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WO2019125031A1 - Transporteur de gène pour la voie orale, et son utilisation - Google Patents

Transporteur de gène pour la voie orale, et son utilisation Download PDF

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Publication number
WO2019125031A1
WO2019125031A1 PCT/KR2018/016406 KR2018016406W WO2019125031A1 WO 2019125031 A1 WO2019125031 A1 WO 2019125031A1 KR 2018016406 W KR2018016406 W KR 2018016406W WO 2019125031 A1 WO2019125031 A1 WO 2019125031A1
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WO
WIPO (PCT)
Prior art keywords
gene
protamine
smcc
carrier
present
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Ceased
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PCT/KR2018/016406
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English (en)
Korean (ko)
Inventor
이용규
차승빈
강성훈
이선화
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Kb Biomed Inc
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Kb Biomed Inc
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Publication date
Priority claimed from KR1020180166594A external-priority patent/KR102177339B1/ko
Application filed by Kb Biomed Inc filed Critical Kb Biomed Inc
Priority to US16/956,784 priority Critical patent/US20200407407A1/en
Publication of WO2019125031A1 publication Critical patent/WO2019125031A1/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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form

Definitions

  • the present invention relates to a gene delivery vehicle for oral administration, and more particularly, to a gene delivery vehicle for oral administration in which a cationic protamine capable of aggregating an anionic gene in an immunoglobulin Fc region is linked by an SMCC linker.
  • the Fc region of the antibody serves to mobilize the immune leukocyte or serum complement molecule to remove damaged cells such as cancer cells or infected cells.
  • the site on the Fc between the C ⁇ 2 and C ⁇ 3 domains mediates the interaction with the neonatal receptor FcRn and its binding recirculates the intracellularly transferred antibody from the endosome into the bloodstream. This process has advantageous antibody serum half-life in the range of 1 to 3 weeks associated with inhibition of kidney filtration due to the enormous size of the full-length molecule.
  • the binding of Fc to FcRn also plays an important role in antibody delivery.
  • the Fc region plays an essential role in maintaining circulating prolonged serum persistence by circulating antibodies through intracellular trafficking and recycling mechanisms.
  • the Fc receptor (FcRn) transport system has the ability to pass through intestinal epithelial cells, thus solving the problem of absorption efficiency as described above.
  • the circulation using the Fc receptor has the ability to circulate for the longest time compared to other circulation methods and has a half-life period of 7 to 21 days in human condition, so it can have an effect superior to other types of IgG .
  • the present invention has been conceived to solve the above-mentioned problems.
  • the present inventors have conducted intensive studies on a carrier for efficiently delivering a gene into a body cell.
  • the present inventors have found that, in order to effectively condense an anionic gene,
  • the present inventors have confirmed that the gene carrier having SMCC linked immunoglobulin Fc region with the protamine having the amino acid sequence shown in SEQ ID NO: 1 has stability against pH and the body enzyme, and confirmed the possibility of use as a gene carrier for oral administration. .
  • the present invention relates to a DNA encoding a protamine
  • It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating diabetes comprising the gene carrier and the GLP-1 gene combined with the carrier as an active ingredient.
  • Protamine which binds to the gene of interest
  • the immunoglobulin Fc region may consist of the amino acid sequence of SEQ ID NO: 1.
  • the immunoglobulin Fc region may comprise the nucleotide sequence of SEQ ID NO: 2.
  • the immunoglobulin Fc region may be derived from any one selected from the group consisting of IgG, IgA, IgD, IgE and IgM.
  • the immunoglobulin Fc region can be derived from IgG.
  • the linker may be SMCC (succinimidyl 4- (N-maleimido-methyl) cyclohexane-1-carboxylate).
  • the target gene and the gene carrier may be prepared by mixing at a ratio of 1: 5 - 1: 50 wt% (w / w).
