WO2017186711A1 - Nouveaux complexes de composés immunostimulateurs, et leurs utilisations - Google Patents

Nouveaux complexes de composés immunostimulateurs, et leurs utilisations Download PDF

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WO2017186711A1
WO2017186711A1 PCT/EP2017/059781 EP2017059781W WO2017186711A1 WO 2017186711 A1 WO2017186711 A1 WO 2017186711A1 EP 2017059781 W EP2017059781 W EP 2017059781W WO 2017186711 A1 WO2017186711 A1 WO 2017186711A1
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complex
cells
pharmaceutical composition
formula
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Fabienne Vernejoul
Cédric BOULARAN
Daniel Drocourt
Thierry Lioux
Grégory QUSHAIR
Jésus ROMO
Gérard TIRABY
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Invivogen
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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.
  • STING interferon genes
  • IFN-a and IFN- ⁇ Type I interferons
  • IRF3 interferon regulatory factor 3
  • pro-inflammatory cytokines IL-1 a, IL- ⁇ ⁇ , IL-2, IL-6, TNF-a, etc.
  • NF- ⁇ pro-inflammatory transcription factor NF- ⁇ (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway.
  • STING agonists include naturally occurring and synthetic cyclic dinucleotides (CDNs), which are used in STING-related research and have recently garnered attention for their therapeutic potential.
  • the present invention proposes use of the cationic lipid complexing agent CL338 (as defined hereafter) to form complexes with cyclic dinucleotides (CDNs), and further proposes uses of such complexes. Specifically, it relates to complexes in which the CDN is a cyclic purine ribodinucleotide or a cyclic purine deoxyribodinucleotide. It further relates to CDNs that are agonists of STING. We show here that the CDN/CL338 complexes of the present invention provide enhanced and/or distinct biologic activities in vitro, ex vivo and in vivo, including therapeutically beneficial activities, relative to the corresponding CDN alone (i.e.
  • 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.
  • Cyclic dinucleotides are small nucleic acids that were originally discovered as microbial messenger molecules and later found to be potent immunostimulants in mammals. Bacteria and other microbes produce three different CDNs (c-diGMP, c-diAMP and c-diGAMP), which they use for their own growth and development and which they release into host cells during infection. In contrast, metazoans synthesize a structurally distinct CDN (2'3'-cGAMP), which serves as a messenger molecule in immune signaling pathways triggered by the presence of pathogenic or self DNA in the cytosol. All four of these compounds directly bind to and activate— albeit to varying degrees— stimulator of interferon genes (STING).
  • STING stimulator of interferon genes
  • CDNs have garnered attention for their therapeutic potential to manipulate the STING pathway in areas such as infectious diseases, oncology and autoimmunity.
  • synthetic CDNs that exhibit favorable drug-like properties and activate all known variants of human STING are currently being sought.
  • CDNs Since naturally occurring CDNs are directly released (by pathogens) into or synthesized (by eukaryotic cells) in the cytoplasm, in physiologic contexts they do not have to cross the cell membrane alone from the extracellular space.
  • 2'3'-cGAMP has been reported to be shuttled from the cells in which it is produced, to neighboring cells, via gap junctions (Ablasser, Schmid-Burgk, ei a/. , 2013) and to be transported, inside of viral particles and extracellular vesicles, from virally infected cells into target cells (Gentili et al., 2015). To date, only one example of a surface receptor for CDNs has been identified: Tosolini et al.
  • CDNs adenosine-containing CDNs (e.g. c-diAMP and c-GAMP), but not other CDNs (e.g. c-diGMP), bind to the G-protein-coupled surface receptor A2a in monocytes.
  • CDNs e.g. c-diAMP and c-GAMP
  • c-diGMP binds to the G-protein-coupled surface receptor A2a in monocytes.
