WO2021191904A1 - Méthodes de prévention et de traitement d'une infection virale - Google Patents

Méthodes de prévention et de traitement d'une infection virale Download PDF

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WO2021191904A1
WO2021191904A1 PCT/IL2021/050330 IL2021050330W WO2021191904A1 WO 2021191904 A1 WO2021191904 A1 WO 2021191904A1 IL 2021050330 W IL2021050330 W IL 2021050330W WO 2021191904 A1 WO2021191904 A1 WO 2021191904A1
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Prior art keywords
composition
virus
carrageenan
casein
lactoferrin
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PCT/IL2021/050330
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English (en)
Inventor
Keren Mevorat-Kaplan
Igal LIAPIS
Nir WOLFOVICH
Danny ROSENBAUM
Dadi Segal
Igor MAKAROVSKI
Meir Stern
Moshe Rubin
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Tree Of Life Pharma Ltd.
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Publication of WO2021191904A1 publication Critical patent/WO2021191904A1/fr

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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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/731—Carrageenans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention generally concerns methods for preventing and treating viral infections, and specifically viral infections related to acute respiratory syndrome, and more specifically infection with SARS-CoV-2 and variants thereof.
  • SARS-CoV-2 the causative agent of COVID-19 in humans is SARS-CoV-2, and the disease is predominantly transmitted by inhalation or contact with SARS-CoV-2 contaminated surfaces or contact with droplets from lung and nasal discharge of patients infected with SARS-CoV-2, with an incubation period of 2-14 days.
  • SARS-CoV-2 is also present in saliva of infected individuals, and that the viral levels in saliva are strongly indicative of a more severe disease.
  • the COVID-19 symptoms are complex. They usually include fever, dry cough, difficulty to breath, loss of smell, headache, fatigue, among others. While in most cases and especially in young patients the disease is mild or asymptomatic [1], in certain risk groups that are associated with age and comorbidities such as cardiovascular disease, diabetes, chronic respiratory disease and cancer the disease can progress to pneumonia, acute respiratory distress syndrome (ARDS), multi-organ dysfunction and even death. More recently with the emergence of new SARS-CoV-2 variants, severe presentations of COVID-19 and increased mortality have been observed outside those risk groups.
  • HSPGs cell surface heparan sulfates proteoglycans
  • HSPGs are highly sulfated and are composed of unbranched negatively charged heparan sulfate (HS) polysaccharides attached to a variety of cell surface or extracellular matrix proteins. Due to this property, HSPGs are broadly employed by a range of pathogens, and especially viruses, for cell entry. As a general concept, HSPGs serve as anchor sites that facilitate initial contact between a virus and host cells and assist in accumulation of viral particles on the cell surface [2, 3, 4].
  • lactoferrin a multifunctional protein that is present in external secretions, is an important host defense molecule during infant development.
  • Several mechanisms were suggested to explain its protective function, i.e., either by binding of lactoferrin to HSPGs and interfering with viral attachment [5] and/or by inhibiting viral replication and enhancing host immunity [6].
  • carrageenan a family of linear sulfated polysaccharides that are extractable from red edible seaweeds. It was shown that administration of carrageenan nasal spray in children and in adults suffering from virus- related common cold or influenza reduced the duration of disease, increased viral clearance and reduced relapses of symptoms [7].
  • the present invention essentially seeks to provide a quick and accessible solution to wide spread infections, such as COVID-19 and other airborne or waterborne viruses.
  • GMP Goat Milk Proteins
  • EXAMPLE 1 A specific example is shown in EXAMPLE 1, where GMP and lactoferrin interfered with the entry of SARS-CoV-2 pseudovirus into HEK293 cells (human embryonic kidney) in vitro , as reflected in the reduction or inhibition of the pseudovirus associated bioluminescence (see also Fig. 1). This can be explained by non-specific interaction of the viral spike (S) protein with HSPGs on the effector cells.
  • S viral spike
  • HSPGs facilitate the interaction between SARS-CoV-2 and its specific receptor, Angiotensin- Converting Enzyme 2 (ACE2), which is also expressed on the same cells.
  • ACE2 Angiotensin- Converting Enzyme 2
  • the SARS-CoV-2 spike protein can interact with both, the HSPGs and ACE2, and that HSPGs function either as adhesion molecules to facilitate viral attachment or as anchors to facilitate viral endocytosis via the specific receptor.
  • the protein fractions of bovine and goat milk are qualitatively similar. The main difference between the two resides in quantitative differences and the amounts of caseins.
  • the hypoallergenicity of goat milk has been related to low levels of asl-casein (asl-cn).
  • GMP are more digestible and have higher levels of 6 out 10 essential amino acids. Upon digestion or technological processing, GMP yield a unique composition of peptides that have been related to antimicrobial, immunomodulatory, antioxidant, antithrombotic, hypocholesterolemic and antiallergic activities. Caseins and lactoferrin are important components of GMP.
  • lactoferrin can inhibit internalization of certain viruses via non-specific binding to HSPGs, by attaching to the receptors and preventing subsequent binding of the vims.
  • lactoferrin can reduce the phenomenon known as cytokine storm via its inhibitory effect on the release of IL-6, a mediator of inflammation. Cytokine storm or hypercytokinemia is one of the main concerns in severe presentations of COVID-19.
