WO2008124210A1 - Procédés et compositions destinés à traiter ou prévenir une infection en utilisant des agents de séquestration des leucocytes - Google Patents

Procédés et compositions destinés à traiter ou prévenir une infection en utilisant des agents de séquestration des leucocytes Download PDF

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Publication number
WO2008124210A1
WO2008124210A1 PCT/US2008/053923 US2008053923W WO2008124210A1 WO 2008124210 A1 WO2008124210 A1 WO 2008124210A1 US 2008053923 W US2008053923 W US 2008053923W WO 2008124210 A1 WO2008124210 A1 WO 2008124210A1
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slp
sequestration agent
receptor agonist
fty720
infection
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PCT/US2008/053923
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English (en)
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John D. Altman
Mary Premenko-Lanier
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Emory University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to compositions and methods for using leukocyte sequestration agents to treat or prevent infection.
  • the present invention relates to the use of agents such as FTY720 to treat or prevent infection, in particular bacterial or viral infection.
  • acyclovir targets the replication stage of herpesvirus infection
  • zidovudine/AZT targets the reverse transcriptase of human immunodeficiency virus (HIV)
  • HIV protease inhibitors target HIV protease.
  • these therapies have many disadvantages, including limited usefulness for only a specific pathogen, toxic side effects, and ineffectiveness due to pathogen variation and the development of drug resistance.
  • Therapeutic approaches directed at targeting host-immune cells rather than the pathogen would be expected to decrease the likelihood of generating resistant mutant viruses or other pathogens.
  • such drugs would be predicted to be useful in both post-exposure prophylaxis and treatment of patients exposed to pathogens that establish chronic infections in humans, such as (but not limited to) HIV, HCV, or mycobacterium tuberculosis.
  • the methods comprise the use of leukocyte sequestration agents as immune enhancing agents.
  • the invention relates to the prevention or treatment of infection (i.e., bacterial, viral, fungal, or parasitic infection), by administering at least one cycle of therapy to a subject in need thereof, where the cycle of therapy comprises administering at least one dose of a therapeutically effective amount of a leukocyte sequestration agent to the subject.
  • the treatment is transient and comprises one cycle of therapy while in other embodiments the treatment is chronic and comprises more than one cycle of therapy.
  • the treatment is initiated immediately following a subject's exposure to a pathogen, while in other embodiments treatment is initiated after a time delay following exposure.
  • the methods comprise use of leukocyte sequestration agents that include but are not limited to lymphocyte sequestration agents such as sphingosine 1 -phosphate (SlP) receptor agonists
  • the infection is a bacterial or viral infection.
  • an immunogenic composition comprising an immunogen and an adjuvant composition that comprises a leukocyte sequestration agent as described above.
  • the immunogen is one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides.
  • the immunogen comprises a bacterial or viral antigen.
  • pharmaceutical kits comprising the immunogenic compositions described above are provided, as are methods of using the immunogenic compositions for immunization or for treating or preventing infection, in particular a bacterial or viral infection, in a subject in need thereof.
  • Figure 1 shows a dose response curve for various concentrations of FTY720 on LCMV clone 13 serum titers at 8 days post-infection.
  • Figure 2 shows that mice treated with FTY720 clear LCMV clone 13 from the serum by day 30.
  • the data points represented by the squares, circles, and triangles are serum titers (pfu/g of tissue) of LCMV clone 13.
  • Individual plot points represented by the squares at top and bottom right at day 60 are virus titers in kidneys of untreated and FTY720 treated mice, respectively.
  • Figure 3 shows that LCMV-specif ⁇ c CD8+ T cell responses at day 60 post infection were maintained in clone 13 infected mice treated with FTY720 at days 0, 1, and 2 of the infection.
  • Splenocytes were stimulated in the presence of Golgistop (BD, Franklin Lakes, IL) by the indicated peptide in 96 well plates for 6 hours then washed and stained for surface CD8 followed by BD cytofix/perm (BD, Franklin Lakes, IL) and stained for intracellular cytokines IL-2, TNF ⁇ and IFNy. All plots are gated on CD8+ T cells.
  • Figure 5 shows that GP33 and NP396 CD8 T cell responses at day 60 were preserved in clone 13 infected mice treated with FTY720 at days 0, 1, and 2 following infection. Splenocytes were collected and stimulated for 6 hours. The cells were surface stained then fixed with BD cytof ⁇ x/perm (BD, Franklin Lakes, IL) and stained for intracellular cytokines. Results were collected on a BD LSRII flow cytometer (BD, Franklin Lakes, IL).
  • Figure 6 shows data demonstrating that treatment of mice chronically infected with clone 13 leads to viral clearance.
  • Viral titers at 6Od post infection (30d post FTY720 treatment) were measured in the kidneys. Similar results were seen in the brain.
  • Figure 7 shows data demonstrating that treatment of mice chronically infected with LCMV clone 13 leads to restoration of functional memory cells.
  • CD62L and PD-I (A and B respectively) expression was measured on LCMV-specific tetramer positive gp33 CD8+ T cells.
  • C Splenocytes were stimulated in vitro and TNF ⁇ and IFN ⁇ were measured.
  • Figure 8 shows a diagram of the experimental design of the GKl.5, CD4 + depletion study.
  • Figure 9 shows data demonstrating that FTY720-mediated preservation of T cell responses in LCMV clone 13 -infected mice is dependent upon CD4+ T cells.
  • Mice were infected with LCMV cl-13 and administered 500 ⁇ g/day GKl.5 on days 0 and 1 post infection. Mice were then treated with FTY720 at different times post infection and GKl.5 treatment.
  • (A) Shows the decline of CD4 T cells in the blood following GKl.5 treatment and the recovery of CD4 cells over time post treatment.
  • Figure 10 shows serum viral titers at up to 60 days post-infection with Cl-13 in mice with either no treatment or treated with GKl.5 or GKl.5 + FTY720. Results demonstrated that mice treated with GKl.5 and administered FTY720 at the same time were unable to control the infection.
  • Figure 11 shows data demonstrating that low dose FTY720 delays disease development following intranasal infection with vaccinia virus (Western Reserve). Groups of 10 C57BL/6J mice were intranasally infected with 5xlO 5 pfu (10 LD50) of vaccinia virus (Western Reserve) and either treated i.v. once-a-day for three days with vehicle, 4 ⁇ g/kg FTY720, or 200 ⁇ g/kg FTY720.
