WO2023018692A1 - Compositions et méthodes de traitement d'infections impliquant un biofilm - Google Patents

Compositions et méthodes de traitement d'infections impliquant un biofilm Download PDF

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WO2023018692A1
WO2023018692A1 PCT/US2022/039797 US2022039797W WO2023018692A1 WO 2023018692 A1 WO2023018692 A1 WO 2023018692A1 US 2022039797 W US2022039797 W US 2022039797W WO 2023018692 A1 WO2023018692 A1 WO 2023018692A1
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inhibitor
infection
administered
tissue
antibiotic
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PCT/US2022/039797
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Manu CAPOOR
Ondrej SLABY
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Ecm Diagnostics, Inc.
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Publication of WO2023018692A1 publication Critical patent/WO2023018692A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/545—IL-1
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the commensal pathogen is Propionibacterium acnes (recently renamed Cutibacterium acnes or C. acnes; the designations of P. acnes and C. acnes are used interchangeably herein).
  • the infection can be an infection in which such commensal pathogens (such as but not limited to C. acnes) are frequently implicated or associated, or one in which microbiological profiling has determined the commensal pathogen (such as but not limited to C. acnes) to be present in an infectious capacity.
  • Such infections are sometimes referred to herein as a low virulence infection.
  • the patient is suspected of having an associated infection based on the detection of a commensal pathogen (e.g., P. acnes) in a tissue of interest, such as intervertebral disc tissue, or other tissue biopsy including but not limited to synovial fluid or periprosthetic tissue.
  • a commensal pathogen e.g., P. acnes
  • the presence of the commensal pathogen is detected in biopsied tissue by one or more techniques selected from: the presence of microbial nucleic acid, host cell RNA profile, culturing of the commensal pathogen from the tissue, immunohistochemistry, microbial-specific staining of tissue, and presence of a metabolite signature in the tissue.
  • the presence of a low-virulent infection is evaluated by culture, including aerobic and/or anaerobic cultivation and subsequent biochemical and spectroscopic (e.g., mass spec., MALDI-TOF MS, or NMR) identification of species.
  • biochemical and spectroscopic e.g., mass spec., MALDI-TOF MS, or NMR
  • nucleic acids e.g., DNA and/or RNA
  • immunochemistry e.g., immunohistochemistry or ELISA
  • therapeutic approaches combining appropriate antibiotic treatment with a therapy or therapies targeting pro-inflammatory cytokines (concomitantly or sequentially) are undertaken.
  • a range of therapies targeting these factors are known, including several monoclonal antibody therapies.
  • a beta-lactam antibiotic such as but not limited to amoxicillin
  • a beta-lactamase inhibitor e.g., clavulanate
  • the antibiotic to be given orally or by i.v. for DDD or CLBP are generally selected from those that can penetrate the intervertebral disc.
  • Antibiotics given by local injection to infected tissue include those that have limitations in their oral bioavailability.
  • the patient will further receive a therapy inhibiting one or more cytokines.
  • the cytokine is a pro- inflammatory cytokine that is expressed at sites of infection, and/or one that induces bacterial virulence, antibiotic resistance, and/or bacterial growth.
  • the cytokine induces or sustains antibiotic resistance.
  • the cytokine induces nerve growth.
  • the IL-ip inhibitor is a monoclonal antibody that binds to and blocks and/or neutralizes IL-ip, or blocks interaction between IL-ip and one or more microbial receptors.
  • the antibody is a single chain antibody, such as a scFv.
  • the antibody is an antibody fragment selected from F(ab')2, Fab, Fab' and Fv.
  • Exemplary IL-ip inhibitors are selected from canakinumab, gevokizumab, LY2189102, and CDP-484 (pegylated F(ab') antibody fragment against IL-ip).
  • agents in various embodiments are administered systemically (e.g., intravenously or subcutaneously), or alternatively by local injection or topical application to the tissues having or suspected of having a low-virulence infection, or the surrounding area.
  • the anti-IL-ip antibody is administered by injection directly to intervertebral disc tissue, periprosthetic tissue, or by intra-articular injection to affected joints.
