WO2016093358A1 - Composition comprenant des nanoparticules en forme de bâtonnet et de l'acide nucléique - Google Patents

Composition comprenant des nanoparticules en forme de bâtonnet et de l'acide nucléique Download PDF

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WO2016093358A1
WO2016093358A1 PCT/JP2015/084853 JP2015084853W WO2016093358A1 WO 2016093358 A1 WO2016093358 A1 WO 2016093358A1 JP 2015084853 W JP2015084853 W JP 2015084853W WO 2016093358 A1 WO2016093358 A1 WO 2016093358A1
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rod
strand
nucleic acid
nanoparticles
composition
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PCT/JP2015/084853
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Japanese (ja)
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謙一 新倉
居城　邦治
澤　洋文
靖子 大場
進太郎 小林
太悠 田崎
忠樹 鈴木
有樹 大原
哲郎 中野
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国立大学法人北海道大学
国立感染症研究所長が代表する日本国
協和発酵バイオ株式会社
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Publication of WO2016093358A1 publication Critical patent/WO2016093358A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates

Definitions

  • the present invention relates to a composition comprising rod-shaped nanoparticles and a nucleic acid.
  • an adjuvant exhibiting an innate immune stimulating action is an additive that can effectively increase immunogenicity.
  • nucleic acid-based adjuvants such as double-stranded RNA that is a ligand for TLR3 (Patent Document 1) and unmethylated oligonucleotide that is a ligand for TLR9 (Non-Patent Document 1) are recognized as highly effective adjuvants.
  • Gold nanoparticles are expected to serve as antigen carriers for vaccines because they produce less antibodies against themselves. Since the first antibody production using glutamic acid-modified gold nanoparticles was reported in 1986, many applied studies of nanoparticles using various antigens have been conducted, and studies using influenza HA antigens have also been reported (non-patented). Reference 2).
  • Non-Patent Documents 3-5 a sufficient immune response that can be put to practical use cannot be obtained only by using a nucleic acid-based adjuvant or nanoparticles alone, and further improvement is necessary.
  • An object of the present invention is to provide a composition comprising nanoparticles and a nucleic acid having an enhanced adjuvant effect as compared with the conventional art.
  • the present invention relates to the following [1] to [11].
  • [1] A composition comprising rod-shaped nanoparticles and a nucleic acid.
  • the length of the short axis of the rod-type nanoparticle is 4 to 20 nm, and the length of the long axis is 2 to 20 times the length of the short axis.
  • Composition [3] The composition according to [1] or [2] above, wherein the material of the rod-type nanoparticles is selected from the group consisting of gold, platinum, silver, titanium oxide, silica, silicon, and a biodegradable polymer. . [4] The composition according to [3] above, wherein the material of the rod-type nanoparticles is gold.
  • nucleic acid is a double-stranded ribonucleic acid.
  • double-stranded ribonucleic acid has a weight average chain length in the range of 0.1 kilobase pair (kbp) to 2.0 kbp.
  • the first strand of the double-stranded ribonucleic acid is composed of two or more single-stranded ribonucleic acids, and all of the two or more single-stranded ribonucleic acids constituting the first strand are composed of the same kind of ribonucleotides.
  • the second strand of the double-stranded ribonucleic acid is composed of one single-stranded ribonucleic acid, and each of the two or more single-stranded ribonucleic acids constituting the first strand constitutes the second strand.
  • composition according to any one of [1] to [7] above wherein the rod-type nanoparticles are bound to a nucleic acid.
  • An immunostimulatory substance, an adjuvant, or a pharmaceutical comprising the composition according to any one of [1] to [9] above.
  • composition according to any one of [1] to [9] above which comprises mixing a suspension containing rod-shaped nanoparticles and an aqueous solution of nucleic acid, and coating the surface of the nanoparticles with nucleic acid. Production method.
  • composition comprising rod-shaped nanoparticles and a nucleic acid having an enhanced adjuvant effect as compared with conventional ones.
  • Example 1 The transmission electron microscope image of the gold nanoparticle used for Example 1 (left figure), the control example 1 (middle figure), and the control example 2 (right figure) is shown.
  • the scale bar indicates 100 nm.
  • Each experimental section is as follows.
