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WO2023029027A1 - Système de vaccin pour la prévention ou le traitement du diabète de type i et son procédé de préparation - Google Patents

Système de vaccin pour la prévention ou le traitement du diabète de type i et son procédé de préparation Download PDF

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WO2023029027A1
WO2023029027A1 PCT/CN2021/116632 CN2021116632W WO2023029027A1 WO 2023029027 A1 WO2023029027 A1 WO 2023029027A1 CN 2021116632 W CN2021116632 W CN 2021116632W WO 2023029027 A1 WO2023029027 A1 WO 2023029027A1
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water
cells
components
diabetes
vaccine
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Chinese (zh)
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刘密
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Suzhou Ersheng Biopharmaceutical Co Ltd
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Suzhou Ersheng Biopharmaceutical Co Ltd
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Definitions

  • the invention relates to the technical field of immunotherapy, in particular to a vaccine system for preventing or treating type I diabetes and a preparation method thereof.
  • Immunity is a physiological function of the human body.
  • the human body relies on this function to identify "self” and “non-self” components, thereby destroying and repelling antigenic substances (such as viruses and bacteria) entering the human body, or damaged cells produced by the human body itself. and tumor cells to maintain human health.
  • Immunotechnology has developed extremely rapidly in recent years, especially in the field of cancer immunotherapy. However, the treatment means for autoimmune diseases, especially type 1 diabetes, is still relatively scarce.
  • Type I diabetes is one of the most common autoimmune diseases. Patients generally have a relatively young age of onset, and once they develop, they need to use insulin for life. The onset of type I diabetes is caused by the abnormal recognition and attack of pancreatic ⁇ cells by T cells specific to pancreatic ⁇ cell-associated antigens. Because ⁇ cells are the cells that produce insulin in the human body, and insulin is the most important component that regulates the body's blood sugar, once the ⁇ cells are attacked and killed by the body's immune cells, the body cannot produce enough insulin to control its own blood sugar. Therefore, ⁇ -cell-associated antigen-specific T cells are the key factors in the development of type I diabetes. If immune tolerance against ⁇ -cell-associated antigens can be induced, the body will not abnormally recognize and attack pancreatic ⁇ -cells, thereby realizing the prevention and treatment of type I diabetes.
  • type I diabetes many antigens such as insulin, glutamic acid decarboxylase 65KD isoform (GAD65), insulinoma-binding protein-2 (IA-2) and zinc transporter 8 (ZnT8) are present in type I diabetes. play an important role in the pathogenesis of diabetes. It is these self-antigens that cause antigen-specific T cells to attack and kill pancreatic ⁇ cells that lead to type 1 diabetes.
  • these antigens and the previous preventive vaccines for type 1 diabetes all use one or several specific antigens, so it is difficult to cover a comprehensive antigen spectrum, so it is difficult to induce the body to produce immune resistance to all antigens. by.
  • islet ⁇ cells are the best source of antigens for inducing immune tolerance.
  • antigenic proteins are transmembrane proteins and thus cannot be dissolved in water under normal conditions, the technology and products that can induce immune tolerance by using the above-mentioned proteins as antigens are limited. Therefore, there is still a need for an immunization product that covers a more comprehensive spectrum of antigens.
  • the present invention provides a vaccine system for preventing or treating type I diabetes, which can be used for the prevention and treatment of type I diabetes by utilizing the immune tolerance generated by these self-antigens in the cell components.
  • a vaccine system for preventing or treating type 1 diabetes of the present invention comprising delivery particles and the cell components loaded therein, the cell components are water-soluble components of cells containing antigens associated with type 1 diabetes or whole cells in tissues and/or water-insoluble components.
  • cells containing antigens associated with type I diabetes are ⁇ cells.
  • ⁇ -cells are pancreatic ⁇ -cells, ⁇ -cell cell lines, ⁇ -cells transformed from pluripotent stem cells or ⁇ -cells prepared by any other means.
  • cells or tissues containing antigens related to type 1 diabetes are frozen at -20°C to -273°C, added with water or an aqueous solution without a solubilizer, and then repeatedly freeze-thawed to lyse the cells, and the supernatant is a water-soluble component, The soluble part of the precipitate after solubilization is the water-insoluble component.
  • the water-soluble component is the original water-soluble part that can be dissolved in pure water or an aqueous solution without a solubilizer;
  • the part that is insoluble in the aqueous solution of the solubilizing agent becomes soluble in the aqueous solution containing the solubilizing agent or the organic solvent.
  • the vaccine system of the present invention can deliver cell components to relevant immune cells, activate and enhance the immune tolerance of the autoimmune system to antigens through the loaded components.
  • the present invention after lysing cells containing antigens associated with type I diabetes or tissues containing such cells, firstly obtain water-soluble components that are soluble in pure water or an aqueous solution without a solubilizer, and then use a solubilizer containing a solubilizer The solubilizing solution dissolves the water-insoluble components in the solubilizing solution, so that all cellular components can be converted into components that can be dissolved in aqueous solution, and then loaded in/outside nanoparticles or microparticles Preparation of nano-vaccine or micro-vaccine.
  • cells or tissues can also be lysed directly with a solubilizing aqueous solution containing a solubilizing agent to dissolve the whole cell components without collecting the water-soluble components and water-insoluble components separately, and the whole cell components dissolved in the solubilizing aqueous solution can be used
  • Cellular components make nanovaccine or microvaccine.
  • the water-insoluble components are solubilized and loaded on the delivery particles.
  • Cell components include water-soluble parts and water-insoluble parts, which include the components and components of the entire cell, ensuring that most of the antigenic substances are loaded in the prepared vaccine system, thereby improving the comprehensiveness and immunity of the vaccine system Originality.