  • inhibitors that target the IL-1 receptor may also be used, such as EBI-005, Anakinra (IL-IRa), MED-8968, or LL-Z1271a. However, in various embodiments it is preferred to target IL-ip directly.
  • the therapy with the IL-ip inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL-ip inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more. Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL-ip inhibitor (e.g., anti-IL-ip antibody or IL-1 trap).
  • an IL-ip inhibitor e.g., anti-IL-ip antibody or IL-1 trap
  • an IL-ip inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, or endoscopic surgery.
  • the IL-ip inhibitor is administered as a co-formulation with one or more antibiotics.
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the inhibitor of NGF is tanezumab, fulranumab, TrkAd5, AMG 403, Appha-Dl l, MNAC13, ALE0540, PD90780, or PPC-1807.
  • the NGF inhibitor is an antisense oligonucleotide targeting the NGF mRNA, or an siRNA or miRNA targeting NGF mRNA expression.
  • the NGF antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor may be administered parenterally, including subcutaneous or percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the NGF inhibitor is a small molecule, and may be administered orally or transdermally in some embodiments.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery and endoscopic surgery.
  • the NGF inhibitor is administered as a co-formulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the BDNF antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous or percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the BDNF inhibitor is a small molecule, and may be administered orally or transdermally in some embodiments.
  • the therapy with the BDNF inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the BDNF inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of a BDNF inhibitor.
  • an BDNF inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery and endoscopic surgery.
  • the BDNF inhibitor is administered as a co-formulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the therapy with the IL-8 inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL-8 inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL-8 inhibitor.
  • an IL-8 inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-8 inhibitor is administered as a co-formulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the therapy with the IL-6 inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL-6 inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL-6 inhibitor.
  • an IL-6 inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-6 inhibitor is administered as a co-formulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient receives therapy with an inhibitor of IL-2, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • the IL-2 inhibitor is a monoclonal anti-IL-2 antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the IL-2 inhibitor is an antisense oligonucleotide targeting the IL-2 mRNA, or an siRNA or miRNA targeting IL-2 mRNA expression.
  • the IL-2 antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the IL-2 inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL-2 inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL-2 inhibitor.
  • an IL-2 inhibitor is administered once locally to the affected tissue during a surgical procedure. The procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-2 inhibitor is administered as a co-formulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient receives therapy with an inhibitor of IL-10, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • the IL-10 inhibitor is a monoclonal anti-IL-10 antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the IL- 10 inhibitor is an antisense oligonucleotide targeting the IL-10 mRNA, or an siRNA or miRNA targeting IL-10 mRNA expression.
  • the IL-10 antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the IL- 10 inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL- 10 inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL- 10 inhibitor.
  • an IL- 10 inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-10 inhibitor is administered as a coformulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the IL-12 antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the IL- 12 inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL-12 inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL-12 inhibitor.
  • an IL-12 inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-12 inhibitor is administered as a coformulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient receives therapy with an inhibitor of IL-17, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • the IL-17 inhibitor is a monoclonal anti-IL-17 antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the IL-17 inhibitor is secukinumab or ixekixumab.
  • the IL-17 inhibitor is an antisense oligonucleotide targeting the IL- 17 mRNA, or an siRNA or miRNA targeting IL- 17 mRNA expression.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-17 inhibitor is administered as a coformulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient receives therapy with an inhibitor of IL-23, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • the IL-23 inhibitor is a monoclonal anti-IL-23 antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the IL-23 inhibitor is risankizumab or ustekinumab. In still other embodiments, the IL-23 inhibitor is an antisense oligonucleotide targeting the IL-23 mRNA, or an siRNA or miRNA targeting IL-23 mRNA expression.
  • the IL-23 inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the IL-23 inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the IL-23 inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an IL-23 inhibitor.
  • an IL-23 inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the IL-23 inhibitor is administered as a coformulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient receives therapy with an inhibitor of interferongamma (INF-y), which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • INF-y interferongamma
  • the INF-y inhibitor is a monoclonal anti-INF-y antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the INF-y inhibitor is an antisense oligonucleotide targeting the INF-y mRNA, or an siRNA or miRNA targeting INF-y mRNA expression.