  • each experimental section is as follows. 1: buffer only, 2: antigen only, 3: antigen + polyIC (40: 400) 10 ⁇ g, no gold particles, 4: 4 antigen + polyIC (40: 400) 400 1 ⁇ g, no gold particles, 5: antigen + polyIC (40: 400) 10 ⁇ g + spherical gold particles (diameter 40nm), 6: antigen + polyIC (40: 400) 1 ⁇ g + spherical gold particles (diameter 40nm), 7: antigen + spherical gold particles (diameter 40nm) only, 8: Antigen + polyIC (40: 400) 10 ⁇ g + spherical gold particles (diameter 20nm), 9: antigen + polyIC (40: 400) 1 ⁇ g + spherical gold particles (diameter 20nm), 10: antigen + spherical gold particles (diameter 20nm) ) Only, 11: antigen + polyIC 40 (40: 400) 10 ⁇
  • composition which consists of a rod-type nanoparticle and nucleic acid of this invention This invention relates to the composition (henceforth the composition of this invention) which consists of a rod-type nanoparticle and nucleic acid.
  • the “rod-type nanoparticle” is a nano-sized particle (that is, a maximum diameter of 1 to 1000 nm), and the ratio of the length in the major axis direction to the length in the minor axis direction (aspect ratio) (Ratio) refers to rod-shaped particles that are greater than 1 (usually greater than 1.2).
  • the size of the rod-type nanoparticles in the complex of the present invention is not particularly limited, but is preferably extremely low in immunogenicity.
  • the minor axis length is preferably 4 to 20 nm, more preferably Preferably in the range of 5-15 nm, most preferably 6-9 nm, and the length of the major axis is preferably 2-20 times, more preferably 3-10 times, most preferably the length of the minor axis 3 to 5 times.
  • the size of the rod-type nanoparticles is preferably a size determined by observation with a transmission electron microscope.
  • a transmission electron microscope eg, Hitachi High-Tech HD-2000 system
  • the size of the rod-type nanoparticles may be the average size of the nanoparticles in the composition. In that case, it is possible to obtain an average size by randomly selecting a large number (eg, 100 or more) of nanoparticles from one or more electron microscope images, determining the size of each particle, and arithmetically averaging them. it can.
  • the material of the rod-type nanoparticles is not particularly limited, but is preferably a substance having extremely low immunogenicity, specifically, inorganic materials represented by gold, platinum, silver, titanium oxide, and silica, and A material selected from the group consisting of silicon and organic materials such as biodegradable polymers is preferable, and gold is particularly preferable.
  • Biodegradable polymers include CHP nanogels (ie hydrophobized pullulan gels in which cholesteryl groups are partially introduced into pullulan, a water-soluble polysaccharide; Sasaki Y. et al., Chemical Record, 10: 366-376 ( 2010)).
  • the nucleic acid is not particularly limited, but is preferably a nucleic acid that exhibits adjuvant activity when used in combination with the rod-type nanoparticles described above.
  • the nucleic acid may be single-stranded or double-stranded, and may be any of DNA, RNA, and DNA / RNA chimera.
  • the chain length of the nucleic acid is not particularly limited, but is preferably 0.1 kb (p) to 2.0 kb (p) from the viewpoint of adjuvant activity and low toxicity.
  • Examples of preferable nucleic acids include double-stranded ribonucleic acid (dsRNA) described in Patent Document 1 (in the present specification, nucleic acid or dsRNA includes salts thereof). Hereinafter, the dsRNA will be described.
  • the dsRNA has a weight average chain length in the range of 0.1 kbp to 2.0 kbp, more preferably a weight average chain length in the range of 0.1 kbp to 1.0 kbp, even more preferably.
  • the dsRNA further has the following characteristics.
  • the terms “first chain” and “second chain” are used synonymously with Patent Document 1.
  • the first strand may have a gap (that is, a portion where the second strand does not form a double bond with the first strand).
  • the first strand of dsRNA is composed of two or more single-stranded ribonucleic acid (ssRNA), and all of the two or more ssRNAs constituting the first strand are homopolymers composed of the same kind of ribonucleotides.
  • the second strand of the dsRNA is composed of one ssRNA, and each of the two or more ssRNAs constituting the first strand is divided into two partial regions of one ssRNA constituting the second strand.
  • the weight average strand length of two or more ssRNAs constituting the first strand is 1 ⁇ 2 or less of the weight average strand length of one ssRNA constituting the second strand.
  • all ssRNAs constituting the first strand are homopolymers composed of the same kind of ribonucleotides.