  • the present invention provides a method for producing the gene carrier, which comprises the following steps.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes, which comprises the gene carrier and a GLP-1 (Glucagon Like Peptide-1) gene combined with the carrier as an active ingredient.
  • GLP-1 Glucagon Like Peptide-1
  • the diabetes may be type 2 diabetes.
  • the GLP-1 gene may comprise the nucleotide sequence of SEQ ID NO: 3.
  • the present invention also provides a method of preventing or treating diabetes, comprising the step of administering the pharmaceutical composition to a subject.
  • the present invention provides the use of the pharmaceutical composition for preventing or treating diabetes.
  • the gene carrier for oral administration of the present invention can effectively induce gene expression in the body by binding protamine, which is a cationic property protein, to the Fc region and condensing it with a gene having an anionic property, and when administered orally, It is possible to transfer the gene to the small intestine by protecting the gene from the degradation due to the immunological action and the half life period is relatively long when the gene is expressed in the small intestine so that the possibility of the long term therapeutic effect is confirmed, Are expected to be usefully useful as carriers for oral administration of various genes.
  • protamine which is a cationic property protein
  • FIG. 1A shows NMR analysis results to confirm the physical properties of protamine-SMCC-Fc according to the present invention.
  • FIG. 1B shows FT-IR analysis results of protamine-SMCC-Fc.
  • FIG. 1C shows the result of confirming whether or not the junction between protamine-SMCC and the Fc region is confirmed using SDS-PAGE.
  • FIG. 2A shows results of dynamic light scattering (DLS) analysis for confirming the particle size of protamine-SMCC-Fc.
  • DLS dynamic light scattering
  • Figure 2b shows SEM imaging results for protamine-SMCC-Fc.
  • FIG. 2C shows the results of DLS analysis and zeta potential measurements of each complex prepared by mixing DNA and protamine-SMCC-Fc at various weight% (w / w) ratios.
  • Figure 3 shows the acid stability results of GLP-1 and protamine-SMCC-Fc complexes (DNA + Protamine-SMCC-Fc) under various pH conditions (pH 7.4, 5.6, 1.2).
  • 4A is a SEM image of DNA / protamine-SMCC-Fc (DNA + Protamine-SMCC-Fc) complex.
  • 4B shows AFM analysis results for DNA / protamine-SMCC-Fc (DNA + Protamine-SMCC-Fc) complex.
  • FIG. 5 shows the result of agarose gel electrophoresis on a complex prepared by varying the ratio of GLP-1 DNA and protamine-SMCC-Fc in order to confirm the junction of DNA / protamine-SMCC-Fc complex.
  • FIG. 6 shows the results of serum stability and DNase analysis to confirm the gene-protecting ability of the protamine-SMCC-Fc gene carrier according to the present invention by serum and enzymatic degradation.
  • FIG. 7 shows FcRn-mediated cellular uptake of protamine-SMCC-Fc of the protamine-SMCC-Fc gene transporter according to the present invention in FcRn-positive cells (HT29) and negative cells (KB), respectively.
  • FIG. 8 shows the cell viability of HT-29 cells treated with the protamine-SMCC-Fc gene transporter at different concentrations.
  • FIG. 9 shows the results of confirming the cell permeability of the protamine-SMCC-Fc gene transporter.
  • FIG. 10 shows the results of confirming GLP-1 condensation on the GLP-1 / protamine-SMCC-Fc complex.
  • FIG. 11 shows the results of in vivo experiments in which the GLP-1-protamine-SMCC-Fc complex was orally administered to the animal model at 4-day intervals and the number of non-fasting blood glucose levels was measured.
  • the inventors of the present invention have conducted extensive studies on a carrier for efficiently transferring a gene into a body cell. As a result, it has been found that a protein having cationic properties, that is, a protein having an anionic property, And the stability against the enzyme in the body, confirming the possibility of use as a gene delivery vehicle for oral administration, thus completing the present invention.
  • the present invention relates to a DNA encoding a protamine
  • the term " protamine " is a natural cationic protein rich in arginine, which is found in animal testis, especially in the sperm nucleus of fishes, including salmon, and through association with DNA or dissociation such as histone It is known as a protein involved in genetic information expression.