  • CDNs For practical applications that involve addition of CDNs directly to cell cultures, blood or tissue samples, or administration of them to organisms, the effective delivery of these molecules into cells can pose a challenge, as they are inherently negatively charged (at their phosphodiester or phosphorothioate bonds). Indeed, practical use of charged molecules both in vitro and in vivo is typically limited by their poor uptake by eukaryotic cells, which are encased in a highly lipophilic cell membrane. Consequently, a CDN that demonstrates strong and specific activity against a particular protein target in a protein-binding assay can later exhibit little or no activity in a whole-cell assay, for the simple reason that it cannot cross the cell membrane.
  • CDNs Different strategies can be used to make cells more permeable to molecules that are negatively charged at physiological pH, such as CDNs. These include electroporation of cells or use of membrane-permeabilizing agents such as digitonin.
  • electroporation of cells or use of membrane-permeabilizing agents such as digitonin.
  • WO/2014/179335 A1 Yi ef al. (Yi ef al. , 2013), and Sauer ef al. (Sauer ef al., 201 1 ) each describes whole-cell assays in which human or murine cells are first treated with digitonin and subsequently, with CDN STING agonists.
  • CDNs Another option to ameliorate the cellular uptake— and consequently, the biological activity— of CDNs is by delivering them into cells using some type of neutralizing (cationic) agent, which can be lipophilic (e.g. Lipofectamine ® ) or non-lipophilic (e.g. Effectene ® and polyethyleneimine [PEI]).
  • lipophilic e.g. Lipofectamine ®
  • non-lipophilic e.g. Effectene ® and polyethyleneimine [PEI]
  • PKI polyethyleneimine
  • Commonly used materials in this class include commercially available transfection reagents such as Viromer ® Lipofectamine ® , Effectene ® or SuperFect.
  • 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.
  • nucleic acids larger than CDNs e.g. DNA, RNA and oligonucleotides [ODNs]
  • ODNs oligonucleotides
  • These include chemical (covalent) modifications of the molecule itself; use of conjugates and complexes (e.g. with liposomes and cationic lipids); use of delivery vehicles such as microparticles and nanoparticles; and/or use of electroporation in vivo (e.g. for intratumoral administration).
  • conjugates and complexes e.g. with liposomes and cationic lipids
  • delivery vehicles such as microparticles and nanoparticles
  • electroporation in vivo e.g. for intratumoral administration
  • lipid vesicle for delivery of nucleic acids, in which structurally and functionally distinct phospholipids are mixed together to form a vesicle that is subsequently added to a therapeutic nucleic acid
  • US/2015/0272886 a family of rapidly-degradable cationic amphipathic lipids for delivery of nucleic acids or polynucleotides into cells
  • US/9107931/B2 a family of rapidly-degradable cationic amphipathic lipids for delivery of nucleic acids or polynucleotides into cells
  • a complex that comprises a carrier and a liposome, in which the liposome contains a helper lipid and can contain a nucleic acid
  • US/2015/0265708 describes a family of cationic lipids for use in multi-component lipid particles that also contain a neutral lipid, a sterol and PEG-DMG, for subsequent use in delivery of therapeutic agents (principally, nucleic acids).
  • nucleic acids are often delivered using multicomponent systems.
  • Another approach to enhance the bioactivity of nucleic acids in vitro or in vivo is to optimize the method or conditions of administration.
  • US 2016/0038612 proposes treatment of a subject by intramuscular or intradermal injection of a chemically modified nucleic acid (e.g. mRNA) or complexes thereof, including lipid complexes, followed by electroporation at or near the injection site.
  • a chemically modified nucleic acid e.g. mRNA
  • complexes thereof including lipid complexes
  • 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.
  • One object of the invention is a complex formed from the following compounds:
  • ⁇ - ⁇ 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;
  • complex means the chemical entity formed by the association of two or more compounds, in the present case compound of Formula I and compound of Formula II.
  • the lipid of Formula I is polycationic at physiological pH (i.e. it is positively charged on its amino groups at physiological pH).
  • X " is a pharmaceutically acceptable anion. It can be a polyatomic anion or a monoatomic anion.
  • Polyatomic anions include for instance acetate, carbonate, nitrate, sulfate, hydrogen phosphate.