  • this ssRNA is not limited to the following, it can be, for example, adenylate homopolymer, uridylate homopolymer, guanylate homopolymer, cytidylate homopolymer, inosinate homopolymer and the like.
  • the ssRNA constituting the second strand is capable of forming a duplex with each of the two or more ssRNAs constituting the first strand in the environment where the dsRNA is used. It has a base sequence complementary to one strand of ssRNA. Therefore, the second strand ssRNA is not limited to a sequence in which all bases are complementary to the bases of the first strand ssRNA.
  • the use environment of the dsRNA of the present invention is, for example, in physiological saline (pH is about 7.4, sodium chloride concentration is about 150 mM) at a temperature of about 37 ° C. It can be considered that it is dissolved in the solution.
  • the second strand ssRNA is not limited to the ssRNA having a sequence in which one or more ribonucleotides complementary to the ribonucleotides constituting each ssRNA of the first strand are combined.
  • Ribonucleotides that are not complementary to the ribonucleotides constituting each ssRNA of the first strand constitute the ssRNA as long as complementary binding to the ssRNA of the first strand is not significantly inhibited.
  • Complementarity between bases of ribonucleotides is well known in the art.
  • the first strand is an adenylic acid homopolymer, uridylic acid and inosinic acid as the complementary ribonucleotides
  • adenylic acid, guanylic acid, cytidylic acid, xanthyl as the non-complementary ribonucleotides
  • adenylic acid is used as the complementary ribonucleotide
  • uridylic acid guanylic acid, inosinic acid, cytidylic acid, xanthyl is used as the non-complementary ribonucleotide.
  • the first strand is a guanylate homopolymer, cytidylic acid as the complementary ribonucleotide, uridylic acid, adenylic acid, guanylic acid, inosinic acid, xanthyl as the non-complementary ribonucleotide
  • the first chain is a cytidylic acid homopolymer
  • the complementary ribonucleotides include guanylic acid and inosinic acid
  • the non-complementary ribonucleotides include adenylic acid, uridylic acid, cytidylic acid, and xanthylic acid
  • the first strand is an inosinic acid homopolymer.
  • the complementary ribonucleotides include adenylic acid and cytidylic acid
  • the non-complementary ribonucleotides include uridylic acid, guanylic acid, inosinic acid, and xanthylic acid.
  • the first strand ssRNA is an inosinate homopolymer and the second strand ssRNA is ssRNA containing cytidylic acid in a proportion of 80% or more, eg, the first strand ssRNA Is an inosinic acid homopolymer, and the second strand ssRNA is a cytidylic acid homopolymer.
  • the weight average strand length of the ssRNA constituting the first strand is, for example, 0.02-1.0 kb, preferably 0.02-0.4 kb, more preferably 0.02-0.2 kb. is there.
  • the weight average strand length of the second strand ssRNA is, for example, 0.04 to 2.0 kb, preferably 0.04 to 0.8 kb, and more preferably 0.04 to 0.4 kb.
  • the weight average chain length of the nucleic acid contained in the complex of the present invention is preferably a chain length determined by gel permeation chromatography (GPC) analysis. Specifically, GPC analysis is performed using a nucleic acid such as dsRNA having a known molecular weight as a standard product, and the average chain length or the median chain length is calculated from the obtained data. The determination of the weight average chain length using GPC analysis can be performed according to the teaching of Patent Document 1 above.
  • the structure of the 5 ′ end and 3 ′ end of the nucleic acid is not limited. Specifically, the 5 ′ end may be either hydroxyl, monophosphate, diphosphate, or triphosphate, and the 3 ′ end may be either hydroxyl, monophosphate, diphosphate, or triphosphate. It may be.
  • examples of the salt include metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like.
  • ammonium salts include salts such as ammonium and tetramethylammonium.
  • the organic amine addition salt include salts such as trishydroxyaminomethane.
  • amino acid addition salts include salts of lysine, arginine, histidine, tryptophan, ornithine and the like.
  • the composition comprising the rod-shaped nanoparticle and nucleic acid of the present invention preferably contains a complex in which the rod-shaped nanoparticle is bound to the nucleic acid by a covalent bond or non-covalent interaction.
  • the nucleic acid may not form the complex.
  • a functional group eg, thiol group, amino group, carbonyl group, etc.
  • a nucleic acid is introduced into a nucleic acid by enzymatic or chemical methods, and these are bonded to the nanoparticle surface by covalent bond with the nanoparticle. It can be performed by immobilizing to.