  • the present invention relates to methods of using leukocyte sequestration agents as immune enhancing agents to prevent or treat infection.
  • the present invention relates to the use of leukocyte sequestration agents to prevent or treat bacterial, viral, fungal, or parasitic infection.
  • the invention relates to the prevention or treatment of infection by administering at least one cycle of therapy to a subject in need thereof, wherein the cycle of therapy comprises administering at least one dose of a therapeutically effective amount of a leukocyte sequestration agent to the subject.
  • the cycle of treatment may be initiated at any time following a subject's exposure to a pathogen (i.e., immediately or after a time delay) and treatment may be transient (one cycle of therapy) or chronic (more than one cycle of therapy) in nature.
  • the invention also relates to immunogenic compositions and pharmaceutical kits comprising leukocyte sequestration agents as adjuvants as well as methods of use thereof.
  • Leukocyte sequestration agents for use within the methods and compositions of the present invention include but are not limited to lymphocyte sequestration agents such as sphingosine 1 -phosphate (SlP) receptor agonists (particularly FTY720), sphingosine kinase inhibitors, and SlP lyase inhibitors.
  • treat refers to the application or administration of a leukocyte sequestration agent, or pharmaceutical composition comprising a leukocyte sequestration agent, to a subject having an infection or symptom of infection (e.g., a bacterial, viral, fungal, or parasitic infection), and where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the infection or any associated symptoms of the infection.
  • an infection or symptom of infection e.g., a bacterial, viral, fungal, or parasitic infection
  • prevent refers to the application or administration of a leukocyte sequestration agent, or pharmaceutical composition comprising a leukocyte sequestration agent, to a subject that has been exposed to a pathogen or otherwise has a predisposition toward development of infection, where the purpose is to inhibit or stop the development of infection.
  • leukocyte sequestration agent refers to an agent that induces or enhances removal of leukocytes from the general blood circulation of a subject for redistribution within the subject's body.
  • leukocyte or “white blood cell” refers to cell types that include dendritic cells, lymphocytes, granulocytes (including neutrophils, eosinophils, and basophils), macrophages, and monocytes.
  • agents for use within the methods and compositions of the invention are lymphocyte sequestration agents.
  • lymphocyte sequestration agent refers to an agent that induces or enhances removal of lymphocytes from the general blood circulation of a subject for redistribution in any of the subject's primary or secondary lympohoid organs. This lymphocyte sequestration activity can be reversible, so that suspending treatment restores normal lymphocyte populations.
  • the lymphocyte sequestration agent may also act to selectively decrease populations of certain lymphocytes in blood or lymph tissue, such as specifically decreasing populations of circulating lymphocytes or spleen lymphocytes.
  • lymphocyte sequestration agents to sequester lymphocytes within lymph nodes is generally viewed in the art as providing an immunosuppressive effect (see, e.g., U.S. Patent No. 6,004,565); presumably because it keeps T cells away from sites of pathology.
  • immunosuppressive effect see, e.g., U.S. Patent No. 6,004,565
  • lymphocyte sequestration may provide an immune enhancing effect and is useful in the treatment or prevention of infection, in particular bacterial, viral, fungal, or parasitic infection.
  • Specific compounds for use within the methods and compositions of the present invention are described more fully below.
  • the present invention relates to a method for preventing or treating infection comprising administering at least one cycle of therapy to a subject in need thereof, where the cycle of therapy comprises administering at least one dose of a therapeutically effective amount of a leukocyte sequestration agent to the subject.
  • the cycle of therapy begins immediately following the subject's exposure to a pathogen (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours following exposure to a pathogen).
  • the cycle of therapy begins after a time delay following the subject's exposure to a pathogen (e.g., more than 24, 36, 48, 60, or 72 hours following exposure to a pathogen, or more than 1, 2, 3, or 4 weeks following exposure to a pathogen).
  • the method comprises transient treatment in which the subject receives only one cycle of therapy.
  • the method comprises chronic treatment in which the subject receives more than one cycle of therapy.
  • cycle of therapy refers to administration of at least one dose of a therapeutically effective amount of a leukocyte sequestration agent to a subject in need thereof for the prevention or treatment of infection.
  • the cycle of therapy comprises administering at least one dose of a therapeutically effective amount of a leukocyte sequestration agent to a subject in need thereof.
  • the cycle of therapy comprises one or more dose per day of a therapeutically effective amount of a leukocyte sequestration agent to a subject in need thereof for 1, 2, 3, 4, 5, or more days.
  • the infection is a bacterial or viral infection.
  • Dosage levels of a leukocyte sequestration agent such as FTY720 on the order of about 1 ⁇ g/kg to about 1 mg/kg may be useful in the treatment or prevention of infections in a subject as noted herein above.
  • leukocyte sequestration may be achieved in subjects with infection using doses of these agents (in particular FTY720) that are lower than those required to achieve leukocyte sequestration in normal non-infected subjects.
  • a therapeutically effective dose of a leukocyte sequestration agent as described herein is an amount between about 1 ⁇ g/kg to about 1 mg/kg, about 1 ⁇ g/kg to about 750 ⁇ g /kg, about 1 ⁇ g/kg to about 500 ⁇ g /kg, about 1 ⁇ g/kg to about 250 ⁇ g /kg, about 1 ⁇ g/kg to about 100 ⁇ g /kg, about 1 ⁇ g/kg to about 50 ⁇ g /kg, about 1 ⁇ g/kg to about 25 ⁇ g /kg, or about 1 ⁇ g/kg to about 10 ⁇ g /kg.
  • the therapeutically effective dose of a leukocyte sequestration agent is an amount of about 1 ⁇ g/kg, about 2 ⁇ g/kg, about 3 ⁇ g/kg, about 4 ⁇ g/kg, about 5 ⁇ g/kg, about 6 ⁇ g/kg, about 7 ⁇ g/kg, about 8 ⁇ g/kg, about 9 ⁇ g/kg, about 10 ⁇ g/kg, about 15 ⁇ g/kg, about 20 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 150 ⁇ g/kg, about 200 ⁇ g/kg, about 250 ⁇ g/kg, about 300 ⁇ g/kg, about 350 ⁇ g/kg, about 400 ⁇ g/kg, about 450 ⁇ g/kg, about 500 ⁇ g/kg, about 550 ⁇ g/kg, about 600 ⁇ g/kg, about 650 ⁇ g/kg, about 700 ⁇ g/kg, about 750 ⁇
  • the dosage levels are based upon a body weight of approximately 70 kg. It will be understood, however, that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including body weight, age, general health, sex, and diet of the subject, the metabolic stability and length of action of the administered compound, mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • the leukocyte sequestration agent can be formulated according to known methods to prepare pharmaceutically useful compositions, and may be administered to a subject by any mode of administration, including oral, rectal, topical, nasal, ophthalmic, or parenteral (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection) administration.
