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WO2008036312A1 - Procédés fongicides utilisant des composés modificateurs de la réponse immunitaire - Google Patents

Procédés fongicides utilisant des composés modificateurs de la réponse immunitaire Download PDF

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Publication number
WO2008036312A1
WO2008036312A1 PCT/US2007/020296 US2007020296W WO2008036312A1 WO 2008036312 A1 WO2008036312 A1 WO 2008036312A1 US 2007020296 W US2007020296 W US 2007020296W WO 2008036312 A1 WO2008036312 A1 WO 2008036312A1
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Prior art keywords
amine
fungicidal
fungal
irm
irm compound
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Inventor
Richard L. Miller
Kathleem E. Silva-Cunningham
David A. Stevens
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Coley Pharmaceutical Group Inc
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Coley Pharmaceutical Group Inc
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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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61P31/10—Antimycotics
    • 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

Definitions

  • IRMs immune response modifiers
  • TLRs Toll-like receptors
  • certain IRMs may be useful for treating viral diseases (e.g., human papilloma virus, hepatitis, herpes), neoplasias (e.g., basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma), and TH2-mediated diseases (e.g., asthma, allergic rhinitis, atopic dermatitis), auto-immune diseases (e.g., multiple sclerosis), and are also useful as vaccine adjuvants.
  • viral diseases e.g., human papilloma virus, hepatitis, herpes
  • neoplasias e.g., basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma
  • TH2-mediated diseases e.g., asthma, allergic rhinitis, atopic dermatitis
  • auto-immune diseases e.g., multiple s
  • IRM compounds are small organic molecule imidazoquinoline amine derivatives (see, e.g., U.S. Pat. No. 4,689,338), but a number of other compound classes are known as well (see, e.g., U.S. Pat. Nos. 5,446,153; 6,194,425; and 6,110,929; and
  • IRMs have higher molecular weights, such as oligonucleotides, including CpGs (see, e.g., U.S. Pat. No. 6,194,388).
  • IRMs have anti-fungal activity.
  • these IRM molecules may be useful for killing fungal cells in therapeutic, prophylactic, diagnostic, or detection methods. Accordingly, the present invention provides a method of killing fungal cells.
  • the method includes contacting an immune response modifier (IRM) compound with a fungicidal effector cell, thereby activating the fungicidal effector cell, and allowing the activated fungicidal effector cell to kill fungal cells.
  • IRM immune response modifier
  • the present invention provides a method of killing fungal cells that generally includes contacting a fungicidal IRM compound with fungal cells in an amount effective to kill fungal cells.
  • the fungicidal activity may be exploited to treat a fungal infection in subject or, alternatively, may be the first step in a method for detecting the presence of fungal cells, generally, or cells of a particular fungal species. Consequently, in another aspect the present invention provides a method of treating a fungal condition in a subject. Generally, the method includes administering to a subject in need of such treatment a fungicidal IRM compound in an amount effective to kill fungal cells.
  • the fungicidal IRM compound may be administered in an amount effective to ameliorate at least one clinical sign or symptom of a fungal condition.
  • the fungicidal IRM compound may be administered in an amount to limit or reduce the likelihood and/or extent of at least one clinical sign or symptom of a fungal condition.
  • the present invention provides a method of detecting fungal cells in a sample.
  • the method includes contacting a sample with a fungicidal IRM compound, allowing fungal cells to be killed, and detecting a cell component that is detectable upon death of fungal cells.
  • the present invention exploits the observation that many IRM compounds possess anti-fungal activity.
  • the anti-ftjngal activity of the IRM compound may be due to direct anti-fungal activity, i.e., the compound itself is capable of killing or slowing the growth of fungal cells.
  • the anti-fungal activity may be due to indirect activity, i.e., the IRM compounds elicits an immune response that includes activating immune cells that kill or slow the growth of fungal cells.
  • IRM compounds may be administered to a patient to treat a fungal infection, to reduce the symptoms of the fungal infection, or may be useful for performing methods that detect fungal cells and/or diagnose fungal conditions.
  • “Ameliorate” refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular condition. “Prophylactic” and variations thereof refer to a treatment that limits, to any extent, the development and/or appearance of a symptom or clinical sign of a condition.
