WO2020085548A1 - Protéine recombinante pour la prévention ou le traitement de la fibrose pulmonaire idiopathique, et composition la comprenant pour la prévention ou le traitement de la fibrose pulmonaire idiopathique - Google Patents
Protéine recombinante pour la prévention ou le traitement de la fibrose pulmonaire idiopathique, et composition la comprenant pour la prévention ou le traitement de la fibrose pulmonaire idiopathique Download PDFInfo
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- WO2020085548A1 WO2020085548A1 PCT/KR2018/012801 KR2018012801W WO2020085548A1 WO 2020085548 A1 WO2020085548 A1 WO 2020085548A1 KR 2018012801 W KR2018012801 W KR 2018012801W WO 2020085548 A1 WO2020085548 A1 WO 2020085548A1
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- idiopathic pulmonary
- pulmonary fibrosis
- recombinant protein
- lung tissue
- fibrosis
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- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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Definitions
- the present invention relates to a recombinant protein for preventing or treating idiopathic pulmonary fibrosis and a composition for preventing or treating idiopathic pulmonary fibrosis comprising the same.
- Idiopathic pulmonary fibrosis is an unknown cause of pulmonary interstitial tissue, and inflammation occurs repeatedly, resulting in permanent scarring and tissue fibrosis, resulting in structural changes in lung tissue, leading to deterioration of lung function and death. It is a fatal disease.
- idiopathic pulmonary fibrosis is difficult to treat because the exact cause of the disease is unknown, and anticoagulants, tyrosine kinase inhibitors, ER-A endothelial receptor antagonists, anti-fibrotic drugs, antacids, and immunosuppressive drugs are used in combination therapy. It is proposed as a treatment.
- the idiopathic pulmonary fibrosis guidelines conditionally recommends only some treatments that have a high incidence of adverse events but have no statistical significance or improve mortality based on clinical trial results, and others recommend strong non-recommendations or recommendations. Delayed.
- the partial treatment effect is provided or the level of providing the effect is insignificant and thus it is not meaningful to delay or treat the onset or progression of pulmonary fibrosis. There was a problem that could not provide a fundamental effect.
- the pharmaceutical composition prepared for the treatment of idiopathic pulmonary fibrosis including the prior art, has a low biocompatibility of the composition based on chemical components, a high incidence of side effects, and difficulties in mass production and quality control considering productivity. Going through.
- the present invention was created to solve the above problems, and an object of the present invention is to fundamentally treat pulmonary tissue in which fibrosis has progressed by idiopathic pulmonary fibrosis to restore pulmonary function to a normal level, and further develop idiopathic pulmonary fibrosis. It is to provide a composition containing a recombinant protein and the same for preventing or treating idiopathic pulmonary fibrosis that can delay or stop the.
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis is a recombinant protein based on the Milk fat globule-EGF factor 8 (MFG-E8) protein, and consists of the amino acid sequence of SEQ ID NO: 1.
- MFG-E8 Milk fat globule-EGF factor 8
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis consisting of the amino acid sequence of SEQ ID NO: 1 by recombination based on milk fat globule-EGF factor 8 (MFG-E8) protein is collagen, ⁇ -SMA ( ⁇ -Smooth Muscle) in lung tissue. Actin) and phosphorylated Extracellular Signal-Regulated Kinase (ERK) can significantly reduce expression.
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis consisting of the amino acid sequence of SEQ ID NO: 1 by recombination based on the milk fat globule-EGF factor 8 (MFG-E8) protein is Col1a1, MMP-2 in lung tissue to be prevented or treated.
- MMP-12 and TIMP1 can be significantly reduced.
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis consisting of the amino acid sequence of SEQ ID NO: 1 that is recombinant based on Milk fat globule-EGF factor 8 (MFG-E8) protein is administered intralesionally, intravascularly, subcutaneously, intranasally It can be formulated for administration or intraperitoneal administration.
- MFG-E8 Milk fat globule-EGF factor 8
- the composition for preventing or treating idiopathic pulmonary fibrosis according to the present invention is idiopathic pulmonary fibrosis consisting of the milk fat globule-EGF factor 8 (MFG-E8) protein-based recombinant amino acid sequence of SEQ ID NO: 1
- the recombinant protein for prevention or treatment is included as an active ingredient.