  • Carrageenans offer yet another attractive candidate that can be obtained from a natural source.
  • Carrageenans have been related to inhibition of certain viral infection, one example is their protective effect against common cold influenza in children and adults.
  • carrageenans are obtained from a vegetable source, and exclusively from edible red seaweed commonly known as Irish Moss.
  • Carrageenans are also widely used in the food industry, mostly as thickeners and gelling agents.
  • the inventors have further hypothesized that all three actives are likely to act through non-specific interactions with viruses and/or effector cells.
  • Carrageenans are structurally similar to HS and are therefore likely to bind and interfere with viruses. More generally, the inventors hypothesized that that the protective effect of these actives against viral entry into the host could be generalized and applied to other RNA and DNA viruses, and potentially to viruses attached to non-biological surfaces.
  • compositions, methods and tools for administering GMP, lactoferrin and/or carrageenan(s) to mucosal tissues i.e., the respiratory, digestive, or reproductive mucosa, being the first target of the attachment and infection of viral pathogens.
  • compositions comprising combinations of GMP, lactoferrin and carrageenan.
  • Additional compositions are currently under development to include combinations with specific GMP components (e.g., specific types and proportions of caseins) and specific types of carrageenans (e.g., kappa-carrageenan).
  • the spray is formulated as a liquid and is converted to a gel upon contact with nasal mucosa. Special attention is given to the concentration of salts and pH as triggers to the conversion of the formulation from liquid to gel.
  • a mucoadhesive tablet for sublingual administration adapted for sustained or controlled release of actives (e.g., within the time span of 5 h).
  • This technology relies on previous experience of the inventor with formulations developed in the context of halitosis or aphthous stomatitis.
  • the formulation uses a surface carbomer component, owing to which the table adheres to the mouth mucosa.
  • Gelcarin carrageenan gel on the basis of Gelcarin carrageenan gel to include specific combinations of actives (e.g., types and proportions of caseins) and specific types of carrageenans (e.g., kappa-carrageenan).
  • compositions for decontamination of biological and non-biological surfaces (also medical and non-medical surfaces).
  • These compositions are formulated as a liquid or an aerosol, and are delivered via a dispenser, a nebulizer or an atomizer.
  • compositions of the invention e.g., nasal dispenser, or an inhaler or aspirator for upper respiratory airway.
  • the three main actives in the above composition are currently being tested for safety and cytotoxicity (see EXAMPLE 5). So far, all three actives have proven to be relatively safe in a form of a mucoadhesive film forming nasal spray. Additional clinical trials in humans are currently ongoing ( see EXAMPLE 6).
  • the invention provides a series of preventive and therapeutic tools for fighting against viral epidemics and pandemics, such as COVID-19 and epidemics of other viruses.
  • the main actives included in the compositions of the invention originate from natural sources, and therefore can be considered as relatively safe for application in the clinical as well as in-house settings.
  • compositions and methods of the invention can offer additional level of protection against the currently emerging and future variants, and the sole level of protection for the sub-groups and populations that cannot be vaccinated.
  • Fig 1 illustrates the inhibitory effect of GMP and lactoferrin on SARS-CoV-2 pseudovirus entry into HEK293 cells as revealed by the luciferase activity assay.
  • the actives are used in non-cytotoxic concentrations ( see Figs 2A-2B).
  • Figs 2A-2B illustrate studies of the cytotoxicity of GMP (2A) and lactoferrin (2B) in vitro using concentrations of actives as 0.1%, 1% and 5% (w/w).
  • Figs 3A-3C illustrate the inhibitory effect of GMP on the CoxA9 infection in BGM cells as revealed by the number of viral plaques in cells exposed to CoxA9 and GMP (3A), exposed to CoxA9 only (3B) negative controls (3C) plated on agar.
  • Figs 4A-4B illustrate direct interaction between GMP and HSV-1 viral particles as revealed by PTA staining and scanning in electron microscope of HSV-1 particles unexposed to GMP (4A) and exposed to GMP (4B).
  • the present invention can be articulated in terms of compositions and methods to provide preventive and therapeutic solutions for widespread infections of airborne and waterborne viruses, notable examples of which are respiratory viruses and viruses of the digestive system such as SARS-CoV-2, influenza and viruses associated with gastroenteritis in children and adults.
  • the invention provides compositions and methods using Goat Milk Protein (GMP), alone or in combination with carrageenan for interfering with viral interaction with or within a mucosal tissue in a mammalian respiratory, nasal, ocular, digestive, or reproductive tracts.
  • GMP Goat Milk Protein
  • composition and methods of the invention apply to human subjects.
  • 'interfering' or 'interference' as used herein imply a wide range of interactions between the actives and virus, which are not necessarily direct or specific and can involve interactions of the actives with the surface of mucosa cells via HSPGs or interaction of the actives with the virus via electrostatic forces.
  • the outcome of these interactions is a reduction in adhesion or binding of the vims to mucosa cells and a reduction in the density of the vims on the cell surface, and as a result, a reduction in the endocytosis and entry of the vims to the mucosa cells.
