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WO2023003406A1 - Composition pharmaceutique comprenant une cellule dendritique immunotolérante exprimant clec5a ou une culture de celle-ci pour la prévention ou le traitement d'une maladie dégénérative du cerveau - Google Patents

Composition pharmaceutique comprenant une cellule dendritique immunotolérante exprimant clec5a ou une culture de celle-ci pour la prévention ou le traitement d'une maladie dégénérative du cerveau Download PDF

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WO2023003406A1
WO2023003406A1 PCT/KR2022/010738 KR2022010738W WO2023003406A1 WO 2023003406 A1 WO2023003406 A1 WO 2023003406A1 KR 2022010738 W KR2022010738 W KR 2022010738W WO 2023003406 A1 WO2023003406 A1 WO 2023003406A1
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dendritic cells
immune
disease
tolerant
pharmaceutical composition
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Korean (ko)
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임대석
최소연
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Pharos Vaccine Inc
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Pharos Vaccine Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/19—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/22—Immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/414—Nervous system antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/204—Animal extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule

Definitions

  • compositions for the prevention or treatment of degenerative brain diseases comprising CLEC5A-expressing tolerant dendritic cells or a culture thereof.
  • Parkinson's disease is a degenerative disease of the nervous system caused by the loss of dopamine neurons.
  • Currently a lot of research is being conducted, but so far it is only a temporary treatment and there is no fundamental treatment.
  • Recently, studies on the effect of neuroinflammation on exacerbation of Parkinson's disease are being conducted, and control of neuroinflammation using immune-tolerant dendritic cells is expected as a new strategy for the treatment of Parkinson's disease (Korean Registered Patent No. 10-2195895).
  • dendritic cells are professional antigen presenting cells (APCs) that provide antigen information to other cells of the immune system, and are cells that play a pivotal role in immune regulation as well as induction of initial immunity.
  • APCs professional antigen presenting cells
  • mDC mature dendritic cells
  • tDC tolerogenic DC
  • One aspect is to provide a pharmaceutical composition for the prevention or treatment of degenerative brain diseases comprising immune-tolerant dendritic cells or a culture thereof.
  • Another aspect is to provide a health functional food for preventing or improving degenerative brain diseases including immune-tolerant dendritic cells or their culture.
  • Another aspect is to provide a method for preventing or treating a degenerative brain disease comprising administering immune-tolerant dendritic cells or a culture thereof to a subject in need thereof.
  • One aspect relates to a pharmaceutical composition for the prevention or treatment of degenerative brain diseases comprising immune-tolerant dendritic cells or a culture thereof.
  • dendritic cell refers to a specialized antigen-presenting cell that takes up antigens into the cell, processes them, and presents antigens or peptides derived from antigens together with MHC (major histocompatibility complex) class I complexes or MHC class II complexes. (professional antigen presenting cell).
  • the dendritic cells include both immunogenic and tolerogenic antigen presenting cells, and depending on the degree of maturity, immature dendritic cells ("imDC”), semi-mature dendritic cells (semi-mature dendritic cells; " smDC”) and mature dendritic cells (“mDC”).
  • implant dendritic cells do not express cell surface markers such as CD14 like mature dendritic cells, express low levels of CCR7 and the cytoplasmic protein DC-LAMP, and express low levels of the costimulatory molecules CD40, CD80 and CD86. and dendritic cells expressing CD1a and CCR1, CCR2, CCR5 and CXCR1 at normal levels.
  • mature dendritic cells refers to cells formed by maturation of immature dendritic cells.
  • Mature dendritic cells show increased expression of MHC class II, CD40, CD80, CD83 and CD86 as well as DC-LAMP, release proinflammatory cytokines, and primitive homologous cells in a mixed lymphocyte reaction. It is characterized by having the ability to cause increased proliferation of allogeneic T cells and syngeneic T cells and/or increased production of dendritic cell cytokines.
  • Mature dendritic cells typically express high levels of CCR7 and CXCR4.
  • immuno-tolerant dendritic cell refers to a dendritic cell that has lost some of the characteristics of an immature dendritic cell and possesses some characteristics of the phenotype of a mature dendritic cell, partially or incompletely mature morphology and phenotypic Dendritic cells that exhibit characteristics. Immune-tolerant dendritic cells generally have the ability to induce tolerogenic responses in response to self-antigens.
  • culture refers to a cultured strain and a culture result when a strain is cultured in a culture medium isolated from the outside.
  • the immune tolerant dendritic cells may mean semi-mature dendritic cells (smDC).
