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WO2024144348A1 - Composition vaccinale comprenant un complexe ionique d'un transporteur moléculaire cationique et d'arnm - Google Patents

Composition vaccinale comprenant un complexe ionique d'un transporteur moléculaire cationique et d'arnm Download PDF

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Publication number
WO2024144348A1
WO2024144348A1 PCT/KR2023/021981 KR2023021981W WO2024144348A1 WO 2024144348 A1 WO2024144348 A1 WO 2024144348A1 KR 2023021981 W KR2023021981 W KR 2023021981W WO 2024144348 A1 WO2024144348 A1 WO 2024144348A1
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WO
WIPO (PCT)
Prior art keywords
mrna
glycero
vaccine composition
propane
liposome
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Ceased
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PCT/KR2023/021981
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English (en)
Korean (ko)
Inventor
이진설
정성기
최한별
박선경
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Biopharma Corp
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Biopharma Corp
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Publication date
Priority claimed from KR1020230195493A external-priority patent/KR20240107033A/ko
Application filed by Biopharma Corp filed Critical Biopharma Corp
Publication of WO2024144348A1 publication Critical patent/WO2024144348A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses

Definitions

  • the present invention relates to an mRNA-based vaccine composition
  • an mRNA-based vaccine composition comprising an ionic complex of a cationic molecular transporter and mRNA.
  • Vaccines can be subdivided into first-generation, second-generation and third-generation vaccines.
  • First-generation vaccines are typically based on live, attenuated, or dead pathogens.
  • live and attenuated vaccines are typically based on live, attenuated, or dead pathogens.
  • dead pathogens may not be as effective as desired for generating specific immune responses.
  • second-generation vaccines have been developed. These are subunit vaccines consisting of antigens or recombinant protein components derived from pathogens.
  • Genetic vaccines are understood as third-generation vaccines. They typically consist of genetically engineered nucleic acid molecules that allow the expression of peptides or protein (antigen) fragments specific for pathogens or tumor antigens in vivo. Genetic vaccines are expressed upon administration to a patient after uptake by target cells. Expression of the administered nucleic acid results in the production of the encoded protein. When these proteins are recognized by the patient's immune system as foreign or non-self, an immune response is triggered.
  • mRNA vaccine There are three main advantages of the above-mentioned mRNA vaccine.
  • Third, in terms of safety there are few side effects, and unlike DNA, single-stranded RNA does not enter the nucleus and thus does not cause modification of the human genome.
  • mRNA vaccines also have disadvantages that need to be addressed.
  • mRNA has a large molecular weight and a high negative charge, and is vulnerable to RNA decomposition enzymes in the body.
  • lipid nanoparticle technology used by Pfizer/BioNTech and Moderna is being applied to vaccines, but it also has the following problems.
  • Pfizer/BioNTech and Moderna vaccines cannot be said to be efficient as they use excessive amounts of mRNA, 30 ⁇ g and 100 ⁇ g, respectively, in one vaccination dose. If we reduce the amount of mRNA used by increasing delivery efficiency, not only will we be able to distribute more vaccines with the same amount of production, but we will also have the effect of reducing the unit cost of the vaccine.
  • lipid nanoparticles are unstable and must be stored at low or ultra-low temperatures.
  • Pfizer/BioNTech and Moderna's vaccines must be distributed and/or stored below -70 °C and -20 °C, so compared to most existing vaccines that are handled at 4 °C, it is necessary to build an ultra-low temperature distribution system and storage facilities at the handling institution. Even though it is the most powerful vaccine, it may face difficulties in distributing it quickly. Therefore, there is an urgent need to develop a new delivery technology that can overcome the shortcomings of the above-mentioned lipid nanoparticles in delivery efficiency and thermal stability.
  • Liposomes are microvesicles in which amphipathic lipid molecules, such as phospholipids, which are components of biological cell membranes, form a bilayer or multiple bilayers, and have a hydrophilic space on the inside and a lipid membrane structure on the outside. Therefore, with the advantage of excellent biocompatibility, liposome preparations are being developed as various drug transporters by combining water-soluble drugs in the hydrophilic space inside and lipid-soluble drugs and charged substances in the external lipid membrane.
