Liposomal compositions for the prophylaxis or early treatment of pathogenic infections

Abstract

The present invention relates to a liposomal composition for use as a medicament. In particular, the present invention relates to the use of a liposomal composition comprising a cationic lipid dimethyldioctadecylammonium bromide (DDA), a monomycolyl glycerol-1 (MMG-1) and at least one immunomodulator selected from c-di-GMP or polyinosinic:polycytidylic acid (poly(I:C)) and c-di-GMP in combination, wherein the liposomal composition does not comprise an antigen, in the manufacture of a medicament for the prevention or treatment of a pathogenic infection of the respiratory tract in a subject.

Description

Technical Field

[0001] This invention relates to liposomal compositions for use as pharmaceuticals. Specifically, this invention relates to liposomal compositions for the prevention or early treatment of pathogenic infections. More specifically, the liposomal compositions are for the prevention or early treatment of pathogenic infections in the respiratory tract, preferably administered via the nasal cavity or lungs. Background Technology

[0002] The innate immune system is designed to act instantly upon encountering new pathogens. Rapid defense against airway pathogen infections can be achieved by strengthening the innate immune response in the airways. This is particularly relevant to individuals with impaired / reduced airway immunity. Unlike adaptive immune responses, activation of the innate immune system provides broad defense against many pathogens and is not compromised by mutations within pathogens.

[0003] Life-saving efforts can be made by strengthening this immune response in the airways, particularly in high-risk groups with weakened airway immunity. A specific example is the coronavirus SARS-CoV-2, which causes COVID-19. Coronaviruses use several methods to evade or even impair the innate immune system, leading to infection and subsequent inefficient adaptive immunity. 1 Therefore, preventing this immune evasion by strengthening the innate first line of defense is crucial. SARS-CoV-2 shows a high degree of similarity to SARS-CoV-1. Studies of SARS-CoV-1 infection clearly demonstrate the importance of innate immunity. In fact, animals can control infection even in the complete absence of T and B cells. This control requires the presence of innate immunity, which is capable of producing various cytokines, especially type I interferon. 2,3 Consistent with this, other studies have shown that both prophylactic and post-exposure strategies involving only innate immune stimulation can prevent infection in animal models. 1 A key component of the host's resistance to viral infection is the Toll-like receptor-3 (TLR-3), which is activated by the viral dsRNA and triggers the production of type I interferon. 4 Interestingly, treating mice with TLR3 agonists via the respiratory tract reduced pulmonary viral titers induced by airway infection from five different influenza strains. 5，6 In a mouse model of SARS, a formulation of a TLR3 agonist based on a mouse-adapted, highly virulent strain of SARS coronavirus produced impressive antiviral activity. This formulation, known as Ampligen, has recently entered human clinical trials for intravenous administration. 11 In humans, Phase I / II clinical trials of TLR3 agonists also demonstrated protection against respiratory infections such as rhinovirus and influenza virus. 7 Therefore, TLR3 stimulation is a very promising strategy to enhance innate antiviral immunity.

[0004] Another key component for respiratory defense against pathogens is the C-type lectin receptor Mincle, which is associated with innate defenses such as mycobacteria and streptococci. The inventors have further demonstrated that the combination of a mincle agonist and TLR3 synergistically increases the ability to induce type I interferon-dependent CD8 T cell responses.

[0005] The general assumption behind this invention is that prophylactic intranasal or pulmonary treatment using the liposomal compositions of this invention will activate the innate immune system, including mucosal immune responses, and result in short-term defense against pathogenic infections (e.g., SARS-CoV-2 infection) and other respiratory pathogens. This treatment can be repeatedly administered to high-risk populations during epidemics and significantly affect morbidity and suppress (e.g., the spread of SARS-CoV-2). Furthermore, this treatment is not impaired by any mutations in the pathogen, as it is nonspecific.

[0006] The National Serum Institute (NSSI) is based on (Catonic adjuvant formulation) technology has been used to develop several vaccine adjuvants / innate immune activators, one of which is currently undergoing human trials. 09b. It is currently being tested as an adjuvant for intramuscular or intraperitoneal administration to induce T and B cell-mediated adaptive immune responses against vaccine antigens (clinical trials in progress: NCT03412786; NCT03715985, NCT03926728). 09b contains the innate immune stimulant MMG (which binds to the innate receptor Mincle) and the TLR3 agonist poly(I:C) that induces type I interferon. As a parenteral adjuvant, 09b produces strong innate immune activation, but without serious side effects. 8 .

[0007] Another member of the family is 04, which induces Th1 activation by releasing IFN-γ.

[0008] This invention focuses on liposome compositions for administration via the airway, such as... 04 or 09b aims to activate innate immune cells in the airways to defend against pathogen infections in the airways. Summary of the Invention

[0009] Using liposome compositions, such as 04 or 09b. Intranasal treatment activates the innate immune system, including mucosal immune responses, and provides short-term defense against respiratory pathogens. This treatment can be repeatedly administered during epidemics, such as to high-risk populations, and can significantly impact morbidity and pathogen transmission.

[0010] Therefore, one object of the present invention relates to a liposome composition comprising a cationic lipid dimethyl dioctadecylammonium (DDA) and at least one immunomodulator, for use as a drug in a subject.

[0011] Another aspect of the invention relates to a liposome composition comprising a cationic lipid dimethyl dioctadecylammonium (DDA) and at least one immunomodulator for the prevention or treatment of pathogenic respiratory infections in a subject.

[0012] The liposome composition may also include an immunomodulator, preferably poly(I:C), more preferably a STING agonist, such as cAMP, cGMP, c-di-AMP or c-di-GMP.

[0013] Pathogenic infection can be a respiratory viral infection caused by a virus, which may be, but is not limited to, parvovirus, rhinovirus, coronavirus, such as MERS-coronavirus, SARS-coronavirus, such as SARS-CoV-2, influenza virus, human parainfluenza virus, human respiratory syncytial virus, adenovirus, enterovirus and metapneumovirus.

[0014] In another embodiment of the invention, the pathogenic infection is a bacterial infection of the upper respiratory tract caused by bacteria, which may be selected from, but is not limited to, Chlamydia pneumoniae, Streptococcus pneumoniae, Streptococcus pyrogenes, Haemophilus influenzae, Moraxella catarrhalis, and mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium microti., and Burkholderia sp.

[0015] Pathogenic infections caused by viruses and bacteria of the respiratory system are particularly severe in elderly and frail patients, as well as those with chronic or congenital respiratory dysfunctions (such as, but not limited to, asthma, cystic fibrosis, or chronic obstructive pulmonary disease (COPD)).

