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WO2009030996A1 - Composés triazole utilisés comme agonistes du récepteur de type toll (tlr) - Google Patents

Composés triazole utilisés comme agonistes du récepteur de type toll (tlr) Download PDF

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Publication number
WO2009030996A1
WO2009030996A1 PCT/IB2008/002217 IB2008002217W WO2009030996A1 WO 2009030996 A1 WO2009030996 A1 WO 2009030996A1 IB 2008002217 W IB2008002217 W IB 2008002217W WO 2009030996 A1 WO2009030996 A1 WO 2009030996A1
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Prior art keywords
cancer
compound
subject
antigen
pharmaceutically acceptable
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PCT/IB2008/002217
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English (en)
Inventor
Grayson B. Lipford
Toan Nguyen
Charles Zepp
Alexandra Forsbach
Risini Weeratna
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Coley Pharmaceutical Group, Inc.
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Application filed by Coley Pharmaceutical Group, Inc. filed Critical Coley Pharmaceutical Group, Inc.
Publication of WO2009030996A1 publication Critical patent/WO2009030996A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0003—Invertebrate antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer

Definitions

  • TLRs Toll-like receptors
  • TLR1 - TLR12 Toll-like receptors
  • TLR9 signals in response to CpG-containing DNA
  • TLR3 signals in response to double-stranded RNA
  • TLR7 and TLR8 signal in response to certain single-stranded RNA.
  • synthetic or artificial ligands for these nucleic-acid responsive TLRs are also known.
  • CpG ODN CpG oligodeoxyribonucleotides
  • ORN oligoribonucleotides
  • R-848 certain small molecules including imiquimod (R-837) and resiquimod (R-848).
  • Imiquimod and resiquimod are classified as imidazoaminoquinoline-4-amines; the former is currently marketed as AldaraTM by 3M Pharmaceuticals for topical treatment of anogenital warts associated with papillomavirus infection.
  • certain TLR agonists are also believed to be useful as adjuvants, antitumor agents, and anti-allergy agents. Because a number of diseases and conditions can be treated by enhancing innate immunity, there is a continued need for additional and improved TLR agonists.
  • the invention provides pharmaceutical compositions and methods useful for modulating an immune response. More particularly, the invention provides pharmaceutical compositions and methods useful for inducing or augmenting an immune response, suitable for vaccinating a subject or treating a subject having a suppressed immune response or a condition such as a cancer, infection, allergy, or asthma.
  • the pharmaceutical compositions and methods are based on the discovery by the inventors that certain triazole compounds are potent agonists of TLR7 and TLR8. As agonists of TLR7 and TLR8, these compounds promote signaling by TLR7 and TLR8 and activation of immune cells expressing these receptors.
  • the invention is a pharmaceutical composition that includes a compound selected from compound 52377
  • the pharmaceutical composition further includes an antigen.
  • the antigen in one embodiment can selected from the group consisting of bacterial antigens, viral antigens, and cancer antigens.
  • the invention is a method of enhancing an immune response in a subject.
  • the method according to this aspect of the invention includes the step of administering to a subject in need of an enhanced immune response an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, to enhance the immune response in the subject.
  • the immune response includes production of a cytokine selected from the group consisting of interferon alpha (IFN- ⁇ ), interleukin 12 (IL-12), and a combination thereof.
  • a cytokine selected from the group consisting of interferon alpha (IFN- ⁇ ), interleukin 12 (IL-12), and a combination thereof.
  • the immune response is a Th1-type immune response.
  • the subject has immune suppression resulting from chemotherapy and/or therapeutic radiation exposure. In one embodiment the subject has immune suppression resulting from accidental radiation exposure.
  • the invention in one aspect is a method of vaccinating a subject against an antigen.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, and the antigen.
  • the antigen is selected from the group consisting of bacterial antigens, viral antigens, and cancer antigens.
  • the invention in one aspect is a method of treating a subject having cancer.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, to treat the cancer.
  • the cancer is melanoma.
  • the method further includes administering to the subject a cancer antigen.
  • the invention in one aspect is a method of treating a subject having an infection.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, to treat the infection.
  • the infection is a bacterial infection.
  • In one embodiment is a viral infection.
  • the invention in one aspect is a method of treating a subject having an allergic condition other than allergic asthma.
  • the method according to this aspect includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, to treat the allergic condition.
  • the method further includes administering to the subject an allergen.
  • the invention in one aspect is a method of treating a subject having asthma.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, to treat the asthma.
  • the asthma is allergic asthma.
  • the invention in one aspect is a method of treating a subject having a wound in need of healing.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, to treat the wound.
  • the wound is a diabetic ulcer.
  • the invention is a pharmaceutical composition that includes a compound selected from compound 52378
  • the pharmaceutical composition further includes an antigen.
  • the antigen in one embodiment can selected from the group consisting of bacterial antigens, viral antigens, and cancer antigens.
  • the invention is a method of enhancing an immune response in a subject.
  • the method according to this aspect of the invention includes the step of administering to a subject in need of an enhanced immune response an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, to enhance the immune response in the subject.
  • the immune response includes production of a cytokine selected from the group consisting of interferon alpha (IFN- ⁇ ), interleukin 12 (IL-12), and a combination thereof.
  • a cytokine selected from the group consisting of interferon alpha (IFN- ⁇ ), interleukin 12 (IL-12), and a combination thereof.
  • the immune response is a Th1-type immune response.
  • the subject has immune suppression resulting from chemotherapy and/or therapeutic radiation exposure.
  • the subject has immune suppression resulting from accidental radiation exposure.
  • the invention in one aspect is a method of vaccinating a subject against an antigen.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, and the antigen.
  • the antigen is selected from the group consisting of bacterial antigens, viral antigens, and cancer antigens.
  • the invention in one aspect is a method of treating a subject having cancer.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, to treat the cancer.
  • the cancer is melanoma.
  • the method further includes administering to the subject a cancer antigen.
  • the invention in one aspect is a method of treating a subject having an infection.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, to treat the infection.
  • the infection is a bacterial infection.
  • In one embodiment is a viral infection.
  • the invention in one aspect is a method of treating a subject having an allergic condition other than allergic asthma.
  • the method according to this aspect includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, to treat the allergic condition.
  • the method further includes administering to the subject an allergen.
  • the invention in one aspect is a method of treating a subject having asthma.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, to treat the asthma.
  • the asthma is allergic asthma.
  • the invention in one aspect is a method of treating a subject having a wound in need of healing.
  • the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, to treat the wound.
  • the wound is a diabetic ulcer.
  • the invention is concerned with compounds and pharmaceutical compositions containing the compounds which are useful for the modulation of immune function by the interaction of these compounds with certain of the Toll-like receptors including TLR7 and TLR8.
  • the compounds are derivatives of 1 ,2,4-triazol-3-thiones.
