EP3448393A1 - Neuartige komplexe von immunostimulatorischen verbindungen und verwendungen davon - Google Patents

Neuartige komplexe von immunostimulatorischen verbindungen und verwendungen davon

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Publication number
EP3448393A1
EP3448393A1 EP17723284.0A EP17723284A EP3448393A1 EP 3448393 A1 EP3448393 A1 EP 3448393A1 EP 17723284 A EP17723284 A EP 17723284A EP 3448393 A1 EP3448393 A1 EP 3448393A1
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European Patent Office
Prior art keywords
cdn
complex
cells
pharmaceutical composition
formula
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EP17723284.0A
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English (en)
French (fr)
Inventor
Fabienne Vernejoul
Cédric BOULARAN
Daniel Drocourt
Thierry Lioux
Grégory QUSHAIR
Jésus ROMO
Gérard TIRABY
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Invivogen SAS
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Invivogen SAS
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A61K47/544—Phospholipids
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention is related to the fields of molecular biology, cell biology, immunology and organic chemistry.
  • Human STING is activated three ways: via binding of the exogenous (3',3) cyclic dinucleotides (CDNs) c-diGMP, c-diAMP and c-GAMP, which are released by invading bacteria or archaea (see (Gomelsky, 201 1 ) and references therein); via binding of the (2',3') CDN cyclic guanosine monophosphate-adenosine monophosphate (2',3')c-GAMP), a recently discovered endogenous cyclic dinucleotide that is produced by the enzyme cyclic GMP-AMP synthase (cGAS; also known as C6orf150 or MB21D1) in the presence of exogenous double-stranded DNA (e.g.
  • viruses that have been employed to deliver CDN STING agonists into cells include virus-like particles (US/2017/0074507); PEGylated phosphatidylcholine nanoparticles (Hanson ef a/., 2015); linear polyethyleneimine/hyaluronic acid (PEI/HA) hydrogels (Lee ef a/., 2016); and an Arg(9) cell- penetrating peptide (Yildiz ef a/., 2015).
  • the delivery vehicle or complexing agent comprises multiple molecules, rather than a single molecule.
  • Lipid formulations of therapeutic molecules can exhibit immunogenicity, which can be advantageous (e.g. by boosting the immune system) or disadvantageous (e.g. by causing unwanted immune responses such as acute inflammation), depending on the context.
  • EP/212501 1/B1 relates to the use of cationic lipid formulations of diverse antigens to deliberately generate an immunostimulatory therapeutic response via MAP-kinase signaling, as a strategy for therapeutic modulation of T cells; and
  • WO2008/148057 proposes lipid-based adjuvants for nucleic acid vaccines that encode immunogens, in which the adjuvants enable enhanced in vivo immune responses to the immunogens.
  • WO/2014/182661 proposes an itinerated dosing approach for administration of lipid-formulated nucleic acids as a strategy to avoid the adverse acute immune responses (known as "infusion-related reactions") that are often observed shortly after treatment.
  • cationic lipids used for delivery of nucleic acids can show toxicity, which inventors have sought to reduce.
  • US/2017/0009637 relates to the delivery of nucleic acids (siRNAs, aptamers or plasmids) using biodegradable cationic lipids that, relative to other cationic lipids, purportedly offer specific pharmacologic benefits (e.g. faster clearance) and consequently, lower toxicity.
  • ⁇ - ⁇ and B 2 are purine bases independently chosen from adenine, guanine or hypoxanthine;
  • Y-i and Y 2 are independently chosen from H, OH or F;
  • Y 3 and Y 4 are independently chosen from O or S;
  • X " can be chosen from chloride, acetate, benzenesulfonate, benzoate, bromide, carbonate, citrate, fluoride, formate, fumarate, galacturonate, gluconate, glutarate, lactate, nitrate, succinate, tartrate, maleate, phosphate, pyruvate, sulfate, tosylate, trifluoroacetate or any other pharmaceutically acceptable anion.
  • the cyclic purine dinucleotide of Formula II is chosen from the following compounds (as defined in Table 1 ), in which the internucleotide linkages in the CDN are two phosphodiester linkages: CL592, CL603, CL605, CL657, CL614, CL674.
  • the pharmaceutical composition further comprises a surfactant.
  • surfactant means any compound having both a lipophilic portion and a hydrophilic portion in particular a ionic or non-ionic surfactant, which confers to the complex an enhancement of a particular aspect of formulation such as, but not limited to, solubility.
  • the concentration of each of the constituent solutions is adjusted prior to mixing such that the desired final compound of Formula l/compound of Formula II ratio and the desired final concentration of compound of Formula II is obtained upon mixing the two solutions.
  • CDNs used in the present invention and their corresponding code numbers (format: CL###) shown below in table 1.
  • CDNs CL592, CL655, CL603, CL632, CL614, CL656, CL674 and CL702 were synthesized in the form of a sodium salt according to a procedure similar to the one described in PCT/EP2015/070635.
  • the remaining CDNs were obtained from InvivoGen:
  • HEK-BlueTM IL-28 This HEK293 cell line is derived from HEK-BlueTM ISG cells (InvivoGen catalog code: hkb-isg). It enables detection of bioactive Type III IFNs (IL-28A [IFN- 2], IL-28B [IFN- 3] and IL- 29 [IFN- ⁇ ]) through monitoring of activation of the ISG54 pathway.
  • HEK-BlueTM IL-28 cells were generated by inactivation of the IFNAR2 and IFNGR1 genes, to abolish (i.e. reduce to undetectable levels) the Type I and Type II IFN response, followed by stable transfection with the human IFNLR1 and IL10R genes, to obtain a strong Type III IFN response.
  • the other genes of the (shared Type I/Type III) IFN pathway are naturally expressed in sufficient amounts.
  • the resultant cells were then transfected with a SEAP reporter gene under control of a promoter that comprises five IFN-stimulated response elements (ISREs) fused to a minimal promoter of the human ISG54 gene, which is unresponsive to activators of the NF- ⁇ or AP-1 pathways.
  • ISREs IFN-stimulated response elements
  • RAW-LuciaTM ISG (InvivoGen catalog code: rawl-isg): These cells were generated from the RAW 264.7 murine macrophage cell line (ATCC ® TIB-71TM).
  • HEK293-T-ISG These cells were generated from the HEK-293T human embryonic kidney cell line (ATCC ® CRL-3216TM).
  • THP1 -DualTM-KO-STING InvivoGen catalog code: thpd-kostg: These cells were generated from the human monocyte THP-1-DualTM, through stable homozygote knockout of the STING gene. Biallelic STING knockout was verified by functional assays, PCR and DNA sequencing. Cytokine quantification
  • Example 2.1 Comparison of CDN/CL338 complexes to the corresponding CDN alone, for STING pathway-dependent cytokine induction in cell cultures
  • test concentration 0 ⁇ g/mL
  • test concentration 0 ⁇ g/mL
  • the level of ISG54 activity (as an indicator of Type I IFN induction) was indirectly quantified using QUANTI-LucTM, which was prepared and used according to the manufacturer's instructions.
  • the level of NF-Kb pathway activation was measured using QUANTI-BlueTM, which was prepared and used according to the manufacturer's instructions.
  • the figures show that: firstly, most of the CDN/CL338 complex provides greater induction of ISG-induced IRF pathway (Type IFNs) and of the NF- ⁇ pathway (proinflammatory cytokines) than does the corresponding CDN alone; and secondly, among the various complexes, those using CL338 gave the strongest response for both activities.
  • ISG-induced IRF pathway Type IFNs
  • NF- ⁇ pathway proinflammatory cytokines
  • Each blood sample was diluted (1 :2 [v/v]) in RPMI medium and aliquoted into 96-well plates (180- ⁇ _ wells) containing either a CDN at one of seven different concentrations (20 ⁇ g mL, 6.7 ⁇ g mL, 2.2 ⁇ g mL, 0.7 ⁇ g mL, 0.2 ⁇ g mL, 0.08 ⁇ g mL or 0.03 ⁇ g mL), or a CDN/CL338 complex (2:5 [w/w]) at one of seven different (CDN) concentrations (20 ⁇ g mL, 2 ⁇ g mL, 200 ng/mL, 20 ng/mL, 2ng/ml_, 200 pg/mL or 20 pg/mL).
  • CDN CDN/CL338 complex
  • CDN ( g mL) CDN/CL338 (Mg/mL)
  • CDN ( g mL) CDN/CL338 (Mg/mL) Fold increase
  • Example 2.4 Comparison of CDNs alone with their corresponding CDN/CL338 complexes for in vitro antiviral activity
  • CDNs and their corresponding CDN/CL338 complexes were tested for their possible effects on infection of human retinal cells by human cytomegalovirus (CMV).
  • CMV cytomegalovirus
  • the anti-CMV drug ganciclovir which is a standard of care for retinal CMV infection (reference: http://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/cytomegalovirus- %28cmv%29-infection), was used as positive control.
  • ARPE19 human retinal pigment epithelial (RPE) cells (reference: ATCC ® CRL-2302 TM ) were seeded in 96-well plates (5,000 cells/well) and treated with the indicated CDN (10 Mg/mL), CDN/CL338 complex (10 ⁇ g/mL CDN cone; 2:5 [w/w]), saline or ganciclovir (3 ⁇ g/mL [12.5 ⁇ ]). Immediately after treatment, the cells were infected with the autofluorescent ANCHORTM strain of human CMV (see Gros ef a/. , ACS Infect Dis, 2015) at a multiplicity-of-infection (MOI) of 1 .
  • MOI multiplicity-of-infection
  • Figure 4 Comparison of transfection agents for NF- ⁇ pathway activation by complexes containing either CL632 (Fig. 4A) or CL702 (Fig. 4B), in ⁇ -DualTM cells.
  • Figure 5. Comparison of CDNs alone with their corresponding CDN/CL338 complexes for ex vivo cytokine induction in human blood: (A) CL614 vs. CL614/CL338 for induction of Type I IFNs; (B) CL614 vs. CL614/CL338 for induction of TNF-a (CL614); (C) CL614 vs. CL614/CL338 for induction of IL-1 ; and (D) f CL656 vs. CL656/CL338 or induction of IFN- ⁇ .
  • Figure 6. Comparison of CDNs alone with their corresponding CDN/CL338 complexes for in vitro antiviral (anti-hCMV) activity in human retinal cells.
  • anti-hCMV antiviral
  • Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants. The Journal of clinical investigation 125, 2532-2546, doi: 10.1 172/JCI79915 (2015).

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP17723284.0A 2016-04-25 2017-04-25 Neuartige komplexe von immunostimulatorischen verbindungen und verwendungen davon Withdrawn EP3448393A1 (de)

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EP16305481 2016-04-25
PCT/EP2017/059781 WO2017186711A1 (en) 2016-04-25 2017-04-25 Novel complexes of immunostimulatory compounds, and uses thereof

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