[0016] Therefore, subjects who will particularly benefit from this invention, compared to healthy subjects, may have chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, or other diseases that impair respiratory function.

[0017] Another aspect of the present invention is to provide a nasal delivery device comprising the liposome composition disclosed herein.

[0018] Brief description of the attached figures

[0019] Figure 1 Indicates the use of liposome composition Intranasal treatment with 09b (including DDA, MMG, and poly(I:C)) can activate the innate immune system and provide short-term protection against respiratory pathogens. This treatment can be repeatedly administered to high-risk populations during epidemics and significantly reduces morbidity and pathogen transmission.

[0020] Figure 2 shows the + / - In the lungs of mice treated with 09b, there was an influx of innate immune cells and the secretion of IFN-α / β.

[0021] Figure 3 Indicates in + / - Gene expression levels of selected pro-inflammatory and type 1 interferon markers in the lungs of mice treated with 09b.

[0022] Figure 4 shows the results in untreated mice or mice that received two or four treatments. Gene expression levels of selected pro-inflammatory and type 1 interferon markers in the lungs of mice treated with 09b.

[0023] Figure 5 shows the + / - Body weight and survival rate of mice treated with 09b and subsequently infected with influenza virus over time.

[0024] Figure 6 This indicates the development of IgG antibodies in the blood of mice shown in Figure 5.

[0025] Figure 7 shows + / - Survival time, viral load, and body weight of mice after 04 and STING agonists, alone or in combination, over time.

[0026] Figure 8 shows + / - Survival time, viral load, and body weight of mice after 09b and STING agonists, alone or in combination, evolved over time.

[0027] Figure 9 shows + / - 04、 Development of intranasal viral replication in mice after 09b and STING agonists, alone or in combination.

[0028] Figure 10 This indicates that SARS-CoV-2, + / - Weight development in hamsters infected with 09B or Mock control.

[0029] The present invention will now be described in more detail. Detailed Implementation

[0030] definition

[0031] Before discussing the invention in further detail, the following terms and conventions will be defined first:

[0032] Subjects

[0033] The term "subject" includes humans of all ages, other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals in general, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds. Humans are the preferred subject.

[0034] The term "subject" also includes healthy subjects in a population, particularly those exposed to pathogens and those in need of protection against infection, such as healthy individuals.

[0035] Viral and bacterial infections of the respiratory system are particularly severe in elderly and frail patients, as well as those with chronic or congenital respiratory dysfunctions such as asthma, cystic fibrosis, or chronic obstructive pulmonary disease (COPD).

[0036] Lung cancer patients can also receive the liposome composition of this invention. Also suitable are smokers, those with a history of smoking, or those currently using cigarettes or other tobacco products, either or both.

[0037] The subjects mentioned above are susceptible to upper respiratory tract infections, therefore administering the composition disclosed in this invention may potentially prevent the onset of common cold symptoms or diseases, thereby preventing their potential disease and the aggravation of symptoms.

[0038] Dosage / Administration

[0039] In the context of this invention, the term "administration" means administration by various means, including systemic administration (e.g., injection) via a delivery system, local administration, intradermal administration, intranasal administration, sublingual administration, or pulmonary administration.

[0040] The liposome compositions of the present invention are typically administered via intranasal topical administration, ranging from once daily to once or twice weekly, to once every two weeks, to once or twice monthly.

[0041] When administered via the nose or intranasal route, the terms “nasal administration,” “nasal delivery,” or “intranasal delivery” are used interchangeably to refer to the delivery of a liposome composition to the nasal mucosa of a subject, so that the contents of the liposome composition are directly absorbed into the nasal tissue or upper respiratory tract.

[0042] The liposome compositions of the present invention can also be administered via pulmonary delivery. The term "pulmonary" refers to administration via the nose or mouth of a subject, delivering the liposome composition to the alveolar lung tissue, where it is absorbed by the body. Pulmonary delivery can be achieved by direct inhalation of the liposome composition, such as a powder, or by inhalation of an aerosol containing the composition. The liposome compositions of the present invention contemplated herein can be administered via combined nasal and pulmonary delivery, wherein a portion of the liposome composition is delivered to the nasal mucosa and a portion to the alveolar lung tissue.

[0043] Infect

[0044] In the context of this invention, the term "infection" refers to an infection in the respiratory tract (e.g., the upper or lower respiratory tract) caused by a pathogen (e.g., a virus or bacteria).

[0045] Viral infections can be caused by human coronaviruses or influenza viruses. Other viral infections can be caused by parvoviruses (such as rhinovirus), human parainfluenza virus, human respiratory syncytial virus, adenovirus, enterovirus, or metapneumovirus.

[0046] Bacterial infections of the respiratory tract can be caused by bacteria selected from Chlamydia pneumoniae, Streptococcus pneumoniae, Streptococcus pyrogenes, Haemophilus influenzae, Moraxella catarrhalis, and mycobacteria such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium microti., and Burkholderia sp.

[0047] "Prevention" of pathogen infection, condition or disease means that, in a statistical sample, the liposome composition reduces the occurrence of infection, condition or disease in treated subjects compared to untreated subjects, or delays the onset of one or more symptoms of infection, condition or disease or reduces their severity compared to untreated control subjects.

[0048] DDA

[0049] One particularly effective adjuvant for promoting cell-mediated immune responses is quaternary ammonium compounds, such as the cationic surfactant dimethyl dioctadecylammonium (DDA). DDA is a synthetic amphiphilic compound comprising a hydrophilic, positively charged dimethylamine head group and two long, hydrophobic alkyl chains. In an aqueous environment, DDA molecules self-assemble to form a vesicular bilayer similar to liposomes made from natural phospholipids.

[0050] Therefore, DDA is a synthetic surfactant consisting of a hydrophilic cationic quaternary ammonium head group and two hydrophobic saturated C18 alkyl chains. Due to its surfactant properties, DDA molecules self-assemble into liposome-like structures when dispersed in aqueous media.

[0051] The liposome compositions of the present invention comprise cationic lipid DDA as various salts, most preferably dimethylbis(octadecyl)ammonium bromide or ammonium chloride (DDA-B or DDA-C) or its sulfate, phosphate or acetate compound (DDA-X), or dimethylbis(octadecyl)ammonium bromide or ammonium chloride (DODA-B or DODA-C) or its sulfate, phosphate or acetate compound (DODA-X). Most preferably, the liposome compositions of the present invention comprise dimethylbis(octadecyl)ammonium bromide. The CAS number of DDA is 3700-67-2.

[0052] However, the liposome compositions of the present invention may also include other cationic lipids.

[0053] MMG

[0054] Mono-branched acylglycerol (MMG) is a glycolipid that stabilizes liposomes formed with the cationic surfactant DDA by introducing it into the liposome membrane.