  • the spray produces a physical barrier that reduces or prevents the viruses from reaching the mucosa, and thereby reducing the adhesion or binding of the vims to the mucosa cells and reducing the density of the vims on the cell surface.
  • the reduction can be expressed in the terms of up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% reduction in the density of vims on the cell surface compared to the cells not exposed to these actives.
  • the same aspect can be further articulated as compositions and methods using Goat Milk Protein (GMP), alone or in combination with carrageenan for preventing and/or treating subjects at risk of being infected or already infected with the vims.
  • GMP Goat Milk Protein
  • the virus can be an RNA or DNA virus infecting and/or replicating in a mucosal tissue of the human respiratory, nasal, ocular, and digestive or reproductive tracts.
  • 'mucosal tissue' or 'mucous membrane' generally imply a layer of cells that surrounds body organs and body orifices. It is a protective epithelial layer containing or secreting mucus and line part of the body that exposed to external environment, and are at risk of being infected by pathogens such as bacteria or viruses.
  • mucous membranes or mucosa
  • mucosa lining the respiratory, nasal, ocular, digestive, or reproductive systems.
  • mucosa of the oral and nasal cavities mucosa of the eye or surrounding the eye
  • mucosa of the gut mucosa of the rectal or vaginal cavities
  • mucosa of the urogenital system mucosa of the urogenital system.
  • GMP herein encompass the sum total of all proteins that can be extracted from goat milk, irrespective of breed, origin and climate (e.g., Alpine La Mancha, Nubian, Saanen breeds) and irrespective of the extract method.
  • the total protein content in goat milk can vary (e.g., from 2.6 to 4.1 g/1).
  • GMP can be enriched in specific components or modified to include specific components in certain concentrations and proportions.
  • aSl -casein (asl-CN), aS2-casein (as2-CN), b-casein (b-CN), K-casein (K-CN), b- Lactoglobulin (b-LG), and a-lactalbumin (a-LA), with CNs constituting approximately 80% of the total milk protein fraction.
  • Goat milk is characterized in that it has a natural whey protein to CN ratio of about 20:80. Goat milk is further characterized in the absence or low levels of asl-CN, owing to which it is less allergenic than the cow milk. Table 1 below shows characteristic CN profiles in the cow and goat milk.
  • b-CN concentration of b-CN is 43% higher in goat milk than in cow milk, which has direct effect on b-CN recovery from GMP. Furthermore, b-CN can be extracted more efficiently from goat rennet casein. As a result, the extraction yield of b-CN can be increased up to 53% from goat milk relative to cow milk.
  • the at least one GMP in the compositions of the invention can be b-CN, alone or in combination with at least one another GMP.
  • compositions can be further enriched in b-CN to a concentration up to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% of the total CN content, or in the range of at least about 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100% of the total CN content.
  • //-CN can be isolated directly from renneted skim milk, based on the preferential solubilization thereof at low temperature.
  • the at least one GMP can be enriched in casein (asl-CN), aS2-casein (as2-CN), b-casein (b-CN), k-casein (K-CN), and sodium caseinate.
  • caseinate refers to the sodium salt of casein.
  • compositions of the invention can be further enriched in K-CN to a concentration up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100% of the total CN content.
  • compositions can be enriched in as2-CN to a concentration up to 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100% of the total CN content.
  • compositions can be enriched in asl-CN to a concentration up to 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100% of the total CN content. It should be noted that, in many cases, asl-CN is allergenic.
  • GMP profile can be further altered by respective extractions of GMP from various breeds. Genetic polymorphisms in different goat breeds have been related to various proportions and functional properties of CN fractions such as stability, solubility, and digestibility, e.g., asl-CN and K-CN. Additional modifications depend on post-translational modifications, such as glycosylation, phosphorylation, acetylation, and proteolytic cleavage. Additional important active in the compositions of the invention is lactoferrin. Lactoferrin herein refers to an iron-binding glycoprotein and is considered a major part of the non-specific disease resistance complex in the mammary gland.
  • Goat colostrum lactoferrin concentration is higher than in cow's milk, i.e., from 455 to 2058 mg/dl in goat colostrum vs. 575 mg/dl in bovine.
  • goat milk lactoferrin has been related to anticancer and antibacterial activities.
  • the lactoferrin in the compositions of the invention constitutes one of the components of GMP.
  • lactoferrin can be provided or supplemented from other sources, such as bovine and human sources.
  • lactoferrin in the compositions of the invention can vary depending on its origin, e.g., goat milk or colostrum, and can be enriched to a concentration up to 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% of the total GMP content, or in the range of at least about 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%- 70%, 70%-80%, 80%-90% and 90%-100% of the total GMP content.
  • compositions can comprise genetic variants of lactoferrin, depending on its origin, and lactoferrins with one or more post-translational modifications, such as glycosylation, phosphorylation, acetylation, and proteolytic cleavage.
  • the methods and compositions of the invention can comprise at least one GMP which is a casein or lactoferrin.
  • the methods and compositions of the invention can comprise at least one GMP which is a casein and lactoferrin.
  • the methods and compositions of the invention can comprise at least one GMP which is b-casein (b-CN) and lactoferrin either from goat and/or bovine source.
  • GMP which is b-casein (b-CN) and lactoferrin either from goat and/or bovine source.