  • the immune-tolerant dendritic cells may be prepared by inducing differentiation of immature dendritic cells, and specifically, may be prepared by culturing immature dendritic cells in the presence of a suitable cytokine.
  • the immune-tolerant dendritic cells may express CLEC5A, and may overexpress CLEC5A compared to immature dendritic cells, mature dendritic cells, or parental cells.
  • the immune-tolerant dendritic cells may have altered surface antigen molecule expression and cytokine secretion compared to mature dendritic cells. Specifically, the expression of at least one protein selected from the group consisting of CD40, CD54, CD80 CD86, IL-12p40, IL-1 ⁇ , TNF- ⁇ and IL-6 may be reduced, and the expression of IL-10 may be decreased. The expression of CD40, CD54, CD80, CD86, IL-12p40, IL-1 ⁇ , TNF- ⁇ , and IL-6 are all decreased, and the expression of IL-10 is increased, compared to mature dendritic cells. it could be
  • the immune-tolerant dendritic cells may not increase the proliferation of T cells more than mature dendritic cells, or may regulate the proliferation of helper T cells compared to mature dendritic cells.
  • the immune-tolerant dendritic cells may inhibit the proliferation of at least one T cell selected from the group consisting of Th1 (IFN- ⁇ + / CD4 +) and Th17 (IL-17A + / CD4 +) compared to mature dendritic cells, , Th2 (IL-4 + / CD4 +) and Treg (Foxp3 + / CD4 + CD25 +) may induce the proliferation of at least one T cell selected from the group consisting of, preferably Th1 (IFN- ⁇ + / CD4 + ) and Th17 (IL-17A+/CD4+) proliferation, and Th2 (IL-4+/CD4+) and Treg (Foxp3+/CD4+CD25+) proliferation may be induced.
  • the immune-tolerant dendritic cells may change cytokine secretion of T cells compared to mature dendritic cells.
  • the immune-tolerant dendritic cells may be those that reduce the expression of IFN- ⁇ in T cells compared to mature dendritic cells, and may increase the expression of TGF- ⁇ , preferably T cells compared to mature dendritic cells. The expression of IFN- ⁇ may be decreased and the expression of TGF- ⁇ may be increased.
  • the immune-tolerant dendritic cells may have a change in the degree of phosphorylation of signaling proteins inside the cells.
  • the immune-tolerant dendritic cells may have NF- ⁇ B phosphorylation inhibited compared to immature dendritic cells, mature dendritic cells, or parental cells, and phosphorylation of at least one protein selected from the group consisting of STAT3 and Syk may be increased.
  • NF- ⁇ B phosphorylation is inhibited, and both STAT3 and Syk phosphorylation are increased compared to immature dendritic cells, mature dendritic cells, or parental cells.
  • the immune-tolerant dendritic cells may have increased expression of DAP12 compared to immature dendritic cells, mature dendritic cells, or parental cells, and may have increased phosphorylation of Syk as the expression of DAP12 increases.
  • Immune-tolerant dendritic cells may exhibit immuno-tolerant characteristics as the expression of CLEC5A is increased compared to immature dendritic cells, mature dendritic cells, or parent cells, and may specifically exhibit an effect of preventing or treating degenerative brain diseases. .
  • prevention may refer to any activity that suppresses or delays the onset of a degenerative brain disease of a subject by administration of a pharmaceutical composition according to one aspect.
  • treatment may refer to any activity that improves or beneficially changes the symptoms of a degenerative brain disease of an individual by administration of a pharmaceutical composition according to one aspect.
  • the pharmaceutical composition may be provided as a pharmaceutical composition including the active ingredient alone or including one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the carrier may be, for example, a colloidal suspension, powder, saline solution, lipid, liposome, microspheres or nano-spherical particles. They may be complexed with or associated with the delivery vehicle and are known in the art such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation reagents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances or fatty acids. It can be delivered in vivo using known delivery systems.
  • the pharmaceutical composition When the pharmaceutical composition is formulated, it is prepared using diluents or excipients such as commonly used lubricants, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc.
  • Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and such solid preparations may contain at least one excipient in the composition, for example, starch, calcium carbonate, sucrose ) or by mixing lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid preparations for oral use include suspensions, solutions for oral use, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to water and liquid paraffin, which are commonly used simple diluents.
  • Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • suppositories As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycero-geratin, etc. may be used, and when prepared in the form of eye drops, known diluents or excipients may be used. there is.
  • the pharmaceutical composition may further include a pharmaceutical composition for preventing or treating other degenerative brain diseases.