- the present invention is a gene encoding a recombinant protein for preventing or treating idiopathic pulmonary fibrosis consisting of an amino acid sequence of SEQ ID NO: 1 that is recombined based on the milk fat globule-EGF factor 8 (MFG-E8) protein. It provides as another aspect.
- the present invention is a gene encoding a recombinant protein for preventing or treating idiopathic pulmonary fibrosis consisting of an amino acid sequence of SEQ ID NO: 1 that is recombined based on the milk fat globule-EGF factor 8 (MFG-E8) protein.
- a recombinant vector comprising the same is provided as another aspect.
- ERK extracellular signal-regulated kinase
- SMAD2 phosphorylated extracellular signal-regulated kinase
- FIG. 1 shows the structure of a backbone vector in which a gene encoding a recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention is inserted.
- NP-011 a recombinant protein
- Figure 2 can be inserted into the structure of the Backbone Vector shown in Figure 1, shows the DNA sequence of the gene encoding a recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention.
- NP-011 a recombinant protein
- Figure 3 shows the amino acid sequence of the recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention.
- Figure 4 is a schematic diagram showing the production process of an animal experimental model designed for verifying the effect of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis of the present invention (NP-011).
- Figure 5 shows the staining results showing the distribution of collagen and ⁇ -SMA in the lung tissue of animal experimental models designed to verify the effect of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis of the present invention (NP-011).
- Figure 6 is a graph showing the expression patterns of lung tissue fibrosis-related biomarkers in lung tissue of animal experimental models designed to verify the effect of recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention.
- Figure 7 shows the expression pattern of the sub-factors of the signaling system related to inducing fibrosis of lung tissue in lung tissue of animal experimental models designed to verify the effect of recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention. It is the graph shown.
- FIG. 8 is a schematic diagram showing the production process of two test groups with different injection timings of NP-011 among animal experimental models designed for verifying the effect of recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention.
- Figure 10 is collagen in the lung tissue of the animal experimental model test group injected with NP-011 at day 5 of the animal experimental model designed for verifying the effect of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis of the present invention (NP-011) And staining results comparing the distribution of ⁇ -SMA distribution.
- Figure 11 is a lung in the lung tissue of the animal experimental model test group injected with NP-011 at day 3 of the animal experimental model designed for verifying the effect of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis of the present invention (NP-011)
- NP-011 idiopathic pulmonary fibrosis of the present invention
- Figure 12 is a lung in the lung tissue of the animal experimental model test group injected with NP-011 at the time of day 5 of the animal experimental model designed for verifying the effect of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis of the present invention (NP-011)
- NP-011 idiopathic pulmonary fibrosis of the present invention
- Figure 13 is a lung in the lung tissue of the animal experimental model test group injected with NP-011 at day 3 of the animal experimental model designed for verifying the effect of the recombinant protein (NP-011) for preventing or treating idiopathic pulmonary fibrosis of the present invention
- NP-011 the recombinant protein
- NP-011 idiopathic pulmonary fibrosis
- NP-011 idiopathic pulmonary fibrosis according to the present invention
- NP-011 recombinant protein for preventing or treating idiopathic pulmonary fibrosis
- NP-011 idiopathic pulmonary fibrosis
- MFG-E8 Origene's MFG-E8 (NM_005928) Human cDNA Clone (Cat. No. RG217163) was purchased, used as a template and subjected to PCR to obtain DNA fragments as shown in FIG. 2 (see SEQ ID NO: 4).
- FIG. 2 obtained through PCR amplification at the HindIII and SalI restriction sites (A portion of FIG. 1) of the pLFCF Vector, which is a Mammalian expression Vector of the structure as shown in FIG. 1 (see SEQ ID NO: 4). Proceed with cloning to insert.
- plasmid DNA is extracted and transfected into HEK293 cells, and after 2 days, the culture is collected, and immunoprecipitation reaction (IP, Immunoprecipitation) is performed with FLAG resin to prevent or treat idiopathic pulmonary fibrosis by Western Blotting.
- IP immunoprecipitation reaction
- NP-011 The expression of the recombinant protein corresponding to the recombinant protein (NP-011) is confirmed.
- NP-011 idiopathic pulmonary fibrosis
- NP-011 idiopathic pulmonary fibrosis
- the culture medium was replaced and further cultured for 6 days, and the culture medium was collected 3 times every 2 days to perform Affinity-type protein purification from the collected culture medium.