  • the invention is a pharmaceutical composition that includes as an active ingredient a compound with the structure
  • This compound is referred to herein as 52377 and also as a TLR agonist compound of the invention.
  • Compound 52377 is a member of a publicly available combinatorial chemistry library of over 100,000 small molecules known as the ASINEX Express Platinum Collection (ASINEX Ltd., Moscow, Russia). It has been discovered according to the instant invention that 52377 is particularly useful as a TLR7 agonist, having an EC 5O of 9.3 ⁇ M as determined in vitro according to methods described herein.
  • the term “EC 50 " refers to an effective concentration at which a biological response is 50 percent of maximum.
  • the pharmaceutical composition encompasses one or more pharmaceutically acceptable salts of 52377.
  • the pharmaceutical composition according to this aspect of the invention further includes a pharmaceutically acceptable carrier.
  • the invention is a pharmaceutical composition that includes as an active ingredient a compound with the structure
  • This compound is referred to herein as 52378 and also as a TLR agonist compound of the invention.
  • Compound 52378 is a member of the ASINEX Express Platinum Collection (ASINEX Ltd., Moscow, Russia). It has been discovered according to the instant invention that 52378 is particularly useful as a combined TLR7 and TLR8 agonist, having an EC 5O of 1.6 ⁇ M for TLR7 and an EC 5O of 2.3 ⁇ M for TLR8 as determined in vitro according to methods described herein.
  • the pharmaceutical composition according to this aspect of the invention further includes a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention includes as an active ingredient at least one pharmaceutically acceptable salt of 52377.
  • Such active ingredient i.e., a salt of 52377
  • a pharmaceutical composition of the invention includes as an active ingredient at least one pharmaceutically acceptable salt of 52378.
  • Such active ingredient i.e., a salt of 52378, can be in addition to or in place of 52378 itself.
  • salts has its usual meaning as understood in the pharmaceutical arts and specifically includes, without limitation, those salts prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts can also be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts of a carboxylic acid group.
  • compositions according the invention further include a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions of the invention contain an effective amount of active ingredient and optionally other therapeutic agents included in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluents 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 are capable of being commingled with each other in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
  • the invention further contemplates methods for the manufacture of the pharmaceutical compositions of the invention. Such methods include the step of placing an amount of active ingredient of the pharmaceutical composition of the invention in a pharmaceutically acceptable carrier.
  • the methods for manufacture of the pharmaceutical compositions of the invention can further include a step or steps that involve shaping or formulating the pharmaceutical composition for a particular route of administration, such as is described elsewhere herein.
  • the pharmaceutical composition of the invention further includes an antigen.
  • an "antigen” as used herein refers to a molecule capable of provoking an adaptive immune response specific for the antigen.
  • An antigen is thus distinct from a TLR agonist or an adjuvant as used herein, although a TLR agonist or adjuvant can boost an adaptive immune response to an antigen.
  • Antigens include but are not limited to cells, cell extracts, proteins, polypeptides, peptides, polysaccharides, polysaccharide conjugates, peptide and non-peptide mimics of polysaccharides and other molecules, small molecules, lipids, glycolipids, carbohydrates, viruses and viral extracts, multicellular organisms such as parasites, and allergens.
  • antigen can encompass allergens, cancer antigens, microbial antigens, and, in the context of autoimmunity, autoantigens (i.e., inappropriate self- antigens).
  • a "cancer antigen” as used herein is a compound, such as a peptide or protein, associated with a tumor or cancer cell surface and which is capable of provoking an immune response when expressed on the surface of an antigen-presenting cell (APC) in the context of a major histocompatibility complex (MHC) molecule.
  • APC antigen-presenting cell
  • MHC major histocompatibility complex
  • Some of these antigens are encoded, although not necessarily expressed, by normal cells. These antigens can be characterized as those which are normally silent (i.e., not expressed) in normal cells, those that are expressed only at certain stages of differentiation and those that are temporally expressed such as embryonic and fetal antigens.
  • cancer antigens are encoded by mutant cellular genes, such as oncogenes (e.g., activated ras oncogene), suppressor genes (e.g., mutant p53), fusion proteins resulting from internal deletions or chromosomal translocations. Still other cancer antigens can be encoded by viral genes such as those carried on RNA and DNA tumor viruses.
  • Cancer antigens can be prepared from cancer cells either by preparing crude extracts of cancer cells, for example, as described in Cohen et al. (1994) Cancer Research, 54:1055, by partially purifying the antigens, by recombinant technology, or by de novo synthesis of known antigens.
  • Cancer antigens include but are not limited to antigens that are recombinantly expressed, an immunogenic portion of, or a whole tumor or cancer. Such antigens can be isolated or prepared recombinantly or by any other means known in the art.
  • cancer antigens examples include MAGE, MART-1/Melan-A, gplOO, dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein (ADAbp), cyclophilin b, colorectal associated antigen (CRC)-COI 7-1 A/GA733, carcinoembryonic antigen (CEA) and its immunogenic epitopes CAP-1 and CAP-2, etv6, aml1 , prostate specific antigen (PSA) and its immunogenic epitopes PSA-1 , PSA-2, and PSA-3, prostate-specific membrane antigen (PSMA), T-cell receptor/CD3-zeta chain, MAGE-family of tumor antigens (e.g., MAGE-A1 , MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A
  • Cancers associated with specific cancer antigens include, for example, acute lymphoblastic leukemia (etv6; aml1 ; cyclophilin b); B cell lymphoma (Ig-idiotype); glioma (E-cadherin; ⁇ -catenin; ⁇ -catenin; ⁇ -catenin; p120ctn); bladder cancer (p21 ras); biliary cancer (p21ras); breast cancer (MUC family; HER2/neu; c-erbB-2); cervical carcinoma (p53; p21 ras); colon carcinoma (p21 ras; HER2/neu; c-erbB-2; MUC family); colorectal cancer (C017-1A/GA733; APC); choriocarcinoma (CEA); epithelial cell cancer (cyclophilin b); gastric cancer (HER2/neu; c-erbB-2; ga733 glycoprotein); he
  • a "microbial antigen” as used herein is an antigen of a microorganism and includes but is not limited to viral antigens, bacterial antigens, parasite antigens, and fungal antigens. Such antigens include the intact microorganism as well as natural isolates and fragments or derivatives thereof and also synthetic compounds which are identical to or similar to natural microorganism antigens and induce an immune response specific for that microorganism. A compound is similar to a natural microorganism antigen if it induces an immune response (humoral and/or cellular) to a natural microorganism antigen. Such antigens are used routinely in the art and are well known to those of ordinary skill in the art.
  • bacterial antigens are well known in the art and include immunogenic components of vaccines directed against specific bacteria, e.g., diphtheria, Mycobacterium tuberculosis.
  • viral antigens are well known in the art and include immunogenic components of vaccines directed against specific viruses, e.g., hepatitis B virus, measles (rubeola) virus, German measles (rubella) virus, mumps virus, polio virus.
