WO2008152471A1 - Antagoniste des récepteurs de type toll et ses utilisations - Google Patents

Antagoniste des récepteurs de type toll et ses utilisations Download PDF

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WO2008152471A1
WO2008152471A1 PCT/IB2008/001486 IB2008001486W WO2008152471A1 WO 2008152471 A1 WO2008152471 A1 WO 2008152471A1 IB 2008001486 W IB2008001486 W IB 2008001486W WO 2008152471 A1 WO2008152471 A1 WO 2008152471A1
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cpg
subject
disease
pharmaceutically acceptable
agents
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PCT/IB2008/001486
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Grayson B. Lipford
Charles M. Zepp
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Coley Pharmaceutical Group, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to generally to the field of immunology. More particularly, the invention relates to compositions and methods for altering immune function. More specifically, the invention relates to compositions and methods for reducing immune stimulation mediated through certain Toll-like receptor (TLR) molecules.
  • TLR Toll-like receptor
  • TLRs Toll-like receptors
  • compositions and methods useful for modulating innate immunity are therefore of great interest, as they may affect therapeutic approaches to conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency.
  • GvHD graft-versus-host disease
  • TLR9 Toll-like receptor 9
  • IgG and nucleic acid can stimulate TLR9 and participate in B-cell activation in certain autoimmune diseases. Leadbetter EA et al. (2002) Nature 416:595-8.
  • Chloroquines have been recognized as useful not only as anti-malarial agents but also as anti-inflammatory agents. Although its mechanism of action is not well understood, chloroquine has been used effectively in the treatment of various autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). For a review, see Wallace DJ (1996) Lupus 5 Suppl 1 :S59-64. i Recently Macfarlane and colleagues described a number of small molecule analogs and derivatives of chloroquine (4-aminoquinoline) and quinacrine (9-aminoacridine) which reportedly inhibit stimulation of the immune system. U.S. Pat. No. 6,221 ,882; U.S. Pat. No.
  • the invention provides a TLR antagonist, compositions including the TLR antagonist, and methods of use of the TLR antagonist and compositions of the invention.
  • the TLR antagonist of the invention referred to herein as CPG 52364, has a structural formula provided as formula I.
  • the invention is a compound of formula I
  • MeO in Formula I represents a methoxy group, CH 3 O-.
  • the invention is a composition including a therapeutically effective amount of the compound of formula I and a pharmaceutically acceptable carrier.
  • the composition in one embodiment includes the free base form of CPG 52364, shown as formula I.
  • the composition in one embodiment includes a pharmaceutically acceptable salt of CPG 52364.
  • the composition is formulated for oral administration.
  • the invention is a method of inhibiting an immune response in a subject. The method according to this aspect includes the step of administering to the subject an effective amount of a compound of formula I
  • the invention is a method of treating a subject having an autoimmune disease.
  • the method according to this aspect includes the step of administering to the subject an effective amount of a compound of formula I
  • the autoimmune disease is selected from systemic lupus erythematosus, insulin-dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, autoimmune hemolytic anemia, Behcet's syndrome, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, sarcoidosis, sclerosing cholangitis, Sjogren's syndrome, systemic sclerosis (scleroderma and CREST syndrome), Takayasu's arteritis, temporal arteritis, and Wegener
  • the invention is a method of treating a subject having or at risk of having transplant rejection.
  • the method according to this aspect includes the step of administering to the subject an effective amount of a compound of formula I
  • the subject is a human.
  • FIG. 1 is a bar graph depicting mean anti-dsDNA antibody levels in MRL Ipr/lpr mice treated with CPG 52364 for 12 weeks.
  • the Y axis represents intensity of kinetoplast staining in a Crithidia luciliae assay at a serum dilution of 1 :100.
  • FIG. 2 is a graph depicting pharmacokinetics of CPG 52364 in blood after single dose administration to rats. Circles: 8.2 mg/kg IV. Triangles: 41.0 mg/kg oral.
  • FIG. 3 is a graph depicting pharmacokinetics of CPG 52364 in blood after single dose administration to cynomolgus monkeys. Circles: 8.2 mg/kg IV. Triangles: 41.0 mg/kg oral.
  • FIG. 4 is a graph depicting pharmacokinetics of CPG 52364 in blood after single dose oral administration (50 mg/kg) to cynomolgus monkeys.
  • the invention provides a particular 2-aminoaryl-4-( ⁇ -aminoalkyl)amino- quinazoline compound having a structure provided as formula I
  • CPG 52364 2-[4-(4-methyl-1-piperazinyl)phenyl]-N-[2-(4-morpholinyl)ethyl]-4-(6,7-dimethoxy- quinazolinamine), referred to herein as CPG 52364, pharmaceutically acceptable salts of CPG 52364, compositions containing CPG 52364, and methods of use of CPG 52364 as a therapeutic immunosuppressive agent.
  • CPG 52364 is a Toll-like receptor (TLR) antagonist that selectively inhibits TLR7, TLR8, and TLR9, a subfamily of TLRs that recognize certain types of nucleic acids, notably CpG DNA and single-stranded RNA. Accordingly, CPG 52364 can be used to inhibit signaling by any one or combination of TLR7, TLR8, and TLR9. Inhibition of signaling by any one or combination of these TLRs can reduce undesirable immune activity. Accordingly, CPG 52364 can be used, either alone or in combination with other agents or treatment modalities, to reduce undesirable immune activity, for example, to treat a subject having a condition characterized by undesirable immune activity. Such conditions include, without limitation, inflammation, autoimmune diseases, acute and chronic transplant rejection, acute and chronic graft-versus-host disease (GvHD), allergy, asthma, and sepsis.
  • TLR Toll-like receptor
  • the invention in one aspect provides a compound having the structure provided in formula I.
  • the invention provides CPG 52364 as the free base having the structure provided in formula I.
  • a method of preparing CPG 52364 is disclosed in Example 1 below.
  • CPG 52364 has a molecular weight of 492.6 Daltons and has the appearance of an off-white to tan solid.
  • the solubilty of the free base in aqueous solution is dependent on pH and exceeds 350 mg/mL between a pH of 1.22 and 5.90. At a pH above 6.90, the solubilty in aqueous solution is less than 1.0 mg/mL.