  • the nucleic acid-liposome complex which is formed through electrostatic interaction by mixing cationic liposomes and anionic nucleic acids in a certain ratio, is easy to endocytosis and passes easily into cells and passes through endosomes to the cytoplasm. Movement can be easy.
  • the present inventors conducted research to develop an mRNA vaccine with excellent neutralizing antibody forming ability while overcoming the problems of delivery efficiency and thermal stability of lipid nanoparticles. As a result, they developed a cationic liposome and a cationic molecular transporter (Sorbitol- The present invention was completed by developing an mRNA vaccine composition using G6; SG6) as a delivery component.
  • the mRNA vaccine composition of the present invention can be useful for preventing or treating not only infectious diseases, but also tumor or cancer diseases, allergies, or autoimmune diseases.
  • the mRNA of the present invention may be selectively coupled to, for example, a reporter gene that facilitates the determination of mRNA delivery to target cells or tissues.
  • Suitable reporter genes may include green fluorescent protein mRNA (GFP mRNA), luciferase mRNA, firefly luciferase mRNA, or any combination thereof.
  • the PEG-dialkyloxypropyl (DAA) conjugate is PEG-dilauryloxypropyl (C12), PEG-dimyristyloxypropyl (C14), PEG-dipalmityloxypropyl (C16), PEG-distearyloxy It may be propyl (C18) or a mixture thereof.
  • compositions of the invention may include adjuvants that enhance the immune response of the injected animal, and many different adjuvants are known to those skilled in the art.
  • the adjuvant may include Freund's complete and incomplete adjuvant, vitamin E, nonionic blocking polymer, muramyl dipeptide, Quil A, mineral oil and non-mineral oil, Carbopol, water-in-oil emulsion adjuvant, etc. may, but is not limited to this.
  • composition of the present invention can be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. there is.
  • the present invention includes the steps of i) preparing an mRNA compound containing an mRNA sequence encoding an antigenic peptide or protein and mixing it with a liposome containing a PEG-conjugated lipid; and
  • Figure 1 shows trimeric Delta variant gene mRNA and Omicron variant (BA.5) S1 RBD based on the SARS-CoV-2 Delta variant (B.1.617.2) S1 RBD region and T4 bacteriophage fibritin foldon (Fd) trimerization domain.
  • BA.5 S1 RBD based on the SARS-CoV-2 Delta variant (B.1.617.2) S1 RBD region and T4 bacteriophage fibritin foldon (Fd) trimerization domain.
  • This is a diagram showing a schematic diagram of gene mRNA.
  • Figure 9 is a diagram confirming whether the mRNA-lipoplex has cytotoxicity against HEK293T, Vero, and HeLa cell lines.
  • Figure 10 is a diagram showing the results of Western blot analysis of the bivalent vaccine.
  • Figure 11 is a diagram quantifying COVID 19 S Protein (S1RBD).
  • Figure 12 shows the results of mRNA loading of cationic liposomes, showing the loading content and encapsulation efficiency of mRNA using the Ribogreen assay.
  • Figure 13 is a diagram showing the results of electrophoresis testing to determine whether mRNA encapsulated in cationic liposomes is protected from ribonuclease (RNase).
  • RNase ribonuclease
  • Figure 14 is a diagram showing the results of a pH stability test using an agarose gel by electrophoresis to confirm the stability of mRNA of the mRNA-liposome complex under in vivo pH conditions.
  • Figure 15 is a graphical representation of the pH stability test results of mRNA of the mRNA-liposome complex.
  • Figure 16 is a diagram showing the encapsulation rate, which is the rate at which mRNA is encapsulated in the mRNA-liposome-SG6 complex, quantified through Ribogreen assay.
  • Figure 17 is a diagram showing the results of quantification by electrophoresis to confirm the stability of mRNA in the mRNA-liposome-SG6 complex.
  • Figure 18 is a diagram showing the evaluation of the stability of mRNA in the mRNA-liposome-SG6 complex, and the expression of mRNA into protein was confirmed through Western blot.
  • the gene sequence based on the SARS-CoV-2 Delta variant (B.1.617.2) S1_RBD region and T4 bacteriophage fibritin foldon (Fd) trimerization domain was optimized with human source codons, and the trimeric receptor binding domain (trimeric A DNA plasmid vector for RBD) expression was constructed and secured ( Figure 1).
  • the gene sequence without the Fd trimerization domain was optimized with human source codons to secure a DNA plasmid vector for expression of the monomeric receptor binding domain (monomeric RBD) ( Figure One).
  • a research cell bank (RCB) was secured by introducing the synthesized plasmid into cells, and a master cell bank (MCB) was established using one or more vials.
  • IVTT In vitro transcription
  • Plasmids obtained from established cell lines were linearized with restriction enzymes to prepare template DNA.
  • mRNA was synthesized from template DNA, and qualitative analysis of mRNA was performed using agarose gel electrophoresis and ChemiDoc XRS+ imaging system (Bio-Rad, USA) ( Figure 2).
  • stability evaluation was conducted for up to 6 weeks through absorbance measurement, electrophoresis, and HPLC analysis.