  • the non-covalent interaction described above may be due to electrostatic interaction, hydrophobic interaction, hydrogen bonding, etc., and preferably due to electrostatic interaction.
  • electrostatic interaction the rod-type nanoparticles and the nucleic acid may be bound via a cation modifier. Any cation modifier may be used as long as it binds rod-shaped nanoparticles and nucleic acids, and preferably 16-mercaptohexadecyltrimethylammonium bromide (hereinafter referred to as MTAB) can be used.
  • the compounding amount of the cation modifying agent can be appropriately determined by those skilled in the art. For example, 0.02 to 2 mg of the cation modifying agent can be usually used for 1 pmol of rod-shaped nanoparticles.
  • the composition of the present invention is preferably obtained by binding 0.03 to 30 mg, more preferably 0.1 to 10 mg, most preferably 0.3 to 3 mg of nucleic acid per 1 pmol of rod-shaped nanoparticles. It is a composition.
  • the rod-shaped nanoparticles may have a protective agent added to ensure dispersibility, but any protective agent that can be used in the present invention is any compound that can be removed by centrifugation or the like. Even things can be used. Examples of such a protective agent include hexadecyl ammonium bromide (hereinafter referred to as CTAB).
  • CTAB hexadecyl ammonium bromide
  • the rod-shaped nanoparticles can be cationized by adding a cation modifying agent such as MTAB, if necessary, after removing the protective agent by centrifugation or the like.
  • a complex of rod-type nanoparticles and nucleic acid in which the surface of the nanoparticle is coated with nucleic acid can be formed.
  • the complex which the nucleic acid covalently bonded to the nanoparticle surface can be formed by mixing the rod-shaped nanoparticle suspension and the aqueous solution of the nucleic acid into which the functional group is introduced.
  • An adjuvant vaccine can be provided by blending a composition comprising rod-shaped nanoparticles and nucleic acids prepared in this way into a vaccine.
  • the composition of the present invention can be used as an immunostimulatory substance.
  • the immune response induced in the individual to which it is administered may be any humoral immunity, mucosal immunity, cellular immunity, etc. Good.
  • the antigen when the composition of the present invention is used as an adjuvant is not particularly limited as long as it can induce an immune reaction derived from the antigen in an individual, but generally the immune reaction derived from this antigen is human or human. Those having the effect of preventing and / or treating diseases of mammals, birds and fish other than those are appropriately selected. Such antigens are known in the art.
  • viruses, mycoplasma, bacteria, parasites, toxins, tumor cells, etc. can be genetically modified, treated with various reagents (formalin, ⁇ -propiolactone, enzyme, etc.), radiation, Those that have been attenuated, detoxified or non-pathogenic by treatment with ultrasound, heat, etc.
  • reagents formalin, ⁇ -propiolactone, enzyme, etc.
  • radiation Those that have been attenuated, detoxified or non-pathogenic by treatment with ultrasound, heat, etc.
  • Those components extracted and purified from viruses, mycoplasma, bacteria, parasites, toxins, tumor cells, etc. eg : Proteins such as membrane surface proteins, nuclear proteins, proteoglycans, polypeptides, membrane components, etc.
  • identifying and identifying antigen genes from viruses, mycoplasma, bacteria, parasites, toxins, tumor cells, etc.
  • Peptides and tampers obtained by incorporating the gene into a vector such as a plasmid and expressing it in a host cell Quality or subunit vaccines, etc. composed of variants thereof are mentioned.
  • More specific antigens or vaccines include BCG, oral live polio (OPV) vaccine, rape seedling (smallpox) vaccine, measles vaccine, rubella vaccine, measles-rubella vaccine (MR vaccine), mumps (mumps) ) Vaccines, chickenpox vaccines, yellow fever vaccines, rotavirus vaccines, influenza vaccines and other live vaccines; influenza virus vaccines, pneumococcal vaccines, influenza bacilli b-type vaccines, rabies vaccines, cholera vaccines, triple-mixed (DPT) vaccines (diphtheria Pertussis / tetanus mixed vaccine, double mixed (DT) vaccine (diphtheria / tetanus mixed vaccine), inactivated polio vaccine (IP
  • the composition of the present invention can be formulated by combining with a pharmaceutically acceptable carrier known in the art.
  • the dosage form may be any form such as injection, oral administration, pulmonary administration, buccal administration, intraocular administration, intranasal administration and the like.