  • “Sign” or “clinical sign” refers to an objective physical finding relating to a particular condition capable of being found by one other than the patient.
  • Symptom refers to any subjective evidence of disease or of a patient's condition.
  • “Therapeutic” and variations thereof refer to a treatment that ameliorates one or more existing symptoms or clinical signs associated with a condition.
  • Treat” or variations thereof when used in the context of, for example, “treating” a fungal infection, refer to reducing, limiting progression, ameliorating, or resolving, to any extent, the symptoms or signs related to a condition.
  • a “an,” “the,” “at least one,” and “one or more” are used interchangeably.
  • a pharmaceutical composition comprising "an” IRM compound can be interpreted to mean that the pharmaceutical composition includes at least one (i.e., one or more) IRM compound.
  • reference to a compound can include the compound in any pharmaceutically acceptable form, including any isomer (e.g., diastereomer or enantiomer), salt, solvate, polymorph, and the like.
  • reference to the compound can include each of the compound's enantiomers as well as racemic and scalemic mixtures of the enantiomers.
  • Fungicidal IRM compounds may be useful for treatment and/or diagnosis of fungal infections.
  • Fungicidal IRM compounds may be used to provide therapeutic and/or prophylactic treatment.
  • fungicidal IRM compounds may be administered to a subject in order to reduce the likelihood or extent to which symptoms or clinical signs develop from a fungal infection.
  • Fungicidal IRM compounds also may be administered to ameliorate at least one existing symptom or clinical sign of a fungal infection.
  • fungicidal IRM compounds may be used to detect fungal cells in a sample.
  • fungal cells may be detected in a sample by contacting the sample with a fungicidal IRM compound, followed by detection of mycospecific or species- specific cell components released and/or otherwise rendered detectable upon the death of the fungal cells.
  • the fungicidal activity may be direct anti-fungal activity or indirect anti-fungal activity. Direct anti-fungal activity and indirect anti-fungal activity are qualitatively distinct and rely on different mechanisms of action.
  • IRM compounds that possess indirect anti-fungal activity activate immune cells - that have the potential, once activated, to become fungicidal effector cells.
  • Potential fungicidal effector cells include, for example, monocytes, neutrophils, macrophages, cytotoxic T lymphocytes (CTLs), and dendritic cells.
  • CTLs cytotoxic T lymphocytes
  • the activated effector cells possess fungicidal activity — they possess the ability to kill fungal cells. Consequently, IRM compounds that possess indirect fungicidal activity require immunocompetence — the presence of potential fungicidal effector cells. Indirect anti-fungal activity, acting through a variety of fungicidal effector cells, is demonstrated in Examples 2-5 (Tables 2-5).
  • IRM compounds that possess direct anti-fungal activity act directly on the fungal cells — they do not require the presence of potential fungicidal effector cells. Consequently, IRM compounds that possess direct anti-fungal activity may be useful for treating fungal infections in immuno-compromised — even immunoincompetent — subjects. Direct ant-fungal activity is demonstrated in Examples 6 and 1, below.
  • Fungal cells killed by practicing the present invention include, for example, Microsporum sp., Trichophyton sp., Epidermophyton sp., Aspergillus sp., Candida sp., Cryptococcus sp., Blastomyces sp., Histoplasma sp., Coccidioides sp., and
  • conditions that may be treated and/or diagnosed using an IRM compound include fungal diseases such as, for example, dermatophytosis, candidiasis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, para coccidioidomycosis, and cryptococcal meningitis.
  • fungal diseases such as, for example, dermatophytosis, candidiasis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, para coccidioidomycosis, and cryptococcal meningitis.
  • certain IRM compounds may be particularly helpful in individuals having compromised immune function.
  • certain compounds may be used for treating the fungal infections that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients, and HIV patients.
  • IRM compounds include compounds that possess potent immunomodulating activity including, generally, but not limited to antiviral and antitumor activity. Certain
  • IRMs modulate the production and secretion of cytokines.
  • certain IRM compounds induce the production and secretion of cytokines such as, e.g., Type I interferons, TNF- ⁇ , IL-I, IL-6, IL-8, IL-I O, IL-12, MIP-I, and/or MCP-I .