  • SG6 ((2R,3R,4R,5S)-hexane-1,2,3,4,5,6-hexayl hexakis(6-guanidinohexanoate) hexa-trifluoroacetic acid designed to effectively deliver the mRNA contained in the vaccine into the cell membrane. salt) was secured.
  • SG6 the cationic molecular transporter of the present invention, has six guanidine groups bonded to D-sorbitol in a side chain, and the amidine at the end of the guanidine group is positively charged, so it can stably and effectively deliver the mRNA/Liposome complex into cells.
  • the stability test of SG6 was performed according to the procedures described in ICH Guideline Q1A (R2).
  • the stability test was analyzed using an in-house test method. Accelerated stability was set to 0, 1, 3 months (40 ⁇ 2 °C/ 75 ⁇ 5% RH) and long-term stability was set to 0, 1, 3 months (25 ⁇ 2 °C/ 60 ⁇ 5% RH).
  • Stability samples were placed in a 50 mL PP vial, blocked from light, and stored in stability chambers at 25 ⁇ 2 °C/60 ⁇ 5% RH and 40 ⁇ 2 °C/ 75 ⁇ 5% RH, respectively.
  • the stability test items are appearance, purity, and moisture.
  • the appearance is a white needle-like solid.
  • HPLC analysis is based on total impurity of 5% or less and purity of 95% or more.
  • Moisture content was analyzed by Karl Fischer Moisture Analysis.
  • test substance SG6 The genetic mutagenicity of the test substance SG6 was tested in the absence and presence of metabolic activation using histidine-auxotrophic Salmonella (TA98, TA100, TA1535, and TA1537 strains) and tryptophan-auxotrophic Escherichia coli (WP2 uvrA strain), respectively. analyzed.
  • the highest dose was 5,000 ⁇ g/plate recommended in the guidelines, and this test was conducted at 2,500, 1,000, 500, 100, 50, 10, 5, and 0 ⁇ g/plate.
  • growth inhibition by the test substance was determined by the ratio of metabolic activation. It was observed at doses above 50 ⁇ g/plate for strains TA98, TA100, TA1535, and TA1537, and at doses above 500 ⁇ g/plate for the WP2 uvrA strain.
  • test substance SG6 did not cause gene mutations under these test conditions (FIG. 6).
  • the treatment concentration of the test substance group was set at 10, 100, and 1,000 ⁇ M in the first test, and 4, 25, and 62.5 ⁇ M in the second test, and the negative control group was not treated.
  • the suppression rate (%) of hERG channel currents of the test substance group at 4 and 10 ⁇ M concentrations was 39.53 ⁇ 7.53 and 50.68 ⁇ 2.46%.
  • necrosis and degeneration of muscle fibers at the administration site occurred in the male and female test substance 0.25, 0.5, and 1 mg/animal groups. and chronic inflammation were observed, and muscle fiber degeneration and chronic inflammation were observed in skeletal muscle (biceps femoris) in the female test substance 0.5 and 1 mg/animal administered groups.
  • the purpose of the rat pharmacokinetic test is to determine changes in blood concentration of SG6. To confirm the blood concentration of the test substance, it was administered intramuscularly to male Sprague-Dawley rats at a concentration of 0.1 mg/head.
  • Cross-sectional blood samples were taken at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 16, 20, and 24 hours after intramuscular administration, and the drug concentration in the blood was analyzed using LC-MS/MS. During the test period, general symptoms were observed and body weight was measured, and euthanasia was performed after administration was completed.
  • the average particle size, polydispersity (PDI), and Zeta-Potential were confirmed using Zetasizer (Zetasizer Nano pro, Malven Panalytical Ltd.) (particle size standard: 150 ⁇ 500) Within nm, PDI standard: 0.500 or less, Zeta-Potential standard: +25 ⁇ 55 mV).
  • mRNA-liposome complex can be efficiently introduced into cells in vitro , encoded as a target protein, and ultimately act as an antigen protein contributing to immunogenicity.
  • the mRNA maintained in the liposome complex was highest at pH 4.0 (77.9%) among pH 4.0 to 9.0, and decreased by about 18% compared to the initial mRNA.
  • the mRNA in the complex in the pH 9.0 solution decreased by about 18% after 1 hour, and decomposition and regeneration proceeded in a short period of time. Therefore, mRNA in the complex at pH 9.0 showed lower mRNA stability compared to pH 4.0. Considering the heat-unstable nature of mRNA, it was observed that the mRNA in the pH 4.0 complex was relatively stable even at 37°C.
  • the mRNA-liposome-SG6 complex used for preliminary efficacy evaluation in vivo was refrigerated for a certain period of time to confirm the functional stability of the mRNA over time.
  • the samples were refrigerated for about 6 weeks and analyzed in the same manner at 3-week intervals using Western blotting to confirm the expression of the target protein.
  • the Delta variant target protein was expressed in the mRNA-liposome-SG6 complex stored for a certain period of time.
  • the mRNA has functional stability so that it can be stably maintained for a certain period of time and effectively express the antigen protein.