  • the INF-y antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the INF-y inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the INF-y inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an INF-y inhibitor.
  • an INF-y inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the INF-y inhibitor is administered as a coformulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient receives therapy with an inhibitor of TGF-P, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • the TGF-P inhibitor is a monoclonal anti-TGF-P antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the TGF-P inhibitor is an antisense oligonucleotide targeting the TGF-P mRNA, or an siRNA or miRNA targeting TGF-P mRNA expression.
  • the TGF-P antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the TGF-P inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the TGF-P inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an TGF-P inhibitor.
  • an TGF-P inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the patient receives therapy with an inhibitor of TNF-a, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy.
  • the TNF-a inhibitor is a monoclonal anti-TNF-a antibody or fragment thereof (including scFv, F(ab')2, Fab, Fab' and Fv).
  • the TNF-a inhibitor is infliximab, adalimumab, golimumab, certolizumab, or etanercept.
  • the TNF-a inhibitor is an antisense oligonucleotide targeting the TNF-a mRNA, or an siRNA or miRNA targeting TNF-a mRNA expression.
  • the TNF-a antagonist or inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, percutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy or surgical procedure.
  • the therapy with the TNF-a inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the TNF-a inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of a TNF-a inhibitor.
  • a TNF-a inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the TNF-a inhibitor is administered as a co-formulation with one or more antibiotics and/or TNF-a inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the patient further receives an anti-angiogenic therapy, which can be provided with antibiotic treatment, or in combination with antibiotic treatment and IL-ip inhibitor therapy (or therapy targeting other pro-inflammatory cytokine) and/or anti-NGF therapy.
  • angiogenesis inhibitor is a VEGF pathway inhibitor, which can be a monoclonal anti-VEGF antibody or fragment thereof (including a scvl), small-peptide mimetics, small-molecule inhibitor (e.g., tyrosine kinase inhibitor), or soluble binding domain of VEGF receptor.
  • Exemplary angiogenesis inhibitors include antibodies directed against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, and tyrosine kinase inhibitors.
  • An exemplary VEGF pathway inhibitor is Bevacizumab. Bevacizumab binds to VEGF and inhibits it from binding to VEGF receptors.
  • the angiogenesis inhibitor can be administered by a route selected from parenteral, oral, topical, and transdermal.
  • the inhibitor is a biologic, such as an antibody or portion thereof or other recombinant protein
  • the inhibitor may be administered parenterally, including subcutaneous injection, intramuscular injection, intravenous injection, or local injection to affected tissue.
  • the therapy is provided during a biopsy procedure.
  • the therapy with the angiogenesis inhibitor is concurrent with antibiotic therapy (e.g., for at least about 1 month, 2 months, or 3 months) or is administered before or after antibiotic therapy.
  • the course of therapy with the angiogenesis inhibitor is shorter or longer than antibiotic therapy, such as about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, or for 6 months or more.
  • Administrations may be given daily, weekly, or every other week, or monthly.
  • the patient receives from 1 to 12, or from 1 to 8, or from 2 to 8 doses of an angiogenesis inhibitor.
  • an angiogenesis inhibitor is administered once locally to the affected tissue during a surgical procedure.
  • the procedure may be selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • the angiogenesis inhibitor is administered as a co-formulation with one or more antibiotics and/or IL-ip inhibitor (as described).
  • the patient may further receive oral antibiotic therapy after the surgical procedure.
  • the cytokine inhibitor is an IL-ip inhibitor (e.g., an IL-1 trap or an antibody neutralizing IL-ip), and the antibiotic includes vancomycin or clindamycin.
  • IL-ip inhibitor e.g., an IL-1 trap or an antibody neutralizing IL-ip
  • the antibiotic includes vancomycin or clindamycin.
  • These agents can be administered by injection or infusion of the affected tissue optionally simultaneously.
  • the composition may be administered by injection or infusion directly to intervertebral disc tissue, periprosthetic tissue, or by intra-articular injection to affected joints.
  • the composition may be administered during a surgical procedure selected from discectomy, debridement, arthroplasty, orthopedic surgery, and endoscopic surgery.
  • treatment can be provided post-surgery to facilitate recovery, prevent infection, or prevent infection progression or recurrence.