  • CPG 52364 is soluble in chloroform, methylene chloride, and dimethylformamide.
  • the invention provides a pharmaceutically acceptable salt of CPG 52364.
  • pharmaceutically acceptable salt(s) includes salts of acidic or basic groups which may be present in the compounds of the present invention.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of CPG 52364 are those that form nontoxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate,
  • At least the following acid addition salts have been prepared: hydrochloride, sulfate, bisulfate, phosphate, tartrate, fumarate, and p- toluenesulfonate.
  • Preparation of the bisulfate salt is described in Example 1 below.
  • the invention also relates to base addition salts of CPG 52364.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of CPG 52364 are those that form non-toxic base salts , i.e., salts containing pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, magnesium, and lithium).
  • This invention also encompasses pharmaceutical compositions containing prodrugs of a compound of formula I. Compounds of formula I having a free amino or amido group can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, are covalently joined through peptide bonds to a free amino group of a compound of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three-letter or single-letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters that are covalently bonded to the above substituents of formula 1 through the carbonyl carbon prodrug sidechain.
  • This invention also encompasses compounds of formula I containing protective groups.
  • compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups is described in "Protective Groups in Organic Chemistry", edited by J. W. F. McOmie, Plenum Press (1973) and “Protective Groups in Organic Synthesis", 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley-lnterscience (1999).
  • Certain isotopically-labeled compounds of the present invention are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon- 14, i.e r .; 14 C 1 isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Examples below, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • the invention in one aspect provides a composition including a therapeutically effective amount of CPG 52364, either as the free base or as a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition of the invention can optionally further include at least one additional therapeutic agent. In one embodiment an additional therapeutic agent is another TLR antagonist.
  • the invention further provides a method of making a pharmaceutical composition. The method includes the step of placing a therapeutically effective amount of CPG 52364, either as the free base or as a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
  • an effective amount refers to any amount that is necessary or sufficient to realize a desired biological effect. In some instances an effective amount is a therapeutically effective amount. A “therapeutically effective amount” is any amount that is necessary or sufficient to realize a desired biological effect in a subject. In one embodiment an effective amount is an amount sufficient to treat an autoimmune disease. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side effects and preferred mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial toxicity and yet is effective to treat the particular subject.
  • pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers, dilutants or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • Various formulations are contemplated by the invention, including those suitable for oral and parenteral administration. These and other formulations contemplated by the invention are described in more detail below.
  • TLR1 to TLR10 Eleven mammalian TLRs have been identified, of which only ten are active in humans (TLR1 to TLR10) and only nine are active in mice (TLR1 to TLR7, TLR9, and TLR11 ). Stop codons in the mouse TIr 10 gene and the human Tlr11 gene have rendered these nonfunctional (Takeda K et al. (2005) lnt Immunol. 17(1 ):1-14). Subsets of the TLRs serve different roles in the innate immune system.
  • TLR7 and TLR8 also signal in response to certain synthetic small molecules, including the imidazoquinoline compounds R-837 (imiquimod; AldaraTM (3M Pharmaceuticals, St. Paul, MN); 1-isobutyl-1/-/-imidazo[4,5-c]quinolin-4-amine) and R-848 (resiquimod; 4-amino-D , D-dimethyl-2-ethoxymethyl-IH-imidazo[4,5-c]quinoline-1 - ethanol), as well as various derivatives of imidazoquinoline compounds, including certain substituted imidazoquinoline amines. See, for example, Hemmi H et al. (2002) Nature Immunol. 3(2):196-200; Jurk M et al. (2002) Nature Immunol. 3(6):499; U.S. Pat. No. 6,331 ,539.
  • the invention provides a method of inhibiting an immune response in a subject.
  • the method includes the step of administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • subject refers to a living mammal.
  • a subject is a mouse, rat, guinea pig, rabbit, cat, dog, goat, sheep, horse, cow, or non-human primate.
  • the subject is a human.
  • the immune response is an antigen-specific immune response. This type of immune response is also known as an adaptive immune response.
  • An antigen-specific immune response is an immune response that involves T lymphocytes or B lymphocytes that are activated in response to contact with a particular antigen.
  • An antigen-specific immune response may be characterized by the development of memory for a particular antigen, and thus an antigen-specific immune response includes both primary and recall antigen-specific immune responses.
  • the immune response in this embodiment can be a cellular immune response, a humoral immune response, or a combination of a cellular immune response and a humoral response.
  • Antigen-specific immune responses may include elaboration of certain cytokines, chemokines, and antibodies. Cytokines associated with antigen-specific immune responses include, without limitation, interleukin-2 (IL-2), interleukin-4 (IL-4), and interleukin-5 (IL-5).
  • Interferon gamma is a cytokine associated with both antigen-specific and antigen-nonspecific immune responses.
  • Chemokines associated with antigen-specific immune responses include, without limitation, interferon-gamma- inducible protein-10 (IP-10).
  • Antibodies include antibodies of various classes or isotypes, including IgG, IgM, IgA, IgE, and IgD.
  • the immune response is an antigen-nonspecific immune response.
  • This type of immune response is also known as an innate immune response.
  • An antigen-nonspecific immune response is an immune response that involves phagocytic cells (macrophages and neutrophils) and natural killer (NK) cells that are activated in response to contact with certain molecular patterns that signal danger or non-self, without specificity for any particular antigen and without the development of memory.
  • an antigen-nonspecific immune response is an inflammatory response.
  • Antigen-nonspecific immune responses may include elaboration of certain cytokines and chemokines, such as interleukin-1 (IL-1), interleukin-12 (IL-12), interferon alpha (IFN-D), and tumor necrosis factor alpha (TNF-D), but not antibodies.
  • Chemokines associated with antigen-nonspecific immune responses include, without limitation, interleukin-8 (IL-8). Inhibiting an immune response means reducing at least one measurable aspect of an immune response.
  • the inhibition can be measured using any suitable technique, including, for example, enzyme-linked immunosorbent assay (ELISA) specific for a particular cytokine or chemokine, flow cytometry to quantify cell surface markers indicative of immune cell activation, mixed lymphocyte reaction, and cytolytic assay.