  • the pharmaceutical composition may further include a conventionally known composition for preventing or treating a degenerative brain disease or a newly developed composition for preventing or treating a degenerative brain disease, and may be provided as a mixture thereof.
  • the pharmaceutical composition further includes a composition for preventing or treating other degenerative brain diseases, it is important to mix the amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art. .
  • the pharmaceutical composition further includes a composition for preventing or treating other degenerative brain diseases
  • a synergistic effect in which the preventive or therapeutic effect of degenerative brain diseases becomes more remarkable than when only the immunotolerant dendritic cells are included as an active ingredient is expected.
  • the pharmaceutical composition may be administered alone or in combination with a composition for preventing or treating other degenerative brain diseases.
  • the composition for preventing or treating other degenerative brain diseases may be a conventionally known composition for preventing or treating a degenerative brain disease or a newly developed composition for preventing or treating a degenerative brain disease.
  • the pharmaceutical composition may be administered in parallel with other compositions for preventing or treating degenerative brain diseases, simultaneously, separately, or sequentially, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • administration refers to introducing a predetermined substance into an object by an appropriate method
  • subject refers to all organisms such as rats, mice, livestock, and the like, including humans that may have degenerative brain diseases. As a specific example, it may be mammals including humans.
  • the pharmaceutical composition may be administered orally or parenterally, and in the case of parenteral administration, external skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraarterial injection, intramedullary injection, intracardiac injection , Intrathecal injection, transdermal injection, intranasal injection, intraenteric injection, local injection, sublingual injection, intrarectal injection, or intrathoracic injection can be selected.
  • the pharmaceutical composition is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the type and severity of the patient's disease, the activity of the drug, and the drug. sensitivity, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitantly used drugs, and other factors well known in the medical field.
  • the pharmaceutical composition may be administered at 0.001 to 1000 mg/kg/day, more specifically at 0.1 to 100 mg/kg/day. The administration may be administered once a day or divided into several times.
  • the degenerative brain disease is a disease caused by the death of the brain nerve cell, which is most important for the transmission of information in the brain nervous system, a problem in the formation or function of a synapse that transmits information between the brain nerve cell and the brain nerve cell, and an ideal symptom or decrease in the electrical activity of the brain nerve. it means.
  • the degenerative brain disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic sclerosis, Creutzfeldt-Jakob disease, stroke, stroke, dementia, multiple sclerosis, mild cognitive impairment, cerebral Amyloid angiopathy, Down syndrome, amyloidogenic stroke, systemic amyloid disease, Dutch-type amyloidosis, Niemann-Pick disease, senile dementia, spinocerebellar atrophy, Tourette's syndrome , Friedrich ⁇ s Ataxia, Machado-Joseph ⁇ s disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy, Frontal It may be at least one disease selected from the group consisting of frontotemporal dementia and amyotrophic lateral sclerosis, and more specifically, it may be Parkinson's disease.
  • the degenerative brain disease may be caused by MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
  • Another aspect relates to a health functional food for preventing or improving degenerative brain diseases including immune-tolerant dendritic cells or cultures thereof.
  • the term “improvement” may refer to any activity that at least reduces a parameter related to the condition being treated, eg, the severity of a symptom.
  • the health functional food may be used before or after the onset of the disease, simultaneously with or separately from the drug for treatment, in order to prevent or improve the degenerative brain disease.
  • the active ingredient may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to conventional methods.
  • the mixing amount of the active ingredient can be suitably determined depending on the purpose of its use (for prevention or improvement).
  • the health functional food may be added in an amount of about 15% by weight or less, more specifically about 10% by weight or less, based on the raw material.
  • the amount may be less than the above range.
  • the health functional food may be formulated as one selected from the group consisting of tablets, pills, powders, granules, powders, capsules and liquid formulations by further including one or more of carriers, diluents, excipients and additives.
  • carriers diluents, excipients and additives.
  • Examples of foods to which a compound according to one aspect may be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, health functional foods, and the like.
  • carrier examples include lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, and microcrystalline cellulose.
  • the health functional food may contain other ingredients as essential ingredients without particular limitation.
  • it may contain various flavoring agents or natural carbohydrates as additional ingredients like a normal beverage.
  • natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents thaumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the ratio of the natural carbohydrates may be appropriately determined by a person skilled in the art.
  • the health functional food is various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and salts thereof , alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like.
  • vitamins, minerals electrophilic acids
  • flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.