  • Suitable formulations and their appropriate carrier vehicles are described, for example, in Remington's Pharmaceutical Sciences (16th ed., Osol, A. (ed.), Mack, Easton PA (1980)).
  • infection refers to a bacterial, viral, fungal, or parasitic (including helminthic and protozoan) infection.
  • Bacterial infectious organisms include, but are in no way limited to, Streptococcus sp., Haemophilus influenzae, Klebsiella sp., Escherichia sp.,
  • Legionella sp. Mycoplasma sp., Pneumocystis carinii, Listeria, Corynebacterium sp., Staphylococcus sp., Serratia, Pseudomonas, Shigella, Vibrio, Hemophilus sp., Yersinia, and Enterobacter, and include also diseases due to Mycobacteria, such as tuberculosis (caused by Mycobacterium tuberculosis) and leprosy (caused by Mycobacterium leprae). Infectious Chlamydiae organisms are also encompassed in this definition (such as C.
  • the invention relates to methods for treating or preventing bacterial infection caused by Escherichia coli, Helicobacter pylori, Listeria monocytogenes, Salmonella typhimurium, Shigella Flexneri, Mycobacterium tuberculosis, Mycobacterium leprae, or Bacillus anthracis. In another embodiment, the invention relates to methods for treating or preventing viral infection.
  • Viral infectious organisms include viruses of the following families: Poxviridae, Herpesviridae, Adenoviridiae, Papovaviridae, Hepadnaviridae, Parvoviridae, Reviridae, Togoviridae, Flaviviridae, Coronaviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Arenaviridae, Retroviridae, Picornaviridae, and Caliciviridae.
  • Viral diseases and viruses include, but are in no way limited to, smallpox, Vaccinia, herpes sp., Influenza sp., Varicella-zoster, cytomegalovirus sp., Epstein-Barr, rubella, yellow fever, rabies, measles, Ebola, polio, and HIV (the cause of AIDS).
  • the invention relates to methods for treating or preventing viral infection caused by a vaccinia virus, a variola virus, a polyomavirus, an arenavirus, a herpes virus, an influenza virus, a hepatitis virus, or a human immunodeficiency virus.
  • the invention in another embodiment, relates to methods for treating or preventing fungal infection.
  • Fungal infectious organisms include, but are in no way limited to Aspergillus sp., Candida sp., Cryptococcus neofonnans, Coccidiodes inmitis, Blastomyces dermatitidis , Rhizopus sp., Mucor sp., and Fusariaum sp.
  • the invention relates to methods for treating or preventing parasitic infection.
  • Parasitic organisms include, but are in no way limited to, those organisms responsible for protozoan infections, e.g., toxoplasmosis (Toxoplasma sp.), malaria (Plasmodium sp.), sleeping sickness and Chagas disease (trypanosomiasis; Tryapanosoma sp.), leishmaniasis (Leishmania sp.), cryptosporidiosis (Cryptosporidium sp.), giardiasis (Giardia sp.), amebiasis (Entamoeba sp.), or trichomoniasis (Trichomonas sp.), cestode infections (tapeworms (Diphyllobothrium latum), or echinococcosis (Echinococcosis sp.), worm (Schistosoma sp.), fluke or nema
  • the present invention also relates to methods for preventing or treating cancers with viral etiologies comprising administration of at least one dose of a therapeutically effective amount of a leukocyte sequestration agent to a subject in need thereof.
  • Cancers with viral etiologies include, but are not limited to, nasopharyngeal cancer, non-Hodgkin's lymphoma, cervical cancer, hepatocellular carcinoma, Kaposi's sarcoma, and adult T-cell leukemia.
  • the present invention also relates to compositions and methods whereby leukocyte sequestration agents (in particular lymphocyte sequestration agents including FTY720) are used to make vaccines more effective.
  • a leukocyte sequestration agent of the present invention allows for safe administration of higher doses of virus to overcome antibody response and permit acquisition of cellular immunity.
  • leukocyte sequestration agents of the present invention facilitate immune clearance of the pathogen. For some chronic viruses
  • leukocyte sequestration agents of the present invention permit immunocompromised individuals to be vaccinated.
  • the invention relates to an immunogenic composition
  • an immunogenic composition comprising an immunogen and an adjuvant composition comprising a leukocyte sequestration agent.
  • the leukocyte sequestration agent is a lymphocyte sequestration agent, more particularly an SlP receptor agonist (such as FTY720), a sphingosine kinase inhibitor, or a SlP lyase inhibitor.
  • SlP receptor agonist such as FTY720
  • sphingosine kinase inhibitor such as FTY720
  • SlP lyase inhibitor a SlP lyase inhibitor.
  • immunogen refers to one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides.
  • an antigenic polypeptide or an immunogenic polypeptide is a polypeptide which, when introduced into a vertebrate, reacts with the immune system molecules of the vertebrate, i.e., is antigenic, and/or induces an immune response in the vertebrate, i.e., is immunogenic. It is quite likely that an immunogenic polypeptide will also be antigenic, but an antigenic polypeptide, because of its size or conformation, may not necessarily be immunogenic. Examples of antigenic and immunogenic polypeptides include, but are not limited to, polypeptides from infectious pathogens such as bacteria, viruses, parasites, or fungi. In a particular embodiment, the immunogenic composition comprises a bacterial or viral antigen as an immunogen.
  • the invention in another embodiment, relates to a method of immunization comprising administering to a subject in need thereof an immunogenic composition comprising: a) an immunogen in an amount sufficient to generate an immune response to the immunogen in the subject; and b) an adjuvant composition comprising a leukocyte sequestration agent; where the immunogen is one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides.
  • the leukocyte sequestration agent is a lymphocyte sequestration agent, more particularly an SlP receptor agonist (such as FTY720), a sphingosine kinase inhibitor, or a SlP lyase inhibitor.