  • Monoatomic anions include for instance halides such as chloride, fluoride, bromide, iodide.
  • 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 dianionic at physiological pH (i.e. it is negatively charged on its phosphate or phosphorothioate groups at physiological pH).
  • the term "cyclic dinucleotide" (abbreviated as "CDN") represents a class of cyclic molecules with two phosphodiester linkages, or two phosphorothioate diester linkages, or one phosphodiester linkage and one phosphorothioate diester linkage, between two nucleosides.
  • nucleoside refers to a glycosylamine comprising a nitrogenous base and a five-carbon sugar, wherein the nitrogenous base is bound to the five-carbon sugar via a beta-g lycos id ic linkage.
  • nucleotide refers to any nucleoside linked to a phosphate group at position 5', 3' or 2' of the sugar moiety.
  • CDNs in which at least one of the ribose sugars is substituted with a fluorine atom at the 2' position.
  • Z + is a pharmaceutically acceptable cation. It can be a polyatomic cation or a monoatomic cation. Polyatomic cations include for instance ammonium, phosphoniums and sulfoniums. Monoatomic cations include for instance cations derived from alkali metals such as potassium and sodium, and alkaline earth metals such as calcium and magnesium.
  • the cyclic purine dinucleotide of Formula II is an agonist of stimulator of interferon genes (STING). In one embodiment, the cyclic purine dinucleotide of Formula II is chosen from the following compounds (as defined in Table 1 ): CL592, CL603, CL605, CL632, CL657, CL655, CL656, CL614, CL661 , CL674, CL695, CL702.
  • 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 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 phosphorothioate linkages: CL632, CL655, CL656, CL661 , CL695, CL702.
  • the cyclic purine dinucleotide of Formula II is chosen from the following compounds (as defined in Table 1 ), in which at least one of the ribose sugars in the CDN is substituted with a fluorine atom at the 2' position: CL603, CL632, CL614, CL656, CL674, CL702.
  • Another object of the invention is a pharmaceutical composition comprising the complex of the invention and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient means an excipient or carrier that is useful in preparing a pharmaceutical composition that is safe, non-toxic and neither biologically nor otherwise undesirable.
  • 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.
  • a complex described in any of the preceding embodiments is added to cell cultures in order to provoke a STING pathway-dependent response such as, but not limited to, production of cytokines (e.g. Type I and Type III interferons, TNF-a, IL- ⁇ ⁇ , IL-6, etc.).
  • cytokines e.g. Type I and Type III interferons, TNF-a, IL- ⁇ ⁇ , IL-6, etc.
  • another object of the invention is the use of the complex of the invention to induce the production of cytokines in mammalian cell cultures, in particular, by activation of a STING pathway.
  • a complex described in any of the preceding embodiments is added to a mammalian blood or tissue sample ex vivo in order to provoke a STING pathway-dependent response such as, but not limited to, production of cytokines (e.g. Type I and Type III interferons, TNF- a, I L- 1 ⁇ , IL-6, etc.).
  • cytokines e.g. Type I and Type III interferons, TNF- a, I L- 1 ⁇ , IL-6, etc.
  • another object of the invention is the use of a complex of the invention to induce the production of cytokines in mammalian blood or tissue samples ex vivo, in particular by activation of a STING pathway.
  • a complex described in any of the preceding embodiments is administered to a living mammal in order to provoke a STING pathway-dependent response such as, but not limited to, production of cytokines (e.g. Type I and Type III interferons, TNF- a, IL- ⁇ ⁇ , IL-6, etc.).
  • cytokines e.g. Type I and Type III interferons, TNF- a, IL- ⁇ ⁇ , IL-6, etc.
  • another object of the invention is the complex of the invention for use to induce the production of cytokines in a mammal, in particular by activation of a STING pathway.
  • a complex described in any of the preceding embodiments is administered to a living mammal in order to provoke a STING pathway-dependent therapeutic response such as, but not limited to, an anti-tumor response, or other therapeutic response that is useful for treatment of cancer, such as an anti-metastatic response.