  • pectic acid and salts thereof alginic acid and its salts
  • organic acids protective colloidal thickeners
  • pH regulators pH regulators
  • stabilizers stabilizers
  • preservatives glycerin
  • alcohol carbonating agents used in carbonated beverages, and the like.
  • the immune-tolerant dendritic cells may express CLEC5A, and may overexpress CLEC5A compared to immature dendritic cells, mature dendritic cells, or parental cells.
  • Immune-tolerant dendritic cells may exhibit immune-tolerant characteristics as the expression of CLEC5A is increased compared to immature dendritic cells, mature dendritic cells, or parent cells, and specifically, may exhibit an effect of preventing or improving degenerative brain disease. .
  • Another aspect relates to a method for preventing or treating a degenerative brain disease comprising administering immune-tolerant dendritic cells or a culture thereof to a subject in need thereof.
  • Another aspect relates to the use of immune-tolerant dendritic cells or cultures thereof for preventing or treating degenerative brain diseases.
  • Immunotolerant dendritic cells may be within the above-described range.
  • Immune-tolerant dendritic cells are immuno-tolerant dendritic cells, which express CLEC5A and change the expression of at least one selected from the group consisting of p-NFkB, p-STAT3, DAP12, and p-Syk to treat degenerative brain diseases, In particular, it may exhibit effects of preventing, improving or treating Parkinson's disease.
  • FIG. 1 is a schematic diagram of Parkinson's disease ( in vivo ) model production and experimentation.
  • FIG. 2 is a diagram showing survival rate and score analysis results when tDC is administered to a Parkinson's disease model.
  • FIG. 3 is a diagram showing Pole test results when tDC is administered to a Parkinson's disease model.
  • FIG. 4 is a diagram showing the stepping test results when tDC is administered to a Parkinson's disease model.
  • FIG. 6 is a diagram showing Brain ELISA results when tDC is administered to a Parkinson's disease model.
  • FIG. 7 is a diagram showing the results of LNs T cell subpopulation when tDC is administered to a Parkinson's disease model.
  • FIG. 8 is a diagram showing the results of SP T cell subpopulation when tDC is administered to a Parkinson's disease model.
  • FIG. 9 is a diagram confirming changes in the expression of surface antigen molecules of immune-tolerant dendritic cells.
  • 10 and 11 are diagrams confirming changes in cytokine secretion of immune-tolerant dendritic cells.
  • FIG. 12 is a diagram confirming the proliferation of T cells by dendritic cells.
  • FIG. 13 is a diagram showing the results of generating helper T cells by dendritic cells.
  • FIG. 14 is a diagram showing the results of cytokine secretion of T cells stimulated with dendritic cells.
  • FIG. 15 is a diagram showing the results of quantifying Clec5a mRNA expression levels in immune-tolerant dendritic cells (tDC) and mature dendritic cells (mDC) using GAPDH.
  • 16 is a diagram showing immunoblotting results to confirm specific biomarkers of immune-tolerant dendritic cells.
  • 17 is a diagram showing the results of immunofluorescence staining to confirm specific biomarkers of immune-tolerant dendritic cells.
  • 18a is a diagram showing the result of confirming the expression level of Clec5a mRNA, as confirmed for RNA interference in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 18B is a diagram showing the result of confirming the expression level of Clec5a by immunoblotting, as confirmed for RNA interference in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 18c and 18d are diagrams showing the result of confirming the Clec5a expression level through immunofluorescence staining, in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 19 to 21 are diagrams showing the results of confirming RNA interference in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • FIG. 22 is a view showing the results of confirming the proliferation of T cells by dendritic cells in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 23 is a view showing the results of generation of helper T cells by dendritic cells to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • FIG. 24 is a diagram showing the results of cytokine secretion of T cells stimulated with dendritic cells to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 25 and 26 are views confirming the causes of changes due to inhibition of Clec5a expression in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 27 to 33 are diagrams confirming physical/biological changes of dendritic cells according to Clec5a expression increase in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 34 is a view showing the survival rate and score for a Parkinson's disease model in order to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • Figure 35a is a view showing the results of observation of Brain TH (Tyrosine hydroxylase) by immunofluorescence staining (IF staining) for a Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells, and the white boxed area is the SN region.
  • IF staining immunofluorescence staining
  • 35B is a view showing the results of observation of Brain TH (Tyrosine hydroxylase) by immunofluorescence staining (IF staining) for a Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells. This is the result of enlargement.