  • carrageenan encompasses herein a family of linear sulfated polysaccharides having the general formula C 23 H 23 FN 4 0 7 Zn and molecular weight of 551.8 g/mol, and molecules referred to as Carrageenan MIV-150/ZA/CG MIV- 150/zinc acetate carrageenan 9000-07-1 zinc l-(5-cyano-2-pyridyl)-3-[(lS,2S)-2-(6-fluoro-2-hydroxy-3- propanoyl-phcnyljcyclopropylj urea diacetate .
  • This term further encompasses herein the three basic types of carrageenans: iota (i-), kappa (K-) and lambda (l-) carrageenans. Molecular structures of the three carrageenans are shown below.
  • the methods and compositions of the invention can comprise one or more carrageenans selected from iota-carrageenan, kappa- carrageenan and lambda-carrageenan.
  • the carrageenan is a heteropolymer (e.g., a carrageenan comprising subunits of at least two carrageenans selected from kappa-carrageenan, iota- carrageenan and lambda carrageenan).
  • a heteropolymer e.g., a carrageenan comprising subunits of at least two carrageenans selected from kappa-carrageenan, iota- carrageenan and lambda carrageenan.
  • a specific carrageenan can further depend on the application or formulation of the composition. In the presence of calcium, for example, i-carrageenan forms a soft gel and k-carrageenan forms a stiff and brittle gel, but in the presence of potassium salts, k-carrageenan forms very firm and elastic gels.
  • Potassium and calcium ions are present in certain concentrations in nasal mucosa. Therefore, in certain embodiments and especially applications involving administering into the nasal cavity can use kappa-carrageenan. Yet in other embodiments the methods and compositions of the invention can use i-carrageenan.
  • carrageenan is in the form of a salt.
  • Carrageenans are negatively charged molecules and have tendency to react with positively charged ions, e.g., potassium, to form salts.
  • compositions and methods of the invention provide prevention and/or treatment of viral infections.
  • the term 'prevention and/or treatment of viral infection' encompasses prevention of inhibition of the attachment of virus to mucosal cells and thereby prevention or inhibition of virus entry into the cells. It further implies minimizing replication of the virus in the host cells and inhibiting viral titer in the body, and ultimately reducing the manifestation of symptoms of viral infection and infectivity of the treated individual.
  • Such prevention and/or treatment can be measured basing on direct measurements of the viral titer in the serum or blood, or in mucosal discharges of affected individuals, and by assessment of clinical symptoms of viral infection as per clinical criteria.
  • Viral titer can be further correlated to additional diagnostic indices obtained by molecular testing for the vims, specific viral antigens and specific antibodies, using PCR, RT-PCR, serological tests.
  • compositions and methods of the invention are apparent by the reduction of viral titer or respective correlates up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 100% of the initial level in the same individual (i.e., the level before treatment).
  • compositions and methods of the invention are apparent by the reduction of clinical symptoms of infection up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% of the initial severity, number and/or recurrence of symptoms in the same individual.
  • the prevention and/or treatment effects of the compositions and methods of the invention are apparent by the reduction of viral titer or its correlates or clinical symptoms of the infection in a population-based sample up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% of their respective or average values in the population sample infected with the vims.
  • compositions and methods of the invention can be applied to a naive (or healthy) population, i.e., non-infected individuals who are at risk of being infected due to general prevalence of the infection in the same population.
  • compositions and methods of the invention are apparent by comparing the viral titer or its correlates or clinical symptoms of the infection in treated population group vs. untreated groups, yielding up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% reduction of their respective or average values.
  • this application can reduce the risk of being infected up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% in a naive uninfected individual or a population.
  • this application can reduce the risk of transmitting infection up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100% to another naive uninfected individual or a population.
  • RNA or DNA viruses that are infecting and/or replicating in a mucosal tissue of the human respiratory, nasal, ocular, and digestive or reproductive tracts.
  • the methods and compositions of the invention are applicable to respiratory viruses, or viruses or replicating in mucosal tissue of the human respiratory, nasal, ocular tracts.
  • Respiratory viruses are usually transmitted through direct contact with an infected person, contact with contaminated mucosal discharges or droplets. These viruses are usually airborne, notable examples are influenza and coronaviruses.
  • the respiratory viruses apart from adenovirus Human bocavirus (HboV), have an RNA genome.
  • the rhinovirus and adenovirus are non-enveloped viruses, while the other are enveloped viruses that belong to several different families, i.e., orthomyxoviruses, paramyxoviruses, and coronaviruses.
  • orthomyxoviruses influenza is the only member
  • respiratory viruses are quite different in their structure and genome, the feature that unites all these viruses is their ability to infect mucosal cells of the respiratory tract and cause clinical symptoms in humans. Certain prominent respiratory viruses are shown in Table 2 below.
  • Diagnosis and identification of specific viruses can be made with a high degree of confidence and specificity using various PCR-based assays on respiratory secretions.
  • composition and methods of the invention are applicable to respiratory viruses belonging to members of families Orthomyxoviridae, Paramyxoviridae, Picornaviridae, Coronaviridae , Parvoviridae or Adenoviridae .