  • the molecular weight of protamine extracted from the sperm nuclei of fish is about 4,000 to 10,000, and 70% or more of the constituent amino acids are present as arginine, but the protamine used in the present invention is not limited thereto.
  • the term " immunoglobulin Fc region &quot refers to the heavy and light chain variable region, the heavy chain constant region 2 (CH2) and the heavy chain constant region (CH1) except for the heavy chain constant region 1 (CH1) 3 (CH3) moiety, and may include a hinge portion in the heavy chain constant region.
  • the immunoglobulin Fc region may contain a heavy chain constant region 1 (CH1) and / or a heavy chain constant region 1 < / RTI > (CL1). It may also be a region in which some long amino acid sequences corresponding to CH2 and / or CH3 have been removed.
  • the immunoglobulin Fc region of the present invention includes a naturally occurring amino acid sequence as well as its sequence derivative (mutant).
  • An amino acid sequence derivative means that at least one amino acid residue in the native amino acid sequence has a different sequence by deletion, insertion, non-conservative or conservative substitution, or a combination thereof.
  • the immunoglobulin Fc region may consist of the amino acid sequence of SEQ ID NO: 1, and the gene encoding the immunoglobulin Fc region may comprise the nucleotide sequence of SEQ ID NO: 2.
  • the amino acid sequence shown in SEQ ID NO: 1 or the nucleotide sequence shown in SEQ ID NO: 2 is 70% or more, preferably 80% or more, more preferably 90% or more, still more preferably 95% And most preferably at least 98% sequence homology.
  • Fc regions may also be obtained from native forms isolated in vivo in animals such as humans, cows, goats, pigs, mice, rabbits, hamsters, rats or guinea pigs and may be obtained from recombinant animal cells or microorganisms Or derivatives thereof.
  • the method of obtaining from the native form may be a method of separating the whole immunoglobulin from the living body of human or animal, and then obtaining the protein by treating the proteolytic enzyme. When papain is treated, it is cleaved into Fab and Fc, and when pepsin is treated, it is cleaved into pF'c and F (ab) 2.
  • the immunoglobulin Fc region is preferably a recombinant immunoglobulin Fc region obtained from a microorganism from a human-derived Fc region.
  • the immunoglobulin Fc region may be a natural type sugar chain, an increased sugar chain as compared to the native type, and a reduced sugar chain or sugar chain as compared with the native type.
  • Conventional methods such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms can be used to increase or decrease immunoglobulin Fc sugar chains.
  • the immunoglobulin Fc region in which the sugar chain is removed from Fc is significantly reduced in binding force with the complement (c1q), and the antibody-dependent cytotoxicity or complement-dependent cytotoxicity is reduced or eliminated, resulting in unnecessary immune response in vivo Do not.
  • forms that are more consistent with the original purpose of the drug as a carrier will be referred to as immunoglobulin Fc regions in which the sugar chain is removed or unglycosylated.
  • the immunoglobulin Fc region may be an Fc region derived from IgG, IgA, IgD, IgE, IgM, or a combination thereof or a hybrid thereof, and most preferably the most abundant ligand binding Derived IgG known to enhance the half-life of the protein.
  • protamine having a cationic property is bound to an immunoglobulin Fc region, wherein the linker for binding the protamine and the Fc region is sulfo-SMCC (sulfosuccinimidyl 4 - (N-maleimido-methyl) cyclohexane-1-carboxylate), but not limited thereto, any linker having a property of selectively reacting with both an amine group and a thiol group can be used without limitation.
  • sulfo-SMCC sulfosuccinimidyl 4 - (N-maleimido-methyl) cyclohexane-1-carboxylate
  • the present invention provides a method for producing the gene carrier comprising the following steps.
  • in vitro and in vivo analyzes were carried out to confirm the characteristics of the gene carriers prepared by the above method and to verify their availability.
  • a gene carrier of protamine-SMCC-Fc in which an immunoglobulin Fc region and protamine are linked, was synthesized using the linker SMCC (see Example 1).
