WO2020085545A1 - Protéine recombinante pour la prévention ou le traitement de l'infarctus du myocarde et composition la comprenant pour la prévention ou le traitement de l'infarctus du myocarde - Google Patents

Protéine recombinante pour la prévention ou le traitement de l'infarctus du myocarde et composition la comprenant pour la prévention ou le traitement de l'infarctus du myocarde Download PDF

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WO2020085545A1
WO2020085545A1 PCT/KR2018/012780 KR2018012780W WO2020085545A1 WO 2020085545 A1 WO2020085545 A1 WO 2020085545A1 KR 2018012780 W KR2018012780 W KR 2018012780W WO 2020085545 A1 WO2020085545 A1 WO 2020085545A1
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myocardial infarction
recombinant protein
treatment
prevention
protein
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PCT/KR2018/012780
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Korean (ko)
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조건식
안근호
이주현
권효성
우동훈
한충성
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(주)넥셀
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1808—Epidermal growth factor [EGF] urogastrone
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone

Definitions

  • the present invention relates to a recombinant protein for preventing or treating myocardial infarction and a composition for preventing or treating myocardial infarction comprising the same.
  • Myocardial infarction is one of the ischemic heart diseases that causes pain due to the fact that the coronary arteries of the heart are completely blocked by blood clots, and part of the heart muscle is destroyed or necrotic, preventing the flow of blood in the blood vessels.
  • Heart disease such as myocardial infarction
  • myocardial infarction has no cure and is not easy to transplant like other organs.
  • Drugs used mainly for the treatment of myocardial infarction currently use aspirin, clopidogrel, beta blockers, ace inhibitors, and angiotensin blockers. It is just slowing down.
  • prior literature on the prior art related to the cell-type therapeutic agent provided for the treatment of myocardial infarction includes "Registration of dendritic cells for immune tube for the treatment of myocardial infarction and its manufacturing method” (hereinafter referred to as 'prior art') Is called).
  • the myocardial infarction necroticized by the myocardial infarction is unable to perform the fundamental myocardial infarction treatment through the treatment of damaged myocardial cells.
  • the tissue was replaced, and as a result, the heart became enlarged, the normal cardiac function was lost, and the patient eventually died.
  • the biocompatibility of the composition based on the chemical component is low, the incidence of side effects is high, and it suffers from mass production and quality control considering productivity. have.
  • the present invention was created to solve the above problems, and an object of the present invention is to fundamentally treat myocardial cell tissues that have undergone fibrosis and have undergone fibrosis, thereby restoring pulsatile functionality to normal levels, and furthermore, enlargement of the heart. It is to provide a composition containing a recombinant protein and the same for preventing or treating myocardial infarction that can be prevented.
  • the recombinant protein for preventing or treating myocardial infarction is a milk fat globule-EGF factor 8 (MFG-E8) protein-based recombinant protein, and consists of an amino acid sequence of SEQ ID NO: 1.
  • MFG-E8 milk fat globule-EGF factor 8
  • milk fat globule-EGF factor 8 (MFG-E8) protein-based recombinant protein for the prevention or treatment of myocardial infarction consisting of the amino acid sequence of SEQ ID NO: 1 is the left ventricular ejection fraction (EF, Ejection Fraction) of the heart to be prevented or treated ) Can be significantly increased.
  • EF left ventricular ejection fraction
  • the recombinant protein for the prevention or treatment of myocardial infarction 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 a fraction of the left ventricular fraction of the heart to be prevented or treated (FS, Fractional shortening) can be significantly increased.
  • the recombinant protein for the prevention or treatment of myocardial infarction 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, or intranasally. Or it can be formulated for intraperitoneal administration.
  • MFG-E8 Milk fat globule-EGF factor 8
  • the composition for preventing or treating myocardial infarction is a milk fat globule-EGF factor 8 (MFG-E8) protein-based recombination to prevent myocardial infarction consisting of the amino acid sequence of SEQ ID NO: 1
  • the recombinant protein for treatment is included as an active ingredient.