- NP-011 for prevention or treatment of idiopathic pulmonary fibrosis, which is prepared based on the milk fat globule-EGF factor 8 (MFG-E8) protein.
- MFG-E8 milk fat globule-EGF factor 8
- NP-011 recombinant protein
- MFG-E8 milk fat globule-EGF factor 8
- a DNA fragment that is cloned into an expression vector in relation to the expression of a recombinant protein for preventing or treating idiopathic pulmonary fibrosis (NP-011), which is prepared based on milk fat globule-EGF factor 8 (MFG-E8) protein
- NP-011 idiopathic pulmonary fibrosis
- MFG-E8 milk fat globule-EGF factor 8
- the structure of fragments is also based on the structure of FIG. 2, but according to an embodiment, a specific DNA sequence encoding a specific signal peptide may be additionally linked to DNA fragments.
- Recombinant protein for prevention or treatment of idiopathic pulmonary fibrosis based on milk fat globule-EGF factor 8 (MFG-E8) protein which is finally prepared through the processes of cloning, separation, production, and purification of the recombinant protein described above.
- 011 has the amino acid sequence structure as shown in SEQ ID NO: 1 or 3 in the following sequence listing.
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis based on the milk fat globule-EGF factor 8 (MFG-E8) protein (NP-011) is a structural component of the MFG-E8 protein, EGF-like Domain, C1 Domain, and C2.
- EGF-like domain (refer to SEQ ID NO: 2)
- C1 domain (refer to SEQ ID NO: 3) are recombined into structures.
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis based on the milk fat globule-EGF factor 8 (MFG-E8) protein of the present invention forms an amino acid sequence of "EGF-like Domain + C1 Domain" It is used as a basic structure, and is characterized in that the C2 domain is excluded from the structure.
- the milk fat globule-EGF factor 8 (MFG-E8) protein-based idiopathic pulmonary fibrosis prevention or treatment recombinant protein (NP-011) of the present invention is a major pharmaceutical composition used for the prevention or treatment of idiopathic pulmonary fibrosis. It can be used as an active ingredient.
- milk fat globule-EGF factor 8 (MFG-E8) protein-based idiopathic pulmonary fibrosis prevention or treatment recombinant protein (NP-011) of the present invention and a pharmaceutical composition using it as a main active ingredient are administered in a lesion, blood vessels It can be formulated for intrathecal administration (artery, vein, etc.), subcutaneous administration, intranasal administration, intraperitoneal administration, or administration in a specific tissue (lung tissue).
- the recombinant protein for preventing or treating idiopathic pulmonary fibrosis based on the milk fat globule-EGF factor 8 (MFG-E8) protein of the present invention (NP-011) is cloned into an expression vector in relation to the expression of the recombinant protein described above.
- additional linkage of a specific signal peptide structure may be made.
- a specific Signal Peptide structure may be implemented in a form that is connected to the EGF-like domain tip by having an amino acid sequence such as "MPRPRLLAALCGALLCAPSLLVA” (see SEQ ID NO: 5), but is not limited thereto.
- an animal model for inducing acute idiopathic pulmonary fibrosis is prepared by instilling 3 mg / kg of bleomycin into the C57BL / 6 mice.
- the experimental group for verifying the effect of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis of the present invention is acute idiopathic pulmonary fibrosis inducing animal of the 'BLM' model group prepared as shown in FIG.
- the model mice were prepared by administering 160 ⁇ g / kg NP-011 in the vein of the tail of the mouse on a daily basis, and are designated as 'BLM + NP011' based on the drawing.
- the experimental group of 'BLM + NP011' prepared as described above was changed for 3 days after injection of bleomycin by varying the administration time of the recombinant protein for preventing or treating idiopathic pulmonary fibrosis (NP-011). It was classified into the first experimental group (CASE 1) in which NP-011 was injected once at the time point and the second experimental group (CASE 2) in which NP-011 was injected once at 5 days after the injection of bleomycin.
- CASE 1 idiopathic pulmonary fibrosis
- 'BLM' model group which is made of animal model mice induced with Idiopathic Pulmonary Fibrosis, and thereby changes in lung tissue. Lung tissues of animal model mice were extracted for 4 times over 3, 5, 7, and 14 days, respectively, to verify tissue staining analysis and expression of specific components related to lung tissue fibrosis.