  • solubilizer used for solubilization is selected from urea, guanidine hydrochloride, sodium deoxycholate, sodium dodecyl sulfate (SDS), glycerin, protein degrading enzymes, albumin, lecithin, 0.1-2000mg/mL inorganic Salt, Triton, Tween, acetic acid, cholesterol, amino acid, glycoside, choline, Brij TM -35, octaethylene glycol monododecyl ether, 3-[3-(cholamidopropyl) dimethyl Amino]propanesulfonic acid inner salt (CHAPS), digitonin (Digitonin), lauryldimethylamine oxide (lauryldimethylamine oxide), One of CA-630, dimethyl sulfoxide (DMSO), acetonitrile, ethanol, methanol, N,N-dimethylformamide (DMF), isopropanol, methylene chloride, propyl
  • immunosuppressive adjuvants can be immunosuppressants derived from microorganisms, products of the human or animal immune system, mRNA, DNA, innate immunosuppressants, adaptive immune stimulants, chemically synthesized drugs, fungal polysaccharides; glucocorticoids Hormone drugs, calcineurin inhibitors, anti-metabolites, antibodies, cytokines, alkylating agents, Chinese medicine ingredients, herbal medicine ingredients, mineral medicine ingredients, etc.
  • cyclosporine rapamycin, tacrolimus (Tacrolimus, FK506), fingolimod, methylprednisolone, tripterygium wilfordii, mycophenolate mofetil, cyclophosphamide, azathioprine, epsilon Vilimus, Sandimin, Cespin, Cyclosporin A, Cyclosporin (Cy-A, Cs-A), Neoral, anti-IL-2 receptor monoclonal antibody, TGF- ⁇ , interleukin, ginseng, at least one active ingredient of astragalus.
  • the surface of the vaccine system is connected with a target head with active targeting function.
  • the target head targets dendritic cells, macrophages, B cells, T cells, NK cells, NKT cells, neutrophils, eosinophils or basophils, which are mostly present in lymph nodes , thymus, spleen or bone marrow.
  • the water-soluble component and/or the water-insoluble component is loaded inside the delivery particle, and/or the water-soluble component and/or the water-insoluble component is loaded on the surface of the delivery particle.
  • water-soluble components are loaded in delivery particles and loaded on the surface of delivery particles at the same time
  • water-insoluble components are loaded in delivery particles and loaded on the surface of delivery particles at the same time
  • water-soluble components are loaded in delivery particles instead of The water-soluble component is loaded on the surface of the delivery particle
  • the water-insoluble component is loaded in the delivery particle and the water-soluble component is loaded on the surface of the delivery particle
  • the water-soluble component and the water-insoluble component are loaded in the delivery particle and only the non-water-soluble component is loaded in the delivery particle.
  • the water-soluble component is loaded on the surface of the delivery particle, the water-soluble component and the water-insoluble component are loaded in the delivery particle and only the water-soluble component is loaded on the surface of the delivery particle, the water-soluble component is loaded in the delivery particle and the water-soluble component and water-insoluble components are simultaneously loaded on the surface of delivery particles, and water-soluble components and water-insoluble components are simultaneously loaded on the surface of delivery particles, and water-soluble components and water-insoluble components are loaded on the surface of delivery particles.
  • the components are simultaneously loaded in the delivery particle and the water-soluble component and the water-insoluble component are simultaneously loaded on the surface of the delivery particle.
  • the structure diagram of the vaccine system of the present invention is shown in Fig. 2-28, and in actual use, it may be one or two or more nanoparticles or microparticles of different structures.
  • the delivery particles are nano-sized particles and/or micron-sized particles, which are prepared from organic synthetic polymer materials, natural polymer materials or inorganic materials.
  • Organic synthetic polymer materials are polylactic acid-glycolic acid copolymer PLGA, polylactic acid PLA, polyglycolic acid PGA, polyethylene glycol PEG, polycaprolactone PCL, Poloxamer, polyvinyl alcohol PVA, polyvinyl pyrrolidone PVP, polyetherimide PEI, polytrimethylene carbonate PTMC, polyanhydride, polydioxanone PDON, polydioxanone PPDO, polymethyl methacrylate PMMA, polyamino acid or polypeptide
  • the natural polymer material is lecithin, cholesterol, sodium alginate, albumin, collagen, gelatin, cell membrane (including whole cell membrane components or part of cell membrane components), exosomes, starch or carbohydrates; the inorganic material is three Ferric oxide, ferric oxide, calcium carbonate or calcium phosphat
  • the particle diameter of the nanoscale particles is 1 nm-1000 nm, and the particle diameter of the micron-scale particles is 1 ⁇ m-1000 ⁇ m.
  • This particle size range ensures that the vaccine can be phagocytized by antigen-presenting cells, and in order to improve the phagocytosis efficiency, the particle size should be within an appropriate range.
  • the nano-scale particle size is 30nm-1000nm, most preferably 100nm-600nm ;
  • the particle size of the micron-sized particles is 1 ⁇ m-10 ⁇ m, most preferably 1 ⁇ m-5 ⁇ m.
  • the delivery particles can be uncharged, negatively charged or positively charged.
  • the delivery particles can be prepared according to the developed preparation methods, including but not limited to solvent evaporation method, dialysis method, extrusion method and hot melt method.
  • the delivery particles are prepared by the double emulsion method in the solvent evaporation method, and the specific steps are as follows:
  • step (2) the mixed solution obtained in step (1) is nanosized or micronized;
  • step (3) adding the mixture obtained in step (2) into a third predetermined volume of an aqueous solution containing an emulsifier with a third predetermined concentration and performing nanometerization or micronization;
  • step (3) (4) adding the liquid obtained in step (3) into a fourth predetermined volume of an emulsifier aqueous solution of a fourth predetermined concentration, and stirring until a predetermined stirring condition is met;
  • step (4) After centrifuging or ultrafiltering the mixed solution obtained in step (4), take the precipitate or ultrafiltration product and mix it with the water-soluble component or the original water-insoluble component dissolved in the solubilizer to obtain the nano-vaccine or micron vaccines.