  • the present invention is a gene encoding a recombinant protein for preventing or treating myocardial infarction 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 includes a gene encoding a recombinant protein for preventing or treating myocardial infarction consisting of an amino acid sequence of SEQ ID NO: 1 by recombination based on the Milk fat globule-EGF factor 8 (MFG-E8) protein.
  • the recombinant vector is provided as another aspect.
  • the heart size and heartbeat function can be restored to a normal level by providing an excellent anti-fibrotic effect to the heart tissue of a treatment target undergoing remodeling through fibrosis through myocardial infarction.
  • EF left ventricular ejection fraction
  • fractional shortening (FS) of the target heart which has undergone remodeling through fibrosis due to myocardial infarction, can be significantly increased.
  • FIG. 1 shows the structure of a backbone vector in which a gene encoding a recombinant protein (NP-011) for preventing or treating myocardial infarction 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 for preventing or treating myocardial infarction (NP-011) of the present invention.
  • Figure 3 shows the amino acid sequence of a recombinant protein (NP-011) for the prevention or treatment of myocardial infarction of the present invention.
  • Figure 4 is a schematic diagram showing the design of the effect verification test for recombinant protein (NP-011) for the prevention or treatment of myocardial infarction of the present invention.
  • Figure 5 is a graph showing the measurement results of the second week left ventricular ejection fraction (EF) and fractional shortening rate (FS) of animal experimental models designed to verify the effect of the recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention to be.
  • EF left ventricular ejection fraction
  • FS fractional shortening rate
  • Figure 6 is a graph showing the results of measurement of the left ventricular ejection fraction (EF) and fractional shortening rate (FS) at week 4 of animal experimental models designed to verify the effect of the recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention to be.
  • EF left ventricular ejection fraction
  • FS fractional shortening rate
  • NP-011 myocardial infarction
  • FIG. 8 is a graph showing the results of measuring changes in left ventricular ejection fraction (EF) according to the progression time of animal experimental models designed to verify the effect of a recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention.
  • FIG. 9 is a graph showing the results of measuring changes in left ventricular fraction shortening rate (FS) according to the progression time of animal experimental models designed to verify the effect of recombinant protein for preventing or treating myocardial infarction of the present invention (NP-011).
  • FS left ventricular fraction shortening rate
  • Figure 10 is a graph showing the results of comparing the changes in body weight according to the treatment progress of animal experimental models designed to verify the effect of the recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention.
  • FIG. 11 is a photograph showing the results of staining of MT and H & E of cardiac tissues of animal experimental models designed to verify the effect of recombinant protein (NP-011) for the prevention or treatment of myocardial infarction of the present invention.
  • FIG. 12 is a result of calculating the area value of the locally fibrous portion compared to the total area of the left ventricle based on FIG. 11 of animal experimental models designed for verifying the effect of the recombinant protein for preventing or treating myocardial infarction of the present invention (NP-011). It is a graph showing.
  • NP-011 The process of obtaining the recombinant protein for preventing or treating myocardial infarction according to the present invention (NP-011) and the structural characteristics of the obtained protein will be described in detail with reference to FIGS. 1 to 3 below.
  • 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 to collect the culture medium after 2 days, and immunoprecipitation reaction (IP, Immunoprecipitation) with FLAG resin is performed to prevent or treat myocardial infarction by Western Blotting.
  • IP Immunoprecipitation reaction
  • NP-011 The expression of the recombinant protein corresponding to the protein (NP-011) is confirmed.
  • NP-011 myocardial infarction
  • the plasmid DNA that has been confirmed is secured through Maxi prep, and HEK293 cells are prepared to prepare a large amount of plasmid DNA. It can be transduced into HEK293 cells to perform mass production of a recombinant protein corresponding to a recombinant protein for preventing or treating myocardial infarction (NP-011).