- mice of the 'BLM' model group were injected with bleomycin, followed by anesthesia after 3 days, 5 days, 7 days, and 14 days, followed by cardiac perfusion through PBS. Lung tissue was removed after injection.
- the extracted lung tissue is refrigerated for 4 days in a 4% PFA solution, and the lung tissue embedded with paraffin is cut to a thickness of 4 ⁇ m using a sectioning machine (CM3050S, Leica), and a slide (silane coated slide) ).
- a sectioning machine C3050S, Leica
- a slide silane coated slide
- the lung tissue sections are first defatted in xylene, hydrated in a 100% alcohol solution, and the slides washed with tap water are stained with Hematoxylin for 5 minutes, Biebrich Scarlet-Acid Fuchsin The dye was stained for 15 minutes, phosphomolybdic / phosphotungstic acid for 10 minutes, aniline blue for 5 minutes, and 1% acetic acid for 3 minutes, then dehydrated and sealed with a cover slip.
- the acute idiopathic pulmonary fibrosis-inducing animal model mice of the 'BLM' model group have an expression distribution of collagen, which is a major fibrosis index in lung tissue from day 3 after injection of bleomycin. Increases little by little, shows a remarkable increase after 5 days, shows the highest increase level on the 7th day, and shows a similar level to the 7th day on the 14th.
- lung tissue of the lung tissue extracted from the 3rd, 5th, 7th and 14th days after injection of bleomycin into the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group, respectively.
- the expression pattern of biomarkers related to fibrosis was verified.
- PCR polymerase chain reaction
- each extracted lung tissue section was extracted with total RNA using an RNeasy mini kit, and cDNA was synthesized through reverse transcriptase PCR (RT-PCR), and the synthesized cDNA was expressed through quantitative RT-PCR.
- RT-PCR reverse transcriptase PCR
- sequence structure (refer to SEQ ID NO: 6 to SEQ ID NO: 9) for the primer used therein is shown in Table 1 below.
- FIG. 6 the results of expression patterns for each extraction time of biomarkers related to lung tissue fibrosis of the extracted lung tissue are as shown in FIG. 6.
- FIG. 6 (refer to the drawing- * P ⁇ 0.05, ** As shown in P ⁇ 0.01, *** P ⁇ 0.001), the acute idiopathic pulmonary fibrosis-inducing animal model mice of the 'BLM' model group were injected with bleomycin, followed by the 'CON' normal control (Wild Type Control). From day 3 compared to normal mice, it can be seen that the expression of Col1a1, MMP-2, MMP-12 and TIMP1, which are biomarkers related to fibrosis in the lung tissue, maintains a high level.
- lung tissue of the lung tissue extracted from the 3rd, 5th, 7th and 14th days after injection of bleomycin into the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group, respectively.
- the expression pattern of sub-factors of the fibrosis-related signaling system was verified.
- each lung tissue extracted was pulverized to obtain a protein, and then proteins were separated by size through SDS-PAGE, transferred to a PVDF membrane, and immunized at 4 ° C as a primary antibody.
- Primary antibodies used for this are ⁇ -SMA (SC-53015), pERK (# 4370), tERK (# 4695), pSMAD2 (3104S), tSMAD2 (3102S) and Actin (SC-47778).
- the immune antibody was reacted with a secondary antibody combined with HRP (Horse Radish Peroxidase) to develop and quantify the band, thereby verifying the expression pattern of the sub-factors of the signal transduction system related to lung tissue fibrosis of the extracted lung tissue.
- HRP Hase Radish Peroxidase
- the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group compared to normal mice of the 'CON' normal control (Wild Type Control) after injection of bleomycin
- the expression of the phosphorylated form of extracellular signal-regulated kinase (ERK), a sub-factor of the MARK signal of the fibrosis-related signaling system increased from the 5th day, and was significantly increased on the 14th day to have the highest level.
- ERK extracellular signal-regulated kinase
- Milk fat globule-EGF factor 8 of the present invention (MFG-E8) protein-based idiopathic pulmonary fibrosis prevention or treatment of the recombinant protein (NP-011) in order to confirm the lung tissue fibrosis preventing function, the first experimental group and the second experimental group
- the expression patterns of collagen and ⁇ -SMA in the lung tissue of the corresponding experimental animal mice were examined.