  • step (5) After centrifugation in step (5), resuspend the precipitate in an aqueous solution containing a lyoprotectant of a fifth predetermined concentration or in PBS (or physiological saline);
  • each component in the cell lysate and the immune adjuvant containing the antigen associated with type 1 diabetes in the aqueous phase solution or the organic phase solution each component in the lysate is a water-soluble component or a soluble component.
  • the original water-insoluble component in the solubilizer The concentration of the water-soluble components from the cells or tissues contained in the aqueous phase solution or the concentration of the original water-insoluble components dissolved in the solubilizer from the cells or tissues, that is, the first predetermined concentration requires that the protein polypeptide concentration is greater than 1ng/ mL, preferably 1 mg/mL-100 mg/mL.
  • the concentration of the immune adjuvant in the initial aqueous phase is greater than 0.01 pg/mL, preferably 0.01 mg/mL-20 mg/mL.
  • organic synthetic polymer materials, natural polymer materials or inorganic materials are dissolved in an organic solvent to obtain an organic phase solution
  • the organic solvent can be selected from DMSO, acetonitrile, ethanol, chloroform, methanol, DMF, Isopropanol, dichloromethane, propanol, ethyl acetate, etc., preferably dichloromethane.
  • the second predetermined concentration is 0.5 mg/mL-5000 mg/mL, preferably 100 mg/mL.
  • the organic synthetic polymer material is preferably PLGA, which has a certain immune regulation function and is suitable as an auxiliary material for vaccine preparation.
  • the second predetermined volume of the organic phase solution is set according to its ratio to the first predetermined volume of the aqueous phase solution, thereby adjusting the size of the prepared delivery particles.
  • the ratio of the first predetermined volume to the second predetermined volume is 1:1.1-5000, preferably 1:10.
  • ultrasonication or stirring or homogeneous treatment or microfluidics are used for nanometerization or micronization, and the time, speed and pressure can control the size of the prepared delivery particles.
  • the ultrasonic power is 50W-500W, and the time is greater than 0.1 seconds, such as 2-200 seconds; when the stirring is mechanical stirring or magnetic stirring, the stirring speed is greater than 50rpm, and the stirring time is greater than 1 minute, such as the stirring speed is 50rpm-1500rpm, Stirring time is 0.5 hours to 5 hours; use high-pressure/ultrahigh-pressure homogenizer or high-shear homogenizer for homogenization, the pressure is greater than 20psi, and the speed of high-shear homogenizer is greater than 1000rpm; the microfluidic flow rate is greater than 0.001mL/min.
  • the emulsifier aqueous solution is polyvinyl alcohol (PVA) aqueous solution
  • the third predetermined concentration is greater than 1 mg/mL, such as 1-100 mg/mL.
  • the third predetermined volume is adjusted according to its ratio to the second predetermined volume.
  • the ratio of the second predetermined volume to the third predetermined volume is 1:1.1-1000, preferably 2:5. In order to control the size of the nanoparticles during specific implementation, the ratio between the two can be adjusted.
  • the fourth predetermined concentration is greater than 0.01 mg/mL, such as 0.01-100 mg/mL.
  • the ratio of the third predetermined volume to the fourth predetermined volume is 1:1.5-2000, preferably 1:10.
  • the predetermined stirring condition is until the organic solvent volatilization is completed.
  • the lyoprotectant is preferably trehalose.
  • the fifth predetermined concentration is 1-15% by mass, which is set so as not to affect the freeze-drying effect in subsequent freeze-drying.
  • the shape of the vaccine system is sphere, ellipsoid, barrel, polygon, rod, sheet, line, worm, square, triangle, butterfly or disc.
  • the present invention also claims to protect the application of the above-mentioned vaccine system in the preparation of vaccines or medicines for preventing or treating type I diabetes.
  • the vaccine system of the present invention induces immune tolerance against all components of cells containing antigens related to type 1 diabetes, the body can no longer recognize and actively attack the cells, thereby achieving the effect of preventing and treating type 1 diabetes.
  • the present invention has at least the following advantages:
  • the invention provides a vaccine system for delivering cell water-soluble components or non-water-soluble components by using nanoscale or micronscale particles, as well as its application in the preparation of vaccines for preventing and treating type I diabetes.
  • a vaccine system for delivering cell water-soluble components or non-water-soluble components by using nanoscale or micronscale particles, as well as its application in the preparation of vaccines for preventing and treating type I diabetes.
  • Fig. 1 is a schematic diagram of the preparation process of the vaccine system of the present invention
  • a is a schematic diagram of collecting and preparing nano-vaccine or micro-vaccine respectively for water-soluble components and non-water-soluble components
  • b is a schematic diagram of dissolving whole cell components using a solubilizing solution containing a solubilizing agent and a schematic diagram of preparing a nano-vaccine or a micro-vaccine;
  • Figure 2-17 is a schematic structural view of nanoparticles or microparticles loaded with water-soluble components or non-water-soluble components; in Figure 2-5, the surface and interior of the nanoparticles or microparticles contain immune adjuvants; Figure 6-9 In Figure 10-13, the nanoparticles or microparticles only contain immune adjuvants on the outer surface; in Figure 14-17, there is no immune adjuvant inside and outside the nanoparticles or microparticles. agent; Fig. 2, Fig. 6, Fig. 10 and Fig.
  • the water-soluble component or the water-insoluble component in the cell or tissue component contained in the nanoparticle or microparticle is located outside the inner core when it is distributed inside the nanoparticle or microparticle.