  • the invention in another embodiment, relates to a method for preventing or treating infection comprising administering to a subject in need thereof an immunogenic composition
  • an immunogenic composition comprising: a) an immunogen in an amount sufficient to generate an immune response to the immunogen in the subject; and b) an adjuvant composition comprising a leukocyte sequestration agent; where the immunogen is one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides.
  • the leukocyte sequestration agent is a lymphocyte sequestration agent, more particularly an SlP receptor agonist (such as FTY720), a sphingosine kinase inhibitor, or a SlP lyase inhibitor.
  • the invention also relates to a pharmaceutical or packaged kit comprising: a) a container holding an immunogen; and b) an adjuvant composition comprising a leukocyte sequestration agent; where the immunogen is provided in a therapeutically effective amount to prevent or treat infection in a subject in need thereof, and where the immunogen is one or more antigenic polypeptides, immunogenic polypeptides or polysaccharides.
  • the leukocyte sequestration agent is a lymphocyte sequestration agent, more particularly an SlP receptor agonist (such as FTY720), a sphingosine kinase inhibitor, or a SlP lyase inhibitor.
  • the packaged or pharmaceutical kit may comprise a container, preferably sealed, for housing the immunogenic composition during storage and prior to use, and instructions for carrying out administration of the composition in a manner effective for preventing or treating infection in a subject.
  • the instructions will typically be written instructions on a package insert and/or on a label.
  • the kit may also include a device for administering the composition.
  • the parts of the kit may be independently held in one or more containers, such as bottles, syringes, plates, wells, blister packs, or any other type of pharmaceutical packaging.
  • the present invention relates to methods of use and compositions comprising leukocyte sequestration agents.
  • the agents mimic the activity of SlP or increase the level or availability of endogenous SlP in a subject.
  • SlPi is believed to be important in lymphocyte trafficking.
  • SlP is a lysosphingophospholipid stored and secreted by platelets as well as other cells such as erythrocytes, neutrophils and mononuclear cells (31-35 - ML).
  • SlP levels are regulated by its synthesis from sphingosine and sphingosine kinase (SK) and its catabolism by lipid phosphatases and by sphingosine lyase (SPL), a pyridoxal 5' phosphate dependent enzyme that resides in the ER and is responsible for the irreversible degration of SlP to ethanolamine phosphate and hexadecenal (36 - ML).
  • SK sphingosine and sphingosine kinase
  • SPL sphingosine lyase
  • SlP binds to five members of this receptor family SlPi, SlP 2 , SlP 3 , SlP 4 , and SlP 5 , previously referred to as endothelial differentiation gene (EDG)-I, -5, -3, -6 and -8.
  • EDG endothelial differentiation gene
  • SlPi is expressed on dendritic cells and on leukocytes such as lymphocytes and monocytes.
  • the leukocyte sequestration agents for use within the methods and compositions of the present invention are SlP receptor agonists.
  • Such agents may be selective, meaning that they actively bind one SlP receptor subtypes, or non-selective, meaning that they actively bind more than one SlP receptor subtype.
  • the SlP receptor agonist is a homolog, analog, or derivative of the compound myriosin or ISP-I, a natural product oilsaria sinclairii (Fujita et al. (1994) J. Antibiotics 47:208-215). Myriocin is depicted below.
  • Homologs, analogs or derivatives of myriocin can be prepared and tested by one skilled in the art to ensure that they possess lymphocyte sequestration activity using assays and procedures known in the art (see, e.g., Fujita et al. (1994) J. Antibiotics 47:208-215 and U.S. Patent No. 6,004,565).
  • the SlP receptor agonist for use within the methods and compositions of the present invention is a 2-aminopropane-l,3-diol compound according to formula I:
  • R is an optionally substituted straight or branched carbon chain, an optionally substituted aryl, an optionally substituted cycloalkyl or the like; and R 2 , R 3 , R 4 , and R 5 are the same or different and each is a hydrogen, an alkyl, an acyl, or an alkoxycarbonyl, or R 4 and R 5 may be bonded to form an alkylene chain, which may be substituted by alkyl, aryl, or an alkoxycarbonyl.
  • the SlP receptor agonist for use within the methods and compositions of the present invention is a benzene compound according to formula II:
  • W is hydrogen; a straight or branched chain alkyl having 1 to 6 carbon atoms; a straight or branched chain alkenyl having 2 to 6 carbon atoms; a straight or branch chain alkynyl having 2 to 6 carbon atoms; a phenyl, which may be substituted by hydroxy; R 4 (CH 2 ) n ; or a straight or branched chain Ci-C ⁇ alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl, and a phenyl, which may be substituted by hydroxy; X is hydrogen, a straight-chain alkyl having carbon atoms in the number of p or a straight-chain alkoxy having carbon atoms in the number of (p-1), wherein the straight-chain alkyl having carbon atoms in the number of p and the straight- chain alkoxy having carbon atoms in the number of (p-1) may
  • the SlP receptor agonists for use in the methods and compositions of the invention share structural features with SlP such as a 2- substituted 2-aminoethanol group (see, e.g., Kiuchi (1998) Bioorg. Med. Chem. Lett. 8: 101-106), as well as a lipophilic tail region and a phosphate head group (see, e.g., Clemens et al. (2003) Bioorg. Med. Chem. Lett. 13:3401-3404).
  • SlP such as a 2- substituted 2-aminoethanol group (see, e.g., Kiuchi (1998) Bioorg. Med. Chem. Lett. 8: 101-106), as well as a lipophilic tail region and a phosphate head group (see, e.g., Clemens et al. (2003) Bioorg. Med. Chem. Lett. 13:3401-3404).
  • SlP receptor agonists is FTY720, 2-amino-2[2-(4- octylphenyl)ethyl]propane-l,3-diol hydrochloride, shown below, or a pharmaceutically acceptable salt thereof.
  • FTY720 is a prodrug that undergoes O-phosphorylation, and it is the phosphorylated FTY720 (phospho-FTY720) that exhibits SlP receptor agonist activity (see, e.g., Clemens et al. (2003) Bioorg. Med. Chem. Lett. 13:3401-3404).