  • a STING pathway-dependent therapeutic response such as, but not limited to, an anti-tumor response, or other therapeutic response that is useful for treatment of cancer, such as an anti-metastatic response.
  • another object of the invention is the complex of the invention for use in the treatment of cancer.
  • cancer refers to the physiological condition in subjects that is characterized by unregulated or dysregulated cell growth or death.
  • the term “cancer” includes solid tumors and blood born tumors, whether malignant or benign.
  • the cancer is acinar adenocarcinoma, acinar carcinoma, acral-lentiginous melanoma, actinic keratosis, adenocarcinoma, adenocystic carcinoma, adenosquamous carcinoma, adnexal carcinoma, adrenal rest tumor, adrenocortical carcinoma, aldosterone secreting carcinoma, alveolar soft part sarcoma, amelanotic melanoma, ameloblastic thyroid carcinoma, angiosarcoma, apocrine carcinoma, Askin's tumor, astrocytoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, biliary cancer, bone cancer, bone marrow cancer, botryoid sarcoma, brain cancer, breast cancer, bronchioalveolar carcinoma, bronchogenic adenocarcinoma, bronchogenic carcinoma, carcinoma ex pleomorphic adenoma, cervical
  • a complex described in any of the preceding embodiments is administered to a living organism in order to provoke the STING pathway-dependent therapeutic response such as, but not limited to, an anti-viral or anti-microbial response, or other therapeutic response that is useful for treatment of infectious diseases.
  • another object of the invention is the complex of the invention for use in the treatment of an infectious disease, typically bacterial, viral, fungal or parasitic infectious diseases.
  • a complex described in any of the preceding embodiments is administered to a living organism as a vaccine adjuvant to a mammal to provoke a STING pathway-dependent therapeutic response. Accordingly, another object of the invention is the complex of the invention for use as a vaccine adjuvant.
  • adjuvant refers to a secondary therapeutic substance that is administered together (either sequentially in any order, or concurrently) with a primary therapeutic substance to achieve some kind of complimentary, synergic or otherwise beneficial effect that could not be achieved through use of the primary therapeutic substance alone.
  • An adjuvant can be used together with a vaccine, chemotherapy, or some other therapeutic substance.
  • Adjuvants can enhance the efficacy of the primary therapeutic substance, reduce the toxicity or side effects of the primary therapeutic substance, or provide some kind of protection to the subject that receives the primary therapeutic substance, such as, but not limited to, improved functioning of the immune system.
  • the complex or pharmaceutical composition described herein can be administered by any suitable route including, but not limited to the following routes: enteral, gastroenteral, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavemous injection, (into the base of the penis), intravaginal administration, intrauterine, intratumoral, extra-am niotic administration, transdermal (diffusion through the intact
  • the complex or pharmaceutical composition described herein is administered in a way which allows them cross the bloodbrain barrier, vascular barrier, or other epithelial barrier. In one embodiment, the complex or pharmaceutical composition described herein are administered via subcutaneous, intravenous, intraperitoneal, intratumoral, intranasal, oral, intravaginal, transdermal or topical administration.
  • Another object of the invention is a method for preparing the complex of the invention, said method comprising the step of contacting the compound of Formula I with the compound of Formula II.
  • the contact between the compound of Formula I and the compound of Formula II can be performed by any means known in the art, e.g., by mixing a solution of the compound of Formula I and a solution of the compound of Formula II.
  • 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.
  • the contact between compound of Formula I and compound of Formula II is preferably performed in an aqueous medium.
  • an aqueous solution of compound of Formula I and an aqueous solution of compound of Formula II are prepared.
  • compound of Formula I can be dissolved first in ethanol, then the resulting solution is diluted with H 2 0, or an aqueous solution, to a predetermined concentration.
  • Compound of Formula II can be dissolved either in H 2 0 or an aqueous solution such as aqueous glucose (e.g. 5%).
  • a volume of the solution of compound of Formula I is added dropwise to a volume of the solution of compound of Formula II.