  • ELISA enzyme-linked immunosorbent assay
  • flow cytometry to quantify cell surface markers indicative of immune cell activation
  • mixed lymphocyte reaction and cytolytic assay.
  • An immune response is deemed to be inhibited if at least one measurable aspect of the immune response is reduced by at least 5 percent compared to a control immune response measured under similar conditions.
  • the inhibition corresponds to at least: 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent reduction of a control immune response measured under similar conditions.
  • CPG 52364 was found to be more than an order of magnitude more potent than hydroxychloroquine as an inhibitor of TLR9 signaling, and closer to two orders of magnitude more potent than hydroxychloroquine as an inhibitor of TLR8 signaling.
  • CPG 52364 at nanomolar concentrations, effectively antagonizes TLR signaling in vitro in human peripheral blood mononuclear cells. Results were similar for TLR7, TLR8, and TLR9. In addition to demonstrated effects in vitro, the examples below also show that CPG 52364 effectively inhibits TLR9-stimulated chemokine production in vivo. In mice it was found, for example, that an oral dose of less than 1 mg/kg body weight produced a 50 percent decrease in TLR9-stimulated IP-10 production. This represents a greater than 37-fold greater potency than chloroquine and more than 200-fold greater potency than hydroxychloroquine in this system.
  • Example 5 shows that CPG 52364 effectively reduces anti- dsDNA titers in a mouse model of lupus.
  • Anti-dsDNA titers have been described in the literature to serve as a marker of clinical activity as well as of clinical severity of systemic lupus erythematosus, an autoimmune disease with a relapsing and remitting pattern of clinical disease.
  • MRL Ipr/lpr mice which develop spontaneous lupus, were treated with CPG 52364 or negative control (phosphate-buffered saline, PBS) for twelve weeks and then assessed for anti-dsDNA antibody titers.
  • PBS phosphate-buffered saline
  • mice treated with CPG 52364 had titers that were only about one quarter to one third of corresponding titers in mice treated with PBS.
  • the invention provides a method of treating a subject having an autoimmune disease.
  • the term "treat” as used herein means to obtain a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a particular condition or disease or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a condition or disease and/or adverse effect attributable to the condition or disease.
  • Treatment covers any treatment (e.g.
  • a condition or disease in a non-human such as a mammal, or more particularly a human
  • a condition or disease in a non-human includes: (a) preventing the condition disease from occurring in a subject that may be at risk of developing or predisposed to having a condition or disease but has not yet been diagnosed as having it; (b) inhibiting the condition or disease, i.e., arresting its development; or (c) relieving or ameliorating the condition or disease, i.e., cause regression of the condition or disease.
  • treat refers to reducing at least one objective manifestation of a disease or condition in a subject having the disease or condition.
  • treat refers to eliminating a disease or condition in a subject having the disease or condition.
  • the term "treat” refers to preventing a disease or condition from developing in a subject at risk of developing the disease or condition.
  • a subject may be at risk of having a disease or condition due to a genetic predisposition for developing the disease or condition.
  • a subject may be at risk of having a disease or condition due to an identified or expected exposure of the subject to, or contact of the subject with, an agent associated with developing the disease or condition.
  • a "subject having a disease or condition” refers to a subject having at least one objective manifestation of the disease or condition.
  • a subject having an autoimmune disease refers to a subject having at least one objective manifestation of the autoimmune disease.
  • a subject at risk of having a disease or condition refers to a subject without at least one objective manifestation of the disease or condition but that is nonetheless at risk of harboring or developing the disease or condition.
  • a subject at risk of having transplant rejection refers to a subject without at least one objective manifestation of transplant rejection but that is nonetheless at risk of developing transplant rejection.
  • Such a subject in one embodiment is a subject that is expected to receive a tissue or organ transplant. In another embodiment such a subject is a subject that has received a tissue or organ transplant.
  • Autoimmune diseases specifically include, without limitation, systemic lupus erythematosus (also known simply as lupus; also referred to herein as SLE), insulin-dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, autoimmune hemolytic anemia, Behcet's syndrome, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, sarcoidosis, sclerosing cholangitis, Sjogren's syndrome, systemic sclerosis (scleroderma and CREST syndrome), Takayasu's arteritis, temporal arteriti
  • the invention provides a method of treating a subject having SLE.
  • Systemic lupus erythematosus (SLE) is a complex, multifactorial, chronic, remitting and relapsing autoimmune disease with a heterogeneous clinical presentation.
  • SLE patients with manifestations of SLE may be young (as young as 2 years old) or elderly (80 years of age or older), SLE most commonly affects women of childbearing age. In this age range, the female to male ratio has been estimated to be approximately 12:1 to 10:1 (Danchenko N et al. (2006) Lupus. 15(5):308-315; Manson JJ et al. (2006) Orphanet J Rare Dis. 1(1 ):6).
  • SLE is characterized by loss of self-tolerance and the development of B cell autoreactivity to certain self-antigens leading to the production of autoantibodies to io DNA, RNA, and associated nuclear proteins, and tissue and organ damage from the resultant inflammation.
  • the clinical features of SLE are diverse with a constellation of potential clinical presentations that can include constitutional symptoms, dermatologic or musculoskeletal signs, and/or hematologic, cardiovascular, renal, and sometimes neurologic (CNS) findings. Despite the disparity in the spectrum of clinical signs and
  • pDC plasmacytoid dendritic cells
  • IFN- ⁇ signature - An interesting recent finding that supports a role of IFN- ⁇ in SLE has come from microarray analyses of RNA isolated from PBMCs collected from SLE patients. Several investigators have demonstrated upregulation of a pattern of genes induced by IFN- ⁇ - known as the IFN- ⁇ signature - in a subset of patients with SLE. In a study of PBMC RNA from 48 patients, approximately half had the IFN- ⁇ signature. However, the study included patients who were in remission or had a mild form of disease and would not have been expected to have either elevated serum concentrations of IFN- ⁇ or, perhaps, an IFN- ⁇ signature.