  • NMR and FT-IR experiments were carried out to confirm the physical properties of the protamine-SMCC-Fc gene transporter.
  • TNBSA analysis was performed to confirm the optimal binding ratio and protamine-SMCC-Fc SDS-PAGE electrophoresis to confirm the junction (see Example 2).
  • the state of the junction between protamine-SMCC-Fc and DNA is specifically confirmed, and the DNA and the protamine-SMCC-Fc are bonded in a weight ratio of 1:10 or more to form a complex And that the complex was stable at various pH conditions (see Example 3).
  • the stability and cytotoxicity of the serum were confirmed, and celluar uptake was confirmed to confirm a remarkably high absorption effect in FcRn-positive HT-29 cells.
  • the cell permeability of the gene transporter was examined by conducting cell membrane permeability test of the HT-29 monolayer to confirm the cell permeability, and finally, the gene condensation effect was specifically confirmed (see Example 4).
  • the GLP-1-protamine-SMCC-Fc complex was orally administered to the animal model at 4-day intervals in vivo , and the fasting glucose level was measured. As a result, (See Example 5).
  • the present inventors confirmed the pH and the enzyme stability of the oral gene carrier according to the present invention through the above results. Since the carrier is absorbed by various organs and has a high absorption rate into the intestinal tract, protamine-SMCC- It is expected that it will have an efficient ability to be used as a gene carrier based on its excellent binding ability. Suggesting that it may be applicable as a carrier of various genes in the future.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes comprising, as an active ingredient, the gene carrier and GLP-1 (Glucagon Like Peptide-1) gene combined with the carrier do.
  • GLP-1 Glucagon Like Peptide-1
  • the diabetes may be, but is not limited to, type 2 diabetes.
  • the GLP-1 may comprise the nucleotide sequence of SEQ ID NO: 3, wherein the nucleotide sequence of the GLP-1 is at least 70%, preferably at least 80%, more preferably at least 90% , Preferably 95% or more, and most preferably 98% or more.
  • &quot prevention &quot
  • &quot treatment " refers to any action that improves or alters the symptoms of diabetes by administration of the pharmaceutical composition according to the present invention.
  • the pharmaceutical composition according to the present invention contains the gene carrier and the GLP-1 gene as an active ingredient, and may further comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are those conventionally used in the formulation and include, but are not limited to, saline, sterilized water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, And may further contain other conventional additives such as antioxidants and buffers as needed.
  • Suitable pharmaceutically acceptable carriers and formulations can be suitably formulated according to the respective ingredients using the methods disclosed in Remington's reference.
  • the pharmaceutical composition of the present invention is not particularly limited to a formulation, but may be formulated into injections, inhalants, external skin preparations, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to the intended method, but preferably can be administered orally, Depends on the condition and the weight of the patient, the degree of the disease, the type of the drug, the administration route and time, but can be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat or diagnose a disease at a reasonable benefit / risk ratio applicable to medical treatment or diagnosis, and the effective dose level will depend on the type of disease, severity, The activity of the compound, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, the degree of absorption of the active ingredient in the body, the rate of inactivation and the excretion rate, the type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, may be administered daily or every other day, or one to three divided doses per day.
  • the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
  • the present invention provides a method for preventing or treating diabetes comprising administering the above pharmaceutical composition to a subject.
  • &quot refers to a subject in need of treatment for a disease, and more specifically refers to a human or non-human primate, mouse, rat, dog, cat, It means mammals.