  • Selective SlPi receptor agonists for use in the methods and compositions of the invention include compounds according to formula III as disclosed and described in U.S. Patent App. Pub. No. 2005/0107345:
  • X is a bond, O, NH, S(O) k , wherein k is 0, 1 or 2;
  • A is selected from the group consisting of: — CO 2 H, — PO 3 H 2 , — PO 2 H 2 , — SO 3 H, PO(R 8 )OH,
  • each R 1 is independently selected from the group consisting of: hydrogen, halo, hydroxy, — CO 2 H, Ci_ 4 alkyl, and aryl, wherein said C 1-4 alkyl,
  • Ci_ 4 alkoxy and Ci_ 4 alkylthio are each optionally substituted from one up to the maximum number of substitutable positions with halo and wherein said aryl is optionally substituted with 1 -5 substituents independently selected from halo and Ci_ 4 alkyl, or two R 1 groups on adjacent carbon atoms may be joined together to form a double bond; each R is independently selected from the group consisting of: hydrogen, halo, hydroxy,
  • Ci_ 4 alkyl Ci_ 4 alkoxy, and aryl, wherein said Ci_ 4 alkyl, and are each optionally substituted from one up to the maximum number of substitutable positions with halo and wherein said aryl is optionally substituted with 1-5 substituents independently selected from halo and Ci_ 4 alkyl, or two R 3 groups on adjacent carbon atoms may be joined together to form a double bond; and
  • R 2 and R 4 are each independently selected from the group consisting of: hydrogen, halo, hydroxy, — CO 2 H, Ci_ 4 alkyl, Ci_ 4 alkoxy, Ci_ 4 alkylthio and aryl, wherein said
  • Ci_ 4 alkyl and are each optionally substituted from one up to the maximum number of substitutable positions with halo and wherein said aryl is optionally substituted with 1 -5 substituents independently selected from halo and or R 1 and R 2 or R 3 and R 4 residing on the same carbon atom may optionally be joined together to form a carbonyl group
  • R 8 is selected from the group consisting of: and aryl, wherein said is optionally substituted with 1-3 halo groups and aryl is optionally substituted with 1-5 substituents independently selected from the group consisting of: halo, Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, Ci_ 6 alkoxy, Ci_ 6 alkylthio and C 3 _ 6 cycloalkoxy, said Ci- ⁇ alkyl, C3_6cycloalkyl, Ci- ⁇ alkylthio and C3_6cycloalkoxy optionally substituted from one up to the maximum number of substitutable positions with halo,
  • R 9 is selected from the group consisting of: hydrogen, halo, hydroxy, C 1- 4 alkylthio and C3_7cycloalkyl, wherein said Ci_ 4 alkoxy, Ci_ 4 alkylthio and C 3 . 7cycloalkyl are each independently optionally substituted from one up to the maximum number of substitutable positions with halo and wherein said aryl is optionally substituted with 1-5 substituents independently selected from halo and C 1- 4 alkyl.
  • a selective SlPi receptor agonist for use in the methods and compositions of the invention is 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3- (trifluoromethyl)phenyl]-l,2,4-oxadiazole (SEW2871), shown below, or a pharmaceutically acceptable salt thereof.
  • a selective SlPi receptor agonist for use in the methods and compositions of the invention is AUY954, shown below, or a pharmaceutically acceptable salt thereof (see Pan et al. (2006) Chem. Bio. 13: 1227- 1234).
  • SlP receptor agonists for use in the methods and compositions of the invention include 3,5-diphenyl-l,2,4-oxadiazole based compounds disclosed in Li et al. (2005) J. Med. Chem. 48:6169-6173; para-alkyl aryl amide analogs of SlP disclosed in Clemens et ⁇ l. (2003) Bioorg. Med. Chem. Lett. 13:3401-3404; selective SlP receptor agonists as described in Forrest (2004) J. Ph ⁇ rm ⁇ ol. Exp. Ther. 309:758-768; 2,2-disubstituted 2-aminoethanols as disclosed in Kiuchi (1998) Bioorg. Med. Chem.
  • the leukocyte sequestration agents for use within the methods and compositions of the present invention are sphingosine kinase (SK) inhibitors.
  • Such agents may be specific, meaning that they inhibit only SK and not other protein and lipid kinases, or non-specific, meaning that they inhibit SK but may also inhibit other protein and lipid kinases.
  • SK inhibitors that may be used within the methods and compositions of the invention include the non-specific SK inhibitors N,N- dimethylsphingosine (DMS), D,L- ⁇ re ⁇ -dihydrosphingosine, and N,N,N- trimethylsphingosine (see, e.g., French et al. (2006) J. Pharmacol. Exp. Ther. 318:596-603 and Edsall (1998) Biochem. 37: 12892-12898).
  • DMS N,N- dimethylsphingosine
  • D,L- ⁇ re ⁇ -dihydrosphingosine D,L- ⁇ re ⁇ -dihydrosphingosine
  • N,N,N- trimethylsphingosine see, e.g., French et
  • the leukocyte sequestration agents for use within the methods and compositions of the present invention are SlP lyase inhibitors.
  • SlP lyase inhibitors that may be used within the methods and compositions of the invention include the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI; see Schwab et al. (2005) Science 309: 1735-1739).
  • the leukocyte sequestration agents for use within the methods and compositions of the present invention include any drug or biological agent, such as SlP receptor antibodies (e.g, SlPi polyclonal antibodies such as those available from Cayman Chemical, Ann Arbor, MI) that induce or enhance redistribution of lymphocytes out of the blood and into secondary lymphoid organs.
  • SlP receptor antibodies e.g, SlPi polyclonal antibodies such as those available from Cayman Chemical, Ann Arbor, MI
  • the leukocyte sequestration agents described herein may be administered in combination with one another, or with other compounds, particularly antipathogenic compounds. Such antipathogenic compounds include conventional antimicrobials.
  • the leukocyte sequestration agents of the present invention are administered as part of a combination therapy to treat or prevent infection, they may be administered concurrently or sequentially, in either order, with the additional compound(s).
  • the present invention encompasses the use not only of the specific compounds described above, but also any pharmaceutically acceptable salts, enantiomers, analogs, esters, amides, prodrugs, metabolites, or derivatives thereof.
  • Persisting pathogens and their evasion of the immune response A functional adaptive immune response is necessary to clear intracellular pathogens such as viruses and bacterial infections. Factors that result in immune dysfunction and an inability to control disease progression are often attributed to the immune evasion properties of the pathogen and T cell exhaustion. Although in some cases a pathogen that causes a chronic illness in one host can be cleared in another and therefore it remains unclear the exact conditions that confer clearance or persistence for many viruses and whether our immune system itself is capable of eliminating immune suppressive agents such as HIV.