  • composition and methods of the invention can be applicable to viruses diagnosed as an Influenza vims, a Respiratory syncytial virus (RSV), an Enterovirus, a Coronavirus, an Adenovirus, a Human bocavirus (HBoV).
  • RSV Respiratory syncytial virus
  • HBV Human bocavirus
  • composition and methods of the invention can be applicable to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This type of applications has been presently exemplified ( see EXAMPLE 1).
  • SARS-CoV-2' encompasses herein the entire range of viral mutants and variants that have been identified so far, as well as future variants with respect to the four structural proteins of SARS-CoV-2 (S, E, M, and N) and 16 non- structural proteins (Nspl-16, e.g., Nspl mediates RNA processing and replication, Nsp2 modulates the survival signaling pathway of host cell, Nsp3 is believed to separate the translated protein).
  • This term further encompasses variants with mutations in the intergenic and regulatory regions.
  • composition and methods of the invention can be applicable to Coxsackieviruses. This type of applications has been presently exemplified ( see EXAMPLE 3).
  • compositions and methods of the invention can be effective against other viruses that have propensity to adhere to other mucosal tissues, such as mucosa of the gut and digestive system.
  • compositions and methods of the invention can be effective against viruses of digestive system or viruses causing acute gastroenteritis. This type of infections is particularly prevalent in children. They are transmitted either through direct contact with contaminated surfaces or through contaminated food.
  • viruses are waterborne.
  • compositions and methods of the invention can be applicable to viruses from families Reoviridae, Caliciviridae, Coronaviridae or Astroviridae .
  • SARS-CoV-2 is also relevant as gastrointestinal symptoms have been observed in certain patients with COVID-19. Further, specific staining of viral nucleocapsid protein was detected in gastric, duodenal, and rectal epithelia cells.
  • compositions and methods of the invention are applicable to SARS-CoV-2 infections in the gastrointestinal tract.
  • compositions of the invention can further comprise carriers, excipients and additives to improve performance and effectiveness of actives.
  • the invention to provides compositions and methods for interfering with viral interaction with biological and non-biological surfaces (also medical and non-medical surfaces.
  • This specific aspect can be further articulated in the sense of interfering with the attachment of the virus to at least one biological or non-biological surface in a medical or non-medical setting.
  • compositions of the invention with GMP, CN, lactoferrin and/or carrageenan can act as natural decontaminants applied to biological as well as non-biological surfaces.
  • compositions and methods of the invention can be applied to the skin of a subject or a part thereof.
  • compositions and methods of the invention can be applied to any surface in a healthcare facility or a part thereof.
  • compositions and methods of the invention can be applied to any surface of a medical instrument or a part thereof.
  • compositions and methods of the invention can be applied to non-medical instruments, or any surface in a house, a vehicle or an office.
  • compositions can be formulated to be applicable onto solid surfaces and sanitary items in order to decrease transmission and reduce viral spread via, e.g., hand-to-hand contact (e.g., embedded in wipes, gloves, hygiene tissues, nasal tissues and handkerchiefs).
  • hand-to-hand contact e.g., embedded in wipes, gloves, hygiene tissues, nasal tissues and handkerchiefs.
  • compositions can be formulated to be applicable onto any part of the human skin.
  • the compositions can be formulated as an ointment, lotion, cream, or wipes to provide a topical barrier that inhibits attachment of the virus to the skin.
  • compositions can be formulated to be applicable to a surface of medical instruments.
  • medical instruments include surgical instruments (e.g., forceps), medical imaging machines, infusion pumps, life support equipment (e.g., respirators, ventilators), medical lasers, medical laboratory equipment, medical monitors, stethoscopes, defibrillators, sterilization trays and hospital racks.
  • life support equipment e.g., respirators, ventilators
  • medical lasers e.g., medical laboratory equipment
  • medical monitors e.g., stethoscopes
  • defibrillators sterilization trays and hospital racks.
  • An exemplary use of such compositions is for disinfecting life support equipment prior to use in a hospital or clinic, e.g., such that viruses can be wiped off with the herein described compositions.
  • compositions can be formulated to be applicable to a surface of non-medical instruments.
  • non-medical instruments include house and garden furniture, kitchenware, cabinets and bookshelves, trash cans, recycling baskets, magazine and coat racks, lamps and lighting equipment, doorknobs, handrails, elevator switches and public transformation vehicles.
  • composition encompasses composite compositions and formulations comprising therapeutically effective amounts of actives of the invention (e.g., GMP, CN, lactoferrin and/or carrageenan), and optionally other suitable additives such as diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
  • actives of the invention e.g., GMP, CN, lactoferrin and/or carrageenan
  • suitable additives such as diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
  • compositions may be liquids or semi solids lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g., Tris-HCl, acetate, citrate, phosphate, Sorenson’s Phosphate Buffer, borate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, Pluronic 127, bile acid salts), solubilizing agents (e.g., tween 80, glycerol, propylene glycol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, m-cresol, benzyl alcohol, parabens, phenethyl alcohol, caprylyl glycol), flavoring (e.g., menthol, lemon) when the composition is in
  • Gellan gum herein refers to a water- soluble anionic polysaccharide produced by the bacterium Sphingomonas elodea. It is typically used as a food additive for binding, stabilizing and texturing purposes.