  • layer a: the water-soluble components of the cells or tissue components are contained inside and on the surface of nanoparticles or microparticles; b: both inside and on the surface of nanoparticles or microparticles are cells or tissue groups c: Nanoparticles or microparticles are loaded with water-insoluble components in cells or tissue components, while those loaded on the surface are water-soluble components in cells or tissue components ; d: Nanoparticles or microparticles contain water-soluble components in cells or tissue components and surface-loaded water-insoluble components in cells or tissue components; e: Nanoparticles or microparticles The water-soluble components and water-insoluble components in the cell or tissue components are simultaneously contained inside, and the surface of nanoparticles or microparticles is also loaded with water-soluble components and water
  • FIGs 18-28 are structural schematic diagrams of nanoparticles or microparticles loaded with water-soluble or water-insoluble cell components that are actively targeted to target modification; Adjuvant; in Figure 20- Figure 21, the immune adjuvant is only distributed in the inside of the nanoparticle or microparticle; in Figure 22- Figure 23, the nanoparticle or microparticle only contains the immune adjuvant on the outer surface; Figure 24- Figure 25 nanoparticle or There is no immune adjuvant inside and outside the microparticles; Figure 26 cell components and/or immune adjuvants are only distributed inside the nanoparticles or microparticles; Figure 27 cell components and/or immune adjuvants are only distributed in the nanoparticles or Outside of microparticles; Figure 28 Cell components and immune adjuvants are distributed inside or outside of nanoparticles or microparticles, respectively.
  • the water-soluble components or water-insoluble components in the cells or tissue components contained in the microparticles are distributed in the outer layer of the inner core formed inside the nanoparticles or microparticles; a: the interior and surface of nanoparticles or microparticles The water-soluble components in the cell or tissue components are all loaded; b: the water-insoluble components in the cells or tissue components are loaded inside and on the surface of nanoparticles or microparticles; c: nanoparticles or microparticles The inside of the microparticle is the water-insoluble component of the cell or tissue component, and the surface load is the water-soluble component of the cell or tissue component; d: the inside of the nanoparticle or microparticle is the cell or water-soluble components in tissue components, while the surface loads are all water-insoluble components in cells or tissue components; e: water-soluble components in cells or tissue components simultaneously contained in nanoparticles or microparticles components and water-insoluble components, while the surface of nanoparticles or microparticles also loads water
  • Figures 29-37 are the experimental results of using nano-vaccine or micro-vaccine to prevent type I diabetes in Examples 1-9.
  • Example 1 The whole cell components of ⁇ cells are loaded inside and on the surface of nano vaccines for the prevention of type I diabetes
  • mouse ⁇ cells NIT-1 cells are used to illustrate how to prepare a nano-vaccine loaded with whole cell components of ⁇ cells, and use the vaccine to prevent type I diabetes.
  • NIT-1 cells are mouse ⁇ -cell models, which can be used as pancreatic islet ⁇ -cells and transformed from stem cells. Firstly, the NIT-1 cells were lysed to prepare the water-soluble fraction and the water-insoluble fraction of the NIT-1 cells. Then, the organic polymer material PLGA is used as the nanoparticle skeleton material, and the rapamycin is used as the immune adjuvant to prepare the nanovaccine loaded with the water-soluble components and the water-insoluble components of the ⁇ cells by solvent evaporation method. The nanovaccine was then employed to prevent type 1 diabetes.
  • the lysate After the cells are lysed, centrifuge the lysate at a speed greater than 100g for more than 1 minute and take the supernatant, which is the water-soluble fraction of NIT-1 ⁇ cells soluble in pure water; add 8M urea to the obtained precipitate to dissolve the precipitate That is, the water-insoluble components that are insoluble in pure water in NIT-1 ⁇ cells can be converted into soluble in 8M urea aqueous solution.
  • the above-mentioned water-soluble components derived from cell lysates and the original water-insoluble components dissolved in 8M urea are the antigen sources for preparing vaccines for preventing type I diabetes.
  • the preparation of nano-vaccine and the blank nano-particles as contrast in the present embodiment adopt the double emulsion method in the solvent volatilization method, the nano-particle preparation material PLGA molecular weight adopted is 24KDa-38KDa, and the immune adjuvant adopted is Rapa
  • the rapamycin and rapamycin are distributed inside the nanoparticles, and the rapamycin and PLGA are dissolved together in the organic phase during preparation.
  • the preparation method is as described above.
  • the average particle diameter of the nano-vaccine obtained after adsorbing cell components on the surface of the nano-particle is about 300nm, and the surface potential of the nano-vaccine is about-5mV.
  • Each 1 mg of PLGA nanoparticle is loaded with about 180 ⁇ g of protein or polypeptide components, and the total amount of rapamycin immune adjuvant used in each 1 mg of PLGA nano vaccine is about 0.05 mg.
  • the particle size of the blank nanoparticles is about 260nm.
  • pure water or 8M urea containing the same amount of rapamycin was used to replace the corresponding water-soluble components and non-water-soluble components.
  • the preparation method of nanoparticles loaded with several type I diabetes antigen polypeptides is the same as that of nano vaccines.
  • the loaded polypeptides are Insulin B 9-23, Insulin A 14-20, IGRP 206-214, and GAD 225-244, each 1mg PLGA nano
  • the particles are loaded with approximately 200 ⁇ g of polypeptide components and the same amount of rapamycin.
  • control groups in this study were the PBS group and the blank nanoparticles + cell lysate group. 3-week-old female NOD mice were selected for this experiment.
  • mice there were 10 NOD mice per group.
  • 200 ⁇ L of 2 mg PLGA nanovaccine loaded internally and externally with water-soluble components in ⁇ -cell lysate and 200 ⁇ L internally and externally loaded with non-water-soluble components in 8M urea were subcutaneously injected every 7 days from the third week.
  • the 2mg PLGA nano-vaccine of sexual component was given continuously for 6 weeks.
  • the PBS control group was subcutaneously injected with 400 ⁇ L PBS every 7 days from the third week for 6 consecutive weeks.