[0055] Cationic liposomes are stabilized by introducing glycolipids, such as MMG and optionally other glycolipids, into the liposome membrane.

[0056] Glycolipids, such as MMG, have immunostimulatory properties and can synergistically enhance immune responses with quaternary ammonium compounds (DDA).

[0057] The synthetic analogue known as MMG-1 comprises a hydrophilic glycerol head group and a lipid acid, which exhibits two hydrophobic saturated C14 / C15 alkyl tails linked by ester bonds. Furthermore, an array of MMG analogues exists that differ in alkyl chain length (MMG-2; C16 / C17, MMG-3; C10 / C11, and MMG-4; C6 / C7) or in the stereochemistry of the head group (MMG-5; 2S) and the lipid tail (MMG-6).

[0058] MMG is preferably a glycolipid MMG-1 synthesized by means of synthesis. The preferred MMG analog has the chemical structure of 3-hydroxy-2-tetradecyl-octadecanoic acid-2,3-dihydroxypropyl ester, and more preferably (2R)-2,3-dihydroxypropyl-3-hydroxy-2-tetradecyl-octadecanoic acid diastereomeric.

[0059] Gather (I:C)

[0060] According to the present invention, the term "poly(I:C)" or "polyI:C" includes single-chain polyinosinic acid (polyI) and single-chain polycytidylic acid (polyC) that are not bound by hydrogen bonds or covalent bonds at the time of administration, as well as double-chain or complex polyI / polyC. Upon administration to a moist mucosal surface, the non-complex polyI and polyC can form a complex poly(I:C), thereby activating the innate immune system and providing resistance to viral infection.

[0061] Preferably, poly(I:C) is a synthetically produced double-stranded RNA analog comprising the annealing of polyinosinic acid chains and polycytidine chains, or analogs thereof. Poly(A:U) (polyadenylate-polyuridine) can be used as an alternative analog.

[0062] The molecular weight of poly(I:C) depends on the length of the polymer. The molecular weight specifications for potassium poly(I:C) range from 10 to 750 kDa, with a preferred range of 100 to 750 kDa. The CAS number for poly(I:C) is 24939-03-5.

[0063] Cyclic dinucleotides

[0064] The term "cyclic dinucleotide" in this invention describes a group of compounds, including c-di-GMP, c-di-AMP, 3',3'-cyclic-GMP-AMP (3',3'cGAMP), and 2',3'-cyclic-GMP-AMP (2',3'cGAMP), which function as potent immunostimulators or immunomodulators. The second messenger c-di-GMP, with a structure containing two guanine bases linked by a ribose and a phosphate group, has been shown to activate "interferon gene stimulator" (STING), i.e., STING agonists, leading to increased IFN-I secretion.

[0065] adjuvant

[0066] In this article, the term "adjuvant" refers to a compound or mixture that can further enhance the immune response. Adjuvants can serve as tissue repositories that slowly release antigens, as well as as lymphatic system activators that nonspecifically enhance the immune response, i.e., immunomodulators.

[0067] Immunomodulators are any components that enhance or synergize with an immune response to achieve an immune response. This synergistic effect can be achieved non-specifically or specifically through pattern recognition receptors (PRRs), including but not limited to C-type lectin receptors (CLRs), RIG-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD) proteins, and Toll-like receptors (TLRs).

[0068] The immunogenicity of liposomes can be enhanced by adding immunostimulatory ligands (also known as immunomodulators) to so-called pattern recognition receptors (PRRs). PRRs recognize conserved molecular structures on pathogens known as pathogen-associated molecular patterns (PAMPs). The ability of PAMPs to regulate innate immune responses, and the resulting adaptive responses, can be advantageously used for the prevention or treatment of respiratory pathogenic infections.

[0069] So-called pattern recognition receptors (PRRs) include C-type lectin receptors, RIG-like receptors, nucleotide-binding oligomeric domain (NOD) proteins, and the growing Toll-like receptor (TLR) family. PAMPs vary depending on the pathogen and include molecules such as toxin factor (TDM), flagellin, lipopolysaccharide (LPS), peptidoglycan, and some nucleic acid variants, such as double-stranded ribonucleic acid (dsRNA). Over the years, many PAMPs-inspired immunomodulators have been developed. These include trehalose disorbate (TDB), synthetic monocranioglycerol (MMG), lipid monophosphate A (MPL), and polyinosinic acid:polycytidylic acid (poly(I:C)). The combination of liposomes with these PAMP / immunomodulators is an attractive approach to developing a method for the prevention or treatment of early pathogenic infections, where the PAMP / immunomodulator stimulates antigen-presenting cells, thereby enhancing the immune response.

[0070] Other adjuvants include, but are not limited to, Quil A, QS21, aluminum hydroxide, Freund's incomplete adjuvant, lipid monophosphate A (MPL), trehalose dimethicone (TDM), muramyl dipeptide (MDP), IC31, saponins, surfactants such as lysophosphatidylcholine, polyols, polyanionic peptides, oil or hydrocarbon emulsions, keyhole hemocyanin, dinitrophenol, or combinations thereof. Preferably, the adjuvants are pharmaceutically acceptable.

[0071] Liposomes

[0072] The term "liposome" or "liposome component" is a broad definition of a vesicle composed of a lipid bilayer enclosing an aqueous chamber. Membrane-forming lipids are amphiphilic and therefore contain both polar and nonpolar regions. The polar region typically consists of a phosphate group, an acidic group, and / or a tertiary or quaternary ammonium salt, and may have a net negative (anionic), neutral, or positive (cationic) surface charge at physiological pH, depending on the composition of the lipid head group. The pH is preferably adjusted to physiological pH, such as by dispersing in Tris or histidine buffer to pH 5.0-8.0, and most preferably to pH 6.5-7.5. The nonpolar region typically consists of one or more fatty acid chains containing at least eight carbons and / or cholesterol. The lipids constituting the vesicular bilayer are organized such that the nonpolar hydrocarbon "tails" face towards the center of the bilayer, while the polar "heads" face towards the interior and exterior of the aqueous phase, respectively.

[0073] Therefore, a "liposome" or "liposomal" is defined as a closed vesicle structure consisting of one or more lipid bilayers surrounding an aqueous core. Each lipid bilayer consists of two lipid monolayers, each with a hydrophobic "tail" region and a hydrophilic polar "head" region. In the lipid bilayer, the hydrophobic "tail" of the lipid monolayer faces inward, while the hydrophilic "head" faces outward. Liposomes possess various physicochemical properties, such as size, lipid composition, surface charge, fluidity, and the number of bilayer membranes. Based on the number of lipid bilayers, liposomes can be classified into monolayer vesicles (UV) or small monolayer vesicles (SUV), which contain a single lipid bilayer or a multilayer vesicle (MLV), each containing two or more concentric bilayers separated from the other by an aqueous layer. Water-soluble compounds are trapped within the aqueous phase / core of the liposome, while the opposing lipophilic compounds are trapped within the core / center of the lipid bilayer membrane.