  • the invention in some aspects relates to methods of use of 52377 and 52378 to modulate an immune response in a subject. In certain aspects the invention provides methods of enhancing an immune response in a subject.
  • enhancing an immune response in a subject refers in one embodiment to inducing an immune response in a subject.
  • enhancing an immune response in a subject refers in one embodiment to augmenting an immune response in a subject.
  • immune response refers to any aspect of an innate or adaptive immune response that reflects activation of an immune cell or population of immune cells to proliferate, to perform an effector immune function, or to produce one or more gene products involved in an immune response.
  • an “immune cell” as used herein refers to any bone marrow-derived cell that can participate in an innate or adaptive immune response.
  • Cells of the immune system include, without limitation, dendritic cells (DC), natural killer (NK) cells, monocytes, macrophages, granulocytes, B lymphocytes, plasma cells, T lymphocytes, and precursor cells thereof.
  • DC dendritic cells
  • NK natural killer cells
  • monocytes e.g., monocytes, macrophages, granulocytes, B lymphocytes, plasma cells, T lymphocytes, and precursor cells thereof.
  • an immune cell is a TLR7-expressing immune cell.
  • an immune cell is a TLR8-expressing immune cell.
  • Gene products involved in an immune response can include secreted products (e.g., antibodies, cytokines, and chemokines) as well as intracellular and cell surface molecules characteristic of immune function (e.g., certain cluster of differentiation (CD) antigens, transcription factors, and gene transcripts).
  • the term "immune response” can be applied to a single cell or to a population of cells.
  • Antibodies are well known in the art and generally include antibodies of any of the various classes (isotypes) IgG, IgA, IgM, IgE, and IgD, as well as their subclasses (e.g., IgGI , lgG2, etc.).
  • Cytokines are well known in the art and generally include interferons, interleukins, tumor necrosis factor (TNF), transforming growth factor beta (TGF- ⁇ ), and chemokines.
  • Interferons are well known in the art and generally include but are not limited to IFN- ⁇ , IFN- ⁇ , IFN- ⁇ .
  • Interleukins are well known in the art and generally include but are not limited to IL-1 , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-15, and IL- 18.
  • Chemokines are well known in the art and generally include but are not limited to RANTES, MIP-1 ⁇ , MIP-1 ⁇ , and IP-10, to name but a few.
  • cytokines Production of cytokines can be assessed by any of several methods well known in the art, including biological response assays, enzyme-linked immunosorbent assay (ELISA), intracellular fluorescence-activated cell sorting (FACS) analysis, and reverse transcriptase/polymerase chain reaction (RT-PCR).
  • biological response assays enzyme-linked immunosorbent assay (ELISA), intracellular fluorescence-activated cell sorting (FACS) analysis, and reverse transcriptase/polymerase chain reaction (RT-PCR).
  • ELISA enzyme-linked immunosorbent assay
  • FACS intracellular fluorescence-activated cell sorting
  • RT-PCR reverse transcriptase/polymerase chain reaction
  • the immune response involves upregulation of cell surface markers of immune cell activation, such as CD25, CD80, CD86, and CD154.
  • Methods for measuring cell surface expression of such markers are well known in the art and include FACS analysis.
  • administering refers to administering, either alone or in combination with at least one other agent, by any suitable route of administration.
  • the administering is systemic administration, for example by enteral or parenteral administration.
  • Enteral administration includes but is not limited to oral administration.
  • Parenteral administration includes but is not limited to intravenous (i.v.), intramuscular (i.m.), intraperitoneal (i.p.), intranasal (i.n.), subcutaneous (s. ⁇ ), inhalational, mucosal, and topical administration.
  • administering is local administration. Local administration includes but is not limited to direct injection into a site to be treated, e.g., intralesional.
  • a "subject” as used herein refers to a mammal.
  • a subject is a human.
  • a subject is a non-human mammal, e.g., a mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, sheep, goat, horse, cow, monkey or other non-human primate.
  • an "effective amount” is an amount that is sufficient to achieve a desired biological effect.
  • an effective amount is an amount sufficient to enhance an immune response in a subject.
  • the effective amount for any particular application can vary depending on any of a number of factors, discussed in further detail below.
  • an immune response involves production of IFN- ⁇ .
  • IFN- ⁇ was the first interferon to be identified and commercialized. It encompasses a family of about twenty structurally related proteins each encoded by a separate gene. IFN- ⁇ is generally secreted in large part by mononuclear phagocytes and so-called interferon producing cells (IPCs) recently identified as plasmacytoid dendritic cells (pDCs). Measurement of secreted IFN- ⁇ can be accomplished, for example, using subtype- specific or subtype-nonspecific IFN- ⁇ -specific ELISA.
  • IPCs interferon producing cells
  • pDCs plasmacytoid dendritic cells
  • Measurement of secreted IFN- ⁇ can be accomplished, for example, using subtype- specific or subtype-nonspecific IFN- ⁇ -specific ELISA.
  • Major effects of IFN- ⁇ include inhibition of viral replication, inhibition of cell proliferation, activation of natural killer (NK) cell lytic functions, and upregulation of class I major histocompatibility complex (MHC).
  • MHC class I
  • IFN- ⁇ has been reported to be useful in the treatment of a variety of diseases including certain malignancies (e.g., hairy cell leukemia, cutaneous T cell leukemia, chronic myeloid leukemia, non-Hodgkins lymphoma, AIDS-related Kaposi's sarcoma, malignant melanoma, multiple myeloma, renal cell carcinoma, bladder cell carcinoma, colon carcinoma, cervical dysplasia) and viral diseases (e.g., chronic hepatitis B, chronic hepatitis C, genital warts (papillomavirus)).
  • Various recombinant forms of IFN- ⁇ are commercially available, including ROFERON®-A (IFN- ⁇ 2a; Roche) and INTRON® A (IFN- ⁇ 2b; Schering).
  • an immune response involves production of IL-12.
  • IL-12 is a principal mediator of the early innate immune response to intracellular microbes and is a key inducer of cell-mediated immunity, the adaptive immune response to these microbes.
  • IL-12 is responsible primarily for the induction of interferon gamma (IFN- ⁇ ) and tumor necrosis factor-alpha (TNF- ⁇ ) from both NK cells and helper T cells.
  • IFN- ⁇ interferon gamma
  • TNF- ⁇ tumor necrosis factor-alpha
  • IL-12 also stimulates the rate at which NK cells and helper T cells proliferate following antigen activation.
  • the lytic capacities of both NK and CD8 + cytolytic T cells are increased by the presence of IL-12.
  • an immune response enhanced according to a method of the invention is a Th1-type immune response.
  • a Th1-type immune response refers to an immune response with a predominantly Th1 character. Such an immune response is characterized by the presence of at least one of the following: IFN- ⁇ , IL-12, IL-18, IgGI (human) or lgG2a (mice), and cell-mediated immunity.