  • HIV hepatitis B and C
  • HBV hepatitis B and C
  • HBV and HCV CD8 T cells fail to contain viral replication.
  • Recently PD-I expression has been found on the surface of both HIV specific and HCV specific T cells (Day et al. (2006) Nature 443:350- 354; Urbani et al. (2006) J. Virol. 80: 11398-11403).
  • PD-I expression has been linked to viral persistence and blocking of PD-Ll during LCMV cl-13 restored CD8 T cell responses (Barber et al. (2006) Nature 439:682-687).
  • PD-Ll blockade may reverse exhausted T cells during persistent human infections such as HIV (Day et al (2006) Nature 443:350-354).
  • LCMV Lymphocytic choriomeningitis virus
  • LCMV Lymphocytic choriomeningitis virus
  • LCMV Armstrong causes an acute infection that is cleared between days 8-10 post infection. During Arm there is expansion of LCMV specific CD8 + T cells that peaks at day 8 and these cells contract of form a stable memory population (Matloubian et al. (1994) J. Virol. 68:8056-8063). In contrast LCMV isolate cl-13 (cl-13) (Ahmed et al. (1984) J. Exp. Med. 160:521-540) causes an infection that persists in several organs for the life of the mouse. During cl-13 infection LCMV specific CD8 + initially expand but become exhausted (Wherry et al. (2003) J. Virol. 77:4911-4927; Zajac et al.
  • T cell dysfunction has been found during human diseases such as HIV, HBV and HCV (Borysiewicz and Sissons (1994) Curr. Top. Microbiol. Immunol. 189:123-150; Chisari and Ferrari (1995) Springer Semin
  • CD8 T cell exhaustion during cl-13 has been linked to CD4 T cell dysfunction (Matloubian et al. (1994) J. Virol. 68:8056-8063), which occurs during the transition to viral persistence.
  • cl-13 targets antigen presenting cells (APC), including dendritic cells (DCs).
  • APC antigen presenting cells
  • DCs dendritic cells
  • Cl-13 infection of DCs impairs the expression of MHC and costimulatory molecules on both splenic myeloid and lymphoid DCs (Borrow et al. (1995) J. Virol. 69: 1059-1070; Sevilla et al. (2000) J. Exp. Med. 192: 1249-1260).
  • cl-13 effects the development and differentiation of DC CD8 ⁇ + and CD8 ⁇ " bone marrow precursors (Sevilla et al.
  • DCs are infected and impaired in their ability to stimulate T cells during several human infections such as Measles virus (Hahm et al.
  • Sphingosine- 1- phosphate is a lysosphingophospholipid stored and secreted by platelets (Zhang et al. (1999) Blood 93:2984-2990) and present in density gradient being high in the serum as compared to tissues (Schwab et al. (2005) Science 309: 1735-1739; Cyster (2005) Annu. Rev. Immunol. 23: 127-159; Rosen and Goetzl (2005) Nat. Rev. Immunol. 5:560-570).
  • platelets are believed to be the major secreted source of SlP, other cells such as erythrocytes, neutrophils and mononuclear cells also secrete SlP (Dahm et al. (2006) J. Thromb. Haemost. 4:2704-2709; Hanel et al. (2007) Faseb. J.).
  • SlP levels are regulated by its synthesis from sphingosine and sphingosine kinase (SK) and its catabolism by lipid phosphatases and by sphingosine lyase (SPL), a pyridoxal 5 phosphate dependent enzyme that resides in the ER and is responsible for the irreversible degration of SlP to ethanolamine phosphate and hexadecenal (Spiegel and Milstien (2000) FEBS. Lett. 476:55-57).
  • SlP binds to five members of this receptor family SlP(I), S1P(2), S1P(3), S1P(4) and S1P(5), previously referred to as endothelial differentiation gene (EDG)-I, -5, -3, -6 and -8.
  • EDG endothelial differentiation gene
  • SlP receptors are expressed in various tissues, and therefore SlP is an important lipid mediator in various physiological processes such as vascular maturation, cardiac development, lymphocyte trafficking, and vascular permeability (Dahm et al. (2006) J. Thromb. Haemost. 4:2704-2709; Hanel et al. (2007) Faseb. J.).
  • SlPl is expressed on lymphocytes, DCs and monocytes.
  • the receptor binds to SlP in a gradient dependent fashion (Schwab et al. (2005) Science 309: 1735-1739) and the binding provides a mechanism for lymphocyte egress from lymph nodes (Matloubian et al. (2004) Nature 427:355-360).
  • IFN interferon
  • a type I interferon (IFN) response induced the global up regulation of CD69 on the cell surface of lymphocytes (Shiow et al. (2006) Nature 440:540-544). This up regulation of CD69 caused the internalization of SlPl and non-responsiveness to SlP gradient. Following type I IFN response lymphocytes became sequestered in lymph nodes.
  • the interaction of SlP with its receptor Sl is important in lymphocyte trafficking and is the believed target of the immunotherapeutic drug FTY720.
  • FTY720 is an immunomodulatory agent that inhibits lymphocytes trafficking.
  • FTY720 is derived from the fungus Isaria sinclairii ISP-I (myiocin), a fungal metabolite that is an eternal youth withm in traditional Chinese herbal medicine (Fujita et al. (1994) J. Antibiot. (Tokyo) 47:208- 215).
  • FTY720 was designed by modification of myriocin by interrupting sphingo lipid metabolism (Fujita et al. (1994) J. Antibiot. (Tokyo) 47:208-215).
  • FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol) targets G protein- coupled receptors (GPCR) and interacts with the heterotrimeric G proteins of the (X 1Z0 subtype (Pabst et al. (2006) J. Immunol. 176: 1474-1480).
  • GPCR G protein- coupled receptors
  • FTY720 is phosphorylated in vivo by SPK-I (Paugh et al. (2003) FEBS Lett. 554: 189-19) and is stable in the presence of active SlP lyase.
  • FTY720P The phosphorylated drug
  • SlPl S1P3, S1P4 and S1P5.
  • SlPl and S1P4 are expressed at high levels on lymphocytes where as SlPl and S1P3 are expressed on DCs (Czeloth et al. (2005) J. Immunol. 175:2960-2967) that are maturing (though not on immature DCs in tissues or DCs that have migrated to draining LNs) and SlPl is also expressed on monocytes (Singer et al (2005) J. Immunol. 175:7151-7161).