  • the blank nanoparticle+cell lysate control group was subcutaneously injected with water-soluble components in ⁇ -cell lysates and original water-insoluble components dissolved in 8M urea, and containing an equal amount of adjuvant every 7 days from the third week. Note that the above three should be administered separately and injected at different subcutaneous sites to prevent free cell lysate from adsorbing on the surface of the blank nanoparticles, and injected continuously for 6 weeks.
  • the polypeptide nanoparticle group was subcutaneously injected with various polypeptide-loaded nanoparticles every 7 days from the third week, and the administration was continuous for 6 weeks.
  • the blood glucose of mice in each group was recorded every day from the 8th week. Diabetes begins when blood sugar is higher than 11.0mmol ⁇ L-1. The onset of diabetes in NOD mice was recorded at different time periods.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. As can be seen from accompanying drawing 29, female NOD mouse has 70%-80% to suffer from diabetes after 25 weeks in the situation of injecting PBS or blank nanoparticle+cell lysate treatment; 50% had diabetes after 25 weeks. But only about 20 percent of the mice in the vaccine-prophylaxis group developed type 1 diabetes after 25 weeks.
  • the nano-vaccine loaded with ⁇ -cell whole cell components of the present invention has a good preventive effect on type 1 diabetes, and the preventive effect is better than that of nanoparticles loaded with several polypeptides.
  • Example 2 Whole cell components of ⁇ cells are loaded on the inside and surface of micron vaccines for the prevention of type I diabetes
  • the preparation of the micron vaccine and the blank micron particle as a control adopt the double emulsion method in the solvent volatilization method, and the PLGA molecular weight of the micron particle preparation material used is 24KDa-38KDa, and the immune adjuvant adopted is Rapa
  • Rapa The rapamycin and rapamycin are distributed inside the microparticles, and the rapamycin and PLGA are dissolved together in the organic phase during preparation.
  • the preparation method is as described above.
  • the average particle size of the micron vaccine obtained after adsorbing the cell component on the surface of the nanoparticle is about 1.5 ⁇ m, and the surface potential of the micron vaccine is about -6mV.
  • Each 1 mg PLGA micron vaccine is loaded with about 200 ⁇ g of protein or polypeptide components, and the rapamycin immune adjuvant used inside and outside each 1 mg PLGA micron vaccine is about 0.05 mg in total.
  • the particle size of the blank microparticles is about 1.3 ⁇ m.
  • pure water or 8M urea containing an equal amount of rapamycin is used to replace the corresponding water-soluble components and non-water-soluble components.
  • the preparation method of microparticles loaded with several type I diabetes antigen polypeptides is the same as that of nano vaccines.
  • the loaded polypeptides are Insulin B 9-23, Insulin A 14-20, IGRP 206-214, and GAD 225-244, each 1mg PLGA micron
  • the particles are loaded with approximately 200 ⁇ g of polypeptide components and the same amount of rapamycin.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. As can be seen from accompanying drawing 30, female NOD mouse has 70%-80% to suffer from diabetes after 25 weeks in the situation of injecting PBS or blank microparticle+cell lysate treatment; 50% had diabetes after 25 weeks. But only about 20 percent of the mice in the vaccine-prophylaxis group developed type 1 diabetes after 25 weeks.
  • the micro-vaccine loaded with ⁇ -cell whole cell components of the present invention has a preventive effect on type I diabetes.
  • Example 3 Water-soluble components of ⁇ cells are loaded on the inside and surface of nano-vaccine for the prevention of type I diabetes
  • the preparation of nano-vaccine and the blank nano-particles as contrast in the present embodiment adopt the double emulsion method in the solvent volatilization method, the nano-particle preparation material PLGA molecular weight adopted is 24KDa-38KDa, and the immune adjuvant adopted is Rapa
  • the rapamycin and rapamycin are distributed inside the nanoparticles, and the rapamycin and PLGA are dissolved together in the organic phase during preparation.
  • the preparation method is as described above.
  • the average particle size of the nano-vaccine obtained after adsorbing cell components on the surface of the nano-particles is about 300nm, and the surface potential Zeta potential of the nano-vaccine is about -5mV.
  • Each 1mg of PLGA nanoparticles is loaded with about 180 ⁇ g of protein or polypeptide components, and the total amount of rapamycin immune adjuvant used in each 1mg of PLGA nanovaccine is about 0.05mg.
  • the particle size of the blank nanoparticles is about 260nm, and the corresponding water-soluble components are replaced by pure water containing the same amount of rapamycin when preparing the blank nanoparticles.
  • control groups in this study were the PBS group and the blank nanoparticles + cell lysate group. 3-week-old female NOD mice were selected for this experiment.
  • Drugs were injected at different subcutaneous sites to prevent free cell lysates from being adsorbed on the surface of blank nanoparticles, and the injections were continued for 6 weeks.
  • the blood glucose of mice in each group was recorded every day from the 8th week. Diabetes begins when blood sugar is higher than 11.0mmol ⁇ L-1. The onset of diabetes in NOD mice was recorded at different time periods.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. It can be seen from Fig. 31 that 70%-80% of female NOD mice suffer from diabetes after 25 weeks of injection of PBS or blank nanoparticles + cell lysate. But in the vaccine-prophylaxis group, only about 40 percent of the mice developed type 1 diabetes after 25 weeks.
  • the nanovaccine loaded with ⁇ -cell water-soluble components of the present invention has a preventive effect on type I diabetes.
  • Example 4 Whole cell components of ⁇ cells are loaded inside and on the surface of nano vaccines for the treatment of type I diabetes
  • control groups in this study were the PBS group and the blank nanoparticles + cell lysate group. 25-week-old female NOD mice with diabetes onset were selected for this experiment.
  • mice there were 10 NOD mice per group.