  • the present invention also provides the use of the pharmaceutical composition for the prevention or treatment of diabetes.
  • protamine-SMCC was dissolved in PBS at pH 6.5-7.4, and the solution was adjusted to a concentration of 3 mg / mL while being stirred for 30 minutes. Then, Cys-Fc was dissolved in PBS (1 mole) And the solution was added dropwise to the protamine-SMCC solution while stirring at room temperature for 1 hour. Thereafter, the cells were cultured overnight at 4 ° C (12 hours) without further agitation, and then dialyzed against dH 2 0 for 24 hours and lyophilized to obtain protamine-SMCC-Fc.
  • FIG. 1A shows NMR spectral results of protamine (No. 1), SMCC (No. 2), Protamine-SMCC (No. 3) and Protamine-SMCC-Fc (No. 4) (a), protamine-SMCC (b) and protamine-SMCC-Fc (c).
  • TNBSA (2,4,6-Trinitrobenzene Sulfonic Acid) analysis was performed to determine the optimal conjugation ratio of protamine and SMCC.
  • Feed mole ratio (Protamine: SMCC) Conjugation ratio 1: 2 1: 0.4 1: 3 1: 0.4
  • the protamine-SMCC particle size was 105.3 nm, while the size of protamine-SMCC-Fc was 161.1 nm.
  • SEM imaging analysis it was confirmed that the protamine-SMCC-Fc particles showed a monodispersed shape as shown in FIG. 2b, and the particle size was measured similarly to the DLS analysis result.
  • the measured protamine-SMCC-Fc particle sizes as a result of DLS and SEM analysis are summarized in Table 2 below.
  • the particle size was measured by DLS analysis on the complex of GLP1 DNA and protamine-SMCC-Fc transporter mixed at various ratios (1: 1, 1: 5, 1:10, 1:15, 1:25) (Zeta potential) analysis.
  • each complex of GLP1 DNA and protamine-SMCC-Fc transporter was mixed at various ratios under the conditions of pH 7.4, 5.6 and 1.2, and analyzed by DLS for time (0, 3, 6, Were measured.
  • the complex was found to be stable at pH 7.4, 5.5, and 1.2, and the particle size was reduced to 1:15 ratio and the 1:25 ratio complex was similar in size
  • the optimization ratio of GLP1 DNA and protamine-SMCC-Fc transporter was confirmed to be 1:15 once again.
  • the complex was prepared at a ratio of 1:10 and 1:15, respectively, and SEM image analysis was performed. 4A.
  • the complexes in which the GLP-1 DNA and the protamine-SMCC-Fc transporter were mixed at various ratios were subjected to agarose gel electrophoresis to confirm the formation of the complex.
  • GLP-1 DNA alone, complexes prepared with various ratios (1: 1, 1: 2, 1: 5, 1:10, 1:12, 1:15, 1:25, 1:30) + 1% agarose gel electrophoresis was performed using a GLP-1 DNA sample.
  • Serum stability and DNase analysis were carried out to verify the ability of the oral type gene transporter according to the present invention to protect the gene and the enzyme against degradation.
  • HT-29 cells were treated with protamine-SMCC-Fc at various concentrations (5, 10, 25, 50, 100 ug / ml) After 72 hours, cell viability was measured by MTT assay.
  • 3 x 10 5 cells / well / 5.5 mL of HT-29 cells were cultured for 7 days and recovered.
  • the medium was washed with HBSS + 0.05% BSA + 10 mM MES pH 6.0 Chamber) and 10 mM HEPES, pH 7.4 (basolateral chamber), respectively.
  • the basolateral portion was recovered after treatment with different samples at different time intervals for fluorescence analysis.
  • the EtBr displacement assay was performed to confirm GLP-1 condensation on the GLP-1 / protamine-SMCC-Fc complex according to the present invention.
  • Example 4 in vivo experiments were conducted to verify the therapeutic effect of GLP-1 / protamine-SMCC-Fc complex according to the present invention on diabetes.
  • BKS.Cg + / + Lepr db / db mouse model a type 2 diabetes model, in which the insulin level started to increase from 10 to 14 days after birth at 4 to 5 weeks And it is a model having the feature that the obesity starts and hyperlipemia occurs and the rate of glucosuria is 100% after 10 weeks.
  • the complex was orally administered to the mouse model at 4-day intervals, and the control group was administered with PBS and daily non-fasting blood glucose levels were measured for up to 32 days.
  • the gene carrier for oral administration according to the present invention can be used as an effective oral gene delivery vehicle capable of stably transferring gene to the small intestine by protecting the gene from the body environment.
  • the gene carrier having the GLP-1 gene loaded on the gene carrier And thus the complex can be usefully used in the field of the prevention or treatment of diabetes.