  • FTY720 induces a peripheral blood lymphopenia (Brinkmann et al (2002) J. Biol. Chem.
  • FTY720 has been used as an immunosuppressive drug and is currently in phase II clinical trials to treat Multiple Sclerosis (MS) (Gardell et al (2006) Trends MoI Med. 12:65-75; Virley (2005) NeuroRx 2:638-649) and phase III trials prevent kidney transplant rejection (Gardell et al (2006) Trends MoI Med 12:65-75,
  • FTY720 interactions with SlPl are responsible for the drug effect on lymphocytes (Matloubian et al (2004) Nature 427:355-360). It functions by acting as an SlPl agonist, down regulating it on the surface of lymphocytes, altering the ability of lymphocytes to respond to the SlP gradient required for egress out of the lymph node. Down regulation of SlPl is thought to be the major effect of FTY720 since lymphocytes lacking SlPl expression emulates the effects of FTY720 on lymphocyte egress and trafficking (Graler and Goetzl (2004) Faseb. J. 18:551-553; Allende et al (2004) J. Biol. Chem.
  • lymphocytes are sequestered in secondary lymphoid tissues and their numbers reduced at the site of chronic inflammation. It is believed that for FTY720 to be and effective immune suppressive drug it must sequester at least 80% of circulating lymphocytes (Park et al. (2005) Braz. J. Med. Biol. Res. 38:683-694).
  • FTY720 can potentiate immune responses to a strain of LCMV (clone 13) that normally establishes a chronic infection that starts in lymphoid tissues and that persists in a variety of organs such as the kidney and the brain.
  • FTY720 was used in two distinct modes: a) when used immediately after infection (on days 0, 1, and 2), it prevented establishment of a chronic infection (this may be called "post- exposure prophylaxis mode", or PEP); and b) when administered for 3 days one month after establishment of a chronic infection, FTY720 led to clearance of the infection.
  • FTY720 acts on host-immune cells and alters their trafficking patterns, it is unlikely to generate resistant mutant viruses or other pathogens.
  • the drug is predicted to be useful in both post-exposure prophylaxis and treatment of patients exposed to pathogens that establish chronic infections in humans, such as (but not limited to) HIV, HCV, or mycobacterium tuberculosis.
  • CD69 Sequestration of T cells away from the blood and into secondary lymphoid organs is now believed to be controlled by expression of CD69, which is upregulated in response to type I interferons that are typically produced in abundance in most viral infections (Shiow et al. (2006) Nature 440:540-544).
  • CD69 inhibits the function of SlPi, one of five receptors for sphingosine 1 -phosphate; this is the principle pathway that regulates T cell egress from secondary lymphoid organs (Cyster (2005) Annu. Rev. Immunol. 23: 127-159).
  • lymphocytes were sequestrated in infected and uninfected animals as well as viral titers on day 8 post infection.
  • B6 mice were infected i.v. with 2xlO 6 pfu of LCMV clone 13 at day 0.
  • FTY720 was given i.v. at various doses. Titers of LCMV in the serum were determined by plaque assay at 8 days post infection.
  • lymphocytes were sequestered but were prevented from re-circulating by day 4-post infection, whereas at the lower doses (67 ⁇ g/kg and 4 ⁇ g/kg) the lymphocytes were re-circulating on day 4.
  • Figure 1 shows a 1.5-2.0 log reduction in viral titers over a broad range of FTY720, including concentrations below those capable of inducing substantial lymphopenia in uninfected mice.
  • doses as low as 4 ⁇ g/kg could induce lymphopenia in clone 13 -infected but not uninfected mice.
  • FIG. 2 shows that mice that were infected with clone 13 and transiently treated with FTY720 on days 0, 1, and 2 following infection were able to clear clone 13 from the serum between days 22 and 30 post-infection and from the kidneys by 60 days post infection. Additionally, as early as day 5 post-infection there was a significant Vi log reduction in serum viral titers in clone 13 -infected FTY720- treated mice as compared to LCMV clone 13 untreated mice.
  • T cells specific for the immunodominant CD8 + T cell epitopes D b /NP396 and K b /GP34 are deleted, while T cells specific for D b /GP33 and D b /GP276 have a significantly reduced capacity to produce the cytokines IFN ⁇ , TNF ⁇ , and IL-2 (Wherry et al. (2003) J. Virol. 77:4911-4927).
  • T Cell Phenotvpes Clone 13 dependent induction of T cell dysfunction is associated with increased expression of the molecule PD-I on the surface of antigen- specific cells (Barber et al. (2005) Nature 439:682-687).
  • PD-I expressing cells have an "exhausted" phenotype that is reversed upon antibody -mediated blockade of its ligand, PD-IL (Barber et al. (2005) Nature 439:682-687).
  • expression of PD-I can also be regarded as a sort of antigen sensor.
  • the final feature of the T cell response that was associated with clearance of the virus was the cell surface phenotype of LCMV-specific cells (identified by MHC tetramer staining (Murali-Krishna et al. (1998) Immunity 8: 177-187)).
  • LCMV-specific T cells expressed high levels of PD-I and failed to regain expression of CD62L (Barber et al.
  • mice In the first set of experiments, we waited until d60 before analyzing the mice for viral titers and T cell responses. Untreated mice often clear clone 13 from the serum and highly vascularized organs (spleen, liver, etc.) between days 40-60 post infection (Wherry et al. (2003) J. Virol. 77:4911-4927), but virus invariably persists at a high titer for much longer periods of time in the kidneys and the brain.
  • FIG. 7A and Figure 7B show cell surface phenotypes of GP33-specif ⁇ c CD8+ T cells, defined by staining with anti-CD8 and the Db/GP33 tetramer (Murali -Krishna et al. (1998) Immunity 8: 177-187).
  • the predominant phenotype of D b /GP33 -specific cells in untreated mice is CD62L 10 and PD-l hl ; the CD62L phenotype is typical of effector or so-called effector memory cells, while the PD-I phenotype indicated the ongoing presence of antigen and in the clone 13 model has been associated with an exhausted response phenotype (Barber et al. (2006) Nature 439:682-687).
  • most of the D /GP33 -specific cells were CD62L ', a phenotype associated with so- called central memory cells (Wherry et al. (2003) Nat. Immunol.