  • 200 ⁇ L of 2 mg PLGA nanovaccine loaded internally and externally with water-soluble components in ⁇ -cell lysates and 200 ⁇ L internally and externally loaded with non-water-soluble components in 8M urea were subcutaneously injected every 3 days from day 0.
  • the 2mg PLGA nano-vaccine of the active component was given 6 times in a row.
  • the PBS control group was subcutaneously injected with 400 ⁇ L of PBS every 3 days from day 0 for 6 consecutive times.
  • the blank nanoparticle + cell lysate control group was subcutaneously injected with the water-soluble components of ⁇ -cell lysate and the original water-insoluble components dissolved in 8M urea every 3 days starting from day 0, and containing an equal amount of adjuvant Note that the above three should be administered separately and injected at different subcutaneous sites to prevent free cell lysates from being adsorbed on the surface of the blank nanoparticles, and injected 6 times in a row.
  • the blood glucose of mice in each group was recorded every day. Diabetes onset was defined as blood glucose higher than 11.0mmol ⁇ L -1 , and remission and cure of diabetes was defined as blood glucose lower than 11.0mmol ⁇ L -1 for three consecutive days. The onset of diabetes in NOD mice was recorded in different time periods.
  • the female NOD mice continued to suffer from diabetes after being injected with PBS or blank nanoparticles + cell lysate.
  • about 40% of mice with type 1 diabetes were cured after treatment with the vaccine. This is because after the onset of type 1 diabetes mice, there are still a small number of ⁇ cells that can continue to secrete insulin in the pancreatic tissue. Once the attack of antigen-specific T cells on ⁇ cells stops, the remaining ⁇ cells can continue to expand.
  • the vaccine of the present invention can activate immune tolerance in the body, thereby inhibiting the attack of antigen-specific T cells on ⁇ cells. This also provides the basis for the cure of type 1 diabetes.
  • the nanovaccine loaded with ⁇ -cell whole cell components of the present invention has a therapeutic effect on type I diabetes.
  • Example 5 Whole cell components of tissues containing ⁇ cells are loaded inside and on the surface of micron vaccines for the prevention of type 1 diabetes
  • This example uses mouse pancreas tissue to illustrate how to prepare a micron vaccine loaded with whole cell components of pancreas tissue with ⁇ cells, and use the vaccine to prevent type I diabetes.
  • the pancreas contains mouse beta cells and can be used as a source of islet beta cells for vaccine preparation. Firstly, the pancreas tissue of the mouse was extracted, and then the water-soluble fraction and the water-insoluble fraction of the whole cells of the obtained tissue were respectively prepared. Then, the organic polymer material PLGA is used as the nanoparticle framework material, and the mRNA encoding TGF- ⁇ is used as an immune adjuvant to prepare micron vaccines loaded with water-soluble components and non-water-soluble components of ⁇ cells by solvent evaporation method. The micron vaccine is then used to prevent type 1 diabetes.
  • pancreas tissues of the mice were harvested.
  • the pancreas tissue was cut into pieces and ground, and an appropriate amount of pure water was added through a cell strainer, followed by repeated freeze-thaw and ultrasonic treatment at least 3 times.
  • tissue cells were lysed, centrifuge the tissue cell lysate at a speed greater than 3000RPM for 5 minutes to get the supernatant, which is the water-soluble component of the tissue cells that can be dissolved in pure water; add 8M aqueous urea solution to the obtained precipitate to dissolve the precipitate
  • Part of the original water-insoluble components that are insoluble in pure water can be converted into soluble in 8M urea aqueous solution.
  • the above-mentioned water-soluble components derived from tissue-derived cell lysates and the original water-insoluble components dissolved in 8M urea are the antigen sources for preparing vaccines for preventing type I diabetes.
  • the preparation of the micron vaccine and the blank micron particle as a contrast adopt the double emulsion method in the solvent volatilization method, and the PLGA molecular weight of the micron particle preparation material adopted is 24KDa-38KDa, and the immune adjuvant adopted is encoded TGF
  • the mRNA of - ⁇ and the mRNA encoding TGF- ⁇ are distributed inside the micron vaccine, and the mRNA is dissolved in the water phase during preparation.
  • the preparation method is as described above.
  • the average particle size of the micron vaccine obtained after adsorbing cell components on the surface of the micron vaccine is about 1.5 ⁇ m, and the surface potential Zeta potential of the micron vaccine is about -8mV.
  • Each 1mg PLGA micron vaccine is loaded with about 200 ⁇ g protein or polypeptide components, and the immune adjuvant used inside and outside each 1mg PLGA micron vaccine is about 0.01mg.
  • the particle size of the blank microparticles is about 1.3 ⁇ m. When the blank microparticles are prepared, pure water or 8M urea containing an equal amount of adjuvant is used to replace the corresponding water-soluble components and non-water-soluble components.
  • control groups in this study were the PBS group and the blank microparticles+tissue cell lysate group. 3-week-old female NOD mice were selected for this experiment.
  • mice there were 10 NOD mice per group.
  • 200 ⁇ L of 2 mg PLGA micron vaccine loaded internally and externally with water-soluble components in tissue cell lysate and 200 ⁇ L internally and externally loaded with non-water-soluble components dissolved in 8M urea were subcutaneously injected every 7 days from the third week.
  • the 2mg PLGA micron vaccine of the sex component was given continuously for 6 weeks.
  • the PBS control group was subcutaneously injected with 400 ⁇ L PBS every 7 days from the third week for 6 consecutive weeks.
  • the control group of blank microparticles + autonomous cell lysate was subcutaneously injected with water-soluble components in cell lysate and original water-insoluble components dissolved in 8M urea, and containing an equal amount of adjuvant every 7 days from the third week. Note that the above three should be administered separately and injected at different subcutaneous sites to prevent free cell lysates from being adsorbed on the surface of the blank microparticles, and injected continuously for 6 weeks.
