β-mannosylceramide and stimulation of NKT cell anti-tumor immunity
Inventors
Berzofsky, Jay A. • O'Konek, Jessica J. • Terabe, Masaki • Illarionov, Petr • Besra, Gurdyal S.
Assignees
University of Birmingham • US Department of Health and Human Services
Publication Number
US-8835613-B2
Publication Date
2014-09-16
Expiration Date
2031-03-11
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 comprising β-mannosylceramides (β-ManCer) or their salts or solvates in a pharmaceutically acceptable carrier for use as Type I natural killer T (NKT) cell agonists. These compositions can be used alone or in conjunction with therapeutically effective amounts of α-galactosylceramide (α-GalCer) or salts or solvates thereof, and/or one or more T-cell co-stimulatory molecules or Toll-like receptor (TLR) ligands. Methods of treatment for tumors and cancer by activating NKT cells with these compositions are also disclosed.
The background describes the recognition that NKT cells bridge innate and adaptive immunity and are activated by glycolipid antigens presented by CD1d molecules. α-GalCer is a potent stimulator of Type I invariant NKT (iNKT) cells that induces strong pro-inflammatory cytokine responses and anti-tumor immunity. However, there remains a need to develop alternative methods to activate NKT cells which could lead to new treatments for cancer or other immune responses.
The invention unexpectedly demonstrates that β-ManCer induces iNKT cell-dependent tumor protection through mechanisms distinct from α-GalCer. β-ManCer provides potent anti-tumor activity even though it does not induce substantial cytokine production such as IFN-γ, IL-4, or IL-13. The tumor protection conferred by β-ManCer is dependent on nitric oxide synthase (NOS) and TNF-α rather than IFN-γ. Furthermore, the invention provides synergistic therapeutic approaches combining β-ManCer with α-GalCer or other immunostimulatory agents to enhance anti-tumor immunity.
Claims Coverage
The patent contains several independent claims covering compositions and methods involving β-mannosylceramide (β-ManCer) for activating NKT cells and treating cancer.
Pharmaceutical compositions comprising β-ManCer with defined structural moieties
A pharmaceutical composition comprising β-ManCer or a salt or solvate thereof in a pharmaceutically acceptable carrier, wherein the β-ManCer consists of a sphingosine moiety and a fatty acid moiety comprising a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms.
Compositions combined with additional immunostimulatory agents or vaccines
Compositions further comprising therapeutically effective amounts of IL-2, α-glycosylceramide or salts/solvates thereof (including α-galactosylceramide), granulocyte/macrophage colony-stimulating factor (GM-CSF), cytokines inducing cellular immunity such as IL-12 and/or IL-15, T-cell co-stimulatory molecules selected from groups including B7 family members, ICAMs, LFA family members, CD40L, OX40L, 4-1BBL, Toll-like receptor (TLR) ligands (e.g., specific ligands for TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9), vaccines such as TARP 29-37-9V peptide and Sargramostin emulsified in Montanide ISA 51 VG, and antibodies targeting immune checkpoint molecules such as CTLA-4, PD-1, and TGF-β.
Method for in vitro activation of mammalian NKT cells using β-ManCer
A method for activating mammalian NKT cells in vitro by culturing a mononuclear cell fraction containing NKT cells in the presence of β-ManCer or a salt or solvate thereof in a pharmaceutically acceptable carrier, sufficient to activate NKT cells without increasing interleukin (IL)-4 production.
Method of treating cancer or inhibiting tumor growth using β-ManCer in vivo
A method of inducing an immune response, treating cancer, or inhibiting tumor growth by administering to a subject a therapeutically effective amount of β-ManCer or salt or solvate thereof in a pharmaceutically acceptable carrier, without increasing IL-4, where the cancer/tumor includes lung cancer, colon cancer, and melanoma and corresponding tumors.
Method of treating cancer by administering activated NKT cells cultured with β-ManCer
A method treating cancer or inhibiting tumor growth by culturing mammalian NKT cells in vitro in presence of β-ManCer for activation without increasing IL-4, then administering the activated NKT cells to a subject, where the cancer/tumor includes lung cancer, colon cancer, and melanoma, with activated NKT cells optionally autologous to the subject.
The independent claims cover pharmaceutical compositions of β-ManCer with defined structural features; compositions combined with cytokines, co-stimulatory molecules, TLR ligands, vaccines, and antibodies; methods for in vitro NKT cell activation; and methods for treating cancers including lung, colon, and melanoma using β-ManCer compositions or activated NKT cells derived therefrom.
Stated Advantages
β-ManCer induces potent iNKT cell-dependent tumor protection through mechanisms distinct from α-GalCer, providing an alternative pathway for anti-tumor immunity.
β-ManCer does not induce strong cytokine production such as IFN-γ or IL-4, reducing potential cytokine-related side effects.
β-ManCer induces less anergy in NKT cells compared to α-GalCer, allowing for repeated treatments and sustained immune activation.
Simultaneous administration of β-ManCer and α-GalCer results in synergistic anti-tumor effects, potentially enhancing therapeutic efficacy.
Documented Applications
Activating NKT cells in a mammal to induce an immune response.
Treatment or inhibition of growth of tumors and cancers including lung, breast, colon, liver, kidney, brain, neck, prostate, ovary, skin, lymphoid tumors, melanoma, skin cancer, lung cancer, kidney cancer, stomach cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, and lymphoid cancer.
Administration of β-ManCer in combination with α-glycosylceramide, cytokines such as IL-2, GM-CSF, IL-12 and IL-15, T-cell co-stimulatory molecules, TLR ligands, cancer vaccines (e.g., TARP 29-37-9V peptide), and antibodies against immune checkpoints (e.g., CTLA-4, PD-1, TGF-β) to enhance immune responses.
In vitro activation of NKT cells with β-ManCer followed by administration of activated cells for cancer therapy.
Interested in licensing this patent?