  • IFN- ⁇ signature was associated with patients with severe manifestations (i.e., CNS or renal involvement) or hematologic findings (especially leukopenia, lymphopenia, or thrombocytopenia) (Baechler EC et al. (2004) Curr Opin Immunol. 16:801-807; R ⁇ nnblom L et al. (2006) Arthritis Rheum. 54(2):408- 420). Inappropriate production of IFN- ⁇ in SLE is by pDCs. These cells normally produce IFN- ⁇ in response to detection of microbial nucleic acids (Krieg AM. (2002) Ann Rev Immunol. 20:709-760; Baechler EC et al.
  • mice which share many of the features and disease heterogeneity experienced by SLE patients, have yielded important insights into the pathogenesis of lupus.
  • These murine models (MRL Ipr/lpr, NZW x NZB F1 , and BXSB mice) share many of the serologic, and clinical features of human lupus including hyperactivity of B cells, circulating auto-antibodies (anti-dsDNA antibodies and ANA), circulating immune complexes, and development of glomerulonephritis (Andrews et al., 1978).
  • the mouse models are not identical and heterogeneity has permitted the investigation of different aspects of lupus.
  • mice Differences among the mouse models include the type or quantity of specific autoantibodies (RF and anti-Sm in MRL Ipr/lpr mice), marked lymphoproliferation in MRL Ipr/lpr mice, and gender incidence (male predominance in BXSB mice, but female predominance in NZB x NZW F1 mice). Investigations with these mouse models have indicated that TLR9 and TLR7 have an important mechanistic role in the pathogenesis of SLE.
  • TLR9 involvement has come from crossbreeding experiments that generated MRL Ipr/lpr mice that express RF-specific autoreactive B cells (Leadbetter et al., 2002). Exposure of these mice to the specific RF antigen elicits an expected response: increased proliferation and autoantibody secretion by the autoreactive B cells. However, the cellular responses were not seen in vitro in the presence of pharmacologic inhibitors of TLR9 and were not seen in similar mice that also had a defect in TLR9 signaling. These results demonstrated that two T cell-independent receptors are essential for the B cell responses: the B cell receptor specific for the autoantigen and TLR9 (Leadbetter EA et al. (2002) Nature. 416(6881 ):603-607; Krieg AM. (2002) Nature Immunol. 3(5):423-424).
  • TLR9 which normally has a ligand repertoire restricted to unmethylated DNA that is characteristic of microbial and not mammalian DNA, would instead be activated by self DNA.
  • Indirect and circumstantial evidence that changes in DNA methylation could lead to recognition of self DNA by TLR9 comes from two observations: DNA from lupus patients is often hypomethylated and drugs that inhibit DNA methylation (procainamide and hydralazine) can induce lupus in predisposed individuals (Lu Q et al. (2005) J Immunol. 174 (10):6212-6219).
  • Standard therapy has included hydroxychloroquine and low-dose glucocorticoids for mild disease and high-dose glucocorticoids coupled with more potent immunosuppressives such as cyclophosphamide or azathioprine for patients with more severe disease or symptoms (Manson JJ et al. (2006) Orphanet J Rare Dis. 1 (1 ):6).
  • transplant rejection refers to acute or chronic immune-mediated damage to cells, tissues, or organs transplanted from one individual to another individual, i.e., from a donor to a recipient.
  • the rejection can be diagnosed by any suitable method, including but not limited to physical examination; noting the presence of at least one clinical sign or symptom consistent with decreased function of the transplanted cells, tissues, or organ; medical imaging such as computed tomography (CT) or magnetic resonance imaging (MRI); and biopsy of the transplanted tissue or organ.
  • Transplants specifically include, without limitation, kidney, heart, liver, pancreas, pancreatic islets, lung, small intestine, bladder, bone, bone marrow, artery, vein, muscle, limb, and any combination thereof.
  • CPG 52364 can be used, alone or in combination with at least one other therapeutic agent, to treat a subject having other conditions characterized by undesirable immune activity, including inflammatory conditions, allergy, asthma, and sepsis.
  • Inflammatory conditions include, but are not limited to, adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis, blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis, cholecystitis, chorditis, cochlitis, colitis, conjuctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mastitis, meningitis, metritis, mucitis, myocarditis, myositis, myringitis, nephritis, neuritis
  • Agrostis alba Alder, Alnus (Alnus gultinoasa); Alternaria (Alternaria alternata);
  • Avena vulgaris e.g. Avena sativa
  • Betula Betula verrucosa
  • Blattella e.g.
  • Cupressus e.g. Cupressus sempervirens, Cupressus arizonica and Cupressus macrocarpa
  • Dactylis e.g. Dactylis glomerata
  • Dermatophagoides e.g.
  • Holcus e.g. Holcus lanatus
  • Juniperus e.g. Juniperus sabinoides, Juniperus virginiana, Juniperus communis and Juniperus ashei
  • Lolium e.g. Lolium perenne or
  • Phalaris e.g. Phalaris arundinacea
  • Phleum e.g. Phleum pratense
  • Plantago e.g. Plantago lanceolata
  • Poa e.g. Poa pratensis or Poa compressa
  • Quercus Quercus alba
  • Secale e.g. Secale cereale
  • Sorghum e.g. Sorghum halepensis
  • Thuya e.g. Thuya orientalis
  • Triticum e.g. Thticum aestivum.
  • the term "asthma” as used herein refers to a disease of the airways that is characterized by inflammation, narrowing of the airways, and increased reactivity of the airways to inhaled agents. Asthma is frequently, although not exclusively, associated with atopic or allergic symptoms. In one embodiment asthma is allergic asthma.
  • Asthma is typically an episodic disease with symptom-free periods between acute exacerbations.
  • Sepsis refers to a systemic inflammatory response syndrome in association with infection. Sepsis is characterized by two or more features of fever or hypothermia, tachypnea, tachycardia, elevated or depressed leukocyte counts, and, in advanced cases, cardiovascular collapse (shock), organ dysfunction or failure, and disseminated intravascular coagulation. Both microbial signals and host immune response are believed to contribute to sepsis.
  • CPG 52364 can be used, alone or in combination with at least one antimalarial agent, to treat malaria.
