Toll-like receptor ligands
Inventors
Bazin-Lee, Helene • ETTENGER, GEORGE • Khalaf, Juhienah • Ryter, Kendal T.
Assignees
National Institutes of Health NIH
Publication Number
US-12150948-B2
Publication Date
2024-11-26
Expiration Date
2039-02-12
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Abstract
Toll-like receptor (TLR) ligands having an allose-based core are stable in aqueous formulation and are useful in treating, preventing, or reducing susceptibility to diseases or conditions mediated by TLRs, such as cancer, infectious disease, allergy, autoimmune disease, sepsis, and ischemia reperfusion.
Core Innovation
The invention relates to novel Toll-like receptor (TLR) ligands possessing an allose-based core that display remarkable stability in aqueous formulation. These compounds or their pharmaceutically acceptable salts are designed for use in treating, preventing, or reducing susceptibility to diseases or conditions mediated by Toll-like receptors, including cancer, infectious diseases, allergies, autoimmune diseases, sepsis, and ischemia reperfusion. The ligands of the invention also serve as modulators of TLR activity and can be utilized in pharmaceutical compositions, methods, and kits for therapeutic and preventive applications.
The problem addressed arises from the existing limitations of known TLR ligands such as lipid A and its derivatives. Lipid A is a glucosamine-based bacterial membrane component that activates TLR4 but exhibits extreme toxicity, including systemic inflammatory response syndrome, limiting its medicinal utility. Attempts to produce less toxic derivatives like monophosphoryl lipid A (MPL) have encountered issues of heterogeneity, low potency, and poor stability, hindering their development and use in various indications. Therefore, there is a need for improved TLR ligands that provide enhanced potency, stability, and purity to advance therapeutic applications.
Claims Coverage
The claims of the patent define inventive features across independent claims that focus on compounds with specific structural features, pharmaceutical compositions, methods of treating immune-responsive diseases, and kits. The key inventive aspects are presented in several independent claims delineating novel compounds, their specific substituents, methods of immune modulation, and therapeutic uses.
Novel TLR ligands with an allose-based core and specific substituents
The patent claims compounds of formula (I) and derivatives thereof featuring an allose-based scaffold with detailed chemical substituents defined for R1, R2a, R2b, R2c, R3a, R3b, R3c, R3d, R4a, R4b, R5, R6, X1, X2, X3, Y1, Y2, Y3, Y4, Z1, Z2, k, and q, conferring stability and activity as TLR ligands.
Pharmaceutical compositions containing the compounds
Compositions comprising a pharmaceutically acceptable carrier and one or more compounds of formula (I) or their pharmaceutically acceptable salts, formulated for administration to treat or prevent TLR-mediated diseases.
Methods for treating or preventing TLR-mediated diseases and modulating immune responses
Methods involving administering therapeutically effective amounts of compounds of formula (I) or pharmaceutical compositions thereof to subjects to treat, prevent, or reduce susceptibility to diseases including cancer, infectious diseases, allergies, autoimmune conditions, sepsis, ischemia reperfusion, and to elicit, enhance, or modify immune responses.
Use of compounds for manufacture of medicaments and kits
Use of compounds of formula (I) or salts to manufacture medicaments for therapy of TLR-mediated diseases, and kits comprising compounds or pharmaceutical compositions with relevant instructions for treatment or prevention.
The independent claims collectively cover novel allose-based TLR ligands with defined substituents, their pharmaceutical formulations, methods of eliciting or modifying immune responses, treating various TLR-mediated conditions, and related uses and kits. These claims define the inventive scope focusing on chemical structure, formulation, therapeutic methods, and manufacturing uses of the compounds.
Stated Advantages
The claimed TLR ligands have remarkable stability in aqueous formulations, enabling improved shelf life and practical pharmaceutical use.
These compounds exhibit improved potency and purity relative to known TLR ligands, addressing previous limitations of heterogeneity and low therapeutic activity.
The compounds provide balanced signaling through MyD88 and TRIF pathways, which may enhance therapeutic index and reduce toxicity.
The formulations enable dose-dependent adjuvant activity, enhancing vaccine-specific antibody responses and providing non-specific protection against viral challenge.
Documented Applications
Treatment, prevention, or reduction in susceptibility to cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and hematologic malignancies.
Treatment, prevention, or reduction in susceptibility to infectious diseases caused by bacterial, viral, fungal, and prion pathogens.
Treatment, prevention, or reduction in susceptibility to allergies including food allergy, allergic rhinitis, asthma, seasonal allergies, allergic conjunctivitis, atopic dermatitis, and psoriasis.
Treatment, prevention, or reduction in susceptibility to autoimmune diseases characterized by aberrant immune responses to self-antigens.
Use as vaccine adjuvants to enhance humoral and cellular immune responses against infectious agents and cancer antigens.
Treatment or prevention of sepsis by antagonizing endotoxin activation of TLR4.
Treatment or prevention of ischemia reperfusion injuries to attenuate inflammatory cytokine release.
Treatment or prevention of ocular diseases such as macular degeneration and ocular hypertension.
Treatment or prevention of epileptic seizures.
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