  • Dosage forms suitable for parenteral administration include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.
  • Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as EDTA
  • buffers such as acetates, citrates or phosphates
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM or phosphate buffered saline (PBS).
  • the carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • compositions for topical application may be formulated as a cream, gel, solution, or ointment.
  • the present disclosure provides an intradiscal injection system with a depot carrier to administer an antibiotic and cytokine inhibitor, such as an IL-1B inhibitor (as described).
  • an antibiotic and cytokine inhibitor such as an IL-1B inhibitor (as described).
  • the invention provides a pharmaceutical composition comprising an effective amount of an antibiotic and an inhibitor or a pro-inflammatory cytokine.
  • Exemplary inhibitors of cytokines may be antibodies or recombinant proteins, or a small molecule inhibitor, targeting one or more of IL-ip, IL-la, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23, INF-y, TNF-a, TGF- , CCL-3, CCL-4, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) (each as described above).
  • the pharmaceutical composition comprises an IL-ip inhibitor, such as canakinumab, gevokizumab, LY2189102, CDP-484, and IL-1 trap.
  • the pharmaceutical composition further comprises one or a combination of antibiotics, including but not limited to beta-lactams, carbapenems, quinolones, macrolides, and cephalosporins.
  • antibiotics include one or more of clindamycin, erythromycin, vancomycin, and daptomycin.
  • the antibiotic is a tetracycline antibiotic, such as tetracycline, minocycline, doxycycline, oxytetracycline and lymecycline.
  • one or more antibiotics are selected from penicillin, benzylpenicillin, amoxicillin, ampicillin, dicloxacillin, methicillin, nafcillin, oxacillin, penicillin G, piperacillin-tazobactam, cephalexin, cefoxitin, cephalothin, ceftriaxone, ciprofloxacin, levofloxacin, chloramphenicol, erythromycin, tetracycline, tigecycline, minocycline, vancomycin, clindamycin, azithromycin, fusidic acid, doxycycline, moxifloxacin, linezolid, rifampicin, rifampin, telavancin, doripenem, ertapenem, imipenem, meropenem, taurolidine, daptomycin, metronidazole, trimethoprim-sulfamethoxazole, or a combination thereof.
  • penicillin benz
  • the pharmaceutical composition may be formulated as a solution, suspension, dispersion, emulsion, or the like.
  • the composition is in the form of a sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use.
  • Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • Other suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM or phosphate buffered saline (PBS).
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • IL-ip various inflammatory mediators from intervertebral disc cells, particularly IL-ip.
  • IL-ip can play a central role in amplifying an inflammatory cascade within the intervertebral disc resulting in degenerative disc disease.
  • the data are consistent with growth enhancing effects of IL-ip on P. acnes in multiple tissues.
  • the disc fragment for culture was weighed, placed into a Micro Bag (Seward) containing 4 ml of Viande-Levure medium, and homogenized with a Stomacher 80 (Seward) under aseptic conditions. 100 pl of the resultant homogenate was inoculated onto Wilkins Chalgren Anaerobic Agar with 7% sheep's blood and vitamin K (Hi Media Laboratories). An Anaerobic Work Station Concept 400 (Ruskinn Technology) was utilized for culture; inoculated plates were incubated for 14 days at 37°C with an atmosphere of 80% N2, 10% CO2, and 10% H2. The same amount of the homogenate was also cultured aerobically on Columbia Blood Agar (Oxoid) for 7 days at 37°C in order to detect aerobic bacteria.
  • CFU colony forming units
  • NP Nucleus pulposus
  • NP nucleus pulposus
  • NP tissue samples were cut into small pieces using a sterile, individually packaged, gamma-irradiated scalpel and, a sterile, gamma-irradiated petri dish and then digested overnight with collagenase A (Roche) at 37°C. After the digestion, the cell suspensions with undigested tissues were filtered through a cell strainer with pores of 40 pm (Millipore) and centrifuged.
  • the cell pellets were resuspended in Dulbecco’s Modified Eagle Medium Nutrient Mixture F-12 (DMEM/F12 (1: 1) lx, Gibco) supplemented with 10% fetal bovine serum and antibiotics penicillin (200 U/ml) and streptomycin (100 U/mL). Cells were cultured at 37°C in a humified atmosphere with 5% CO2 and were maintained in monolayer culture. In the experiment with antibiotic, 0.25 pg/mL clindamycin treatment was used.