[0074] The term “cationic lipid” or “cationic liposome” is intended to include any amphiphilic lipid, including natural and synthetic lipids and lipid analogs, that has a hydrophobic and polar head portion, a net positive charge at a physiologically acceptable pH, and can form bilayer vesicles or micelles in water.

[0075] Other cationic lipids as adjuvants

[0076] Additional cationic lipid compounds that can be added to the liposome compositions of the present invention as adjuvants are 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dimyristoyl-3-trimethylammonium propane, 1,2-dipalmitoyl-3-trimethylammonium propane, 1,2-distearate-3-trimethylammonium propane, dioleoyl-3-dimethylammonium propane (DODAP), N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium (DOTMA), octadecenoyloxy(ethyl-2-heptadecenyl-3-hydroxyethyl)imidazoline (DOTIM), 1,2-dioleoyl-sn-glycerol-3-ethylphosphocholine (DOEPC), and 3-tetradecylamino-tert-butyl-N-tetradecylpropanediamine (diC14-amane).

[0077] A fatty acid chain refers to a saturated or unsaturated hydrocarbon chain with or without branches of alkyl or acyl groups.

[0078] In pharmaceutical terms, acceptable means a substance that does not interfere with the effectiveness or biological activity of the active ingredient and is non-toxic to the host or patient.

[0079] Cationic liposomes are stabilized by introducing glycolipids, such as MMG and optionally other glycolipids, into liposome membranes. Introduction refers to the process of embedding the hydrophobic and hydrophilic regions of a molecule into the corresponding hydrophobic and hydrophilic regions or moieties of a membrane, micelle, liposome, or bilayer. The process of adding glycolipids into liposomes can be a “thin-film method,” “reverse-phase evaporation method,” “organic solution injection method,” “double emulsion method,” “high-shear mixing method,” “microfluidic method,” and future, currently unknown methods with the same effect of introducing glycolipids into liposome membranes. Known methods are mentioned in the background section of this invention.

[0080] Glycolipids are defined as any compound comprising one or more monosaccharide or glycerol residues bound by a glycosidic bond to a hydrophobic moiety such as a long-chain fatty acid, acylglycerol, sphingosine, ceramide, or isoprene phosphate. The additional glycolipids of this invention may be of synthetic, plant, or microbial origin, such as those derived from mycobacteria.

[0081] Besides MMG, a class of glycolipids used as adjuvants in this invention are acylated (or alkylated) glycosides comprising one or two sugar residues esterified with one, two, or even three fatty acids. The fatty acids can be linear, including saturated fatty acids such as myristic acid C14:0, pentadecanoic acid C15, palmitic acid C16:0, heptadecanoic acid C17:0, octadecanoic acid C18:0, nonadecanoic acid C19, eicosanoic acid C20, dodecanoic acid C21:0, and docosanoic acid C22, and unsaturated fatty acids such as oleic acid C18:1n-9 and linoleic acid 18:2n-6; or complex branched fatty acids such as mycolic acid, methoxymycolic acid, ketone mycolic acid, epoxy mycolic acid, and corynomycolic acid. The sugar residues can be simple monosaccharides, such as glucose and fructose; or disaccharides comprising two covalently linked monosaccharides, such as sucrose composed of glucose and fructose, and trehalose in which two glucose units are linked by glycosidic bonds. One class of glycolipids used in this invention are cell wall glycolipids isolated from mycobacteria, comprising disaccharides esterified with one, two, or three n-hexadecanoic acid C16:0, oleic acid C18:1n-9, linoleic acid 18:2n-6, or complex hydroxy branched fatty acids, i.e., mycolic acid residues in the range of 60 to 90 carbon atoms in length. Other bacterial glycolipids used in this invention have shorter fatty acid chains, such as mycolic acid (22-36 carbons) or mycolic acid (44-60 carbons) isolated from Corynobacterium and Nocardia. Preferred mycobacterial glycolipids are α,α'-trehalose 6,6'-dimethicone ester (TDM), commonly known as a mycotoxin factor, which is one of the most important immunomodulatory components of the mycobacterial cell wall. In a particularly preferred embodiment, the glycolipid comprises the disaccharide α,α'-trehalose esterified with two docosanoic acid fatty acids (betaine), such as α,α′-trehalose 6,6′-dimethicone ester (TDB), a pure synthetic analog of TDM. Other preferred mycobacterial glycolipids are monocranoylglycerols, or preferably synthetic analogs such as 3-hydroxy-2-tetradecyl-octadecanoate-2,3-dihydroxypropyl ester or closely related compounds having shorter or longer acyl skeletons.

[0082] Other types of glycolipids that can be used in this invention include, but are not limited to, glycerol-based glycolipids: these lipids comprise a monosaccharide or oligosaccharide moiety linked to a hydroxyl group of glycerol via a glycosidic bond, wherein the glycerol may be acylated (or alkylated) with one or two fatty acids. Furthermore, these glycolipids may be uncharged and are therefore commonly referred to as neutral glycerol glycolipids, or may contain sulfate or phosphate groups. Preferred glycolipids of this type in this invention are monobranched acylglycerols (MMG) (Andersen et al. 2009a, Andersen et al. 2009b) or synthetic analogues thereof, such as 3-hydroxy-2-tetradecyl-octadecanoate-2,3-dihydroxypropyl ester, or closely related compounds having shorter or longer acyl skeletons (Andersen et al. 2009b, Nordly et al. 2011).

[0083] Ceramide-based glycolipids: Based on the structure of the carbohydrate moiety, glycosphingolipids are classified into neutral glycosphingolipids containing unsubstituted glycosyl groups and acidic glycosphingolipids containing acidic carboxyl, sulfate, or phosphate groups.

[0084] Lipopolysaccharides (LPS) can be used as adjuvants. These complex compounds are endotoxin antigens (S-lipopolysaccharides) found in the cell walls of Gram-negative bacteria. The lipid moiety (lipid A) forms a complex with the polysaccharide via glycosidic bonds. Lipid A comprises a β-1,6-glucosaminyl-glucosamine backbone with two phosphate groups at the 1-position of glucosamine I and the 4-position of glucosamine II. At the 3-position of glucosamine II, an acid-labile glycosidic bond is formed with the long-chain polysaccharide. Other groups (in Escherichia coli) are replaced with hydroxylated fatty acids such as hydroxymyristate (bonded with two esters and two amides) and conventional fatty acids (laurates). A particularly preferred LPS of this invention is a monophosphoryl derivative (MPL) of lipid A, which is non-toxic and has excellent adjuvant properties.