  • Antimalarial agents include, without limitation, various quinoline-based agents including chloroquine, hydroxychloroquine, primaquine, quinine, amodiaquine, mefloquine.
  • CPG 52364 can be combined with other therapeutic agents.
  • CPG 52364 and other therapeutic agent may be administered simultaneously or sequentially.
  • the other therapeutic agents When the other therapeutic agents are administered simultaneously they can be administered in the same or separate formulations, but are administered at the same time.
  • the other therapeutic agents are administered sequentially with one another and with CPG 52364, when the administration of the other therapeutic agents and CPG 52364 is temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer.
  • Other therapeutic agents include but are not limited to anti-inflammatory drugs, glucocorticoids, other immunosuppressive agents, cytokines, antibodies, antimicrobial agents, etc.
  • CPG 52364 may be administered to a subject with an anti-microbial agent.
  • An anti-microbial agent refers to a naturally-occurring or synthetic compound which is capable of killing or inhibiting infectious microorganisms.
  • the type of anti-microbial agent useful according to the invention will depend upon the type of microorganism with which the subject is infected or at risk of becoming infected.
  • Antimicrobial agents include but are not limited to anti-bacterial agents, anti-viral agents, anti-fungal agents and anti-parasitic agents.
  • anti-parasitic agents also referred to as parasiticides useful for human administration
  • examples of anti-parasitic agents include but are not limited to albendazole, amphotericin B, benznidazole, bithionol, chloroquine HCI, chloroquine phosphate, clindamycin, dehydroemetine, diethylcarbamazine, diloxanide furoate, eflomithine, furazolidaone, glucocorticoids, halofantrine, iodoquinol, ivermectin, mebendazole, mefloquine, meglumine antimoniate, melarsoprol, metrifonate, metronidazole, niclosamide, nifurtimox, oxamniquine, paromomycin, pentamidine isethionate, piperazine, praziquantel, primaquine phosphate, proguanil, pyrantel
  • Antiviral agents are compounds which prevent infection of cells by viruses or replication of the virus within the cell. There are many fewer antiviral drugs than antibacterial drugs because the process of viral replication is so closely related to DNA replication within the host cell, that non-specific antiviral agents would often be toxic to the host. There are several stages within the process of viral infection which can be blocked or inhibited by antiviral agents. These stages include, attachment of the virus to the host cell (immunoglobulin or binding peptides), uncoating of the virus (e.g. amantadine), synthesis or translation of viral mRNA (e.g. interferon), replication of viral RNA or DNA (e.g. nucleotide analogues), maturation of new virus proteins (e.g.
  • Nucleotide analogues are synthetic compounds which are similar to nucleotides, but which have an incomplete or abnormal deoxyribose or ribose group. Once the nucleotide analogues are in the cell, they are phosphorylated, producing the triphosphate formed which competes with normal nucleotides for incorporation into the viral DNA or RNA. Once the triphosphate form of the nucleotide analogue is incorporated into the growing nucleic acid chain, it causes irreversible association with the viral polymerase and thus chain termination.
  • the interferons are cytokines which are secreted by virus-infected cells as well as immune cells.
  • the interferons function by binding to specific receptors on cells adjacent to the infected cells, causing the change in the cell which protects it from infection by the virus, ⁇ and ⁇ -interferon also induce the expression of Class I and Class Il MHC molecules on the surface of infected cells, resulting in increased antigen presentation for host immune cell recognition, ⁇ and ⁇ -interferons are available as recombinant forms and have been used for the treatment of chronic hepatitis B and C infection. At the dosages which are effective for anti-viral therapy, interferons have severe side effects such as fever, malaise and weight loss.
  • Anti-viral agents useful in the invention include but are not limited to immunoglobulins, amantadine, interferons, nucleotide analogues, and protease inhibitors.
  • Specific examples of anti-virals include but are not limited to Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclo
  • Anti-fungal agents are sometimes classified by their mechanism of action. Some antifungal agents function as cell wall inhibitors by inhibiting glucose synthase. These include, but are not limited to, basiungin/ECB. Other anti-fungal agents function by destabilizing membrane integrity. These include, but are not limited to, immidazoles, such as clotrimazole, sertaconzole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconacole, as well as FK 463, amphotericin B, BAY 38-9502, MK 991 , pradimicin, UK 292, butenafine, and terbinafine. Other anti-fungal agents function by breaking down chitin (e.g. chitinase) or immunosuppression (501 cream). CPG 52364 may also be administered in conjunction with an anti-cancer therapy.
  • immidazoles such as clotrimazole, sertaconzole, fluconazole,
  • the chemotherapeutic agent may be selected from the group consisting of methotrexate, vincristine, adriamycin, cisplatin, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MMI270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor, MMP, MTA/LY231514, LY264618/Lometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412, Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682,
  • the immunotherapeutic agent may be selected from the group consisting of Ributaxin, Herceptin, Quadramet, Panorex, IDEC-Y2B8, BEC2, C225, Oncolym, SMART M195, ATRAGEN, Ovarex, Bexxar, LDP-03, ior t6, MDX-210, MDX-11 , MDX- 22, OV103, 3622W94, anti-VEGF, Zenapax, MDX-220, MDX-447, MELIMMUNE-2, MELIMMUNE-1 , CEACIDE, Pretarget, NovoMAb-G2, TNT, Gliomab-H, GNI-250, EMD- 72000, LymphoCide, CMA 676, Monopharm-C, 4B5, ior egf.r3, ior c5, BABS, anti-FLK- 2, MDX-260, ANA Ab, SMART 1 D10 Ab, SMART ABL 364 Ab and ImmuRAIT-CEA, but it
  • the cancer vaccine may be selected from the group consisting of EGF, Anti- idiotypic cancer vaccines, Gp75 antigen, GMK melanoma vaccine, MGV ganglioside conjugate vaccine, Her2/neu, Ovarex, M-Vax, O-Vax, L-Vax, STn-KHL theratope, BLP25 (MUC-1 ), liposomal idiotypic vaccine, Melacine, peptide antigen vaccines, toxin/antigen vaccines, MVA-based vaccine, PACIS, BCG vacine, TA-HPV, TA-CIN, DISC-virus and ImmuCyst/TheraCys, but it is not so limited.