  • a suspension suspended in a commonly used solvent for injection can be used, and it is usually administered by injection subcutaneously or intramuscularly.
  • the orally-administered agent include usual orally-administered preparations such as tablets, granules, fine granules, capsules, etc., but dosage forms designed to release the drug in the small intestine, such as enteric tablets, Enteric granules, enteric capsules and enteric fine granules are preferred.
  • an inhalant delivered to the alveoli by a pulmonary inhaler is preferable.
  • Oral administration agents, intraocular administration agents and intranasal administration agents include oral tablets, oral sprays, eye drops, nasal drops, aerosols, ointments, gels, creams, solutions, suspensions, lotions, A dry powder agent, a sheet agent, a patch, etc. are mentioned.
  • the antigenic substance may be included in the preparation as it is without modification or alteration, or in order to increase the antigenicity or stability of the antigenic substance, for example, Modifications or alterations such as covalent or non-covalent binding to proteins with higher molecular weight than antigen (eg ⁇ -galactosidase and core protein), addition of appropriate sugar chains, encapsulation in liposomes, etc. .
  • the amount of the composition of the present invention and the antigenic substance contained in the immunopotentiating preparation can be appropriately adjusted by those skilled in the art according to the mixing ratio with other components, the size of the preparation, and the like.
  • the composition containing the composition of this invention can also be manufactured as an adjuvant formulation separate from a vaccine.
  • An adjuvant other than the composition of the present invention may be appropriately contained in the preparation.
  • the above dosage forms include excipients, binders, disintegrants, lubricants and other carriers that are commonly used in producing specific dosage forms, sweeteners, surfactants, suspending agents, emulsifiers, and coloring. Appropriate amounts of various formulation additives such as preservatives, preservatives and stabilizers can be appropriately contained.
  • the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples.
  • the size of the nanoparticles was measured by the method described above.
  • rod-shaped gold nanoparticles having a major axis of 27 ⁇ 3.1 nm and a minor axis of 7.3 ⁇ 0.97 nm whose surface was protected with hexadecylammonium bromide (CTAB) were prepared. After centrifuging the suspension of the rod-shaped gold nanoparticles and discarding the supernatant, the operation of adding pure water to suspend and centrifuging and discarding the supernatant was repeated three times. Thereafter, 16-mercaptohexadecyl trimethylammonium bromide (MTAB) was added to modify the gold nanoparticle surface with MTAB.
  • MTAB 16-mercaptohexadecyl trimethylammonium bromide
  • Example 1 Formation of 40 nm spherical gold nanoparticle-poly (I: C) complex Centrifugal supernatant of spherical gold nanoparticle suspension with a diameter of 38 ⁇ 4.3 nm protected with hexadecylammonium bromide (CTAB) on the surface Then, the same operation as in Example 1 was performed to obtain a 40 nm gold nanoparticle composite coated with polyIC (40: 400).
  • CTAB hexadecylammonium bromide
  • Example 1 Transmission Electron Microscope Image of Gold Nanoparticles Gold nanoparticles used in Example 1 and Control Examples 1 and 2 were observed with a transmission electron microscope. As is clear from FIG. 1, the nanoparticles used in Example 1 are rod-shaped, and the nanoparticles of Comparative Examples 1 and 2 are spherical. The length of the bar in FIG. 1 is 100 nm.

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Abstract

La présente invention concerne une composition comprenant des nanoparticules et de l'acide nucléique, la composition ayant un effet adjuvant amélioré. La présente invention concerne une composition comprenant des nanoparticules en forme de bâtonnet et de l'acide nucléique. Des exemples de nanoparticules en forme de bâtonnet préférées comprennent des particules constituées d'or, de platine, d'argent, d'oxyde de titane, de silice, de silicium, de polymères biodégradables et d'autres matériaux de ce type, les particules ayant une longueur d'axe court de 4-20 nm et une longueur d'axe long égale à 2 à 20 fois la longueur de l'axe court. Des exemples d'acides nucléiques préférés comprennent un acide ribonucléique bicaténaire ayant une longueur de chaîne moyenne en poids comprise dans la plage de 0,1 à 2,0 kb. Dans un mode de réalisation préféré, la composition contient des complexes de nanoparticules en forme de bâtonnet et d'acide nucléique.
PCT/JP2015/084853 2014-12-12 2015-12-11 Composition comprenant des nanoparticules en forme de bâtonnet et de l'acide nucléique WO2016093358A1 (fr)

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