  • a Th1-type immune response in one embodiment is a Th1 immune response.
  • a Th2- type immune response is characterized by at least one of the following: IL-4, IL-5, IL-13, IgE, and humoral immunity.
  • Th1 and Th2 immune responses are counter-regulatory, such that a Th1 immune response down-regulates a Th2 immune response, and a Th2 immune response down-regulates a Th1 immune response.
  • the pharmaceutical compositions and methods of the invention thus are particularly useful whenever it is desirable to promote a Th 1 -type immune response or to inhibit a Th2-like immune response.
  • the subject being treated has immune suppression.
  • Immune suppression is an undesirably weak or absent ability to mount an effective immune response to a suitable immune stimulus.
  • Various factors and conditions are related to immune suppression, including congenital and acquired immunodeficiencies.
  • Congenital immunodeficiencies include various forms of severe combined immunodeficiency (SCIDs), adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase (PNP) deficiency, X-linked agammaglobulinemia, Ig heavy chain deletions, DiGeorge syndrome, selective Ig isotype deficiencies, X-linked hyper-lgM syndrome, common variable immunodeficiency, X-linked lymphoproliferative syndrome, bare lymphocyte syndrome, transporter associated with antigen processing (TAP) deficiency, Wiskott-Aldrich syndrome, ataxia-telangiectasia, chronic granulomatous disease, leukocyte adhesion deficiency-1 , leukocyte deficiency-2,
  • Acquired immunodeficiencies include those related to human immunodeficiency virus (HIV) infection, protein-calorie malnutrition, burns, cancer, bone marrow transplantation, anti-rejection immunosuppressive drugs, other drugs, chemotherapy, and irradiation.
  • HIV human immunodeficiency virus
  • the subject being treated has immune suppression resulting from chemotherapy and/or therapeutic radiation exposure.
  • Chemotherapy refers to administration of a chemotherapy agent for the treatment of cancer. Many chemotherapeutic agents are known in the art to induce immune suppression due to their toxic effects on bone marrow cells.
  • Chemotherapeutic agents include, without limitation, 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, 9-AC, AG
  • YM 116 Iodine seeds, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/Dexifosamide, Ifes/Mesnex/lfosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331 , Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphalan and cyclophosphamide, Aminoglutethimide, Asparaginase, Busulfan, Carboplatin, Chlorambucil, Cytarabine HCI, Dactinomycin, Daunorubicin HCI, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flut
  • Therapeutic radiation exposure refers to administration of prescribed amounts of ionizing irradiation directed or delivered systemically or to specified portions of the body to treat a condition such as a cancer.
  • This type of radiation exposure can include, for example, X-rays, gamma rays (e.g., from cobalt 60), particle beams (e.g., electron beam radiation), or other external beam irradiation; internal radiation therapy
  • brachytherapy e.g., iodine seeds
  • systemic radiation therapy e.g., iodine 131 and strontium 89.
  • accidental radiation exposure is any radiation exposure other than therapeutic radiation exposure. In one embodiment accidental radiation exposure is the result of uncontrolled release of ionizing radiation, for example from detonation of a nuclear weapon.
  • the invention in certain aspects relates to methods of vaccinating a subject against an antigen.
  • the method of vaccinating a subject against an antigen includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377, and the antigen.
  • the method of vaccinating a subject against an antigen includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378, and the antigen.
  • Antigens are described above and can include, in certain embodiments, bacterial antigens, viral antigens, and cancer antigens.
  • the administering can be accomplished by any suitable route or routes with respect to the compound and the antigen.
  • the antigen and the compound of the invention are administered together, for example either as a single preparation or as separate preparations administered substantially simultaneously.
  • the individual preparations can be administered to the same or different sites, by the same or different routes of administration.
  • the antigen and the compound of the invention are not administered substantially simultaneously.
  • the administering the compound of the invention takes place before the administering the antigen.
  • the administering the antigen takes place before the administering the compound of the invention.
  • the period between the administering of the antigen and the administering the compound of the invention can be minutes, hours, or days, even up to a week.
  • the individual components, i.e., antigen and compound of the invention can be administered to the same or different sites, by the same or different routes of administration.
  • Routes of administration for vaccination include, without limitation, intramuscular, subcutaneous, and mucosal.
  • the compound is administered intravenously.
  • the amount of antigen administered to the subject is less than an effective amount of the antigen by itself to induce protective immunity.
  • the administering the same amount of antigen is effective to induce protective immunity, i.e., to vaccinate the subject, against the antigen.
  • the invention in certain aspects relates to methods of treating a subject having cancer.
  • the method of treating a subject having cancer includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377.
  • the method of treating a subject having cancer includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378.
  • “treat” or “treating” refers to preventing, ameliorating, or eliminating a disease or condition in a subject having the disease or condition.
  • “treat” or “treating” refers to ameliorating or eliminating a disease or condition in a subject having the disease or condition.
  • treating can refer to reducing the size of a tumor (including a metastasis), slowing the rate of growth or the rate or extent of spreading of a cancer, inducing a remission of a cancer, or curing a cancer.
  • a “subject having cancer” is a subject that has at least one objective manifestation of a cancer.
  • Cancer refers to an uncontrolled growth of cells which interferes with the normal functioning of the bodily organs and systems. Cancers which migrate from their original location and seed vital organs can eventually lead to the death of the subject through the functional deterioration of the affected organs. Hematopoietic cancers, such as leukemia, are able to outcompete the normal hematopoietic compartments in a subject, thereby leading to hematopoietic failure (in the form of anemia, thrombocytopenia and neutropenia) ultimately causing death.
  • Cancers include, but are not limited to, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and other central nervous system (CNS) cancer; breast cancer; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer; leukemias, including hairy cell leukemia; liver cancer; lung cancer (e.g. small cell and non-small cell); lymphomas including Hodgkin's and non-
  • oral cavity cancer e.g., lip, tongue, mouth, and pharynx
  • ovarian cancer pancreatic cancer
  • prostate cancer retinoblastoma
  • rhabdomyosarcoma rectal cancer
  • renal cancer cancer of the respiratory system
  • sarcoma skin cancer
  • stomach cancer testicular cancer
  • thyroid cancer thyroid cancer
  • uterine cancer cancer of the urinary system, as well as other carcinomas and
  • a metastasis is a region of cancer cells, distinct from the primary tumor location resulting from the dissemination of cancer cells from the primary tumor to other parts of the body.
  • the subject may be monitored for the presence of metastases. Metastases are most often detected through the sole or combined use of magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, blood and platelet counts, liver function studies, chest X-rays and bone scans in addition to the monitoring of specific symptoms.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • the cancer is melanoma (primary or metastatic). In one embodiment the cancer is breast cancer. In one embodiment the cancer is lung cancer. In one embodiment the cancer is prostate cancer. In one embodiment the cancer is colon cancer. In one embodiment the cancer is hairy cell leukemia.