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Abstract

La présente invention concerne une composition vaccinale à base d'ARNm comprenant de l'ARNm codant pour un peptide ou une protéine antigénique, un liposome et un transporteur moléculaire cationique (SG6). La composition vaccinale de la présente invention ne présente aucune cytotoxicité, mais se caractérise par une grande efficacité d'administration d'ARNm, une excellente stabilité et une très grande innocuité, de même que par une remarquable efficacité d'expression de peptides ou de protéines antigéniques, et peut ainsi être efficacement utilisée en tant que composition vaccinale à base d'ARNm. Par ailleurs, la présente invention a été réalisée avec le soutien du Projet de développement et de recherche en matière de technologies médicales et de santé de l'Institut coréen de développement et de recherche sur la santé financé par le ministère de la Santé et de la Protection sociale (numéro d'identification du projet : HQ21C0274).
PCT/KR2023/021981 2022-12-29 2023-12-29 Composition vaccinale comprenant un complexe ionique d'un transporteur moléculaire cationique et d'arnm Ceased WO2024144348A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2022-0188512 2022-12-29
KR20220188512 2022-12-29
KR10-2023-0195493 2023-12-28
KR1020230195493A KR20240107033A (ko) 2022-12-29 2023-12-28 양이온성 분자 수송체 및 mRNA의 이온복합체를 포함하는 백신 조성물

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WO2024144348A1 true WO2024144348A1 (fr) 2024-07-04

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060112791A (ko) * 2005-04-28 2006-11-02 학교법인 포항공과대학교 당 또는 당 유사체를 골격으로 하는 분자 수송체 및 그의제조방법
WO2021159985A1 (fr) * 2020-02-13 2021-08-19 Stemirna Therapeutics Co., Ltd. Agent de vaccin pour le traitement ou la prévention d'une maladie de coronavirus
KR20220117133A (ko) * 2021-02-15 2022-08-23 주식회사 바이오파마 양이온성 분자 수송체 및 SARS-CoV-2 mRNA의 이온 복합체를 포함하는 코로나바이러스감염증-19 예방 백신 조성물
KR20220126235A (ko) * 2021-03-08 2022-09-15 아이진 주식회사 Rna의 체내 전달용 조성물 및 이의 제조방법
US20220378701A1 (en) * 2020-11-06 2022-12-01 Sanofi LIPID NANOPARTICLES FOR DELIVERING mRNA VACCINES

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060112791A (ko) * 2005-04-28 2006-11-02 학교법인 포항공과대학교 당 또는 당 유사체를 골격으로 하는 분자 수송체 및 그의제조방법
WO2021159985A1 (fr) * 2020-02-13 2021-08-19 Stemirna Therapeutics Co., Ltd. Agent de vaccin pour le traitement ou la prévention d'une maladie de coronavirus
US20220378701A1 (en) * 2020-11-06 2022-12-01 Sanofi LIPID NANOPARTICLES FOR DELIVERING mRNA VACCINES
KR20220117133A (ko) * 2021-02-15 2022-08-23 주식회사 바이오파마 양이온성 분자 수송체 및 SARS-CoV-2 mRNA의 이온 복합체를 포함하는 코로나바이러스감염증-19 예방 백신 조성물
KR20220126235A (ko) * 2021-03-08 2022-09-15 아이진 주식회사 Rna의 체내 전달용 조성물 및 이의 제조방법

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