  • certain IRM compounds can inhibit production and secretion of certain TH2 cytokines, such as IL-4, IL-5
  • IRM compounds are small organic molecules (e.g., molecular weight under about 1000 Daltons, preferably under about 500 Daltons, as opposed to large biological molecules such as proteins, peptides, nucleic acids, and the like) such as those disclosed in, for example, U.S. Patent Nos. 4,689,338; 4,929,624; 5,266,575; 5,268,376; 5,346,905;
  • WO 2005/048933 WO 2005/048945, WO 2005/051317, WO 2005/051324, WO 2005/066169, WO 2005/06617O 5 WO 2005/066172, WO 2005/076783, WO 2005/079195,
  • IRM compounds include certain purine derivatives (such as those described in U.S. Patent Nos.6,376,501, and 6,028,076), certain imidazoquinoline amide derivatives (such as those described in U.S. Patent No. 6,069,149), certain imidazopyridine derivatives (such as those described in U.S. Patent No. 6,518,265), certain benzimidazole derivatives (such as those described in U.S. Patent 6,387,938), certain derivatives of a 4-aminopyrimidine fused to a five membered nitrogen containing heterocyclic ring (such as adenine derivatives described in U. S. Patent Nos.
  • IRMs include large biological molecules such as oligonucleotide sequences.
  • Some IRM oligonucleotide sequences contain cytosine-guanine dinucleotides (CpG) and are described, for example, in U.S. Patent Nos. 6,194,388; 6,207,646; 6,239,116;
  • CpG-containing oligonucleotides can include synthetic immunomodulatory structural motifs such as those described, for example, in U.S. Patent Nos. 6,426,334 and 6,476,000.
  • Other IRM nucleotide sequences lack CpG sequences and are described, for example, in International Patent Publication No. WO 00/75304.
  • Still other IRM nucleotide sequences include guanosine- and uridine-rich single-stranded RNA (ssRNA) such as those described, for example, in Heil et al., Science, vol. 303, pp. 1526- 1529, March 5, 2004.
  • ssRNA guanosine- and uridine-rich single-stranded RNA
  • IRMs include biological molecules such as aminoalkyl glucosaminide phosphates (AGPs) and are described, for example, in U.S. Patent Nos. 6,113,918; 6,303,347; 6,525,028; and 6,649,172.
  • AGPs aminoalkyl glucosaminide phosphates
  • the IRM compound may be an agonist of at least one TLR such as, for example, TLR7 or TLR8.
  • the IRM may also in some cases be an agonist of TLR9.
  • the IRM compound may be a small molecule immune response modifier (e.g., molecular weight of less than about 1000 Daltons).
  • the IRM compound may include a 2-ami ⁇ o ⁇ yridine fused to a five membered nitrogen-containing heterocyclic ring, or a 4- aminopyrimidine fused to a five membered nitrogen-containing heterocyclic ring.
  • IRM compounds suitable for use in the invention include compounds having a 2- aminopyridine fused to a five membered nitrogen-containing heterocyclic ring.
  • Such compounds include, for example, imidazoquinoline amines including but not limited to substituted imidazoquinoline amines such as, for example, amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, hydroxylamine substituted imidazoquinoline amines, oxime substituted imidazoquinoline amines, 6-, 7-, 8-, or 9
  • the IRM compound may be an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, a thiazolonaphthyridine amine, a pyrazolopyridine amine, a pyrazoloquinoline amine, a tetrahydropyrazoloquinoline amine, a pyrazolonaphthyridine amine, or a tetrahydropyrazolonaphthyridine amine.
  • the IRM compound may be a substituted im ⁇ dazoquinoline amine, a tetrahydroimidazoquinoline amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a 6,7-rused cycloalkylimidazopyridi ⁇ e amine, an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, a thiazolonaphthyridine amine, a.
  • pyrazolopyridine amine a pyrazoloquinoline amine, a tetrahydropyrazoloquinoline amine, a pyrazolonaphthyridine amine, or a tetrahydropyrazolonaphthyridine amine.