  • 36 is a view showing the results of a stepping test for a Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • FIG. 37 is a view showing the results of a Pole test on a Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 38 is a view showing the degree of tremor in a Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 39 is a view showing the results of Brain ELISA for Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 40 is a view showing the results of LNs T cell subpopulation in the Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • 41 is a view showing the results of SP T cell subpopulation for Parkinson's disease model to confirm the function of Clec5a in immune-tolerant dendritic cells.
  • the behavioral analysis experiment was conducted on Day 4, and practice for the behavioral analysis experiment was conducted before the first MPTP injection on Days 0 and 2.
  • mice The mouse was hung upside down on top of a pole with a diameter of 1 cm and a length of 40 cm, and the time it took to turn around and come down to the floor was measured. The time for the mouse to completely turn from the pole (t-turn) and the time to completely come down to the floor were measured. For mice that could not hang on the pole or fell, both the t-turn and the time to come down were recorded as maximum time (T-turn: 90 seconds, maximum time to come down to the floor was 180 seconds). A total of 3 consecutive runs were performed per mouse, and all results were analyzed as the average of 3 results.
  • the number of steps stepping on the ground was measured while pulling the tail backward for 1 m for 5 seconds while the mouse was placed on the floor and the tail was lifted so that only the front paws touched the ground.
  • a total of 3 discontinuous sessions per mouse were performed, and all results were analyzed as the average of 3 results.
  • the degree of tremor was measured in the region between the neck and the hip of the Parkinson's model mouse.
  • the range of shaking of the mouse for 10 seconds was measured, and the length and width of the range were specified and displayed as a graph (FIG. 5).
  • For the tremor length 5 locations were selected at equal intervals and the length of the tremor range was measured at the corresponding locations.
  • Sacrifice was performed on the 5th day of induction of Parkinson's disease (Day 4). After removing the lymph nodes near the spleen and brain, the brain tissue was removed by perfusion with 4% PFA.
  • Brain protein was obtained by adding a protein extraction solution (PRO-PREPTM Protein Extraction Solution), and after measuring the concentration using a Bradford assay kit (Sigma aldrich), IFN- ⁇ and IL-1 ⁇ were measured through an ELISA technique. Specifically, 100 ⁇ g of protein was quantified and the expression levels of IL-1 ⁇ and IFN- ⁇ , which are inflammatory cytokines, were analyzed using ELISA technique.
  • LNs were ground and flow cytometric analysis was performed using fluorescently labeled anti-CD4-APC antibody (Biolegend), anti-CD25-FITC antibody (BD Antibodies), and anti-Foxp3-PE antibody (eBioscience).
  • the spleen was pulverized and red blood cells were removed using ACK lysis buffer (LONZA), and then passed through a nylon wool (Polysciences Inc., Warrington, PA, USA) column. After co-culture, fluorescently labeled anti-CD4-APC antibody (Biolegend), anti-CD25-FITC antibody (BD Antibodies), anti-Foxp3-PE antibody (eBioscience), anti-IFN- ⁇ -PE antibody (BD Antibodies) , Flow cytometry was performed using an anti-IL-17A-PE antibody (BD Antibodies). The ratio of T cell subtypes secreting each cytokine was measured and analyzed with FlowJo10 software.
  • the T cell subpopulation in the spleen was confirmed.
  • the ratio of Treg was the same as in LNs, and the highest number was confirmed in the tDC-injected group. Furthermore, as a result of confirming the ratio of Th1 (CD4+IFN- ⁇ +) and Th17 (CD4+IL-17a+), which are confirmed to have a significant effect on the induction of Parkinson's disease, the ratio of Th1 and Th17 decreases when tDC is injected. It was confirmed (FIG. 8).
  • a medium having the same composition was prepared and 10 mL was added to the culture dish.
  • the same medium was prepared and half of the culture dish, 10 mL, was replaced with a fresh medium.
  • the obtained bone marrow cells were treated with 1 ⁇ g/ml of Lipopolysaccharide (LPS) (Sigma-Aldrich) and 10 ⁇ g/ml of Keyhole limpet hemocyanin (KLH) (JW creagene).
  • LPS Lipopolysaccharide
  • KLH Keyhole limpet hemocyanin
  • Immature dendritic cells were differentiated into mature dendritic cells by culturing in RPMI1640 medium containing the cells for about 24 hours at 37° C. and 5% CO 2 conditions.
  • a fluorescent material-conjugated antibody was added to 1 x 10 5 dendritic cells, and incubated at about 4° C. for about 20 minutes to stain the cells.