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Abstract

La présente invention concerne un transporteur de gène administré par voie orale, et, plus spécifiquement, un transporteur de gène administré par voie orale comprenant une protamine cationique reliée par un lieur SMCC, la protamine cationique permettant la coagulation d'un gène anionique sur une région Fc d'immunoglobuline. Le transporteur de gène administré par voie orale de la présente invention permet à la protamine, qui est une protéine possédant des propriétés cationiques, d'être couplée à une région Fc et condensée avec un gène possédant des propriétés anioniques, et peut ainsi induire efficacement l'expression in vivo du gène, et, lorsqu'il est administré par voie orale, peut permettre au gène d'être transféré au niveau de l'intestin grêle en protégeant le gène de la dégradation résultant de la réaction immunitaire des globules blancs et de l'action de l'acide gastrique, ce qui peut résulter en une demi-vie du gène relativement longue lorsque le gène est exprimé au niveau de l'intestin grêle, confirmant ainsi un potentiel pour un effet thérapeutique sur le long terme. Il est par conséquent attendu que le transporteur de gène de la présente invention puisse être utilisé utilement en tant que transporteur administré par voie orale pour divers gènes.
PCT/KR2018/016406 2017-12-22 2018-12-21 Transporteur de gène pour la voie orale, et son utilisation Ceased WO2019125031A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/956,784 US20200407407A1 (en) 2017-12-22 2018-12-21 Oral Gene Carrier And Use Thereof

Applications Claiming Priority (4)

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KR20170177676 2017-12-22
KR10-2017-0177676 2017-12-22
KR10-2018-0166594 2018-12-20
KR1020180166594A KR102177339B1 (ko) 2017-12-22 2018-12-20 경구용 유전자 전달체 및 이의 용도

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160083810A (ko) * 2014-12-31 2016-07-12 주식회사 제넥신 GLP 및 면역글로불린 하이브리드 Fc 융합 폴리펩타이드 및 이의 용도
KR101741977B1 (ko) * 2016-04-26 2017-05-31 한국교통대학교산학협력단 경구 투여용 유전자 전달을 위한 나노입자 및 이를 포함하는 약학 조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160083810A (ko) * 2014-12-31 2016-07-12 주식회사 제넥신 GLP 및 면역글로불린 하이브리드 Fc 융합 폴리펩타이드 및 이의 용도
KR101741977B1 (ko) * 2016-04-26 2017-05-31 한국교통대학교산학협력단 경구 투여용 유전자 전달을 위한 나노입자 및 이를 포함하는 약학 조성물

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BAUMER, N.: "Anti body-coupled siRNA as an efficient method for in vivo mRNA knockdown", NATURE PROTOCOLS, vol. 11, 3 December 2015 (2015-12-03), pages 22 - 36, XP055238099 *
DATABASE NCBI 17 April 2017 (2017-04-17), "hypothetical protein [Roseimaritima ulvae", Database accession no. 084427682.1 *
DATABASE NCBI 28 April 2017 (2017-04-28), "PREDICTED: Odocoileus virginianus texanus glucagon (GCG), transcript variant X2, mRNA", Database accession no. 020881848.1 *

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