  • Mucoadhesive properties of Gellan gum have been previously suggested on the basis of studies of nasal spray formulations containing Gellan gum. It has been shown that such formulations have a viscosity sufficient to spray out from the device and elasticity great enough to adhere to the mucosal membrane.
  • Various modifications of Gellan gum may further increase the adherence time on mucosal surfaces, and the overall retention of the drugs at the site uptake.
  • the compositions of the invention can be formulated with Gellan gum. This type of formulation is particularly applicable to nasal spray of the invention.
  • formulations with Gellan gum can provide controlled release of the actives (see below).
  • compositions are pharmaceutical composition in a form suitable for administration to a human subject.
  • compositions of the invention are formulated as a liquid or an aerosol, and are delivered via an aerosol dispenser, a nebulizer, an atomizer.
  • Aerosol herein encompasses a suspension of fine solid particles or liquid droplets in air or another gas. Aerosols can be natural or anthropogenic. Examples of natural aerosols are fog, mist, dust, forest exudates and geyser steam.
  • the choice of pharmaceutically acceptable carriers comprised in the nasal and oral dosage form of the composition depends upon the exact formulation, e.g., an emulsion, a solution, a suspension, an ointments/lubricant or a gel.
  • compositions of the invention can be adapted for various applications, i.e.: administered orally (e.g., via a lozenge, troche or a gargle solution), nasally (e.g., via drops, lubricant, viscous gel, irrigation, nebulizer aerosol, spray), into the eye (e.g., via drops or ointment), buccally, vaginally or rectally (e.g., using a suppository).
  • the composition may be formed as a nasal spray, an aerosol, nasal drops, a nasal irrigation or a nasal lubricant (e.g., gel).
  • compositions are administered into the oral cavity or oral mucosa in the form of a lozenge, troche, a tablet or a mucoadhesive tablet.
  • a lozenge, troche, a tablet or a mucoadhesive tablet Such forms can be further presented as chewable lozenge, troche, a tablet and can further comprise one or more sweeteners, flavorings, or physical binders.
  • lozenge and troches can comprise the active ingredient, a flavor, a sweetener as sucralose or xylitol or mannitol or sucrose.
  • Pastilles or a mucoadhesive tablets can comprise active ingredient in an inert base, such as gelatin and glycerin, or sucralose or xylitol or mannitol sucrose and, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • Lozenges and troches provide an efficient mucosal delivery mode for the composition's constituents (GMO, CN, lactoferrin and/or carrageenan) which enable attachment of the constituents to the oral mucosal surface.
  • compositions are administered into the nasal cavity or nasal mucosa in the form of a nasal spray, nasal drops, a nasal viscous gel, a nasal ointment, nasal powder a nebulizer or an aerosol.
  • compositions are administered into the eye.
  • Ocular delivery of the composition of the present invention may be carried out using suitable mode, such as topical administration (e.g., using drops, viscous solution, gel or an ointment), periocular administration, tissue specific microinjection, intraorbital administration or intravitreal injection.
  • suitable mode such as topical administration (e.g., using drops, viscous solution, gel or an ointment), periocular administration, tissue specific microinjection, intraorbital administration or intravitreal injection.
  • compositions are formulated as a liquid, a semiliquid, a solid, a powder, an ointment, a gel.
  • the appropriate dosages of the composition of the present invention are administered to human subjects that are at risk of being infected with a vims (e.g., by either nasal spray or oral lozenge).
  • the term 'therapeutically effective dose' to an amount or a concentration of active that induces the desired clinical effect or change in the relevant clinical condition as measured by respective definition criteria.
  • the term applies to viral titer or its correlates or clinical symptoms of the respective viral infection.
  • a therapeutically effective dose can be determined using 'trial-and-error' considering, apart from the amount actives, also age, weight, health condition, sex, diet of individual patient. This constitutes a personalized approach.
  • a therapeutically effective dose can be determined on populational basis in human clinical trials.
  • the oral composition and methods of the invention are meant to provide sustained or controlled release of actives.
  • the terms 'controlled release', 'sustained release' or 'modified release' generally relate to tailor-made formulations designed to release a drug at a predetermined rate. This kind of properties can be provided by various types of coating and additives.
  • controlled release can be achieved by dissolution-mediated controlled release formulations, including reservoir and matrix types.
  • Matrix dissolution systems are the most used technique with the active being homogeneously distributed throughout a polymer matrix. As the polymer matrix dissolves (typically via an erosion-mediated process), drug molecules are released into the external environment. In this system, the size of the formulation (and hence matrix) decreases over time, thereby resulting in a non-linear drug release.
  • Reservoir systems involve a drug core that is coated with a rate-limiting polymer. Using this system, drug release is determined by the thickness and the dissolution rate of the polymer membrane surrounding the drug core. Once the coated polymer membrane dissolves, the drug will be released similarly to an immediate release preparation.
  • compositions of the invention can comprise coating with hydroxypropyl methylcellulose (HPMC) polymer.
  • HPMC hydroxypropyl methylcellulose
  • the invention provides a kit comprising the compositions of invention and instructions of use.
  • the kit of the invention comprises at least one GMP, alone or in combination with carrageenan.