  • CPG 52364 may be administered to a subject with an anti-inflammatory agent.
  • an "anti-inflammatory agent” refers to an agent which is administered to a subject for the purpose of down-regulating an inflammatory response.
  • Anti- inflammatory agents are generally less potent than immunosuppressive agents, and they specifically include, without limitation, non-steroidal anti-inflammatory agents, prostaglandin inhibitors, gold, colchicine, and methotrexate.
  • Anti-histamines include, but are not limited to, acrivastine, astemizole, azatadine, azelastine, betatastine, brompheniramine, buclizine, cetirizine, cetirizine analogs, chlorpheniramine, clemastine, CS 560, cyproheptadine, desloratadine, dexchlorpheniramine, ebastine, epinastine, fexofenadine, HSR 609, hydroxyzine, levocabastine, loratidine, methscopolamine, mizolastine, norastemizole, phenindamine, promethazine, pyrilamine, terfenadine, and tranilast.
  • Corticosteroids include, but are not limited to, methylprednisolone, prednisolone, prednisone, beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone propionate, and triamcinolone.
  • dexamethasone is a corticosteroid having antiinflammatory action, it is not regularly used for the treatment of allergy or asthma in an inhaled form because it is highly absorbed and it has long-term suppressive side effects at an effective dose.
  • Dexamethasone can be used according to the invention for treating allergy or asthma because when administered in combination with a composition of the invention it can be administered at a low dose to reduce the side effects.
  • CPG 52364 may be administered to a subject with an agent useful for the treatment of asthma.
  • Agents useful for the treatment of asthma are generally separated into two categories, quick-relief medications and long-term control medications.
  • Asthma patients take the long-term control medications on a daily basis to achieve and maintain control of persistent asthma.
  • Long-term control medications include anti-inflammatory agents such as corticosteroids, chromolyn sodium and nedocromil; long-acting bronchodilators, such as long-acting ⁇ 2 agonists and methylxanthines; and leukotriene modifiers.
  • the quick-relief medications include short-acting ⁇ 2 agonists, anticholinergics, and systemic corticosteroids.
  • Bronchodilator/ ⁇ 2 agonists include, but are not limited to, salmeterol, salbutamol, albuterol, terbutaline, D2522/formoterol, fenoterol, bitolterol, pirbuerol methylxanthines and orciprenaline.
  • Long-acting ⁇ 2 agonists and bronchodilators are compounds which are used for long-term prevention of symptoms in addition to the anti-inflammatory therapies.
  • Long-acting ⁇ 2 agonists include, but are not limited to, salmeterol and albuterol. These compounds are usually used in combination with corticosteroids and generally are not used without any inflammatory therapy. They have been associated with side effects such as tachycardia, skeletal muscle tremor, hypokalemia, and prolongation of QTc interval in overdose.
  • Methylxanthines including for instance theophylline, have been used for long- term control and prevention of symptoms. These compounds cause bronchodilation resulting from phosphodiesterase inhibition and likely adenosine antagonism. Dose- related acute toxicities are a particular problem with these types of compounds. As a result, routine serum concentration must be monitored in order to account for the toxicity and narrow therapeutic range arising from individual differences in metabolic clearance. Side effects include tachycardia, tachyarrhythmias, nausea and vomiting, central nervous system stimulation, headache, seizures, hematemesis, hyperglycemia and hypokalemia.
  • Chromolyn sodium and nedocromil are used as long-term control medications for preventing primarily asthma symptoms arising from exercise or allergic symptoms arising from allergens. These compounds are believed to block early and late reactions to allergens by interfering with chloride channel function. They also stabilize mast cell membranes and inhibit activation and release of mediators from inosineophils and epithelial cells. A four to six week period of administration is generally required to achieve a maximum benefit.
  • Anticholinergics are generally used for the relief of acute bronchospasm. These compounds are believed to function by competitive inhibition of muscarinic cholinergic receptors. Anticholinergics include, but are not limited to, ipratropium bromide. These compounds reverse only cholinerigically-mediated bronchospasm and do not modify any reaction to antigen. Side effects include drying of the mouth and respiratory secretions, increased wheezing in some individuals, and blurred vision if sprayed in the eyes.
  • daily oral doses of CPG 52364 will be from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 5 to 500 milligrams/kg, in one or several administrations per day, will yield the desired results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from an order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.
  • the therapeutically effective amount can be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for CPG 52364 which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration.
  • the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
  • compositions of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients.
  • the compounds i.e., CPG 52364 and other therapeutic agents
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, i.e. EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
  • the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of hydrolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • the increase in overall stability of the component or components and increase in circulation time in the body examples include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone and polyproline.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the stomach the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of CPG 52364 (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 is essential.
  • examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac.
  • These coatings may be used as mixed films.
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e. powder; for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper.
  • moist massing techniques can be used.
  • the therapeutic can be included in the formulation as fine multiparticulates in the form of granules or pellets of particle size about 1 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic could be prepared by compression.
  • Disintegrants may be included in the formulation of the therapeutic into a solid dosage form.
  • Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab.
  • Sodium starch glycolate, Amberiite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins.
  • Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methylcellulose (MC), ethylcellulose (EC) and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
  • An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process.
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
  • stearic acid including its magnesium and calcium salts
  • PTFE polytetrafluoroethylene
  • Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
  • surfactant might be added as a wetting agent.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride.
  • non-ionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of CPG 52364 or derivative either alone or as a mixture in different ratios.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • CPG 52364 is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • Other reports of inhaled molecules include Adjei et al., 1990, Pharmaceutical Research, 7:565-569; Adjei et al., 1990, International Journal of Pharmaceutics, 63:135-144 (leuprolide acetate); Braquet et al., 1989, Journal of Cardiovascular Pharmacology, 13(suppl. 5):143-146 (endothelin-1); Hubbard et al., 1989, Annals of Internal Medicine, Vol. IM, pp.
  • Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Missouri; the Acom Il nebulizer, manufactured by Marquest Medical Products, Englewood, Colorado; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Massachusetts.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
  • Formulations suitable for use with a nebulizer will typically comprise CPG 52364 (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active CPG 52364 per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for CPG 52364 stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the CPG 52364 caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing CPG 52364 (or derivative) suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1 ,1 ,1 ,2-tetrafluoroethane, or combinations thereof.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing CPG 52364 (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • CPG 52364 (or derivative) should most advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (Dm), most preferably 0.5 to 5 Dm, for most effective delivery to the distal lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro )capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer, Science 249:1527-1533, 1990, which is incorporated herein by reference.
  • CPG 52364 and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004- 0.02% w/v).
  • compositions of the invention contain an effective amount of CPG 52364 and optionally therapeutic agents included in a pharmaceutically-acceptable carrier.
  • the therapeutic agent(s), including specifically but not limited to CPG 52364, may be provided in particles.
  • Particles as used herein means nano or microparticles (or in some instances larger) which can consist in whole or in part of CPG 52364 or the other therapeutic agent(s) as described herein.
  • the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
  • the therapeutic agent(s) also may be dispersed throughout the particles.
  • the therapeutic agent(s) also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
  • the particles may be microcapsules which contain CPG 52364 in a solution or in a semi-solid state. The particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
  • Such polymers may be natural or synthetic polymers.
  • the polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described by H. S. Sawhney, CP. Pathak and J.A. Hubell in Macromolecules, (1993) 26:581-587, the teachings of which are incorporated herein.
  • polyhyaluronic acids casein, gelatin, glutin, polyanhyd rides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
  • the therapeutic agent(s) may be contained in controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations.
  • sustained release also referred to as “extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. "Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be 'sustained release.”
  • Long-term sustained release implant may be particularly suitable for treatment of chronic conditions.
  • Long-term release as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days.
  • Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
  • This example describes the synthesis of CPG 52364 as the free base (Steps 1-6) and as a bisulfate salt (Step 7).
  • the acid chloride can be formed without using a catalyst as follows. To a stirred slurry of 2-nitro-4,5- dimethoxybenzoic acid (11.4 gm, 0.05 moles) in toluene (100 mL) was added thionyl chloride (6.0 gm, 0.504 moles). The slurry was stirred and heated in an oil bath set at 100°C which caused the thionyl chloride to reflux. The solution was kept at reflux until a clear solution resulted and then heating was continued an additional 30 minutes by which time most of the thionyl chloride had been consumed and reflux had slowed to a few drops per minute. The total time was about two hours.
  • 4,5-dimethoxyanthranilamide (66.0 gm, 0.336 moles) and N-methyl-N'- (4-formylphenyl)piperazine (68.7 gm, 0.336 moles) were combined with sodium metabisulfite (NaHSO 3 , 47.9 gm, 0.251 moles) and water (4.53 ml_, 0.251 moles) in dimethylacetamide (DMAC, 500 ml_). This mixture was stirred at 150 - 155°C for 90 minutes. The slurry, containing precipitated product, was cooled to 90 0 C and was poured into water and ice (1000 mL) which caused the product to crystallize.
  • sodium metabisulfite NaHSO 3 , 47.9 gm, 0.251 moles
  • DMAC dimethylacetamide
  • the dimethoxyquinazolinone (113 gm, 0.297 moles) was placed in a 1000 mL round bottom flask and phosphorous oxychloride (500 mL) was added. This mixture was stirred and refluxed for 8 hours to provide an orange slurry.
  • the dimethoxyquinazolinone can be added slowly to the phosphorous oxychloride as the latter is stirred, prior to the refluxing. After cooling, the slurry was filtered and washed with diethyl ether.
  • the orange solid chloroquinazoline salt was stirred in a mixture of methylene chloride (1000 ml_) water (500 ml_) as a 20% solution of potassium carbonate was carefully added.
  • the dimethoxyquinazolinone (64.4 gm, 0.169 moles) was placed in a 2000 mL round bottom flask along with 1 ,2-dichlorobenzene (250 ml_) and this mixture was stirred and heated to 130 0 C. At this temperature phosphorous oxychloride (POCI 3 , 57.9 gm, 0.339 moles, 31.6 mL) was added slowly through a dropping funnel. As the phosphorous oxychloride was added, the initial slurry became an orange solution. This solution was stirred and heated at 130°C for one hour to provide an orange slurry.
  • POCI 3 phosphorous oxychloride
  • CPG 52364 (59.1 gm, 0.12 moles) was stirred in boiling methanol (600 ml_) and the hot slurry was treated, rapidly, with a solution of sulfuric acid (35.3 gm, 0.36 moles) in methanol (200 ml_) which caused the formation of a yellow solution. Once all of the acid had been added, the solution was cooled on ice which caused the bisulfate salt to crystallize. The slurry was stirred at ice temperature for 30 minutes and was then filtered to isolate the product. The yellow solid was washed with methanol and then with diethyl ether. After drying at 100 0 C to constant weight there was obtained 84.5 gm (89.5% based on the free base) of the bisulfate salt as a yellow powder.
  • Concentrations of hydroxychloroquine and CPG 52364 necessary to inhibit agonist-stimulated human TLR9 and TLR8 signaling were assessed in human embryonic kidney (HEK293) cells that had been cotransfected with a reporter vector (NF ⁇ B-luciferase) and either recombinant human TLR9 (hTLR9) or TLR8 (hTLR8). Cells were incubated with varying concentrations of CPG 52364 or hydroxychloroquine for 1 hour before addition of specific agonists (unmethylated CpG DNA for hTLR9; RNA for hTLR8; or IL-1 for control cells, which had been transfected with reporter vector alone).
  • Table 1 Human TLR9 and TLR8 Antagonism by CPG 52364 and Hydroxychloroquine in Transfected HEK Cells
  • IC 50 Inhibitory concentration (50%): Concentration that produced a 50% decrease in signaling in presence of agonist alone.
  • CPG 52364 Antagonizes TLR Signaling in Transfected Human Cells and in Isolated
  • TLR7/8/9 antagonism was also evaluated in isolated human peripheral mononuclear cells (PBMCs).