  • the method of treating a subject having cancer further includes administering to the subject a cancer antigen.
  • the cancer antigen and the compound of the invention are administered together, for example either as a single preparation or as separate preparations administered substantially simultaneously. When separate preparations are administered substantially simultaneously, the individual preparations can be administered to the same or different sites, by the same or different routes of administration.
  • the cancer antigen and the compound of the invention are not administered substantially simultaneously.
  • the administering the compound of the invention takes place before the administering the cancer antigen.
  • the administering the cancer antigen takes place before the administering the compound of the invention.
  • the period between the administering of the cancer antigen and the administering the compound of the invention can be minutes, hours, or days, even up to a week.
  • the individual components, i.e., cancer antigen and compound of the invention can be administered to the same or different sites, by the same or different routes of administration.
  • the invention in certain aspects relates to methods of treating a subject having an infection.
  • the method of treating a subject having an infection includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377.
  • the method of treating a subject having an infection includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378.
  • treating can refer to reducing at least one symptom of an infection, shortening the duration of an infection, slowing the rate or extent of spreading of an infection, or curing an infection.
  • an "infection” refers to an infectious disease arising from the invasion of a host, superficially, locally, or systemically, by an infectious microorganism or infectious agent.
  • a subject having an infection is a subject that has at least one objective manifestation of an infection.
  • Infectious microorganisms and infectious agents include viruses, bacteria, parasites, and fungi.
  • a viral infection refers to an infection by a virus.
  • a bacterial infection refers to an infection by bacteria. Examples of viruses that have been found in humans include but are not limited to: Retroviridae (e.g.
  • human immunodeficiency viruses such as HIV-1 (also referred to as HDTV-III, LAVE or HTLV-I I I/LAV, or HIV-III, and other isolates, such as HIV-LP)); Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g.
  • HIV-1 also referred to as HDTV-III, LAVE or HTLV-I I I/LAV, or HIV-III, and other isolates, such as HIV-LP
  • Picornaviridae e.g. polio viruses, hepatitis A virus; enterovirus
  • coronaviruses coronaviruses
  • Rhabdoviradae e.g. vesicular stomatitis viruses, rabies viruses
  • Filoviridae e.g. ebola viruses
  • Paramyxoviridae e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus
  • Orthomyxoviridae e.g. influenza viruses
  • B ⁇ nyaviridae e.g. Hantaan viruses, bunya viruses, phleboviruses and Nairo viruses
  • Reoviridae e.g. reoviruses, orbiviruses and rotaviruses
  • Birnaviridae Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papillomaviruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g.
  • African swine fever virus African swine fever virus
  • Gram positive bacteria include, but are not limited to, Pasteurella species, Staphylococci species, and Streptococcus species.
  • Gram negative bacteria include, but are not limited to, Escherichia coli, Pseudomonas species, and Salmonella species.
  • infectious bacteria include but are not limited to, Helicobacter pyloris, Borrelia burgdorferi, Legionella pneumophilia, Mycobacteria sps (e.g. M. tuberculosis, M. avium, M. intracellular, M. kansasii, M.
  • fungi examples include Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis, Candida albicans, Pneumocyctis carinii, Aspergillus.
  • Other infectious organisms i.e., protists
  • Plasmodium spp. such as
  • Plasmodium falciparum Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax and Toxoplasma gondii.
  • Blood-borne and/or tissues parasites include Plasmodium spp., Babesia microti, Babesia divergens, Leishmania tropica, Leishmania spp., Leishmania braziliensis, Leishmania donovani, Trypanosoma gambiense and Trypanosoma rhodesiense (African sleeping sickness), Trypanosoma cruzi (Chagas' disease), and Toxoplasma gondii.
  • the invention in certain aspects relates to methods of treating a subject having an allergic condition.
  • the method of treating a subject having an allergic condition includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377.
  • the method of treating a subject having an allergic condition includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378.
  • treating can refer to preventing at least one symptom of an allergic condition, reducing at least one symptom of an allergic condition, or shortening the duration of an allergic condition. Also in the context of allergic condition, in a non-limiting embodiment treating can refer to reducing the frequency of developing at least one symptom of an allergic condition.
  • an "allergic condition" refers to an acquired hypersensitivity to a substance (allergen).
  • a subject having an allergic condition is a subject that has at least one objective manifestation of an allergic reaction in response to exposure to or contact with an allergen. Allergic conditions are thus often situational, but the subject having the allergic condition is continuously primed to respond to the allergen.
  • a subject having an allergic condition can but need not necessarily have the at least one objective manifestation of an allergic reaction at the time the subject is treated according to the method of the invention.
  • Allergic conditions include, without limitation, eczema, allergic rhinitis or coryza, hayfever, allergic asthma, urticaria (hives), food allergies, and other atopic conditions.
  • the allergic condition is allergic asthma.
  • asthma has its usual meaning and refers to a disorder of the respiratory system characterized by inflammation, narrowing of the airways, and increased reactivity of the airways to inhaled agents.
  • allergic asthma refers to asthma triggered by contact of a susceptible subject with an allergen. A diagnosis of allergic asthma can be made even without knowledge of the identity of a specific triggering allergen.
  • allergic asthma is a very common form of asthma, the compounds and pharmaceutical compositions of the invention are also believed to be useful for the treatment of other forms of asthma in addition to allergic asthma, e.g., asthma associated with upper respiratory tract infection, exercise-induced asthma, and cold (temperature)-induced asthma.
  • the allergic condition excludes allergic asthma.
  • This embodiment includes other allergic conditions including, without limitation, eczema, allergic rhinitis or coryza, hayfever, urticaria (hives), food allergies, and combinations thereof.
  • the method of treating a subject having an allergic condition further includes administering to the subject an allergen.
  • allergen as used herein is a molecule capable of provoking an immune response characterized by production of IgE.
  • An allergen is also a substance that can induce an allergic or asthmatic response in a susceptible subject.
  • allergen means a specific type of antigen which can trigger an allergic response which is mediated by IgE antibody.
  • allergens can include pollens, insect venoms, animal dander dust, fungal spores and drugs (e.g., penicillin).