  • a substituted imidazoquinoline amine refers to an amide substituted imidazoquinoline amine, a sulfonamide substituted imidazoquinoline amine, a urea substituted imidazoquinoline amine, an aryl ether substituted imidazoquinoline amine, a heterocyclic ether substituted imidazoquinoline amine, an amido ether substituted imidazoquinoline amine, a sulfonamido ether substituted imidazoquinoline amine, a urea substituted imidazoquinoline ether, a thioether substituted imidazoquinoline amine, a hydroxylamine substituted imidazoquinoline amine, an oxime substituted imidazoquinoline amine, a 6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy or arylalkyleneoxy substituted imidazoquinoline amine, or an imidazoquinoline diamine.
  • substituted imidazoquinoline arnines specifically and expressly exclude l-(2- methylpropyl)- l/f-imidazo[4,5-c]quinolin-4-amine and 4-amino- ⁇ , ⁇ -dimethyl-2- ethoxymethyl- 1 J7-imidazo[4,5-c]qui ⁇ olin- 1 -ethanol.
  • an IRM compound having direct fungicidal activity may be an imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a6,7-fused cycloalkylimidazopyridine amine, an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, a thiazolonaphthyridine amine, a pyrazolopyridine amine, a pyrazoloqutnoline amine, a tetrahydropyrazoloquinoline amine, a pyra
  • An IRM compound with direct fungicidal activity may be, for example, a sulfonamide substituted imidazoquinoline amine such as, for example, N-[4-(4-amino-2-ethyl-li7-imidazo[4,S- c]quinolin-l-yl)butyl]methanesulfonamide
  • an IRM compound having indirect fungicidal activity may be a substituted imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a 6,7-fiised cycloalkylimidazopyridine amine, an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, a thiazolonaphthyridine amine, a pyrazolopyridine amine, a pyrazoloquinoline amine, a pyrazoloquinoline amine, a tetrahydropyrazolo
  • An IRM compound having indirect fungicidal activity may be, for example, a tetrahydroimidazoquinoline amine such as, for example, 4- amino-2-(ethoxymethyl)- ⁇ , ⁇ -dimethyl-6,7,8,9-tetrahydro- l/f-imidazo ⁇ S-cJquinoline- 1 - ethanol.
  • Suitable IRM compounds also may include the purine derivatives, imidazoquinoline amide derivatives, benzimidazole derivatives, adenine derivatives, aminoalkyl glucosaminide phosphates, small molecule imm ⁇ no-potentiator compounds, and oligonucleotide sequences described above.
  • the IRM compound may be a compound identified as an agonist of one or more TLRs.
  • IRM compounds include, but are not limited to N-(2-(4-amino-2- (ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl)-l,l-dimethylethyl)methanesulfonamide, 5-(4- amino-2-methyl-lH-imidazo[4,5-c]quinolin-l-yl)-4,4-dimethylpentan-2-one, N-(4-(4-amino-2- methyl- ⁇ J.S.P-tetrahydro-lH-imidazo ⁇ .S-cjquinolin-l-yObutyOmo ⁇ holine ⁇ -carboxamide, and l-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinoIin-l-yl)-2-methyIpropan-2-ol.
  • the IRM compound may be provided in any suitable formulation.
  • the IRM compound may be provided in any suitable form including but not limited to a solution, a suspension, and emulsion, or any
  • the formulation may include additional active components such as, for example, other anti-fungal components, antibodies, markers, buffers, and the like.
  • the compound may be provided in any formulation suitable for administration to a subject. Suitable types of formulations are described, for example, in U.S. Pat. No. 5,238,944; U.S. Pat No. 5,939,090; U.S. Pat. Mo. 6,245,776; European Patent No. EP 0394026; and U.S. Patent Publication No. 2003/0199538.
  • the compound may be provided in any suitable form including but not limited to a solution, a suspension, an emulsion, or any form of mixture.
  • the compound may be delivered in formulation with any pharmaceutically acceptable excipient, carrier, or vehicle.
  • the formulation may be delivered in a conventional topical dosage form such as, for example, a cream, an ointment, an aerosol formulation, a non-aerosol spray, a gel, a lotion, and the like.
  • the formulation may further include one or more additives including but not limited to adjuvants, skin penetration enhancers, colorants, fragrances, flavorings, moisturizers, thickeners, and the like.
  • An in vivo formulation may be administered in any suitable manner such as, for example, non-parenterally or parenterally.