  • the blood glucose of mice in each group was recorded every day from the 8th week. Diabetes begins when blood sugar is higher than 11.0mmol ⁇ L-1. The onset of diabetes in NOD mice was recorded at different time periods.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. It can be seen from Fig. 33 that 70%-80% of female NOD mice suffer from diabetes after 25 weeks of injection of PBS or blank microparticles + cell lysate. But only about 30 percent of the mice in the vaccine-prevented group developed type 1 diabetes after 25 weeks. In summary, the micro-vaccine loaded with ⁇ -cell whole cell components of the present invention has a preventive effect on type I diabetes.
  • Example 6 Stimulated ⁇ -cell whole cell components loaded inside and on the surface of nano-vaccine for the prevention of type 1 diabetes
  • This example uses the stimulated mouse ⁇ cells—NIT-1 cells to illustrate how to prepare a nano-vaccine loaded with whole cell components of ⁇ cells, and use the vaccine to prevent type I diabetes.
  • ⁇ cells After being stimulated by certain conditions or certain substances, ⁇ cells will increase the production and secretion of antigen-containing substances such as insulin granules. Therefore, in this embodiment, before collecting and processing the mouse ⁇ cells, the ⁇ cells are stimulated to increase the content of antigens such as insulin granules contained in the cells, thus increasing the content and proportion of antigens in the whole cell components.
  • NIT-1 cells are mouse ⁇ -cell models, which can be used as pancreatic islet ⁇ -cells and transformed from stem cells. Firstly, the NIT-1 cells were lysed to prepare the water-soluble fraction and the water-insoluble fraction of the NIT-1 cells. Then, the organic polymer material PLGA is used as the nanoparticle skeleton material, and the rapamycin is used as the immune adjuvant to prepare the nanovaccine loaded with the water-soluble components and the water-insoluble components of the ⁇ cells by solvent evaporation method. The nanovaccine was then employed to prevent type 1 diabetes.
  • the lysate After the cells are lysed, centrifuge the lysate at a speed greater than 100g for more than 1 minute and take the supernatant, which is the water-soluble fraction of NIT-1 ⁇ cells soluble in pure water; add 8M urea to the obtained precipitate to dissolve the precipitate That is, the water-insoluble components that are insoluble in pure water in NIT-1 ⁇ cells can be converted into soluble in 8M urea aqueous solution.
  • the above-mentioned water-soluble components derived from cell lysates and the original water-insoluble components dissolved in 8M urea are the antigen sources for preparing vaccines for preventing type I diabetes.
  • the preparation of nano-vaccine and the blank nano-particles as contrast in the present embodiment adopt the double emulsion method in the solvent volatilization method, the nano-particle preparation material PLGA molecular weight adopted is 24KDa-38KDa, and the immune adjuvant adopted is Rapa
  • the rapamycin and rapamycin are distributed inside the nanoparticles, and the rapamycin and PLGA are dissolved together in the organic phase during preparation.
  • the preparation method is as described above.
  • the average particle size of the nano-vaccine obtained after adsorbing cell components on the surface of the nano-particles is about 300nm, and the surface potential Zeta potential of the nano-vaccine is about -5mV.
  • Each 1 mg of PLGA nanoparticle is loaded with about 180 ⁇ g of protein or polypeptide components, and the total amount of rapamycin immune adjuvant used in each 1 mg of PLGA nano vaccine is about 0.05 mg.
  • the particle size of the blank nanoparticles is about 260nm.
  • control groups in this study were the PBS group and the blank nanoparticles + cell lysate group. 3-week-old female NOD mice were selected for this experiment.
  • mice there were 10 NOD mice per group.
  • 200 ⁇ L of 2 mg PLGA nanovaccine loaded internally and externally with water-soluble components in stimulated ⁇ -cell lysate and 200 ⁇ L internally and externally loaded with 8 M urea were injected subcutaneously every 7 days starting from the third week.
  • the 2mg PLGA nano-vaccine of the Zhongyuan non-water-soluble component was given continuously for 6 weeks.
  • the PBS control group was subcutaneously injected with 400 ⁇ L PBS every 7 days from the third week for 6 consecutive weeks.
  • the blank nanoparticle+cell lysate control group was subcutaneously injected with water-soluble components in ⁇ -cell lysates and original water-insoluble components dissolved in 8M urea, and containing an equal amount of adjuvant every 7 days from the third week. Note that the above three should be administered separately and injected at different subcutaneous sites to prevent free cell lysate from adsorbing on the surface of the blank nanoparticles, and injected continuously for 6 weeks.
  • the blood glucose of mice in each group was recorded every day from the 8th week. Diabetes begins when blood sugar is higher than 11.0mmol ⁇ L-1. The onset of diabetes in NOD mice was recorded at different time periods.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. It can be seen from Fig. 34 that 70%-80% of female NOD mice suffer from diabetes after 25 weeks of injection of PBS or blank nanoparticles + cell lysate. But only about 10 percent of the mice in the vaccine-prophylaxis group developed type 1 diabetes after 25 weeks.
  • the nanovaccine loaded with ⁇ -cell whole cell components of the present invention has a preventive effect on type I diabetes.
  • Example 7 6M guanidine hydrochloride dissolves ⁇ cells and pancreatic tissue components and loads them inside and on the surface of microparticles for the prevention of type I diabetes
  • the lysed mixture of mouse NIT-1 ⁇ cells and mouse pancreatic tissue was used as an antigen, and after dissolving the whole cell components with 6M guanidine hydrochloride, the micron vaccine loaded with whole cell components was used to prevent type I diabetes.
  • the NIT-1 ⁇ cells and pancreatic tissue cells were inactivated and denatured, and the cells and tissues were lysed with 6M guanidine hydrochloride to dissolve their whole cell components.
  • the microvaccine loaded with ⁇ cells and pancreatic tissue components was prepared by the solvent evaporation method. The micron vaccine is then used to prevent type 1 diabetes.