  • natural animal and plant allergens include proteins specific to the following genuses: Canis (Canis familiaris); Dermatophagoides (e.g., Dermatophagoides farinae); Felis (Felis domesticus); Ambrosia (Ambrosia artemisiifolia); Lolium (e.g., Lolium perenne and Lolium multiflorum); Cryptomeria (Cryptomeria japonica); Alternaria ⁇ Alternaria alternata); Alder; Alnus (Alnus gultinosa); Betula ⁇ Betula verrucosa); Quercus (Quercus alba); Olea (Olea europa); Artemisia (Artemisia vulgaris); Plantago (e.g., Plantago lanceolata); P
  • Pehplaneta e.g., Periplaneta americana
  • Agropyron e.g., Agropyron repens
  • Secale e.g., Secale cereale
  • Triticum e.g., Triticum aestivum
  • Dactylis e.g., Dactylis glomerata
  • Festuca e.g., Festuca elatior
  • Poa e.g., Poa pratensis and Poa compressa
  • Avena e.g., Avena sativa
  • Holcus e.g., Holcus lanatus
  • Anthoxanthum e.g., Anthoxanthum odoratum
  • Arrhenatherum e.g., Arrhenatherum elatius
  • Agrostis e.g., Agrostis alba
  • Phleum e.g., Phleum pratense
  • the allergen and the compound of the invention are administered together, for example either as a single preparation or as separate preparations administered substantially simultaneously. When separate preparations are administered substantially simultaneously, the individual preparations can be administered to the same or different sites, by the same or different routes of administration. In one embodiment the allergen and the compound of the invention are not administered substantially simultaneously.
  • the administering the compound of the invention takes place before the administering the allergen. In one embodiment the administering the allergen takes place before the administering the compound of the invention.
  • the period between the administering of the allergen and the administering the compound of the invention can be minutes, hours, or days, even up to a week.
  • the individual components, i.e., allergen and compound of the invention can be administered to the same or different sites, by the same or different routes of administration.
  • the invention in certain aspects relates to methods of treating a subject having asthma.
  • the method of treating a subject having asthma includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of 52377.
  • the method of treating a subject having asthma includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378.
  • treating can refer to preventing at least one symptom of asthma, reducing at least one symptom of asthma, or shortening the duration of an asthma attack. Also in the context of asthma, in a non- limiting embodiment treating can refer to reducing the frequency of developing at least one symptom of asthma.
  • asthma is allergic asthma.
  • the invention in certain aspects relates to methods of treating a subject having a wound in need of healing.
  • the method of treating a subject having a wound in need of healing includes the step of administering to the subject an effective amount of a compound selected from 52377 and pharmaceutically acceptable salts of
  • the method of treating a subject having a wound in need of healing includes the step of administering to the subject an effective amount of a compound selected from 52378 and pharmaceutically acceptable salts of 52378.
  • a wound refers to any physical disruption of normal tissue integrity, usually arising from mechanical or other contact-related injury to the tissue. Wounds can include abrasions, lacerations, surgical incisions, punctures, bed sores, ulcers, and burns.
  • a wound is a wound involving skin.
  • a wound is a diabetic ulcer, which may typically be a non-healing area of skin in a foot or lower extremity of a subject having diabetes mellitus. Diabetic ulcers are believed to arise from otherwise avoidable or trivial skin injuries as a complication of diabetic neuropathy and compromised vascular supply.
  • a wound in need of healing refers to a wound that is failing to heal in a normal manner. Such a wound may, for example, be healing at an abnormally slow rate, or it may not be healing.
  • treating can refer to reducing extension of a wound, promoting closure or repair of a wound, and healing a wound.
  • TLR agonist compounds of the invention can be combined with other therapeutic agents.
  • the TLR agonist compound of the invention 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 the TLR agonist compound of the invention, when the administration of the other therapeutic agents and the TLR agonist compound of the invention 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-microbial agents, anti-cancer agents, anti-allergy agents, and anti-asthma agents.
  • the TLR agonist compounds of the invention 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 or infectious agents.
  • the type of anti-microbial agent useful according to the invention will depend upon the type of microorganism or infectious agent with which the subject is infected or at risk of becoming infected.
  • Anti-microbial agents include but are not limited to anti-bacterial agents, anti-viral agents, anti-fungal agents and anti-parasitic agents.
  • Anti-bacterial agents kill or inhibit bacteria and include antibiotics as well as other synthetic or natural compounds having similar functions.
  • Antibiotics are low molecular weight molecules which are produced as secondary metabolites by cells, such as microorganisms. In general, antibiotics interfere with one or more bacterial functions or structures which are specific for the microorganism and which are not present in host cells.
  • Anti-viral agents can be isolated from natural sources or synthesized and are useful for killing or inhibiting viruses.
  • Anti-fungal agents are used to treat superficial fungal infections as well as opportunistic and primary systemic fungal infections. Anti- parasitic agents kill or inhibit parasites.
  • Anti-bacterial agents kill or inhibit the growth or function of bacteria.
  • a large class of anti-bacterial agents is antibiotics. Antibiotics which are effective for killing or inhibiting a wide range of bacteria are referred to as broad spectrum antibiotics. Other types of antibiotics are predominantly effective against the bacteria of the class gram- positive or gram-negative. These types of antibiotics are referred to as narrow spectrum antibiotics. Other antibiotics which are effective against a single organism or disease and not against other types of bacteria are referred to as limited spectrum antibiotics.
  • Antibacterial agents are sometimes classified based on their primary mode of action. In general, antibacterial agents are cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors, nucleic acid synthesis or functional inhibitors, and competitive inhibitors.
  • Antibiotics include, without limitation, natural penicillins, semi-synthetic penicillins, clavulanic acid, cephalosporins, bacitracin, ampicillin, carbenicillin, oxacillin, azlocillin, mezlocillin, piperacillin, methicillin, dicloxacillin, nafcillin, cephalothin, cephapirin, cephalexin, cefamandole, cefaclor, cefazolin, cefuroxine, cefoxitin, cefotaxime, cefsulodin, cefetamet, cefixime, ceftriaxone, cefoperazone, ceftazidine, moxalactam, carbapenems, imipenems, monobactems, euztreonam, vancomycin, polymyxin, amphotericin B, nystatin, imidazoles, clotrimazole, miconazole, ketoconazole, it
  • Cefaclor Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium;
  • Cefaparole Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium;
  • Cefbuperazone Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol; Cefixime;
  • Cefmenoxime Hydrochloride Cefmetazole; Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxime
  • Cefpirome Sulfate Cefpodoxime Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium;
  • Cephalexin Cephalexin Hydrochloride; Cephaloglycin; Cephaloridine; Cephalothin
  • Chloramphenicol Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex;
  • Chloramphenicol Sodium Succinate Chlorhexidine Phosphanilate; Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin;
  • Ciprofloxacin Hydrochloride Cirolemycin; Clarithromycin; Clinafloxacin Hydrochloride;
  • Demeclocycline Hydrochloride Demecycline; Denofungin; Diaveridine; Dicloxacillin;
  • Dicloxacillin Sodium Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin;
  • Doxycycline Doxycycline Calcium; Doxycycline Fosfatex; Doxycycline Hyclate;
  • Fludalanine Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin;
  • Kanamycin Sulfate Kitasamycin; Levofuraltadone; Levopropylcillin Potassium;
  • Lexithromycin Lincomycin; Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline;
  • Neomycin Sulfate Neomycin Undecylenate
  • Netilmicin Sulfate Neutramycin
  • Nifuradene Nifuraldezone; Nifuratel; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol;
  • Nifurquinazol Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam
  • Rolitetracycline Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate;
  • Rosaramicin Propionate Rosaramicin Sodium Phosphate
  • Rosaramicin Stearate Rosaramicin Stearate
  • Sulfacytine Sulfadiazine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sulfamerazine;
  • Sulfameter Sulfamethazine; Sulfamethizole; Sulfamethoxazole; Sulfamonomethoxine;
  • Anti-viral 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. protease inhibitors), and budding and release of the virus.