  • non-parenterally refers to administration through the digestive tract, including by oral ingestion.
  • Parenterally refers to administration other than through the digestive tract such as, for example, intravenously, intramuscularly, transdermally, subcutaneously, transmucosally (e.g., by inhalation), or topically.
  • composition of an in vivo formulation suitable for practicing the invention will vary according to factors known in the art including but not limited to the physical and chemical nature of the IRM compound, the nature of the carrier, the intended dosing regimen, the state of the subject's immune system (e.g., suppressed, compromised, stimulated), the method of administering the IRM compound, and the species to which the formulation is being administered. Accordingly, it is not practical to set forth generally the composition of a formulation effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate formulation with due consideration of such factors.
  • the methods of the present invention include administering
  • IRM to a subject in a formulation of, for example, from about 0.0001% to about 20% (unless otherwise indicated, all percentages provided herein are weight/weight with
  • the IRM compound may be administered using a formulation that provides IRM compound in a concentration outside of this range.
  • the method includes administering to a subject a formulation that includes from about 0.01% to about 1% IRM compound, for example, a formulation that includes about from about 0.1 % to about 0.5% IRM compound.
  • An amount of an IRM compound effective for killing fungal cells is an amount sufficient to either directly kill fungal cells or induce fungicidal effector cells to kill fungal cells.
  • the precise amount of IRM compound that is effective for killing fungal cells will vary according to factors known in the art including but not limited to the physical and chemical nature of the IRM compound, the nature of the carrier, the intended dosing regimen, the state of the subject's immune system (e.g., suppressed, compromised, stimulated), the method of administering the IRM compound, and the species to which the formulation is being administered. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of IRM compound effective for all possible applications. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.
  • the methods of the present invention include administering sufficient IRM compound to provide a dose of, for example, from about 100 ng/kg to about 50 mg/kg to the subject, although in some embodiments the methods may be performed by administering IRM compound in a dose outside this range.
  • the method includes administering sufficient IRM compound to provide a dose of from about 10 ⁇ g/kg to about 5 mg/kg to the subject, for example, a dose of from about 100 ⁇ g/kg to about 1 mg/kg.
  • the methods of the present invention may include administering sufficient IRM compound to provide a dose of, for example, from about 0.01 mg/m 2 to about 10 mg/m 2 .
  • the dosing regimen may depend at least in part on many factors known in the art including but not limited to the physical and chemical nature of the IRM compound, the nature of the carrier, the amount of IRM being administered, the state of the subject's immune system (e.g., suppressed, compromised, stimulated), the method of administering the IRM compound, and the species to which the formulation is being administered.
  • the IRM compound may be administered, for example, from a single dose to multiple doses per day. In certain embodiments, the
  • IRM compound may be administered on an "as needed" basis, i.e., as frequently as needed to ameliorate a clinical sign or symptom of a fungal infection.
  • the IRM compound may be administered from about once per day to once per month such as, for example, once per day.
  • the methods of the present invention may be performed on any suitable subject.
  • Suitable subjects include but are not limited to animals such as but not limited to humans, non-human primates, poultry, fowl, rodents, dogs, cats, horses, pigs, sheep, goats, or cows.
  • the IRM compounds used in the examples are shown in Table 1.
  • Blood was obtained from female BALB/c mice (Charles Rivers Lab, Willmington, MA) by cardiac puncture into EDTA vacutainer tubes (Becton Dickinson, Franklin Lakes, NJ). Blood was pooled; diluted 1 : 1 (vol:vol) with Phosphate Buffered Saline (PBS) or Hank's Balance Salt Solution (HBSS), diluted blood was overlayed on ACCUPAQUE (Accurate Chemical and Scientific Co., Westbury, NY) 1 :1 (volrvol), and ce ⁇ trifuged (30 minutes, 200 x g, room temperature (RT)).
  • PBS Phosphate Buffered Saline
  • HBSS Hank's Balance Salt Solution
  • 10% RPMI complete media consisted of RPMI 1640 (Celox Laboratories, Inc., St. Paul, MN); 1% (vokvol) each of HEPES (Cat. No. P305-100, Biofluids, Inc., Rockville, MD), MEM non-essential amino acid solution (Cat. No. M7145, Sigma Chemical Co., St. Louis, MO), L-glutami ⁇ e (Cat. No.