  • the resultant solution is vortexed and then, incubated for at least 20 minutes at room temperature.
  • the size of the complex of the invention is typically from 100 nm to 200 nm, as measured by using a Zetasizer Nano ZS (Malvern) at a scattering angle of 90° at 25 °C.
  • 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:
  • phosphorothioate CDNs The phosphodiester linkages in naturally occurring CDNs are both non-chiral and prochiral sites. Substitution of one of the oxygen atoms of the phosphate moiety of a nucleotide with another atom yields an asymmetric center on the phosphorus atom. Since a nucleotide unit already contains a first asymmetrical center within its sugar moiety, further asymmetry at the phosphorus atom of the nucleotide yields a diasymmetric nucleotide. Such a diasymmetric nucleotide is a chiral nucleotide having Sp and Rp diastereomers.
  • Phosphorothioate CDNs can be synthesized using known procedures, which generate racemic mixtures of Rp and Sp diastereomers at the individual phosphorothioate linkages.
  • a phosphorothioate CDN can have 2 n possible diastereoisomeric forms, in which n is the number of phosphorothioate internucleosidic linkages in the molecule.
  • a CDN with two phosphorothioate linkages can have 2 2 (four) possible stereoisomers.
  • Example 1.2 Characterization of CDNs by HPLC/MS, H-NMR and 3 P-NMR Abbreviations used in this section: A: adenosine; d: doublet; dA: deoxyadenosine; dd: doublet of doublets; dl: deoxyinosine; D 2 0: deuterium oxide; ES: electrospray ionization; H: proton; Hz: hertz; I: inosine; LC: liquid chromatography; m: multiplet; m/z: mass-to-charge ratio; MHz: megahertz; MS: mass spectrometry; NMR: nuclear magnetic resonance; s: singlet; t: triplet; ⁇ : chemical shift.
  • LC/MS Analytical LC/ES-MS was performed on an Agilent 1290 Infinity UHPLC system coupled to a diode array detector (DAD; Agilent 1260 Infinity), and on an Agilent 6130 Quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source, controlled by ChemStation (Agilent) software.
  • the LC system was equipped with an Aquity CSH C18 50x2.1 mm 1.7 ⁇ column using gradients of 10 mM ammonium formate and acetonitrile at a flow-rate of 300 ⁇ _/ ⁇ .
  • the UV detection wavelength was 254 nm.
  • the mass spectrometer was operated in positive and negative ESI modes.
  • H-NMR spectra were acquired on a Bruker 300 MHz (Fourier 300) at room temperature and are reported in ppm downfield from the reference peak of the indicated solvent.
  • 3 P-NMR spectra were acquired on a Bruker 500 MHz at room temperature and reported in ppm downfield from the reference peak of the indicated solvent.
  • CL338 (CAS# 1510712-65-8) was synthesized as described in patent n° EP 2 674 170.
  • CL338 was dissolved (50 mg/mL) in 100% EtOH and then, the resulting solution was diluted in H 2 0 to a final concentration of 1 mg/mL.
  • the CDN was dissolved (400 ⁇ g/mL) in either H 2 0 or 5% aqueous glucose in a glass container.
  • An aliquot of the CL338 solution was added dropwise to an aliquot (of equal volume) of the CDN solution.
  • the resultant solution was vortexed, and then incubated for at least 20 minutes at room temperature.
  • Example 1.5 Characterization of complexes for particle size, polydispersity and net charge
  • Test samples of CDN/CL338 complexes were diluted in H 2 0.
  • the mean particle size (Z; in nm), particle-size distribution (polydispersity index [PDI]; unit-less) and net charge (zeta potential [ ⁇ ]; in mV) were measured using a Zetasizer Nano ZS (Malvern).
  • the particle size was measured at a scattering angle of 90° at 25 °C.
  • the values represent the mean of at least three measurements.