  • 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
  • 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.
  • Nucleotide analogues include, but are not limited to, acyclovir (used for the treatment of herpes simplex virus and varicella- zoster virus), gancyclovir (useful for the treatment of cytomegalovirus), idoxuridine, ribavirin (useful for the treatment of respiratory syncitial virus), dideoxyinosine, dideoxycytidine, zidovudine (azidothymidine), imiquimod, and resimiquimod.
  • 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
  • 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, imidazoles, 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).
  • chitin e.g. chitinase
  • immunosuppression 501 cream
  • 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, efldmithine, furazolidaone, glucocorticoids, halofantrine, iodoquinol, ivermectin, mebendazole, mefloquine, meglumine antimoniate, melarsoprol, metrifonate, metronidazole, niclosamide, nifurtimox, oxamniquine, paromomycin, pentamidine isethionate, piperazine, praziquantel, primaquine phosphate, proguanil, pyr
  • Anti-cancer therapies include anticancer agents or, equivalent ⁇ , cancer medicaments, as well as radiation and surgical procedures.
  • an "anti-cancer agent” or “cancer medicament” refers to an agent which is administered to a subject for the purpose of treating a cancer.
  • a cancer medicament is administered to a subject at risk of developing a cancer for the purpose of reducing the risk of developing the cancer.
  • chemotherapeutic agents for the treatment of cancer are described herein.
  • anti-cancer agents or, equivalent ⁇ , cancer medicaments are classified as chemotherapeutic agents, immunotherapeutic agents, cancer vaccines, hormone therapy, and biological response modifiers.
  • 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,
  • Taxotere/Docetaxel prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide, Aminoglutethimide, Asparaginase, Busulfan, Carboplatin, Chlorambucil, Cytarabine HCI, Dactinomycin,
  • Daunorubicin HCI Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alfa-2a, Alfa-2b, Leuprolide acetate (LHRH-releasing factor analogue), Lomustine (CCNU), Mechlorethamine HCI (nitrogen mustard), Mercaptopurine, Mesna, Mitotane (o.p ' -DDD), Mitoxantrone HCI, Octreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Amsacrine (m-AMSA), Azacitidine, Erthropoietin, Hexamethylmelamine (HMM), lnterleukin 2, Mitoguazone (methyl-GAG; methyl
  • the immunotherapeutic agent may be selected from the group consisting of
  • the immunotherapeutic agent may be selected from the group consisting of Ributaxin, Rituxan, Herceptin, Quadramet, Panorex, IDEC-Y2B8, BEC2, C225, Oncolym, SMART M195, ATRAGEN, Ovarex, Bexxar, LDP-03, ior t ⁇ , 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
  • 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.
  • 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.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular TLR agonist compound being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular
  • TLR agonist compound and/or other therapeutic agent without necessitating undue experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate system levels can be determined by, for example, measurement of the patient's peak or sustained plasma level of the drug. "Dose” and “dosage” are used interchangeably herein.
  • daily oral doses of active compounds 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 0.5 to 50 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. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • the therapeutically effective amount can be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for TLR agonist compounds 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, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the TLR agonist compound can be administered to a subject by any mode that delivers the TLR agonist compound to the desired surface.
  • Administering the pharmaceutical composition of the present invention may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to oral, parenteral, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal.
  • the compounds i.e., TLR agonist compounds, and other therapeutic agents
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • 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, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, e.g., 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 proteolysis; 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 are also contemplated.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, 1981 , "Soluble Polymer-Enzyme Adducts" In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-lnterscience, New York, NY, pp. 367-383; Newmark, et al., 1982, J. Appl. Biochem. 4:185-189.
  • Other polymers that could be used are poly-1 ,3- dioxolane and poly-1 ,3,6-tioxocane.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the TLR agonist compound (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 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.
  • TLR agonist compound or derivative
  • an edible product such as a refrigerated beverage containing colorants and flavoring agents.
  • these diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
  • 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, Amberlite, 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.
  • MC methyl cellulose
  • EC ethyl cellulose
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • 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.
  • Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added.
  • the glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • 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.
  • Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride.
  • the list of potential 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 the TLR agonist compound or derivative either alone or as a mixture in different ratios.
  • Pharmaceutical preparations 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.
  • 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.
  • the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
  • TLR agonist compounds or derivatives thereof.
  • the TLR agonist compound (or derivative) 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.
  • 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.
  • Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Missouri
  • Acorn Il nebulizer manufactured by Marquest Medical Products, Englewood, Colorado
  • the Ventolin metered dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina
  • the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Massachusetts.
  • TLR agonist compound or derivative
  • 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.
  • the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
  • Chemically modified TLR agonist compound may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer will typically comprise TLR agonist compound (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active TLR agonist compound per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for TLR agonist compound stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the TLR agonist compound 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 the TLR agonist compound (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.
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing TLR agonist compound (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.
  • the TLR agonist compound (or derivative) should most advantageously be prepared in particulate form with an average particle size of less than 10 ⁇ m (or microns), most preferably 0.5 to 5 ⁇ m, for most effective delivery to the distal lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
  • Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the pharmaceutical composition of the present invention.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
  • the compounds when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • 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.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • 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.
  • the TLR agonist compounds 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.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • 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 a TLR agonist compound and optionally therapeutic agents included in a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, diluents 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.
  • the therapeutic agent(s) including specifically but not limited to the TLR agonist compound, 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 the TLR agonist compound 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 the TLR agonist compound 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, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), 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.
  • TLR7 and TLR8 Responsiveness of TLR7 and TLR8 to 52377 and 52378 HEK293 cells were transiently transfected by electroporation with vectors expressing human or murine TLR7, human TLR8, and a 6xNF- ⁇ B luciferase reporter construct, as previously described.
  • Cells were incubated for 16 h at 37°C in a humidified incubator with various concentrations of 52377 and 52378 added. Cells were lysed and the amount of luciferase was determined with BriteLite on a luminometer (both from PerkinElmer).
  • 52378 was found to have an EC 50 of 1.6 ⁇ M for human TLR7 and an EC 50 of 2.3 ⁇ M for human TLR8. Compound 52378 was thus determined to be a potent agonist of both human TLR7 and human TLR8.
  • Human peripheral blood mononuclear cells include immune cells that naturally express TLR7 (plasmacytoid dendritic cells (pDC)) and TLR8 (monocytes and myeloid dendritic cells (mDC)).
  • Human PBMC are isolated from whole blood.