  • PBMCs peripheral blood mononuclear cells
  • PBMCs were resuspended in RPMI media containing 10% fetal bovine serum (FBS), 100 U/mL penicillin, 100 ⁇ g/mL streptomycin at a concentration of 5 x 10 6 cells/mL in this complete tissue culture media (CTCM).
  • FBS fetal bovine serum
  • penicillin 100 U/mL
  • streptomycin 100 ⁇ g/mL
  • the PBMCs were dispensed at 200 ⁇ L per well (Costar Cat. No. 5936, Corning, Inc., Corning, NY), incubated for two hours at 37°C in 5% CO ⁇ , and non-adherent cells were removed by aspiration.
  • the number of adherent monocytes per well was estimated to be 5 x 10 5 per well by subtracting the number of non-adherent cells from the number of total cells originally plated.
  • the monocytes were then treated with 200 ⁇ L per well of CTCM alone or containing DMSO; CTCM containing 250 or 1000 U/mL of recombinant mouse IFN- ⁇ (Genentech, Inc., South San Francisco, CA); or the supernatants from Example 1.
  • Monocytes were incubated for 20 hours at 37 0 C in 5% COz, supernatants were aspirated, and monocytes were challenged with 200 ⁇ L per well of CTCM containing Candia albicans at a monocyte to C. albicans ratio of 50:1 for two hours at 37 0 C in 5% CO 2 .
  • PC Peritoneal cells
  • non-adherent cells were removed by aspiration.
  • the number of adherent cells (peritoneal macrophages, PMs) per well was estimated to be 1 x 10 5 per well by subtracting the number of non-adherent cells from the number of total cells originally plated.
  • PMs were treated with CTCM, CTCM containing DMSO, CTCM containing recombinant mouse IFN- ⁇ , or the supernatants from Example 1. PMs were incubated, supernatants were aspirated, challenged with C. albicans, harvested, and CFU counts were made as described in Example 2. Fungicidal activity was determined and statistics were performed as described in Example 2. Results are shown in Table 4 below.
  • Peritoneal macrophages were isolated as described in Example 4. The PMs were treated with 0.1 , 1.0, or 10 ⁇ g/mL of IRM 1 ; 1000 U/mL recombinant mouse IFN- ⁇ , or CTCM alone. Cells were incubated for 20 hours at 37°C in 5% CO 2 , supernatants were aspirated and PMs were challenged with C. albicans at a 100:1 ratio for two hours at 37°C in 5% CO2. Harvested materials from the plate and CFU counts were made as described in Example 2. Fungicidal activity was determined and statistics were performed as described in Example 2. Results are shown in Table 5 below.
  • IRM2 was dissolved in a 0.0005 M citric acid solution (pH 3.65) or 0.0125 M acetic acid solution (pH 3.61) by adding 100 milligrams of IRM2 to 5 mL of either solution.
  • the IRM2 solutions were added to wells containing 100 ⁇ L of either Fluid Sabaroud's Medium (FSM) or a defined media of 30% sucrose/0.01% peptone and 5 ⁇ L of inoculum containing approximately 3 x 10 4 colony forming units (CFUs) of Aspergillus niger (ATCC No. 16404, Manassas, VA).
  • FSM Fluid Sabaroud's Medium
  • CFUs colony forming units
  • IRM2 was tested for antifungal activity as described in Example 6.
  • the amount of the IRM2 solution added to each well were 100 ⁇ L, 75 ⁇ L, 50 ⁇ L, 25 ⁇ L, or 12.5 ⁇ L.
  • No hyphal elements were present in the 100 ⁇ L or 75 ⁇ L 1RM2 citric acid solution wells.
  • No hyphal elements were present in the 100 ⁇ L, 75 ⁇ L, 50 ⁇ L, and 25 ⁇ L IRM2 acetic acid solution wells.