  • PBMCs peripheral mononuclear cells
  • results of TLR8 and TLR9 antagonism in both the transfected HEK cells and isolated PBMCs were pooled: TLR8 and TLR9 antagonism from assays with transfected HEK293 cells or isolated PBMCs and TLR7 antagonism from human PBMCs.
  • CPG 52364 is a 6- fold more potent TLR9 antagonist with an IC 50 of 18 nM ( ⁇ 9 ng/mL); a 52-fold more potent TLR8 antagonist with an IC 50 of 35 nM ( ⁇ 17 ng/mL); and a 62-fold more potent TLR7 antagonist with an IC 50 of 13 nM ( ⁇ 6 ng/mL).
  • CPG 52364 is a potent antagonist for all three members of the TLR7/8/9 family: TLR7, TLR8, and TLR9.
  • CPG 52364 would appear to be an improvement over hydroxychloroquine not only in potency for TLR7/8/9 antagonism but also in cross-family antagonism.
  • Table 2 Antagonist Potency of CPG 52364 Relative to Reference Antimalarial Compounds (Pooled Data)
  • IC 5O Inhibitory concentration (50%): Concentration that produced a 50% decrease in signaling in presence of agonist alone
  • Example 4 Inhibits TLR9-Stimulated IP-10 Production In Vivo
  • CPG 52364 and antimalarials were compared in vivo by evaluation of the inhibitory dose 50% (ID 50 ) of these agents on TLR9- and " Unstimulated IP-10 production in mice.
  • Mice were given various doses of CPG 52364 or antimalarial agents or PBS (vehicle controls) either by intraperitoneal (IP) injection or oral gavage before administration of a TLR9 or TLR7 agonist.
  • IP intraperitoneal
  • Agonist activity was assessed by measurement of plasma IP-10 concentration at three hours after agonist administration.
  • ID 50 Inhibitory dose 50%: Dose that produced a 50% decrease in TLR9-stimulated
  • IP-10 production (mg/kg based on 20 g mouse).
  • ND Not Determined.
  • CPG 52364 The activity of CPG 52364 was compared with that of hydroxychloroquine in the well-studied mouse model of lupus, lupus-prone MRL Ipr/lpr mice that have many disease sequelae similar to human SLE. Andrews BS et al., J Exp Med. 1978; Nov 1 ; 148(5): 1198-1215. Affected mice develop spontaneous systemic autoimmunity with both molecular (IFN signature) and clinical (autoantibody production and glomerulonephritis) features similar to human SLE.
  • IFN signature molecular
  • clinical autoantibody production and glomerulonephritis
  • the lpr (lymphoproliferative) mutation arose as a spontaneous mutation on the MRL genetic background and was found to be a null allele for Fas (CD95), a member of the tumor necrosis factor (TNF) family of receptors involved in programmed cell death.
  • Mice develop serum autoantibody by 6 weeks of age and evidence of lymphadenopathy by 12 weeks of age.
  • Massive lymphadenopathy observed in these animals has been shown to be due to the accumulation of an unusual population of B220+CD4-CD8- (double negative) T cells, a condition not found in human lupus.
  • Animals develop progressive renal disease and marked proteinuria by 16 weeks of age. Mortality is approximately 50% by 20 weeks of age. Therefore, these animals have an inherent genetic mutation contributing to aggressive disease.
  • the TLRs presumably have no direct role in the genetically driven etiology of disease but may contribute to disease exacerbation (Leadbetter EA et al., Nature. 2002; Apr 11 ;416(6881 ):603-607; Krieg AM, Nature Immunology. 2002; 3(5):423-424), thus allowing any potential TLR contribution to be monitored.
  • CPG 52364 and hydroxychloroquine were evaluated in MRL Ipr/lpr mice.
  • animals were euthanized and serum was analyzed for anti-dsDNA antibodies (Crithidia luciliae assay).
  • Anti-dsDNA antibodies are correlated with human SLE and the reduction in anti-dsDNA antibodies is believed to be of potential clinical benefit.
  • Data in FIG. 1 are presented as group mean ( ⁇ SD). The scoring was performed relative to a positive control serum from a MRL-/pr mouse at 21 weeks of age given a score of 3.0 and the negative control serum from a BALB/c mouse given a score of 0. Hydroxychloroquine was ineffective at the maximum tolerated dose of 500 ⁇ g daily.
  • CPG 52364 as single IV dose (8.2 mg/kg). After IV administration, CPG 52364 was eliminated slowly from blood with a mean elimination half-life of approximately 22 to 24 hours. CPG 52364 appeared to be well-distributed outside of the blood compartment based on a mean volume of distribution at steady state (V dss ) greater than 7200 ml_/kg, which exceeds the range of estimated total body water for female beagle dogs (approximately 537 to 589 mL/kg). Wamberg S et al., J Nutr. 2002; 132 (6 Suppl. 2):1711S-1713S. No gender differences were apparent.
  • CPG 52364 Pharmacokinetic parameters in whole blood and oral bioavailability of CPG 52364 were characterized in cynomolgus monkeys (3/sex/dose) after single dose oral administration (41 or 50 mg/kg). After oral administration (41 mg/kg), CPG 52364 was absorbed slowly with mean T ma ⁇ of 7.3 hours for both males and females (FIG. 3). CPG 52364 appeared to be eliminated slowly from blood and was still present in blood at the last measured time point of 24 hours. Mean oral bioavailability of CPG 52364 (normalized for dose) was 31.0% for males and 35.8% for females, when calculated based on AUCo-24h- No noteworthy gender differences were apparent.

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Abstract

L'invention porte sur un composé CPG 52364 ayant la formule I et sur les sels pharmaceutiquement acceptables de celui-ci qui sont des inhibiteurs de la signalisation par les récepteurs de type Toll TLR7, TLR8 et TLR9, et qui sont utiles dans le traitement d'une activité immunitaire non souhaitée. L'invention porte sur une composition pharmaceutique qui comprend CPG 52364 ou sur un sel pharmaceutiquement acceptable de celui-ci et qui peut être utilisée pour traiter des états comprenant une maladie autoimmune, un rejet de greffe, une réaction du greffon contre l'hôte, une allergie, l'asthme, une sepsis et d'autres états inflammatoires.
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