  • FTY720 is promoting T cell-mediated control of an otherwise chronic infection by sequestering virus-specific precursors and effector T cells at sites of significant viral replication.
  • Ssequestering virus-specific cells in secondary lymphoid organs may also increase their potency and permit them to control the virus infection before the cells become overstimulated and dysfunctional.
  • Effects on CD4 T cells, B cell and dendritic cells may also play a role, all of which express the SlPl receptors and other receptors that FTY720 has been demonstrated to interact with.
  • FTY720 manipulates the host response in a non-specific way — both at the T cell level and at the pathogen level — and because data from clinical trials already suggests that FTY720 works the same way in humans as it does in mice, it is predicted that FTY720 treatment immediately following infection of humans with chronic persisting pathogens will also permit immunological control of the infections. Furthermore, because FTY720 is acting at the host level and does not interact with pathogens in a specific way, development of pathogen-specific resistance to the drug is highly unlikely. In this way, FTY720 constitutes a completely generalized treatment for pathogens such as HIV, HCV, mycobacterium tuberculosis, and others as described elsewhere herein.
  • pathogens such as HIV, HCV, mycobacterium tuberculosis, and others as described elsewhere herein.
  • FTY720 is also predicted to be efficacious in postexposure treatment of otherwise lethal acute infections such as pandemic influenza, where a faster effective immune response may reduce severe morbidity or mortality.
  • a non-exhaustive list of human pathogens that might be treated with FTY720 is presented in Table 3.
  • FIG. 8 shows the experimental design of the GKl.5, CD4 + depletion study.
  • groups of mice were treated with FTY720 beginning at different times post cl-13 infection and GKl.5 treatment.
  • Mice were infected with cl- 13 and all were treated with GKl.5 at 500 ⁇ g i.p. on days 0 and 1 post infection.
  • GKl.5 0.5 mg/mouse/day
  • CD4 cells (measured in the spleen) did not start coming back until dl5 and the frequency of CD4+ splenocytes continued to increase monotonically through d30 (Figure 9A); neither the infection nor the FTY720 treatment had a significant effect upon the return of CD4 cells in the spleen.
  • Robust GP33-specif ⁇ c T cell responses including cells that produced both IFN ⁇ and TNF ⁇ , did not appear until 15 days after treatment with FTY720 that occurred from dl5-17 ( Figure 9B, plot j), and the two- week-post-treatment GP33 specific responses were even stronger when treatment with FTY720 is delayed ( Figure 9B, plots k-1).

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Abstract

L'invention concerne des compositions et des procédés pour l'utilisation d'agents de séquestration des leucocytes afin de traiter une infection. En particulier, les procédés et compositions comprennent des agents de séquestration des leucocytes qui sont des agents de séquestration des lymphocytes tels que les agonistes du récepteur du sphingosine 1 -phosphate (SlP) (en particulier, FTY720), les inhibiteurs de la sphingosine kinase et les inhibiteurs de la SlP lyase. Les infections qui doivent être traitées ou empêchées selon la présente invention comprennent les infections bactériennes, virales, fungiques ou parasitaires, en particulier des infections bactériennes ou virales.
PCT/US2008/053923 2007-02-14 2008-02-14 Procédés et compositions destinés à traiter ou prévenir une infection en utilisant des agents de séquestration des leucocytes WO2008124210A1 (fr)

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WO2010051349A1 (fr) * 2008-10-31 2010-05-06 Lexicon Pharmaceuticals, Inc. Agonistes des récepteurs s1p destinés au traitement du paludisme cérébral
WO2010051353A1 (fr) * 2008-10-31 2010-05-06 Lexicon Pharmaceuticals, Inc. Inhibiteurs de la s1p lyase destinés au traitement du paludisme cérébral
ITRM20120083A1 (it) * 2012-03-07 2013-09-08 Ist Superiore Sanita Uso di modulatori dei recettori della sfingosina 1 fosfato per migliorare le immunizzazioni vaccinali.
US20130303490A1 (en) * 2010-12-13 2013-11-14 Centre National De La Recherche Scientifique-Cnrs Inhibitors of HIV Infections and uses thereof
EP2906570A4 (fr) * 2012-10-15 2016-06-08 Yeda Res & Dev Utilisation de bases à chaînes longues sphingoïdes et de leurs analogues dans le traitement et la prévention d'infections bactériennes
US20170114060A1 (en) * 2014-06-03 2017-04-27 The Trustees Of The University Of Pennsylvania Novel effective antiviral compounds and methods using same
WO2020101977A1 (fr) * 2018-11-13 2020-05-22 University Of Florida Research Foundation, Incorporated Composés d'amine éther lipidique pour le traitement topique de maladies cutanées
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010051349A1 (fr) * 2008-10-31 2010-05-06 Lexicon Pharmaceuticals, Inc. Agonistes des récepteurs s1p destinés au traitement du paludisme cérébral
WO2010051353A1 (fr) * 2008-10-31 2010-05-06 Lexicon Pharmaceuticals, Inc. Inhibiteurs de la s1p lyase destinés au traitement du paludisme cérébral
US20130303490A1 (en) * 2010-12-13 2013-11-14 Centre National De La Recherche Scientifique-Cnrs Inhibitors of HIV Infections and uses thereof
ITRM20120083A1 (it) * 2012-03-07 2013-09-08 Ist Superiore Sanita Uso di modulatori dei recettori della sfingosina 1 fosfato per migliorare le immunizzazioni vaccinali.
WO2013132526A1 (fr) * 2012-03-07 2013-09-12 Istituto Superiore Di Sanita' Utilisation de modulateurs des récepteurs de la sphingosine-1-phosphate pour améliorer l'immunisation vaccinale
EP2906570A4 (fr) * 2012-10-15 2016-06-08 Yeda Res & Dev Utilisation de bases à chaînes longues sphingoïdes et de leurs analogues dans le traitement et la prévention d'infections bactériennes
US20170114060A1 (en) * 2014-06-03 2017-04-27 The Trustees Of The University Of Pennsylvania Novel effective antiviral compounds and methods using same
US11471430B2 (en) 2018-07-19 2022-10-18 Yeda Research And Development Co. Ltd. Sphingosine analogs and use thereof against bacterial lung infections
WO2020101977A1 (fr) * 2018-11-13 2020-05-22 University Of Florida Research Foundation, Incorporated Composés d'amine éther lipidique pour le traitement topique de maladies cutanées

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