[0085] Sterol glycosides can be used as adjuvants. This family comprises a carbohydrate unit bonded to a hydroxyl group of a monosterol molecule. Identified sterol moieties include various sterols: cholesterol, campesterol, stigmasterol, sitosterol, brassosterol, and dihydrositosterol. Sugar moieties include glucose, xylose, and even arabinose.

[0086] Glycosides of fatty acids or fatty alcohols can be used as adjuvants. Many simple glycolipids are found in bacteria, yeast, and lower organisms (sponges). These compounds consist of a glycosyl moiety (one or more units) bonded to a hydroxyl group of a fatty alcohol or hydroxy fatty acid, or to a carboxyl group of a fatty acid (ester bond). These compounds often possess interesting physical or biological properties. Some of them are industrially produced due to their detergent properties (alkyl glycosides).

[0087] Furthermore, macromolecules such as oligonucleotides, peptides, or protein antigens can be encapsulated in the aqueous phase of monolayer and multilayer liposomes of the compositions of the present invention.

[0088] The combination of substances includes, but is not limited to, non-covalent bonding, such as electrostatic interactions between macromolecules and liposomes with the same or opposite charges, and hydrophobic attraction.

[0089] Macromolecules can be used as adjuvants. A macromolecule is defined as a very large molecule composed of many smaller structural units linked together, such as proteins; very large and complex molecules, such as DNA and RNA, are also defined as macromolecules. The term applies to four common biopolymers (nucleic acids, proteins, carbohydrates, and lipids), as well as non-polymerized molecules with large molecular weights. The use of macromolecules in this invention includes, but is not limited to, oligonucleotides, peptides, proteins, carbohydrates, and lipids.

[0090] This invention discloses the homogeneous mixing of lipid components of liposomes, such as cationic surfactants (e.g., DDA) and glycolipids (e.g., TDB), prior to hydration and after hydration, which may be used for subsequent complexation with other macromolecules. Mixing of lipid components with other macromolecules (e.g., oligonucleotides) can also be performed prior to hydration, exhibiting high shear mixing during complexation. Complexes between cationic lipids and, in particular, negatively charged macromolecules (e.g., oligonucleotides) are generally thermodynamically unstable, leading to the formation of large aggregates, wide size distributions, and structural inhomogeneities over time. The binding of highly charged polyelectrolytes to oppositely charged liposomes enhances the instability of the membrane itself. The reduction in external surface area accompanying charge neutralization results in a gradient of lateral pressures in the normal orientation of the bilayer. This generates a bending moment, which in turn causes instability in the liposomes.

[0091] It should be noted that the embodiments and features described in the context of one aspect of the invention are also applicable to other aspects of the invention.

[0092] One aspect of the present invention relates to a liposome composition comprising a cationic lipid dimethyl dioctadecylammonium (DDA) and at least one immunomodulator, for use as a drug in a subject.

[0093] Another aspect of the invention relates to a liposome composition comprising a cationic lipid dimethyl dioctadecylammonium (DDA) and at least one immunomodulator for the prevention or treatment of pathogenic respiratory infections in a subject.

[0094] One embodiment of the present invention relates to a liposome composition for preventing pathogenic infections, wherein the pathogenic infection is selected from viral infections or bacterial infections.

[0095] Pathogenic infections can be respiratory infections, such as those in the upper or lower respiratory tract.

[0096] Therefore, in another embodiment of the present invention, the pathogenic infection may be a respiratory viral infection caused by a virus selected from parvovirus, rhinovirus, coronavirus (e.g., MERS coronavirus), SARS coronavirus, such as SARS-CoV-2, influenza virus, human parainfluenza virus, human respiratory syncytial virus, adenovirus, enterovirus and metapneumovirus.

[0097] In another embodiment of the invention, the viral infection is a bacterial infection of the respiratory tract caused by bacteria selected from Chlamydia pneumoniae, Streptococcus pneumoniae, Streptococcus pyrogenes, Haemophilus influenzae, Moraxella catarrhalis, and mycobacteria such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium microti., and Burkholderia sp.

[0098] One embodiment of the present invention relates to a liposome composition as disclosed herein, which further comprises at least one glycolipid, such as a monocranioglycerol analog (MMG).

[0099] Immunomodulators can be selected from those that can signal to inhibit viral replication, or those that can signal to activate or recruit pro-inflammatory cells (such as granulocytes, macrophages, and NK cells) to eliminate pathogens.

[0100] The immunomodulator is selected from STING agonists, such as cyclic-GMP-AMP (cGAMP), cAMP, c-di-AMP, cGMP, and c-di-GMP; TLR2 agonists, such as yeast glycans; TLR3 agonists, such as double-stranded ribonucleic acid (dsRNA), such as polyinosinic acid:polycytidylic acid (poly(I:C)); TLR4 agonists, such as MPL-A; TLR5 agonists, such as flagellin; TLR7 / 8 agonists, such as resiquimod, imiquimod, and gardiquimod; and also includes lipotropic analogs, C-type lectin receptors, such as thymol factor (TDM) or synthetic analogs TDB, and nucleotide-binding oligomerization domain (NOD) receptor agonists, such as MDP. Preferably, the immunomodulator is polyinosinic acid:polycytidylic acid (poly(I:C)), more preferably a synthetic double-stranded poly(I:C) RNA analog.

[0101] In one embodiment of the present invention, the immunomodulator is preferably a STING agonist, selected from cGAMP, cAMP, cGMP, c-di-AMP and c-di-GMP, more preferably c-di-GMP.

[0102] In another embodiment of the invention, the monobranched glycerol (MMG) of the liposome composition is preferably an analogue of 2,3-dihydroxypropyl 3-hydroxy-2-tetradecyl-octadecanoate.

[0103] In another embodiment of the invention, the DDA of the liposome composition is preferably dimethyl dioctadecyl ammonium bromide.

[0104] Another embodiment of the invention relates to the liposome composition disclosed herein, comprising the cationic lipid dimethyl dioctadecylamine (DDA) and monocranioglycerol (MMG). A preferred embodiment of the invention relates to the liposome composition disclosed herein, comprising 1-3 mg / ml DDA and 0.1-1.0 mg / ml MMG-1. The liposome composition preferably comprises 2.5 mg / ml DDA and 0.5 mg / ml MMG-1.

