Beta-mannosylceramide and stimulation of NKT cell anti-tumor immunity
Inventors
Berzofsky, Jay A. • O'Konek, Jessica J. • Terabe, Masaki • Illarionov, Petr A. • Besra, Gurdyal S.
Assignees
University of Birmingham • US Department of Health and Human Services
Publication Number
US-9517243-B2
Publication Date
2016-12-13
Expiration Date
2031-03-11
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Abstract
β-mannosylceramides or salts or solvates thereof in a pharmaceutically acceptable carrier, for use as a Type I NKT cell agonist in conjunction with a therapeutically effective amount of α-galactosylceramide or a salt or a solvate thereof, and/or at least one or more T-cell co-stimulatory molecules, disclosed. Compositions comprising β-mannosylceramide, as well as methods of treatment of tumors are also provided.
Core Innovation
The invention provides compositions and methods for activating Type I natural killer T (iNKT) cells in mammals using β-mannosylceramide (β-ManCer) or its salts or solvates in pharmaceutically acceptable carriers. These compositions may include β-ManCer alone, or combined with therapeutically effective amounts of α-galactosylceramide (α-GalCer), other α-glycosylceramides, cytokines (such as IL-2, GM-CSF, IL-12, IL-15), T-cell co-stimulatory molecules, Toll-like receptor (TLR) ligands, vaccines, antibodies, or chemotherapeutic agents. The methods involve administering these compositions to induce NKT cell activation and anti-tumor immune responses.
The problem addressed arises from the need for novel methods to activate NKT cells to treat cancers and induce immune responses effectively and safely. While α-GalCer is a known potent NKT cell agonist that stimulates cytokine production and tumor immunity, there is a need for alternative or complementary agents that may act via distinct mechanisms, potentially offering synergistic anti-tumor effects and reduced adverse events like NKT cell anergy.
The invention unexpectedly found that β-ManCer induces strong protection against tumor formation in an iNKT cell-dependent manner despite inducing little cytokine production compared to α-GalCer. β-ManCer mediates tumor immunity via mechanisms dependent on nitric oxide synthase and TNF-α, distinct from the IFN-γ-dependent pathway utilized by α-GalCer. Furthermore, β-ManCer and α-GalCer act synergistically in inducing tumor protection when used in combination at subtherapeutic doses, revealing complementary modes of NKT cell activation and anti-cancer activity.
Claims Coverage
The patent contains one independent composition claim and one independent method claim, covering compositions comprising β-mannosylceramide with specified features and associated therapeutic agents, and methods for inducing immune responses or treating cancers using such compositions.
Composition comprising β-mannosylceramide with defined ceramide moiety and chemotherapeutic agents
The composition includes a β-mannosylceramide (β-ManCer) or its salt or solvate in a pharmaceutically acceptable carrier, wherein the β-ManCer consists of a β-mannosyl moiety linked to a ceramide moiety composed of a sphingosine moiety and a fatty acid moiety with a linear or branched, saturated or unsaturated aliphatic hydrocarbon chain of about 8 to about 49 carbon atoms. The composition further comprises a therapeutically effective amount of one or more chemotherapeutic agents.
Fatty acid moiety chain length variants in the β-mannosylceramide composition
The β-ManCer fatty acid moiety can specifically have from about 8 to about 15 carbon atoms or from about 18 to about 30 carbon atoms.
Co-formulation with immune-stimulating cytokines and molecules
The composition can further include therapeutically effective amounts of IL-2, an α-glycosylceramide (such as α-galactosylceramide), GM-CSF, and other cytokines inducing cellular immunity like IL-12 and/or IL-15, one or more T-cell co-stimulatory molecules (e.g., B7 family members, ICAMs, LFA molecules, CD40L, OX40L, 4-1BBL), and one or more Toll-like receptor ligands targeting TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, or TLR9.
Inclusion of vaccines and antibodies for enhanced immunotherapy
The composition may also comprise vaccines such as TARP 29-37-9V peptide or Sargramostin (GM-CSF) emulsified in Montanide ISA 51 VG, and antibodies targeting immune checkpoints or regulators such as CTLA-4, PD-1, or TGF-beta to overcome negative regulation and enhance β-ManCer's effect.
Method of inducing immune response or treating cancer with defined cancer types
A method of inducing an immune response, treating cancer, or inhibiting tumor growth in a subject by administering an effective amount of the β-ManCer composition, where the cancer includes liver, brain, neck, skin, lung, kidney, stomach, colon, prostate, breast, ovarian, melanoma, or lymphoid cancers, and tumors include lung, breast, colon, liver, brain, neck, prostate, ovarian, skin, melanoma, and lymphoid tumors.
Method of manufacturing β-mannosylceramide composition
The method involves reacting 2-amino-1-O-β-mannopyranosyl-D-ribo-1,3,4-octadecanetriol with an electrophile to form β-ManCer, then combining it with a pharmaceutically acceptable carrier and one or more chemotherapy agents to make the final composition.
The claims cover pharmaceutical compositions comprising β-mannosylceramide with defined structural features, optionally combined with cytokines, α-glycosylceramides, co-stimulatory molecules, TLR ligands, vaccines, antibodies, and chemotherapeutic agents, and methods of using these compositions to induce immune responses and treat a variety of cancers and tumors. The manufacturing method of β-ManCer compositions is also claimed.
Stated Advantages
β-ManCer induces strong iNKT cell-dependent tumor protection with distinct and synergistic mechanisms compared to α-GalCer.
β-ManCer activates iNKT cells with reduced cytokine production, avoiding strong induction of NKT cell anergy seen with α-GalCer.
Combinations of β-ManCer and α-GalCer yield synergistic anti-tumor effects at subtherapeutic doses.
β-ManCer shows broad anti-tumor efficacy across multiple tumor types and mouse strains, including colon carcinoma and melanoma.
β-ManCer activates human iNKT cells, indicating potential clinical utility.
Documented Applications
Treatment or inhibition of growth of tumors or cancers in subjects, including lung, breast, colon, liver, kidney, brain, neck, prostate, ovary, skin, melanoma, and lymphoid cancers.
Inducing immune responses in subjects to enhance anti-tumor immunity via activation of NKT cells.
Use alone or in combination with α-glycosylceramides, cytokines, T-cell co-stimulatory molecules, TLR ligands, vaccines (e.g., TARP 29-37-9V peptide), antibodies (e.g., anti-CTLA-4, anti-PD-1), and chemotherapeutic agents to improve cancer immunotherapy outcomes.
In vitro activation of NKT cells for adoptive cell therapy to treat or inhibit tumor growth in subjects.
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