- NP-011 was injected once on the 3rd day, and then anesthetized at the 6th day. After infusion of PBS through perfusion, lung tissue was removed.
- Trichrome staining and Sirius red staining process for evaluating the expression distribution of collagen and ⁇ -SMA in lung tissue using lung tissue of the first and second experimental groups extracted as described above and the process of deriving the results are described above. It is omitted because it is the same as the method for acute idiopathic pulmonary fibrosis-induced animal model mice in the 'BLM' model group.
- the lung tissue slides of each animal model mice of the first experimental group after Trichrome staining and Sirius red staining were obtained by fluorescence microscopy (BX61; Olympus), as shown in FIG. 9.
- the lung tissue slides of each animal model mice of the second experimental group after Trichrome staining and Sirius red staining were obtained by fluorescence microscopy (BX61; Olympus), as shown in FIG. 10.
- the animal model mice of the first experimental group and the second experimental group of 'BLM + NP011' are acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group after injection of NP-011. It can be seen that the expression distribution of collagen, which is a major fibrosis index in lung tissue, is significantly reduced compared to those of the above.
- the animal model mice of the first experimental group and the second experimental group of 'BLM + NP011' are acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group after injection of NP-011.
- ⁇ -SMA a major fibrosis index in lung tissue
- NP-011 when NP-011 is administered to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group at the time of day 3 or 5 after injection of bleomycin, collagen, which is a major fibrosis index in lung tissue ( Collagen) and ⁇ -SMA are significantly reduced in expression distribution, thereby providing an excellent level of antifibrosis effect for preventing lung tissue fibrosis.
- Milk fat globule-EGF factor 8 of the present invention (MFG-E8) protein-based idiopathic pulmonary fibrosis prevention or treatment of the recombinant protein (NP-011) in order to confirm the lung tissue fibrosis preventing function, the first experimental group and the second experimental group
- the expression patterns of the subfactors of the MARK signal and the TGF ⁇ signal in the lung tissue fibrosis-related signaling system in the lung tissue of experimental animal mice were examined.
- NP-011 was injected once on the 3rd day, and then anesthetized at the 6th day. After infusion of PBS through perfusion, lung tissue was removed.
- the animal model mice of the first experimental group of 'BLM + NP011' compared to those of the animal model mice inducing acute idiopathic pulmonary fibrosis of the 'BLM' model group after injection of NP-011
- ERK extracellular signal-regulated kinase
- the animal model mice of the 'BLM + NP011' first experimental group compared to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group after injection of NP-011 lung tissue in the lung tissue. It can be seen that the expression of SMAD2 in the phosphorylated form, which is a subfactor of the TGF ⁇ signal of the fibrosis-related signaling system, is also significantly reduced.
- the animal model mice of the 'BLM + NP011' second experimental group compared to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group after injection of NP-011 lung tissue in the lung tissue. It can be confirmed that the expression of the extracellular signal-regulated kinase (ERK) in the phosphorylated form, which is a sub-factor of the MARK signal of the fibrosis-related signaling system, is significantly reduced, which can be confirmed to be similar to that of normal mice.
- ERK extracellular signal-regulated kinase
- the animal model mice of the 'BLM + NP011' second experimental group were in lung tissue compared to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group after injection of NP-011. It can be seen that the expression of ⁇ -SMA, a major pulmonary tissue fibrosis indicator, is significantly reduced, which is similar to that of normal mice.
- NP-011 when NP-011 is administered to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group at the time of day 3 or 5 after injection of bleomycin, lung tissue fibrosis-related signaling in lung tissue System MARK signal sub-factor phosphorylated form of ERK and TGF ⁇ signal sub-factor phosphorylated form of SMAD2 rapidly decreased, and further, the expression of ⁇ -SMA, a major lung tissue fibrosis index, was also significantly reduced, resulting in the expression of normal mice. Similar to the level, it can provide an excellent level of antifibrosis effect for preventing lung tissue fibrosis.
- NP-011 was injected once on the 3rd day, and then anesthetized at the 6th day. After infusion of PBS through perfusion, lung tissue was removed.
- PCR Polymerase chain reaction
- the animal model mice of the first experimental group 'BLM + NP011' showed lung in lung tissue compared to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group after injection of NP-011. It can be confirmed that the expression of tissue fibrosis-related biomarkers Col1a1, MMP-2, MMP-12, and TIMP1 is markedly reduced, thereby approaching the expression level of normal mice.