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Abstract

La présente invention se rapporte à des procédés permettant de détruire les cellules fongiques à l'aide de composés modificateurs de la réponse immunitaire. Selon un aspect, ce procédé comprend en général la mise en contact d'un composé modificateur de la réponse immunitaire (IRM) avec une cellule effectrice fongicide, entraînant l'activation de la cellule effectrice fongicide et permettant à la cellule effectrice ainsi activée d'éliminer les cellules fongiques. Sous un autre aspect, le procédé comprend en général la mise en contact d'un composé IRM fongicide avec les cellules fongiques, avec une quantité dudit composé IRM permettant d'éliminer les cellules fongiques.
PCT/US2007/020296 2006-09-19 2007-09-19 Procédés fongicides utilisant des composés modificateurs de la réponse immunitaire Ceased WO2008036312A1 (fr)

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US60/826,151 2006-09-19

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US7897767B2 (en) 2003-11-14 2011-03-01 3M Innovative Properties Company Oxime substituted imidazoquinolines
US7897597B2 (en) 2003-08-27 2011-03-01 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted imidazoquinolines
US7897609B2 (en) 2004-06-18 2011-03-01 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
US7923429B2 (en) 2003-09-05 2011-04-12 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
US7943609B2 (en) 2004-12-30 2011-05-17 3M Innovative Proprerties Company Chiral fused [1,2]imidazo[4,5-C] ring compounds
US7943636B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
US7968563B2 (en) 2005-02-11 2011-06-28 3M Innovative Properties Company Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US8034938B2 (en) 2004-12-30 2011-10-11 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
US8598192B2 (en) 2003-11-14 2013-12-03 3M Innovative Properties Company Hydroxylamine substituted imidazoquinolines
US8673932B2 (en) 2003-08-12 2014-03-18 3M Innovative Properties Company Oxime substituted imidazo-containing compounds
US8691837B2 (en) 2003-11-25 2014-04-08 3M Innovative Properties Company Substituted imidazo ring systems and methods
US8697873B2 (en) 2004-03-24 2014-04-15 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8735421B2 (en) 2003-12-30 2014-05-27 3M Innovative Properties Company Imidazoquinolinyl sulfonamides
US8802853B2 (en) 2003-12-29 2014-08-12 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
EP3708167A1 (fr) 2016-10-25 2020-09-16 Urogen Pharma Ltd. Traitements immunomodulateurs de cavités corporelles

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WO2003043572A2 (fr) * 2001-11-16 2003-05-30 3M Innovative Properties Company Procedes et compositions lies a des composes irm et a des voies de recepteurs de type toll (tlr)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003043572A2 (fr) * 2001-11-16 2003-05-30 3M Innovative Properties Company Procedes et compositions lies a des composes irm et a des voies de recepteurs de type toll (tlr)

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US8673932B2 (en) 2003-08-12 2014-03-18 3M Innovative Properties Company Oxime substituted imidazo-containing compounds
US7897597B2 (en) 2003-08-27 2011-03-01 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted imidazoquinolines
US7923429B2 (en) 2003-09-05 2011-04-12 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US7879849B2 (en) 2003-10-03 2011-02-01 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
US8598192B2 (en) 2003-11-14 2013-12-03 3M Innovative Properties Company Hydroxylamine substituted imidazoquinolines
US7897767B2 (en) 2003-11-14 2011-03-01 3M Innovative Properties Company Oxime substituted imidazoquinolines
US8691837B2 (en) 2003-11-25 2014-04-08 3M Innovative Properties Company Substituted imidazo ring systems and methods
US8802853B2 (en) 2003-12-29 2014-08-12 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
US8735421B2 (en) 2003-12-30 2014-05-27 3M Innovative Properties Company Imidazoquinolinyl sulfonamides
US8697873B2 (en) 2004-03-24 2014-04-15 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US7897609B2 (en) 2004-06-18 2011-03-01 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
US7943609B2 (en) 2004-12-30 2011-05-17 3M Innovative Proprerties Company Chiral fused [1,2]imidazo[4,5-C] ring compounds
US8034938B2 (en) 2004-12-30 2011-10-11 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
US10071156B2 (en) 2005-02-04 2018-09-11 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
US7968563B2 (en) 2005-02-11 2011-06-28 3M Innovative Properties Company Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US7943636B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
EP3708167A1 (fr) 2016-10-25 2020-09-16 Urogen Pharma Ltd. Traitements immunomodulateurs de cavités corporelles

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