  • the kit can comprise at least one GMP that is CN and/or lactoferrin and/or at least one carrageenan.
  • casein generally refers to a phosphoprotein that is commonly found in mammalian (e.g., cow, goat, sheep, or buffalo) milk.
  • CN may be a genetic variant of b-CN and may also be in the form of sodium caseinate.
  • the casein comprises at least one CN selected from aSi- CN, aS 2 -CN, b-CN and k- CN.
  • the CN is a CN derived from goat milk.
  • lactoferrin generally refers to a multifunctional protein of the transferrin family that is a globular glycoprotein with a molecular mass of about 80 kDa and which is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin can be isolated from mammalian (e.g., goat, sheep, buffalo) milk or produced by recombinant methods.
  • mammalian e.g., goat, sheep, buffalo
  • the components of the present composition may act synergistically to prevent, mitigate, or decrease symptoms of viral infection.
  • synergistic effect in the combination of CN, lactoferrin and/or carrageenan included in the present compositions or formulations may or may not be dose dependent.
  • kit can include containers such as vials, bottles, cans, pressurized cans, dispenser, packages, compartments or others, for preserving and storing the compositions of the invention in predetermined amounts and forms.
  • the containers e.g., nasal spray, aerosol
  • the composition can be dispensed in a spray liquid or solid, an aerosol, or in a liquid form or semi-solid form.
  • the containers can have spray, pump, or squeeze mechanisms.
  • the instructions for use may include variations that can be implemented and explanations on how to apply the compositions and the components of kit (e.g., apply the drops or nasal spray into the nostrils or eyes).
  • a device for mucosal delivery of the present compositions include, although non-limited to, aerosol dispensers, nebulizers and atomizers for formulations to be applied to nasal and oral mucosa. Additional examples can include specific applicators to the eye.
  • the study used the pseudovirus luciferase platform designed for SARS-CoV-2 with pseudovirus particles expressing the viral spike (S) protein and the luciferase bioluminescence assay in HEK293 (human embryonic kidney) effector cells.
  • HEK 293T cells were seeded at 50% confluency in a flat 96 well plate.
  • SARS-CoV-2 pseudoviruses (5 ⁇ l per well, Cat# 79992-1 BPS Bioscience) were incubated with 1% GMP or 0.1% lactoferrin in PBS (w/w) or control (PBS only) for 30 min. Following incubation, the mixture was added to the HEK 293T cells.
  • luciferase luminescence values are shown in Fig. 1 and Table 3 below.
  • the pseudovirus SARS-CoV-2 particles express the viral spike (S) protein.
  • HEK293 cells express HSPGs and Angiotensin-Converting Enzyme 2 (ACE2) cell surface receptors.
  • ACE2 was proposed as a receptor for HCoV-NL63, another type of human coronavirus known since 2004, and more recently, a receptor for the new SARS-CoV-2.
  • the SARS-CoV-2 spike protein interacts with both, HSPGs and ACE2, and HSPGs function either as adhesion molecules to facilitate binding of the virus or as anchors to facilitate viral endocytosis via its specific receptor.
  • GMP and lactoferrin have demonstrated significant inhibition effect on the SARS- CoV-2 pseudovirus entry into HEK293 cells. Irrespective of the mechanism of action, these actives proved to be successful candidates for inhibiting SARS-CoV-2 infection.
  • Cytotoxic effect of GMP and lactoferrin was studied in HEK293 cells.
  • the actives were tested in serial concentrations in using PBS.
  • HEK 293T cells were seeded in a flat 96 well plate to the density of 30,000 cells per plate. The experiment was performed in triplicates.
  • GMP and lactoferrin can be considered relatively safe up to the concentrations of 1% and 0.1% (w/w). Antiviral effects of the two actives at the same concentrations were demonstrated in EXAMPLE 1 above.
  • BGM African green monkey
  • Coxsackievirus a9 Cox A9
  • BGM cells were plated on agar plates and cultured until creating a uniform layer. Cells were incubated with Cox A9 (100 pfu) with and without 50% GMP for 1 h at 37°C. Cells were washed and incubated at 37°C, 5% CO 2 for 72 h until plaques were visible.
  • HSV viral particles were concentrated 10 min at 1000 rpm in 4°C, twice, separated by ultracentrifugation for 2 h at 6000 rpm at 4°C. Concentrated virus was incubated with and without 50% GMP for 45 min at 37 °C. Samples were stained with PTA negative staining and studies under Transmission Electron Microscope (TEM) under magnification X 40,000. Results
  • Two prototype formulations have been developed to include the actives of the invention, i.e., GMP, lactoferrin and carrageenan: i. Nasal spray containing mucoadhesive liquid formulations with the respective actives. Upon contact with nasal mucosa, the liquid formulation is converted to a gel, thereby producing a protective layer inside the nasal cavity and inhibiting viral entry.
  • the currently developed formulations contain GMP, lactoferrin and carrageenan as a compound active in various concentrations. Additional formulations are under development.
  • Film forming nasal spray stock 20% solution was prepared by dissolving 2 mL of Film Forming Nasal Spray in 8 mL PBS. The stock was serially diluted to 10, 5, 2.5, 1.25, 0.625, 0.312, 0.156% in culture media. The stock and the dilutions were tested.