  • an antibody phycoerythrin (PE) conjugated anti-CD11c antibody, Fluorescein isothiocyanate (FITC) conjugated anti-CD14 antibody, PE conjugated anti-CD40 antibody, FITC conjugated anti-CD54 antibody, PE conjugated anti-CD80 antibody, FITC conjugated anti-CD86 antibody, FITC conjugated anti-MHC I antibody, and PE conjugated anti-MHC II antibody (BD Pharmingen) were used.
  • the cells were washed with phosphate-buffered saline (PBS), and the washed cells were suspended in PBS and analyzed with a flow cytometer NovoCyte® 3000 (ACEA).
  • PBS phosphate-buffered saline
  • ACEA flow cytometer NovoCyte® 3000
  • the fluorescence intensity of a total of 10,000 cells was measured and analyzed with FlowJo10 software from BD Biosciences.
  • IL-10 an anti-inflammatory cytokine
  • BD GolgiStopTM
  • IL-12p40, IL-1 ⁇ , TNF- ⁇ , and IL-6 in immune-tolerant dendritic cells were significantly decreased compared to mature dendritic cells, and thus the prepared cells exhibited cytokine secretion characteristics similar to those of tolerogenic dendritic cells It was confirmed (FIG. 10).
  • CD11c expressed on the surface of dendritic cells was stained to measure the sensitivity of IL-10 expressed in dendritic cells.
  • IL-10 was significantly increased in tolerogenic dendritic cells compared to mature dendritic cells, and it was confirmed that the prepared cells exhibited cytokine secretion characteristics similar to those of tolerogenic dendritic cells (FIG. 11).
  • red blood cells were removed from the pulverized spleens using ACK lysis buffer (LONZA). After that, a nylon wool (Polysciences Inc., Warrington, PA, USA) column was prepared, and CD3+ T cells were isolated by passing the spleen fragments through. FITC-conjugated carboxyfluorescein succinimidyl ester (CFSE) (eBioscience) was added to the isolated CD3+ T cells to stain the T cells.
  • CFSE carboxyfluorescein succinimidyl ester
  • Dendritic cells and CD3+ T cells were co-cultured for 3 days. Fluorescently labeled anti-CD4-APC antibody (Biolegend), anti-CD25-FITC antibody (BD Antibodies), anti-Foxp3-PE antibody (eBioscience), anti-IFN- ⁇ -PE antibody (BD Antibodies), anti-IL- Flow cytometry was performed using the 17A-PE antibody (BD Antibodies). The ratio of T cell subtypes secreting each cytokine was measured and analyzed with FlowJo10 software.
  • Th1 cells IFN- ⁇ +/CD4+
  • Th17 IL-17A+/CD4+
  • Th2 IL-4+/CD4+
  • Treg Foxp3+/CD4+CD25+
  • the supernatant was obtained by centrifuging the culture medium in which dendritic cells and CD3+ T cells were co-cultured for 3 days.
  • each cytokine was measured using ELISA technique. Specifically, interferon (IFN)- ⁇ (BD Bioscience), IL-4 (Biolegend), IL-10 (BD Bioscience), and TGF- ⁇ (eBioscience) were measured using ELISA kits.
  • IFN interferon
  • IL-4 Biolegend
  • IL-10 BD Bioscience
  • TGF- ⁇ eBioscience
  • T cells stimulated with immune-tolerant dendritic cells significantly decreased the amount of IFN- ⁇ cytokine secretion and significantly increased the secretion amount of TGF- ⁇ compared to mature dendritic cells (Fig. 14).
  • RT-PCR reverse transcription polymerase chain reaction
  • RNA was isolated from prepared immune-tolerant dendritic cells and mature dendritic cells using LABOzol (Invitrogen).
  • Complementary DNA cDNA was synthesized from the isolated total RNA using a cDNA synthesis kit (LabopassTM). Using the synthesized cDNA as a template, Clec5a and GAPDH were amplified using the primer sets shown in Table 1 below.
  • primer direction order sequence number Clec5a forward 5′-TCTGCTGTATTTCCCACAGG-3′
  • Total protein was obtained from the prepared immune-tolerant dendritic cells and mature dendritic cells. The concentration of the obtained protein was measured using Bradford assay kit (Sigma aldrich).
  • Equal amounts of protein were electrophoresed on SDS-PAGE, anti-Clec5a antibody (0.1 ⁇ g/mL dilution, R&D system) and anti-GAPDH antibody (1:1000 dilution, BioSS) were used as primary antibodies, and secondary antibodies were used. Immunoblotting was performed using a horseradish peroxidase (HRP)-conjugated secondary antibody (1:2000 dilution; Cell Signaling Technologies) as the antibody. The detected band intensity was calculated using a Luminescent image analyzer LAS-4000 (GE Healthcare).