[0105] Another embodiment of the present invention relates to a liposome composition comprising 0.1-1.0 mg / ml poly(I:C), preferably 0.5 mg / ml poly(I:C) (corresponding to...). The content of 0.09 is particularly preferred at 0.125 mg / ml poly(I:C) (corresponding to 0.09 content), especially 0.125 mg / ml poly(I:C) (corresponding to 0.09 content). (Content of 09b).

[0106] Another embodiment of the invention relates to the liposome composition disclosed herein, wherein the liposome composition comprises the cationic lipid dimethyl dioctadecylamine (DDA), monocranylglycerol (MMG), and at least one additional immunomodulator.

[0107] Another embodiment of the invention relates to the liposome composition disclosed herein, wherein the liposome composition comprises a cationic lipid dimethyl dioctadecylamine (DDA), monocranylglycerol (MMG), poly(I:C), and at least one additional immunomodulator.

[0108] Another embodiment of the present invention relates to a liposome composition disclosed herein, wherein the liposome composition comprises the immunomodulator c-di-GMP.

[0109] Another embodiment of the invention relates to the liposome composition disclosed herein, wherein the liposome composition comprises the cationic lipids dimethyl dioctadecylamine (DDA), monobranched glycerol (MMG), and c-di-GMP.

[0110] Another embodiment of the present invention relates to the liposome composition disclosed herein, wherein the liposome composition comprises the cationic lipid dimethyl dioctadecylamine (DDA), monobranched glycerol (MMG), poly(I:C), and c-di-GMP.

[0111] In another embodiment, the liposome composition further comprises a STING agonist, preferably c-di-GMP, at a concentration of 0.025-2.5 g / ml, for example 0.05-2.0 mg / ml, for example 0.05-1.5 mg / ml, for example 0.05-1.0 mg / ml, for example 0.025-0.5 mg / ml, preferably 0.05-0.2 mg / ml, for example 0.1-0.2 mg / ml.

[0112] In another embodiment, the liposome composition comprises 2.5 mg / ml DDA, 0.5 mg / ml MMG-1, and 0.1 mg / ml c-di-GMP.

[0113] In another embodiment of the invention, the liposome composition disclosed herein can be administered via systemic, nasal, and / or pulmonary administration. The liposome composition can also be administered simultaneously via systemic and nasal administration.

[0114] In another embodiment, the liposome composition can be administered via nasal and / or pulmonary administration after exposure to pathogens to treat early respiratory infections.

[0115] In another embodiment of the invention, the liposome composition is administered via nasal or pulmonary administration to prevent respiratory infections. The liposome composition may also be administered simultaneously via nasal and pulmonary administration. In yet another embodiment, the liposome composition is administered one to seven times per week, for example, twice, three, four, five, or six times per week.

[0116] Therefore, subjects who may benefit particularly from the present invention compared to healthy subjects may suffer from chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, or other diseases that impair respiratory function. Subjects with lung cancer may also receive the liposomal compositions of the present invention. In some embodiments, the subject may be a smoker with a history of smoking or currently using one or both of cigarettes or other tobacco products. These subjects are susceptible to upper respiratory tract infections, and therefore administration of the disclosed compositions may prevent the onset of common cold symptoms or illnesses, thereby preventing the exacerbation of their underlying diseases and symptoms.

[0117] In one embodiment of the invention, the subjects are selected from humans of all ages, other primates (such as cynomolgus monkeys and rhesus monkeys), general mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and dogs, and birds. Most preferably, the subjects are humans.

[0118] In another embodiment of the invention, the subject is a subject with impaired / reduced airway immunity.

[0119] In another embodiment of the invention, the subject suffers from a disease selected from chronic obstructive pulmonary disease, asthma, cystic fibrosis, lung cancer, and diabetes. Furthermore, the subject may have a history of smoking or may be a current smoker.

[0120] In another implementation, the subjects are healthy subjects in a population or healthy subjects exposed to pathogens who need to prevent infection, such as healthy individuals.

[0121] Another aspect of the present invention relates to a device comprising the liposome composition for administration via the nasal cavity or lungs.

[0122] A particularly preferred liposome composition of the present invention is 04、 09 and 09b.

[0123] 04 is a two-component cationic liposome adjuvant system developed by the National Serum Institute of Denmark. It consists of cationic DDA liposomes containing glycolipids and immunomodulators, and mono-branched glycerol (MMG) introduced into the bilayer of the liposome membrane.

[0124] 09b is a three-component cationic liposome adjuvant system developed by the National Serum Institute of Denmark. It consists of a cationic DDA liposome containing glycolipids and an immunomodulator, mono-branched glycerol (MMG) introduced into the bilayer of the liposome membrane, and the immunomodulator polyI:C bound to the surface of the liposome.

[0125] 04、 09 and Contents of 09b:

[0126] 04: 2500 / 500 μg / mL DDA:MMG-1 was dispersed in 10 mM Tris + 4% glycerol and adjusted to pH 7.0.

[0127] 09: 2500 / 500 / 500 μg / mL DDA:MMG-1:poly(I:C) was dispersed in 10 mM Tris + 4% glycerol and adjusted to pH 7.0.

[0128] 09b: 2500 / 500 / 125ug / mL DDA:MMG-1:poly(I:C) dispersed in 10mM Tris + 4% glycerol and adjusted to pH 7.0.

[0129] All patent and non-patent references cited in this application are incorporated herein by reference in their entirety.

[0130] The invention will now be described in further detail in the following non-limiting embodiments.

[0131] Example

[0132] These embodiments are intended to illustrate the present invention.

[0133] In the following embodiments, 04 and 09b is an exemplary liposome composition used in this invention.

[0134] 04 is a two-component cationic liposome adjuvant system developed by the National Serum Institute of Denmark, comprising a cationic DDA liposome carrying glycolipids and an immunomodulator, and mono-branched glycerol (MMG) introduced into the bilayer of the liposome membrane.

[0135] 04 2500 / 500 has a strength of 2500 μg DDA and 500 μg MMG per mL, dispersed in 10 mM Tris + 4% glycerol and adjusted to pH 7.0.

[0136] 09b is a three-component cationic liposome adjuvant system developed by the National Serum Institute of Denmark. It consists of a cationic DDA liposome containing glycolipids and an immunomodulator, mono-branched glycerol (MMG) introduced into the bilayer of the liposome membrane, and the immunomodulator polyI:C bound to the surface of the liposome.

[0137] 09b 2500 / 500 / 125 has a strength of 2500 μg DDA, 500 μg MMG and 125 μg polyI:C per mL, dispersed in 10 mM Tris + 4% glycerol and adjusted to pH 7.0.