  • the mean Z and PDI values for the CDN/CL338 complexes of the present invention are shown in Figure 1 , which reveal that the complexes range in diameter from ca. 120 nm to ca. 180 nm (left side of figure) and are relatively homogeneous in terms of PDI (values of ca. 0.1 to 0.2; right side of figure).
  • the corresponding mean ⁇ values are shown in Figure 2, which illustrates that all of the CDN/CL338 complexes are stable (i.e. not prone to aggregation in solution), as the magnitude of each value exceeds the commonly accepted cutoff value of 30 mV (see, for example: Duffy ef a/. , 201 1 ).
  • EXAMPLE 2 BIOLOGICAL ASSAYS
  • HEK-BlueTM IFN-a/p-KO-STING These cells, in which the STING gene has been inactivated, are derived from HEK293 cell line known as HEK-BlueTM IFN- ⁇ / ⁇ (InvivoGen catalog code: hkb-ifnab).
  • HEK-BlueTM IFN- ⁇ / ⁇ cells enable detection of bioactive human type I IFNs through monitoring of activation of the ISG3 pathway.
  • These cells were generated by stable transfection of HEK293 cells with the human STAT2 and IRF9 genes to obtain a fully active Type-I IFN signaling pathway.
  • the other genes of the pathway (IFNAR1 , IFNAR2, JAK1 , TyK2 and STAT1 ) are naturally expressed in sufficient amounts.
  • the cells were further transfected with a SEAP reporter gene under control of an IFN-a ⁇ -inducible ISG54 promoter.
  • This promoter 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-KB or AP-1 pathways.
  • ISREs IFN-stimulated response elements
  • Stimulation of HEK-BlueTM IFN- ⁇ / ⁇ cells with human IFN-a or IFN- ⁇ activates the JAK/STAT/ISGF3 pathway and subsequently induces production of SEAP. Production of Type I interferons in these cells is measured using QUANTI-BlueTM.
  • HEK-BlueTM IL-1 R (InvivoGen catalog code: hkb-il1 r): The HEK293 cell line known as HEK-BlueTM IL-1 R was designed to detect bioactive human and murine IL-1 through monitoring of activation of the NF-KB and AP-1 pathways. Additionally, these cells detect bioactive IL-1 from cynomolgus monkeys, dogs, hamsters and rats. In fact, HEK-BlueTM IL-1 R cells can detect IL-1 a and I L-1 ⁇ , as these cytokines bind to the same receptor, IL-1 R.
  • HEK-BlueTM IL-1 ⁇ cells InvivoGen catalog code: hkb-il 1 b), in which the TNF-a response is blocked. Therefore, HEK-BlueTM IL-1 R cells respond specifically to IL-1. These cells endogenously express the human IL-1 receptor and were stably transfected with the murine IL-1 receptor, rendering them sensitive to both human and murine I L-1 ⁇ .
  • HEK-BlueTM IL-1 R cells express a SEAP reporter gene under control of an IFN- ⁇ minimal promoter fused to five NF- ⁇ and five AP-1 binding sites.
  • Binding of I L-1 ⁇ to IL-1 R on the surface of HEK-BlueTM IL-1 R cells triggers a signaling cascade that leads to the activation of NF- ⁇ and subsequent production of SEAP. Production of I L-1 ⁇ in these cells is measured using QUANTI BlueTM.
  • 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
  • HEK-BlueTM TNF-a (InvivoGen catalog code: hkb-tnfdmyd): HEK-BlueTM TNF-a cells are a HEK293 cell line that enables detection of bioactive human and murine TNF-a through monitoring of activation of the NF- ⁇ pathway. These cells were generated by stable transfection of HEK293 cells with a SEAP reporter gene under control of an IFN- ⁇ minimal promoter fused to five NF- ⁇ and five AP-1 binding sites. They were further rendered unresponsive to I L-1 ⁇ by knocking out the MyD88 gene.
  • ISG Cell lines The following three cell lines express a secreted luciferase (Lucia) reporter gene under control of an IRF-inducible promoter. This composite promoter 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. Hence, these cells enable monitoring of the IRF pathway based on luciferase (Lucia) or SEAP activity. In the present invention, monitoring of the IRF pathway is used to measure STING activity:
  • 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).