  • HRP horseradish peroxidase
  • Clec5a protein was significantly higher expressed in immune-tolerant dendritic cells than in mature dendritic cells (FIG. 16).
  • the same number of dendritic cells were attached to a glass slide coated with poly-L-lysine, fixed with 1% paraformaldehyde, and then permeabilized using a 0.1% Triton-X 100 solution.
  • Anti-Clec5a antibody (1:200 dilution) and FITC-conjugated anti-CD11c antibody (1:200, FITC) were used as the primary antibody, and Alexa Fluor Plus 647 conjugated secondary antibody (1:1000 dilution, FITC) was used as the secondary antibody.
  • thermo was used to perform immunofluorescence staining. Slide samples were fixed using a mounting agent to which DAPI was added. Observation was performed using a Leica TCS-NT SP confocal microscope.
  • Clec5a protein was expressed higher in immune-tolerant dendritic cells than in mature dendritic cells. Accordingly, it was found that immunotolerant dendritic cells could be detected using Clec5a (FIG. 17).
  • Clec5a shRNA small hairpin RNA (shRNA)
  • shRNA small hairpin RNA
  • the recombinant vector was co-transfected with the packaging plasmid into 293T cells to construct a lentivirus.
  • a negative control a lentivirus made of a vector into which only the sequence for GFP was inserted was used.
  • a total of 10 ml was added to a culture dish having a diameter of 100 mm, followed by incubation at 37° C. and 5% CO 2 conditions. After 24 hours, the culture medium was replaced with a fresh culture medium without virus, and on the 8th day of culture, the cultured cells were obtained and differentiated into immune-tolerant dendritic cells.
  • the Clec5a RNA expression level and the amount of Clec5a protein were measured by RT-PCR, immunoblotting and immunofluorescence staining, respectively, as described above.
  • Dendritic cells transfected with Clec5a shRNA were prepared in the same manner as described above. Dendritic cells and CFSE-stained CD3+ T cells were mixed at a cell count ratio of 1:10, and co-cultured for about 72 hours under conditions of 37°C and 5% CO 2 . Co-cultured cells were identified by flow cytometry.
  • results were as shown in FIG. 22, and dendritic cells transfected with Clec5a shRNA tended to induce more T cell proliferation than the control group.
  • the numerical values shown in FIG. 22 represent the percentage of proliferated T cells.
  • Dendritic cells transfected with Clec5a shRNA were prepared in the same manner as described above. Fluorescently labeled anti-CD4-APC antibody (Biolegend), anti-CD25-FITC antibody (BD Antibodies), anti-Foxp3-PE antibody (eBioscience), anti-IFN- ⁇ -PE antibody (BD Antibodies), anti-IL- Flow cytometry was performed using the 17A-PE antibody (BD Antibodies). The ratio of T cell subtypes secreting each cytokine was measured and analyzed with FlowJo10 software.
  • dendritic cells (shClec5a) transfected with Clec5a shRNA showed increased ratios of Th1 cells (IFN- ⁇ +/CD4+), Th2 (IL-4+/CD4+), and Treg (Foxp3+) compared to the control group (shCon). /CD4+CD25+) was confirmed to decrease (FIG. 23).
  • the supernatant was obtained by centrifuging the culture medium in which dendritic cells and CD3+ T cells were co-cultured for 3 days.
  • each cytokine was measured using ELISA technique. Specifically, interferon (IFN)- ⁇ (BD Bioscience), IL-4 (Biolegend), IL-10 (BD Bioscience), and TGF- ⁇ (eBioscience) were measured using ELISA kits.
  • IFN interferon
  • IL-4 Biolegend
  • IL-10 BD Bioscience
  • TGF- ⁇ eBioscience
  • T cells stimulated with immune-tolerant dendritic cells suppressing Clec5a expression significantly increased the expression of the inflammatory cytokine, IFN- ⁇ , compared to the control immune-tolerant dendritic cells (shCon).
  • IL-10 an anti-inflammatory cytokine
  • shClec5a a tendency to decrease in shClec5a
  • TGF- ⁇ a tendency to decrease in shClec5a
  • the protein levels of NF- ⁇ B, STAT3, Erk1/2, p38, and JNK and their phosphorylated forms in immunotolerant dendritic cells whose expression was inhibited by Clec5a shRNA were confirmed by Western blotting, as shown in FIG. 25 . Specifically, it was confirmed that the expression of p-NFkB increased and the expression of p-STAT3 decreased in immune-tolerant dendritic cells in which Clec5a expression was decreased compared to the control group.