  • pDCs and monocytes are isolated with the BDCA-4 pDC or CD14 monocyte isolation kit (Miltenyi Biotec), and mDCs are isolated with the BDCA-1 (CD1c) mDC isolation kit after depleting CD19+ B cells (Miltenyi Biotec).
  • mAb monoclonal antibody
  • CD11c Diaclone
  • CD14 CD14
  • HLA-DR HLA-DR
  • CD123 all from BD Biosciences
  • Purity of mDC fractions is confirmed by staining with mAb to CD14, CD19, and streptavidin.
  • Cells are incubated for 16 h at 37°C in a humidified incubator with various concentrations of 52377 and 52378 added. Culture supematants are harvested and assayed by suitable ELISA for various specific cytokines including IFN- ⁇ and IL-12.
  • Results show that human PBMC are responsive to 52377 and 52378.
  • the B16 (H-2 b ) tumor line is an OVA-transfected clone derived from the murine
  • B16 melanoma Mayordomo Jl et al. (1995) Nat. Med. 1 :1297-1302.
  • B16 tumor cells are cultured in vitro in conditioned medium in the presence of geneticin (2 mg/ml) and hygromycin B (60 ⁇ g/ml).
  • the murine colon adenocarcinoma CT26 tumor cell line (H-2 d ) is purchased from American Type Culture Collection (Rockville, Maryland, USA) and maintained in vitro in conditioned medium.
  • mice Six- to ten-week-old male C57BL/6 (H-2 b ) and BALB/c (H-2 d ) mice are obtained from The Jackson Laboratory (Bar Harbor, Maine, USA).
  • 5 x 10 4 B16 or 2 x 10 6 CT26 tumor cells are resuspended in 0.1 ml of phosphate buffered saline (PBS) and inoculated subcutaneously in the flanks of mice.
  • PBS phosphate buffered saline
  • 52377 or 52378 (0-100 ⁇ g each) are suspended in 30 ⁇ l of PBS and injected into B16 tumors at day 11 and 14 after tumor inoculation. Up to five injections of 52377 or 52378 are delivered every 4 days into the tumors beginning day 11 after tumor challenge.
  • Mice are examined twice a week for the presence and size of tumors. Tumor size represents the product of two perpendicular diameters. Mice are sacrificed when tumors reach 20 mm in their largest dimension or when ulceration and/or bleeding develop.
  • Schistosoma mansoni eggs Six- to ten-week-old male C56BL/6 mice obtained from The Jackson Laboratory (Bar Harbor, Maine, USA) are immunized with 5,000 Schistosoma mansoni eggs by intraperitoneal (i.p.) injection on days 0 and 7. Schistosoma mansoni eggs contain an antigen (Schistosoma mansoni egg antigen (SEA)) that induces a Th2 immune response (e.g. production of IgE antibody). IgE antibody production is known to be an important cause of asthma.
  • SEA Schosoma mansoni egg antigen
  • mice are then treated with 52377 or 52378 (30 ⁇ g in 200 ⁇ l saline by i.p. injection) or saline alone (negative control).
  • Soluble SEA (10 ⁇ g in 25 ⁇ l of saline) is administered by intranasal instillation on days 14 and 21.
  • mice are sacrificed at various times after airway challenge.
  • Whole lung lavage is performed to harvest airway and alveolar inflammatory cells.
  • Cytokine levels are measured from lavage fluid by appropriate ELISA.
  • RNA is isolated from whole lung for Northern analysis and RT-PCR studies using CsCI gradients. Lungs are inflated and perfused with 4% paraformaldehyde for histologic examination.
  • mice are initially injected with the eggs i.p. and then inhale the egg antigen, many inflammatory cells are present in the lungs. However, when the mice are initially given 52377 or 52378 along with the eggs, the inflammatory cells in the lung are not increased by subsequent inhalation of the egg antigen.
  • mice are treated with saline at the time of the initial exposure to the eggs, there is little effect on the subsequent influx of eosinophils into the lungs after inhalation of SEA.
  • mice inhale the eggs on days 14 or 21 they develop an acute inflammatory response in the lungs.
  • giving 52377 or 52378 along with the eggs at the time of initial antigen exposure on days 0 and 7 almost completely abolishes the increase in eosinophils when the mice inhale the egg antigen on day 14.
  • Results indicate that very low doses of 52377 or 52378 ( ⁇ 10 ⁇ g) can give this protection.
  • Results further show that the resultant inflammatory response correlates with the levels of the Th2 cytokine IL-4 in the lung. Results also show that administration of 52377 or 52378 can actually redirect the cytokine response of the lung to production of IL-12, indicating a Th1-type of immune response.
  • Results further show that administration of 52377 or 52378 can also redirect the cytokine response of the lung to production of IFN- ⁇ , indicating a Th1-type of immune response.

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Abstract

L'invention concerne certains composés triazole utilisés comme agonistes du récepteur de type Toll. Les composés de l'invention et des compositions pharmaceutiques comprenant ces composés conviennent pour stimuler la signalisation TLR, et plus spécifiquement la signalisation par les TLR7 et les TLR8. Les composés et les compositions pharmaceutiques de l'invention conviennent dans des procédés destinés à renforcer une réponse immune, à traiter un cancer, une infection, une allergie et un asthme et, à vacciner un sujet. Les composés et les compositions pharmaceutiques peuvent être utilisées seules, en combinaison entre eux, en combinaison avec un antigène et en combinaison avec des agents et des modalités thérapeutiques additionnelles.
PCT/IB2008/002217 2007-09-05 2008-08-25 Composés triazole utilisés comme agonistes du récepteur de type toll (tlr) WO2009030996A1 (fr)

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WO2013142346A1 (fr) * 2012-03-23 2013-09-26 The Regents Of The University Of California Composés de translecture de codons de terminaison prématurés
US20140242135A1 (en) * 2011-05-06 2014-08-28 Vanderbilt University Compositions for inhibition of insect sensing
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US10071079B2 (en) 2016-06-29 2018-09-11 Bristol-Myers Squibb Company [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
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WO2021003445A1 (fr) 2019-07-03 2021-01-07 Codiak Biosciences, Inc. Vésicules extracellulaires ciblant des lymphocytes t et leurs utilisations
WO2021062317A1 (fr) 2019-09-25 2021-04-01 Codiak Biosciences, Inc. Compositions de vésicules extracellulaires
WO2021184017A1 (fr) 2020-03-13 2021-09-16 Codiak Biosciences, Inc. Vésicules extracellulaires pour le traitement de troubles neurologiques
WO2021189047A2 (fr) 2020-03-20 2021-09-23 Codiak Biosciences, Inc. Vésicules extracellulaires pour thérapie
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US11180474B2 (en) 2016-07-30 2021-11-23 Bristol-Myers Squibb Company Dimethoxyphenyl substituted indole compounds as TLR7, TLR8 or TLR9 inhibitors
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