  • HEK293-PEAKrapid-ISG These cells were generated from the HEK-293 PEAKrapid human embryonic kidney cell line (ATCC ® CRL-2828TM).
  • THP1 -DualTM (InvivoGen catalog code: thpd-nfis): These cells were derived from the human monocytic cell line THP-1 by stable integration of two inducible reporter constructs. They enable simultaneous study of the two main signaling pathways for STING: the NF- ⁇ pathway, by monitoring the activity of secreted embryonic alkaline phosphatase (SEAP); and the IRF pathway, by assessing the activity of a secreted luciferase (Lucia).
  • SEAP secreted embryonic alkaline phosphatase
  • IRF pathway by assessing the activity of a secreted luciferase (Lucia).
  • 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
  • the aforementioned reporter proteins (SEAP and Lucia luciferase) are readily measurable in the cell culture supernatant when using QUANTI-BlueTM (InvivoGen catalog code: rep-qb1 ), a SEAP detection reagent that turns purple/blue in the presence of SEAP (quantified by 20 measuring the optical density from 620 nm to 655 nm), or QUANTI-LucTM (InvivoGen; catalog code: rep-qlc1 ), a luminometric enzyme assay that measures luciferase expression to report on ISG54 expression (as an indicator of IRF pathway induction and thus, IFN- ⁇ / ⁇ production).
  • QUANTI-BlueTM InvivoGen catalog code: rep-qb1
  • QUANTI-LucTM InvivoGen; catalog code: rep-qlc1
  • a luminometric enzyme assay that measures luciferase expression to report on ISG54 expression (as an indicator of IRF pathway induction and thus,
  • Example 2.1 Comparison of CDN/CL338 complexes to the corresponding CDN alone, for STING pathway-dependent cytokine induction in cell cultures
  • a CDN alone concentration: 200 ⁇ g mL in sterile water
  • a CDN/CL338 complex see above
  • the plate was incubated for 24 h at 37 °C in 5% C0 2 .
  • Type I IFN induction was indirectly quantified using QUANTI-LucTM (for the THP1-DualTMand RAW-LuciaTM ISG) or QUANTI-BlueTM (for the HEK293-PEAKrapid-ISG), which were prepared and used according to the manufacturer's instructions.
  • NF- ⁇ pathway induction was indirectly quantified using QUANTI-BlueTM, which was prepared and used according to the manufacturer's instructions.
  • CDNs or CDN/CL338 complexes induces cytokines in cells that lack STING (data not shown).
  • TABLE 3 Comparison of CDNs alone vs. their corresponding CDN/CL338 complexes for in vitro cytokine induction in THP-1 DualTM cells: ISG-induced IRF pathway, to report on Type I IFNs (top); and NF-KB pathway, to report on pro-inflammatory cytokines (bottom). NC: not calculable.
  • Example 2.2 Comparison of CL338 with commercially available transfection reagents, for delivery of CDN STING agonists into 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 CL702/CaCI 2 complex was formed as follows: 20 ⁇ g CL702 was mixed with 12.4 ⁇ _ CaCI 2 (aq. 2M), and the resulting mixture was brought to a total volume of 100 ⁇ _ and then, carefully added dropwise to 100 ⁇ _ 2x HBS (HEPES buffered saline). After 30 minutes at room temperature, the resulting precipitate was serially diluted to provide a final range of six concentrations: 0.0082 ⁇ g/mL, 0.025 ⁇ g/mL, 0.0074 ⁇ g/mL, 0.22 ⁇ g/mL, 0.67 ⁇ g/mL and 2.0 ⁇ g/mL. The rest of the experiment was performed as described above for the transfection reagents, except that the cells were added to each well before the CL702/CaCI 2 complex was added.