  • Clec5a also known as MDL-1 (Myeloid DAP12-Associating Lectin-1), is a protein that affects syk phosphorylation as it is related to a signal transduction receptor called DAP12.
  • the Clec5a RNA expression level and the amount of Clec5a protein were measured by RT-PCR, immunoblotting and immunofluorescence staining, respectively, as described above.
  • cytokines secreted from dendritic cells were detected by ELISA.
  • Fig. 27A As a result of analysis by qRT-PCR (Fig. 27A), western blot (Fig. 27B), and flow cytometry (Fig. 27C), dendritic cells (ovClec5a) with increased Clec5a expression were found in control dendritic cells (shCon). In comparison, Clec5a expression was significantly increased in dendritic cells. It was confirmed that the expression of Clec5a was increased at the mRNA level, the protein level, and the cell surface expression level.
  • dendritic cells with increased Clec5a expression showed higher levels of Th1 cells (IFN- ⁇ +/CD4+), Th2 (IL-4+/CD4+), and Th17 (IL-17A+/CD4+) cells compared to control dendritic cells (shCon).
  • Treg Foxp3+/CD4+CD25+ ratios were all increased (FIG. 31).
  • T cells stimulated with dendritic cells (ovClec5a) with increased Clec5a expression tended to increase the expression of TGF- ⁇ compared to the control group. It was confirmed that this increased (FIG. 32).
  • Dendritic cells were prepared by the manufacturing method described above, and a Parkinson's model was prepared by the manufacturing method and analysis method described above, and score, behavioral analysis, brain ELISA, and LNs/SP T cell subpopulation were confirmed.
  • Brain TH Teyrosine hydroxylase
  • Sacrifice was performed on the 5th day (Day 4) of Parkinson's disease induction. Specifically, after removing the lymph node near the spleen and brain, brain tissue was extracted by perfusion with 4% PFA. The excised brain tissue was incubated for about 24 hours at about 4 ° C in the order of 4% PFA solution, 15% sucrose, and 30% sucrose. After that, a block was made using OCT (Optimal cutting temperature) compound (Sakura) and cut into 30 ⁇ m thick to prepare tissue sections.
  • OCT Optimal cutting temperature
  • Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN)
  • brain sections with SN regions were picked and attached to glass slides for immunofluorescence staining.
  • Permeabilization using 0.3% Triton-X 100 solution, anti-TH antibody (1:250 dilution, thermo) as the primary antibody, Alexa Fluor Plus 488 conjugated secondary antibody (1:1000 dilution, thermo) as the secondary antibody ) was used to perform immunofluorescence staining. Slide samples were fixed using a mounting agent to which DAPI was added. Observation was performed using a Leica TCS-NT SP confocal microscope.
  • TH Tyrosine hydroxylase
  • the area between the neck and the hip of the mouse was measured in the same way. Specifically, the length and width of the range were measured by measuring the range of the degree of shaking of the mouse for 10 seconds, and the length of the range was selected at 5 locations at equal intervals and the length of the range of the degree of shaking at the corresponding location was measured.
  • IL-1 ⁇ and IFN- ⁇ which are inflammatory cytokines
  • the T cell subpopulation in the spleen was confirmed.
  • Clec5a expression affects the therapeutic effect on Parkinson's disease, and as a result, it was confirmed that Clec5a expression has a major effect on the immune tolerance of tDCs.

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Abstract

Un aspect de l'invention concerne une composition pharmaceutique et un aliment fonctionnel de santé, chacun comprenant des cellules dendritiques immunotolérantes pour la prévention, l'atténuation ou le traitement de maladies dégénératives du cerveau. Les cellules dendritiques immunotolérantes expriment CLEC5A et modifient l'expression d'au moins un élément choisi dans le groupe consistant en p-NFkB, p-STAT3, DAP12 et p-Syk, ce qui permet de présenter des effets prophylactiques, palliatifs ou thérapeutiques sur les maladies dégénératives du cerveau, en particulier la maladie de Parkinson.
PCT/KR2022/010738 2021-07-23 2022-07-21 Composition pharmaceutique comprenant une cellule dendritique immunotolérante exprimant clec5a ou une culture de celle-ci pour la prévention ou le traitement d'une maladie dégénérative du cerveau Ceased WO2023003406A1 (fr)

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