[0138] Example 1 - Influx of innate immune cells

[0139] CB6F1 mice 09b was treated nasally twice, 72 hours apart. The study was terminated 24 hours later, and the perfused lungs were isolated and analyzed by flow cytometry to determine the influx of innate immune cells (Figure 2A). Intranasal administration 09b promoted the growth of monocytes (MHC II+, CD11b+, Ly6C+). Increased influx of MHC II+, F4 / 80+, DCs (MHC II+, CD11 c+), neutrophils (Ly6G+), and NK cells (NK1.1+) into the lungs. Electrochemiluminescence (MSD) analysis was performed to determine IFN-I in the lung cell supernatant. After 09b treatment, both IFN-α (Figure 2B) and IFN-β (Figure 2C) increased.

[0140] Example 2 – Pro-inflammatory and Type 1 Interferon Markers

[0141] CB6F1 mice 09b was administered nasally twice, 72 hours apart, or four times, 24 hours apart. After 24 hours, the study was terminated, the perfused lungs were isolated, and qPCR analysis of pro-inflammatory and type 1 interferon markers was performed using a Qiagen RT2 Profiler PCR Array to determine the genes upregulated after treatment. Data showed that upregulated genes associated with both type 1 interferon and pro-inflammatory responses included surface activation markers: CD69, CD86, Tap1, H2-BI, H2-DI, and H2-KI; secretion signaling markers: CCL2, CCL4, CCL5, Timp1, and CXCL10; interferon-I-related pattern recognition receptors: Adar, RIG-I, MDA-5, TLR3, TLR7, and TLR9; IFN-I regulatory genes: stat1, stat2, irf9, isg15, socs1, eif2ak2, and isg20; inhibition of viral translation and replication: ifit1, ifit2, ifit3, mx1, and mx2; and interferon-I products: irf7, ifi204, and pMI. Figure 3 +4A-F). These data indicate that, 09b induces the innate immune response required to defend against viruses.

[0142] Example 3 – Body weight and survival rate after influenza infection

[0143] CB6F1 mice 09b mice were treated nasally twice, with a 3-day interval. The mice... first Mice were infected with influenza 4 and 10 days after immunization. Body weight (Fig. 5A) and survival rate (Fig. 5B) were monitored for 7 days. Four-six mice in the control group and mice treated the previous week... In group 09b, only one-sixth of the mice reached the compassionate endpoint weight and had to be removed. During the study, the mice were given [a treatment / treatment] the day before the challenge. Mice treated with 09b did not reach the benevolent endpoint. This study indicates that the treatment effect lasts for at least one week.

[0144] Example 4 – HA-specific antibody

[0145] In Example 3, blood was drawn from mice on the day the experiment was terminated to investigate whether innate protection led to a decrease in adaptive immunity. Influenza HA-specific antibodies were measured using ELISA. Figure 6 ).

[0146] Data shows that although symptoms have lessened, 09b treatment does not affect the induction of infection-driven acquired immunity because In the 109b treatment group, the antibody levels after infection were comparable to, if not higher, those in the untreated group.

[0147] Example 5 – 04 Combined with STING agonist

[0148] Will The efficacy of 04 (2500 / 500 μg / mL DDA / MMG-1) was validated in combination with 100 μg / mL of the STING (interferon gene stimulator) agonist c-di-GMP. This agonist controls the transcription of host defense genes, including pro-inflammatory cytokines and chemokines, as well as type I interferon (IFN). Mice were tested using c-di-GMP alone, alone... 04 or 04+c-di-GMP treatment was administered four times, with each treatment spaced 24 hours apart, and in first Infection with influenza 5 days after immunization. Survival rate ( Figure 7A Viral load () Figure 7B Mice in the control group (Figure 7C-F) were monitored for 14 days for body weight and other vital signs. Figure 7A , C), 6 / 8 mice in the c-di-GMP group ( Figure 7A D) and Group 04 4 / 8 mice ( Figure 7A E), and Only 3 / 8 of the mice in the 04+C-di-GMP group reached the benevolent endpoint weight and had to be removed. This study indicates that... O4 and c-di-GMP have a synergistic effect in treatment, producing better results when used in combination. This is also reflected in their ability to reduce viral load. Figure 7B ).

[0149] Example 6 – 09b in combination with STING agonist

[0150] Will The efficacy of 09b (2500 / 500 / 125 μg / mL DDA / MMG-1 / polyIC) was validated in combination with 100 μg / mL of the STING (interferon gene stimulator) agonist c-di-GMP. This agonist controls the transcription of host defense genes, including pro-inflammatory cytokines and chemokines, as well as type I interferon (IFN). Mice were tested using c-di-GMP alone, alone... 09b or 09 b+c-di-GMP treatment twice Three days apart, and first Five days after immunization, patients received a high dose of influenza. This had an impact on survival rates. Figure 8A Viral load () Figure 8BMice in the control group (Figure 8C-F) were monitored for 14 days for body weight and other parameters. Figure 8A ,C), 7 / 8 mice in the c-di-GMP group ( Figure 8A D) and 6 / 8 mice from group 09b (see) Figure 8A E), and Only 5 / 8 of the mice in the 08b+C-di-GMP group reached the benevolent endpoint weight and had to be removed. This study indicates that... 09b and c-di-GMP have a synergistic effect in treatment, producing better results when used in combination. This is also reflected in their ability to reduce viral load. Figure 8B ).

[0151] Example 7 – 04、 The combined use of 09 and STING agonists

[0152] Will 04 (2500 / 500 μg / mL DDA / MMG-1) and The efficacy of 09b (2500 / 500 / 125 μg / mL LDA / MMG-1 / polyIC) in combination with 100 μg / mL of the STING agonist c-di-GMP was validated to investigate its ability to block intranasal viral replication. Mice were treated with c-di-GMP, 04、 09b、 04+c-di-GMP 09b+c-di-GMP treatment twice Three days apart, and first Five days after immunization, patients received a high-dose influenza infection. Two days after the challenge, nasal viral load was analyzed (measured by relative influenza mRNA expression). Figure 9A ) and CT value ( Figure 9B The CT value equals the total number of cycles required to find RNA; each positive test has its own CT value. If no RNA is found within 37 to 40 cycles, the test is negative. This study indicates that c-di-GMP helps reduce viral replication in the nasal cavity by interacting with... 04 and The combination of 09b and other treatments can further promote this replication; therefore, this combination can work synergistically in terms of therapeutic efficacy by preventing viral proliferation in the nasal cavity. This is related to the ability of adjuvants containing c-di-GMP to recruit more activated NK cells (Fig. 9C), inflammatory monocytes (Fig. 9D), and neutrophils (Fig. 9E) before infection. Only 09b+c-di-GMP significantly increased the levels of macrophages (Fig. 9F) and dendritic cells (Fig. 9G).