  • Vehicle control stock was prepared in culture media (MEM, 10% HS) and PBS in 1:1 ratio was used as the vehicle control.
  • Positive control stock was prepared in DPBS. 2mg/mL solution was prepared by diluting 0.5 mL stock in 5.0 mL culture media (2.0 mg/mL final). Concentrations of 0.0062, 0.0125, 0.025, 0.050, 0.075, 0.1, 0.15 and 0.2 mg/mL were prepared in diluent media maintaining a final DMSO concentration at 0.5%. Seeding cells (Day 1)
  • Cells were removed by trypsinization, centrifuged at 1000 rpm for 5 min and re- suspended in culture medium. Cell concentration was adjusted to lxlO 5 cells/mL. 100 ⁇ L culture medium was added into the peripheral wells of a 96-well microtiter plate. 100 ⁇ L cell suspension was added to the wells subjected to the treatment and controls. Cells were incubated for 24 h (5% CO2, 37°C) to form a half-confluent monolayer. Samples were tested in triplicates.
  • Relative cell viability was calculated as a percentage of vehicle control.
  • Patients are being treated with daily administration of the Film Forming Nasal Spray (4 times) per day and GMP sustained release tablets (2 times, every 12 h) during the period of 1 month. Patients are subjected to medical evaluation every 10 days. The severity of symptoms is scored from 0 to 5 (from the lowest to the most severe symptoms). There is no control group.
  • Findings of reduction of symptoms can be indicative as to the therapeutic effect of the Film Forming Nasal Spray and the GMP sustained release tablet on the progression of disease in patients with COVID-19.
  • the invention provides a method for prevention and treatment of viral infection caused by a respiratory virus selected from coronaviridae/corona-virus, orthomyxoviridae, paramyxoviridae Coxsackie family of viruses and adenoviridae family in a subject in need thereof or who is at risk of being infected with the virus, the method comprising administering to a mucosal tissue or a membrane of the subject a composition comprising at least one casein, alone or in combination with at least one lactoferrin and/or at least one carrageenan, and a pharmaceutically acceptable carrier.
  • a respiratory virus selected from coronaviridae/corona-virus, orthomyxoviridae, paramyxoviridae Coxsackie family of viruses and adenoviridae family in a subject in need thereof or who is at risk of being infected with the virus
  • the composition is administered into the oral cavity of a human subject in the form of a lozenge, troche or mucoadhesive tablet.
  • the composition is administered into the nasal cavity of a human subject in a form of a nasal spray, nasal drops, a viscous gel, a nasal ointment, a nasal powder, a nebulizer or an aerosol.
  • the composition is administered into the eye in the form of drops, a viscous solution, a gel or an ointment.
  • the invention provides a composition comprising at least one casein, alone or in combination with at least one lactoferrin and at least one carrageenan for use in prevention and treatment of viral infection in a subject in need thereof or at risk of being infected with the virus, wherein the vims is selected from coronaviridae/corona- virus, orthomyxoviridae, paramyxoviridae Coxsackie family of viruses and adenoviridae family.
  • composition of the invention can be used in preventing infection of coronavirus.
  • the coronavirus is a COVID-19 causing pathogen.
  • the COVID-19 causing pathogen is SARS-CoV-2.
  • the at least one casein comprised in the composition of the invention is selected from al casein, ab -casein, aS2-casein, b casein, k-casein and sodium caseinate.
  • the composition of the invention comprises a mammalian milk comprising the lactoferrin and casein portion of the composition.
  • the mammalian milk in the composition is goat milk.
  • the carrageenan comprised in the composition of the invention is kappa-carrageenan.
  • the carrageenan is provided in the form of a salt.
  • the invention provides a composition comprising at least one casein, alone or in combination with at least one lactoferrin and at least one carrageenan for use in preventing the attachment of a vims selected from coronaviridae/coronavirus, orthomyxoviridae, paramyxoviridae and adenoviridae family onto a variety of medical or non-medical surfaces.
  • the medical surface to which the composition is applied is any part of a skin of a subject.
  • the medical surface is a surface of a medical instrument.
  • the medical surface is a surface of a non-medical instrument.
  • compositions of the invention that are used for clinical purposes in humans.

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Abstract

La présente invention concerne des méthodes, des compositions et des outils pour prévenir et traiter des infections virales, et spécifiquement des infections virales provoquées par un syndrome respiratoire aigu sévère, et plus spécifiquement une infection par le SARS-CoV-2 humain, ses variants et des virus apparentés.
PCT/IL2021/050330 2020-03-26 2021-03-24 Méthodes de prévention et de traitement d'une infection virale WO2021191904A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP4260869A1 (fr) * 2022-04-11 2023-10-18 Reckitt Benckiser Health Limited Composition comprenant une combinaison de lactoferrine et un polysaccharide sulfaté
WO2023198611A1 (fr) * 2022-04-11 2023-10-19 Reckitt Benckiser Health Limited Composition comprenant une association de lactoferrine et d'un polysaccharide sulfaté
GB2619403A (en) * 2022-04-11 2023-12-06 Reckitt Benckiser Health Ltd Composition comprising a combination of lactoferrin and a carrageenan

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