- NP-011 when NP-011 is administered to the acute idiopathic pulmonary fibrosis-induced animal model mice of the 'BLM' model group at the third day after injection of bleomycin, Col1a1, a biomarker related to lung tissue fibrosis in the lung tissue,
- MMP-2, MMP-12 and TIMP1 are significantly reduced, which is similar to that of normal mice, and thus can provide an excellent level of antifibrosis effect for preventing lung tissue fibrosis.
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Abstract
La présente invention concerne une protéine recombinante pour la prévention ou le traitement de la fibrose pulmonaire idiopathique, laquelle est recombinée sur la base de la protéine globule gras du lait de facteur 8 (MFG-E8) et possède la séquence d'acides aminés représentée par SEQ ID NO : 1. La protéine recombinante peut traiter de manière fondamentale un tissu pulmonaire qui a subi une fibrose à cause d'une fibrose pulmonaire idiopathique et, ce faisant, peut permettre la récupération d'une fonction pulmonaire de niveau normal. De plus, la présente invention concerne une composition pharmaceutique comprenant comme principe actif une protéine recombinante pour la prévention ou le traitement de la fibrose pulmonaire idiopathique, laquelle est recombinée sur la base de la protéine de globule gras du lait de facteur 8 (MFG-E8) et possède la séquence d'acides aminés représentée par SEQ ID NO : 1.
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| KR20230066169A (ko) * | 2021-11-05 | 2023-05-15 | (주) 넥셀 | 궤양성 대장염 예방 또는 치료용 재조합 단백질 및 이를 포함하는 궤양성 대장염 예방 또는 치료용 조성물 |
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| KR20130060670A (ko) * | 2011-11-30 | 2013-06-10 | 고려대학교 산학협력단 | Ｍｉｌｋ ｆａｔ ｇｌｏｂｕｌｅ ― ＥＧＦ ｆａｃｔｏｒ ８（ＭＦＧＥ８）을 이용한 간 재생 및 간 질환 개선 용도 |
| KR20170013621A (ko) * | 2015-07-28 | 2017-02-07 | (주) 넥셀 | Ｍｉｌｋ ｆａｔ ｇｌｏｂｕｌｅ－ＥＧＦ ｆａｃｔｏｒ（ＭＦＧ－Ｅ８）을 이용한 조직섬유화 예방 또는 치료용 조성물 |
| KR20170055626A (ko) * | 2015-11-11 | 2017-05-22 | (주)나디안바이오 | 특발성 폐섬유증의 치료 또는 예방을 위한 약학적 조성물 |
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| KR20130060670A (ko) * | 2011-11-30 | 2013-06-10 | 고려대학교 산학협력단 | Ｍｉｌｋ ｆａｔ ｇｌｏｂｕｌｅ ― ＥＧＦ ｆａｃｔｏｒ ８（ＭＦＧＥ８）을 이용한 간 재생 및 간 질환 개선 용도 |
| KR20170013621A (ko) * | 2015-07-28 | 2017-02-07 | (주) 넥셀 | Ｍｉｌｋ ｆａｔ ｇｌｏｂｕｌｅ－ＥＧＦ ｆａｃｔｏｒ（ＭＦＧ－Ｅ８）을 이용한 조직섬유화 예방 또는 치료용 조성물 |
| KR20170055626A (ko) * | 2015-11-11 | 2017-05-22 | (주)나디안바이오 | 특발성 폐섬유증의 치료 또는 예방을 위한 약학적 조성물 |
Non-Patent Citations (3)
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| A N, S. Y. ET AL.: "Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells , protects against liver fibrosis in mice", GASTROENTEROLOGY, vol. 152, 2017, pages 1174 - 1186, XP029955901, DOI: 10.1053/j.gastro.2016.12.003 * |
| ATABAI, KAMRAN ET AL.: "Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 119, no. 12, 2009, pages 3713 - 3722, XP055350117, DOI: 10.1172/JCI40053 * |
| DATABASE GenBank 25 July 2016 (2016-07-25), "Homo sapiens milk fat globule-EGF factor 8 protein, partial [synthetic construct", XP055710669, Database accession no. AAP36434.1 * |
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