  • the collection method of cells and pancreatic tissue is the same as above.
  • the obtained ⁇ cells and pancreatic tissue cells were inactivated and denatured by ultraviolet light and high temperature heating, respectively, and then the ⁇ cells and pancreatic tissue cells were lysed with an appropriate amount of 6M guanidine hydrochloride to dissolve the tissue and cell lysate, and the tissue lysate and cell lysate
  • the 1:1 mixture is the source of raw materials for vaccine preparation.
  • the micron vaccine and blank micron particles used PLGA (50:50) with a molecular weight of 38KD-54KD, and the preparation method was as described above.
  • Tacrolimus (FK506) is used as an immune adjuvant, and tacrolimus and PLGA are dissolved in the organic phase during preparation.
  • the average particle size of the prepared micron vaccine is about 2.5 ⁇ m, and the Zeta potential on the surface of the micron particle is -4mV.
  • Each 1mg of PLGA microparticles is loaded with 200 ⁇ g of protein and peptide components inside and outside, and the immune adjuvant used inside and outside of each 1mg of PLGA nanoparticles is 0.05mg in total.
  • control groups in this study were the PBS group and the blank microparticle + cell lysate group. 3-week-old female NOD mice were selected for this experiment.
  • mice there were 10 NOD mice per group.
  • 200 ⁇ L of 2 mg PLGA micron vaccine loaded internally and externally with water-soluble components in cell lysates and 200 ⁇ L internally and externally loaded with non-water-soluble components dissolved in 8M urea were injected subcutaneously every 7 days from the third week.
  • the 2mg PLGA micron vaccine of the component was given continuously for 6 weeks.
  • the PBS control group was subcutaneously injected with 400 ⁇ L PBS every 7 days from the third week for 6 consecutive weeks.
  • Blank microparticles + cell lysate control group were subcutaneously injected with the water-soluble components of ⁇ -cell lysates and the original water-insoluble components dissolved in 8M urea every 7 days from the third week, and containing the same amount of adjuvant Note that the above three should be administered separately and injected at different subcutaneous sites to prevent free cell lysates from being adsorbed on the surface of the blank microparticles, and injected continuously for 6 weeks.
  • the blood glucose of mice in each group was recorded every day from the 8th week. Diabetes begins when blood sugar is higher than 11.0mmol ⁇ L-1. The onset of diabetes in NOD mice was recorded at different time periods.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. It can be seen from Fig. 35 that 70%-80% of female NOD mice suffer from diabetes after 25 weeks of injection of PBS or blank microparticles + lysate. But only about 30 percent of the mice in the vaccine-prevented group developed type 1 diabetes after 25 weeks. To sum up, the micro-vaccine loaded with ⁇ cells and pancreatic tissue whole cell components of the present invention has a preventive effect on type I diabetes.
  • Example 8 The whole cell components of stimulated ⁇ cells are loaded inside the nano vaccine for the prevention of type I diabetes
  • the preparation of nano-vaccine and the blank nano-particles as contrast in the present embodiment adopt the double emulsion method in the solvent volatilization method, the nano-particle preparation material PLGA molecular weight adopted is 24KDa-38KDa, and the immune adjuvant adopted is Rapa
  • the rapamycin and rapamycin are distributed inside the nanoparticles, and the rapamycin and PLGA are dissolved together in the organic phase during preparation.
  • the preparation method is as described above, but the surface of the nano-vaccine is not loaded with antigen.
  • the average particle size of the nano-vaccine is about 280nm, and the surface potential Zeta potential of the nano-vaccine is about -25mV.
  • Each 1mg of PLGA nanoparticles is loaded with about 60 ⁇ g of protein or polypeptide components, and the total amount of rapamycin immune adjuvant used in each 1mg of PLGA nanovaccine is about 0.05mg.
  • the particle size of the blank nanoparticles is about 260nm.
  • Example 6 (3) The vaccine of Example 6 is replaced by the vaccine prepared in this example, and the rest are the same as Example 6.
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. It can be seen from Fig. 36 that 70%-80% of female NOD mice suffer from diabetes after 25 weeks of injection of PBS or blank nanoparticles + cell lysate. But only about 30 percent of the mice in the vaccine-prophylaxis group developed type 1 diabetes after 25 weeks.
  • the nanovaccine loaded with ⁇ -cell whole cell components of the present invention has a preventive effect on type I diabetes.
  • Example 9 The non-water-soluble components of ⁇ cells are loaded inside and on the surface of nano-vaccine for the prevention of type I diabetes
  • NOD mice are type I diabetes model mice. Approximately 60%-85% of female NOD mice without prophylaxis develop type 1 diabetes after 22 weeks. It can be seen from Fig. 31 that 70%-80% of female NOD mice suffer from diabetes after 25 weeks of injection of PBS or blank nanoparticles + cell lysate. But in the vaccine-prophylaxis group, only about 40 percent of the mice developed type 1 diabetes after 25 weeks.
  • the nanovaccine loaded with ⁇ -cell water-soluble components of the present invention has a preventive effect on type I diabetes.

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Abstract

L'invention concerne un système de vaccin pour la prévention ou le traitement du diabète de type I. Le système de vaccin utilise des particules d'administration pour administrer un composant hydrosoluble et/ou un composant non hydrosoluble de cellule entière dans une cellule ou un tissu contenant un antigène associé au diabète de type I. La tolérance immunitaire générée par un auto-antigène dans un composant de cellule entière peut être utilisée pour prévenir et traiter le diabète de type I, et est une alternative puissante pour un vaccin ou un médicament associé au diabète de type I.
PCT/CN2021/116632 2021-08-31 2021-09-06 Système de vaccin pour la prévention ou le traitement du diabète de type i et son procédé de préparation Ceased WO2023029027A1 (fr)

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