[0153] Example 10 – 09b and SARS-CoV-2

[0154] Use the Syrian Gold Hamster 09b was treated nasally twice, with a 3-day interval. Five days after the first immunization, the hamsters were infected with SARS-CoV-2 (1.9 x 10⁻⁶). 5 TCID 50 Weight was monitored for 7 days as an indicator of health status. (Not accepted) The weight loss of hamsters treated with 09b was significantly greater than that of other hamsters. The 109b treatment group did not regain their weight by day 7, which is... The situation of treatment group 09 ( Figure 10 ).

[0155] References:

[0156] 1Hackett, CJInnate immune activation as a broadspectrum biodefensestrategy:Prospects and research challenges.J ALLERGY CLIN IMMUNOL112,8(2003).

[0157] 2Hogan,RJet al.Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1.J Virol78,11416-11421,doi:10.1128 / JVI.78.20.11416-11421.2004(2004).

[0158] 3Taylor, DRObstacles and advances in SARS vaccine development. Vaccine24, 863-871, doi:10.1016 / j.vaccine.2005.08.102(2006).

[0159] 4Uematsu,S.&Akira,S.Toll-like receptors and Type I interferons.J BiolChem282,15319-15323,doi:10.1074 / jbc.R700009200(2007).

[0160] 5Lau,Y.F.,Tang,L.H.,McCall,A.W.,Ooi,E.E.&Subbarao,K.An adjuvant forthe induction of potent,protective humoral responses to an H5N1 influenzavirus vaccine with antigen-sparing effect in mice.J Virol84,8639-8649,doi:10.1128 / JVI.00596-10(2010).

[0161] 6Lau,Y.F.,Tang,L.H.,Ooi,E.E.&Subbarao,K.Activation of the innateimmune system provides broad-spectrum protection against influenza A viruseswith pandemic potential in mice.Virology406,80-87,doi:10.1016 / j.virol.2010.07.008(2010).

[0162] 7Martins,K.A.,Bavari,S.&Salazar,A.M.Vaccine adjuvant uses of poly-ICand derivatives.Expert Rev Vaccines14,447-459,doi:10.1586 / 14760584.2015.966085(2015).

[0163] 8Pedersen,G.K.,Andersen,P.&Christensen,D.Immunocorrelates of CAFfamily adjuvants.Semin Immunol39,4-13,doi:10.1016 / j.smim.2018.10.003(2018).

[0164] 9Abraham,S.et al.Safety and immunogenicity of the chlamydia vaccinecandidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide:afirst-in-human,randomised,double-blind,placebo-controlled,phase 1trial.Lancet Infect Dis19,1091-1100,doi:10.1016 / S1473-3099(19)30279-8(2019).

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[0166] 11.Virology.2009 Dec 20;395(2):210–222.

Claims

1. The use of a liposomal composition in the preparation of a medicament for the prevention or treatment of pathogenic infections of the respiratory tract in a subject, said liposomal composition comprising the cationic lipid dimethyl dioctadecylammonium bromide (DDA), monocranylglycerol-1 (MMG-1), and an immunomodulator selected from c-di-GMP or polyinosinic acid: polycytidylic acid (poly(I:C)) and c-di-GMP in combination, wherein said liposomal composition does not contain an antigen.

2. The application according to claim 1, wherein the liposome composition comprises 1-3 mg / ml DDA and 0.1-1.0 mg / ml MMG-1.

3. The application according to claim 2, wherein the liposome composition comprises 2.5 mg / ml DDA and 0.5 mg / ml MMG-1.

4. The application according to claim 1, further comprising 0.05-1.0 mg / ml poly(I:C).

5. The application according to claim 4, comprising 0.1-0.5 mg / ml poly(I:C).

6. The application according to claim 5, comprising 0.5 mg / ml poly(I:C).

7. The application according to claim 5, comprising 0.125 mg / ml poly(I:C).

8. The application according to claim 1, wherein the liposome composition comprises an immunomodulator c-di-GMP at a concentration of 0.05-0.2 mg / ml.

9. The application according to claim 8, wherein the liposome composition comprises an immunomodulator c-di-GMP at a concentration of 0.1 mg / ml.

10. The application according to claim 8, wherein the liposome composition comprises the cationic lipid dimethyl dioctadecylammonium bromide (DDA), monobranched acylglycerol-1 (MMG-1), and c-di-GMP.

11. The application according to claim 9, wherein the liposome composition comprises the cationic lipid dimethyl dioctadecyl ammonium bromide (DDA), monobranched acylglycerol-1 (MMG-1), poly(I:C), and c-di-GMP.

12. The application according to any one of the preceding claims, wherein the pathogenic infection is selected from viral infections and bacterial infections.

13. The application according to claim 12, wherein the pathogenic infection is a respiratory viral infection caused by a virus selected from parvovirus, rhinovirus, coronavirus, influenza virus, human parainfluenza virus, human respiratory syncytial virus, adenovirus, enterovirus and metapneumovirus.

14. The application according to claim 12, wherein the pathogenic infection is a bacterial infection of the respiratory tract caused by bacteria selected from Chlamydia pneumoniae, Streptococcus pneumoniae, Streptococcus pyrogenes, Haemophilus influenzae, Moraxella catarrhalis, and mycobacteria.

15. The application according to any one of claims 1-11, wherein monobranched acylglycerol-1 (MMG-1) is 2,3-dihydroxypropyl 3-hydroxy-2-tetradecyl-octadecanoate.

16. The application according to claim 1, wherein the liposome composition is administered via systemic administration, nasal administration, and / or pulmonary administration.

17. The application according to claim 16, wherein the liposome composition is administered simultaneously via systemic and nasal administration.

18. The application according to claim 16, wherein the liposome composition is administered via nasal and / or pulmonary administration after exposure to a pathogen to treat an early respiratory infection.

19. The application according to claim 16, wherein the liposome composition is administered via nasal and / or pulmonary administration to prevent respiratory tract infections.

20. The application according to any one of claims 16-19, wherein the liposome composition is applied two or three times a week.

21. The application according to any one of claims 16-19, wherein the subject is selected from humans of all ages, cynomolgus monkeys, rhesus monkeys, cattle, pigs, horses, sheep, goats, cats, dogs, or birds.

22. The application according to claim 21, wherein the subject is a human.

23. The application according to claim 21, wherein the subject is an individual with impaired or reduced airway immunity.

24. The application according to claim 21, wherein the subject suffers from a disease selected from chronic obstructive pulmonary disease, asthma, cystic fibrosis, lung cancer, and diabetes.

25. The application according to claim 22, wherein the subject has a history of smoking or is a current smoker.

26. A nasal delivery device comprising the liposome composition as described in any one of claims 1-11.

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