burkhart, David • Evans, Jay
Assignees
University of Montana Missoula
Publication Number
US-11964014-B2
Publication Date
2024-04-23
Expiration Date
2040-05-22
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Abstract
Lipidated oxoadenines of formula (I) are TLR7/8 receptor ligands useful for modulating immune responses. The compounds may have therapeutic application in the treatment of cancer, infectious diseases, allergy, or autoimmune disorders.
Core Innovation
The invention relates to PEGylated and lipidated oxoadenine compounds that act as ligands for Toll-Like Receptors 7 and 8 (TLR7/8). These compounds, described by formula (I) and its pharmaceutically acceptable salts, have been developed to modulate immune responses and serve as novel vaccine adjuvants and immunotherapeutic agents. The compounds can be formulated alone or within pharmaceutical compositions, adjuvant compositions, or vaccine compositions, and may be incorporated into microparticles or nanoparticles such as liposomes.
A significant problem addressed by the invention is the lack of effective and safe TLR7/8 ligands for use in vaccines and immunotherapeutics. Existing TLR7/8 agonists, including non-PEGylated oxoadenines and imidazoquinolines, often suffer from toxicity, poor solubility, instability, or insufficient immunostimulatory activity, and can cause systemic inflammatory responses that limit their use in clinical applications.
The central innovation lies in developing PEGylated and lipidated oxoadenine compounds that demonstrate immunomodulatory activity, including induction of Th1-type cytokines such as IFN-α and IL-12p70. These compounds can be used to modulate immune responses in subjects, induce or enhance immunogenicity of antigens, and in the treatment, prevention, or reduction of susceptibility to cancer, infectious diseases, allergies, and autoimmune conditions. The invention also encompasses compositions and methods for using these compounds as adjuvants or in combination with antigens, chemotherapeutic agents, or immune modulatory agents.
Claims Coverage
The patent contains several independent claims centered on compounds, compositions, and methods comprising lipidated and PEGylated oxoadenine TLR7/8 ligands.
Compounds of formula (I) as TLR7/8 ligands
A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: - R1 is C1-C8 alkyl; - R2 is H, C6-C20 alkyl, C6-C20 alkenyl, or C(O)R4; - R3 is C6-C20 alkyl, C6-C20 alkenyl, or C(O)R4; - R4, at each occurrence, is independently C6-C20 alkyl or C6-C20 alkenyl; - n is 1–6; - m is 2–6; - Z is (C2-C6 alkylene-O)q; - q is 1–20. The compounds optionally include specific substituents for R4, including (CH2)14CH3, (CH2)10CH3, (CH2)12CH3, and (CH2)16CH3.
The inventive coverage centers on structurally defined PEGylated and lipidated oxoadenine compounds as TLR7/8 receptor ligands for use in immunomodulatory applications.
Stated Advantages
The compounds possess an improved activity-toxicity profile in comparison to other known oxoadenine-based TLR7/8 ligands.
The introduction of a PEGylated linker increases IFNα induction and synergy with TLR4 agonists for cytokine production.
The compounds can be formulated in various delivery systems, including liposomes and as salts, for enhanced application flexibility.
Documented Applications
Use in modulating an immune response in a subject.
Use as a vaccine adjuvant to induce or enhance the immunogenicity of an antigen.
Treatment, prevention, or reduction of susceptibility to cancer.
Treatment, prevention, or reduction of susceptibility to infectious diseases, including those caused by viruses, bacteria, or prions.
Treatment, prevention, or reduction of susceptibility to allergies.
Treatment, prevention, or reduction of susceptibility to autoimmune conditions.
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