  • 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
  • Example 2.3 Comparison of CDN/CL338 complexes with the corresponding CDN alone for STING pathway-dependent cytokine induction ex vivo in human whole-blood samples treated ⁇ Complexes tested: CL592/CL338; CL603/CL338; CL605/CL338; CL614/CL338;
  • TNF-a using HEK-BlueTM TNF-a cells
  • IFN- ⁇ using HEK-BlueTM IL-28 cells
  • 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
  • the plates were incubated at 37 °C in a C0 2 incubator for 18 to 20 hours. Then, the supernatants were collected, transferred into the corresponding wells of round-bottom 96-well plates, and either stored at -80 °C, or immediately tested in the reporter cell line. Testing of human blood samples
  • a new 96-well plate was prepared for each of the four reporter cell lines tested, as follows: 10 ⁇ _ of supernatant from the previous plate (containing the incubated CDNs and plasma) were added to the corresponding well in the new reporter cell plate. Then, a 180- ⁇ _ aliquot of cells of the desired reporter cell line, previously harvested in medium containing heat-inactivated serum and counted, was added to each well (approximately 50,000 cells/well), and the plate was incubated for approximately 20 hours. The desired cytokine induction activity was determined using the QUANTI-Blue assay, as previously described. Briefly, 30 [it of supernatant from the previously incubated plate was transferred to the corresponding well of a new 96-well plate in which 170 [it of QUANTI-BlueTM reagent had previously been added.
  • IFN- ⁇ also known collectively as “Type III interferons (IFNs)"; and individually, as IL-28A [IFN- 2], IL-28B [IFN- 3] and IL-29 [IFN- ⁇ ]
  • IFNs Type III interferons
  • the present invention represents the first report of ex vivo induction of IFN- ⁇ by CDN STING agonists in human blood, and the first report that such activity could differ greatly between phosphodiester CDNs and their corresponding phosphorothioate CDNs.
  • CDN ( g mL) CDN/CL338 (ng/mL) Fold increase
  • CDN (Mg/mL) CDN/CL338 (Mg/mL) Fold increase
  • 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
  • the cells were fixed in formalin for 20 min at room temperature, and then incubated in PBS containing Hoetsch 33342 (1 ⁇ g/mL). Micrographs of the cells were acquired on a Thermo Cellomics Arrayscan microscope. Viral DNA in the nucleus of the cells was quantified based on green fluorescent protein (GFP) signal intensity (expressed as fluorescence units [FU]), and then normalized using the compartmental analysis algorithm. In the cells whose GFP intensity was greater than the background GFP intensity, the total GFP fluorescence intensity in the nucleus was scored automatically for at least 10,000 cells/well. The results were normalized according to the control (untreated) cells. The indicated values are the mean +/-SD of duplicate wells.
  • GFP green fluorescent protein
  • Figure 1 Particle size (Z; in nm) and polydispersity index (PDI; unit-less) for the CDN/CL338 complexes of the present invention.
  • Figure 2. Zeta potential ( ⁇ ; in mV) for the CDN/CL338 complexes of the present invention.
  • FIG. 3A Comparison of transfection agents for ISG-induced IRF activation by complexes containing either CL632 (Fig. 3A) or CL702 (Fig. 3B), in ⁇ -DualTM cells.
  • 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
  • FIG. 7 Comparison of CL592 alone (2.5 mg/Kg) with its corresponding complex CL592/CL338 at five times lower concentration (0.5 mg CL592/Kg) for in vivo anti-tumor activity in a hamster model of pancreatic cancer (orthotopic PC1.0 tumors). The results are shown relative to the control (saline) group.
  • Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants. The Journal of clinical investigation 125, 2532-2546, doi: 10.1 172/JCI79915 (2015).

Abstract

La présente invention concerne la préparation de complexes formés entre un lipide cationique et au moins un des divers agonistes dinucléotidiques cycliques (CDN) de STING, et des utilisations desdits complexes. Plus spécifiquement, ces complexes peuvent être utilisés pour obtenir des activités biologiques améliorées ou distinctes in vitro, ex vivo ou in vivo, par rapport à l'utilisation du composant CDN correspondant seul.
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