  • DEM/F12 Modified Eagle Medium Nutrient Mixture F-12
  • RNA was extracted by use of the Direct-zol RNA kit (Zymo Research) as described in the manufacturer’s instructions. The concentration and purity of RNA were determined at 260 and 280 nm using a NanoDrop 2000 (Thermo Scientific).
  • Lipase activity was measured in cell-free culture supernatants collected at 3 h, 24 h and 48 h time points. The procedure was performed using Lipase Activity Assay Kit II (MAK047, Sigma-Aldrich) according to manufacturer protocol.
  • Type 1 secretion systems are wide-spread among Gram-negative bacteria.
  • An important example is the secretion of the hemolytic toxin HlyA from uropathogenic strains. Secretion is achieved in a single step directly from the cytosol to the extracellular space.
  • the translocation machinery is composed of three indispensable membrane proteins, two in the inner membrane, and the third in the outer membrane.
  • the inner membrane proteins belong to the ABC transporter and membrane fusion protein families (MFPs), respectively, while the outer membrane component is a porin- like protein. Assembly of the three proteins is triggered by accumulation of the transport substrate (HlyA) in the cytoplasm, to form a continuous channel from the inner membrane, bridging the periplasm and finally to the exterior.
  • GPCR G protein-coupled receptor
  • the first GPCR to be described on the human neutrophil was formyl peptide receptor 1 (FPR1) which, when activated, triggers a wide variety of functions, including chemotaxis, degranulation, ROS production, and phagocytosis.
  • FPR1 formyl peptide receptor 1
  • the principal ligands for FPR1 are bacterial and mitochondrial formylated peptides, actively secreted by invading pathogens or passively released from dead and dying host cells after tissue injury.
  • N-formylated version of any peptide containing a methionine residue at the 5' terminus is at least 100-fold more potent than the identical nonformylated peptide.
  • P. acnes strains have a number of proteins that have the fMLF and fMLP pattern which has been identified in E.coli, but not fMIFL a pattern derived from S. aureus. Nevertheless, as in other bacterial species, P. acnes may release formylated peptides to its environment, which can trigger an inflammatory response.
  • proteins that have the peptides of interest there are two membrane proteins and one secreted. Although these proteins are likely to serve a different function in the cell, it is possible that they can be released to the environment and elicit the neutrophil response. Similarly, a number of hypothetical proteins are detected in the genome, which may play a similar role, however they are not predicted to contain any release mechanism.
  • the three genes are present in all species/strains of Propionibacterium acnes (aka Cutibacterium acnes).
  • sequence similarity searches we tried to identity protein sequences in C. acnes with similarity to any of the IL-ip binding proteins from other organisms.
  • genes belonging to certain protein families i.e., Pfam, COG etc.
  • regions in the genomes sharing common gene organization we assumed that similar function genes are grouped together to functional clusters and the order of genes can help identity protein functions.
  • OprF protein from P. aeruginosa which is present in all C. acnes strains. There wasn’t any high-quality homologs/orthologs of the identified IL-ip receptors in C. acnes, other than the OprF from P. aeruginosa which is similar to proteins annotated as OmpA family. These genes are shared among all C. acnes genomes with almost identical sequence.
  • C. acnes is not generally considered as such an organism. It is of course possible that other proteins in C. acnes have cytokine-binding functions with entirely new sequence and structure.

Abstract

Dans les divers aspects et modes de réalisation, l'invention concerne des compositions et des méthodes pour traiter des infections bactériennes associées à un biofilm, comprenant, mais sans y être limitées, des infections impliquant un agent pathogène commensal. L'invention concerne des compositions et des méthodes pour traiter une infection impliquant un biofilm bactérien chez un patient, la méthode comprenant l'administration au patient d'un antibiotique et d'un inhibiteur de cytokine.
PCT/US2022/039797 2021-08-09 2022-08-09 Compositions et méthodes de traitement d'infections impliquant un biofilm WO2023018692A1 (fr)

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