  • 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 recombinant protein
  • MFG-E8 milk fat globule-EGF factor 8
  • DNA fragments (fragments) that are cloned into an expression vector in relation to expression of a recombinant protein for prevention or treatment of myocardial infarction (NP-011) prepared based on milk fat globule-EGF factor 8 (MFG-E8) protein
  • MFG-E8 protein milk fat globule-EGF factor 8
  • the structure of) is also based on the structure of FIG. 2, but according to an embodiment, a specific DNA nucleotide sequence encoding a specific signal peptide may be additionally linked to DNA fragments.
  • Recombinant protein for prevention or treatment of myocardial infarction 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 (NP-011) )
  • MFG-E8 protein milk fat globule-EGF factor 8
  • NP-011 Has the amino acid sequence structure as shown in SEQ ID NO: 1 or FIG. 3 in the sequence listing below.
  • the recombinant protein for preventing or treating myocardial infarction based on the milk fat globule-EGF factor 8 (MFG-E8) protein is a structural component of the MFG-E8 protein, EGF-like Domain, C1 Domain, and C2 Domain.
  • Heavy EGF-like Domain see SEQ ID NO: 2
  • C1 Domain see SEQ ID NO: 3
  • the recombinant protein for preventing or treating myocardial infarction 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 recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention is a main active ingredient of a pharmaceutical composition used for preventing or treating myocardial infarction Can be used as
  • milk fat globule-EGF factor 8 (MFG-E8) protein-based recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention and a pharmaceutical composition having the same as its main active ingredient are administered in lesions, blood vessels ( It can be formulated for intrathecal administration, subcutaneous administration, intranasal administration, intraperitoneal administration, or administration in specific tissues (left ventricular tissue).
  • the recombinant protein for preventing or treating myocardial infarction 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.
  • the fragments (fragments) may be made according to the implementation of additional linkage of a specific Signal Peptide structure.
  • 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 inducing acute myocardial infarction (AMI) using an 8-10 week old male rat weighing 180-200 g is produced.
  • the experimental group as shown in Figure 4, the normal (Normal) comparative animal model (first experimental group), acute myocardial infarction (AMI) induced rat animal model (second experimental group), acute myocardial infarction ( AMI) -induced rats infused with saline (PBS, Phosphate Buffered Saline) in an animal model (3rd experimental group) and MFG-E8 (Milk fat globule-EGF factor 8) in acute myocardial infarction (AMI) -induced rats
  • PBS Phosphate Buffered Saline
  • MFG-E8 Milk fat globule-EGF factor 8
  • AMI acute myocardial infarction
  • 2nd experimental group 2nd experimental group
  • ketamine Ketamine
  • Hydrochloride Hydrochloride
  • Milk fat globule-EGF factor 8 (MFG-E8) protein-based myocardial infarction prevention or treatment of the present invention in order to confirm the cardiac function improvement of the recombinant protein (NP-011), based on the electrocardiogram measurement of the left ventricle The yield rate (EF) and fractional shortening rate (FS) were confirmed.
  • each of the first experimental group and the fifth experimental group were set for Day 0 (Day 0), Day 1 (Day1), Day 14 (Day 14), Day 28 (Day28), and Day 56 (Day56) for 8 weeks.
  • the ECG was measured using a Vivid 7 (GE medical systems) system and a 10 MHz small linear array transducer (i13L, GE medical systems) for a total of five times.
  • rats corresponding to each experimental group were injected intraperitoneally by mixing ketamine 60mg / kg and hydrochloride 7.5mg / kg, and then electrocardiogram during two consecutive cardiac cycles under complete anesthesia was measured. Therefore, it is preferable to use the average value.
  • EF ejection rate
  • FS fractional shortening rate
  • the fractional shortening (FS) of the left ventricle is measured by a representative cardiac contraction value
  • the ejection fraction (EF) of the left ventricle is the end-diastolic volume and the end-systolic volume. volume).
  • the level of the rate (FS) can be increased with greater certainty and a greater increase, providing a steady and fast recovery rate of the heart rate function and a high level of recovery close to the normal level.
  • Milk fat globule-EGF factor 8 (MFG-E8) protein-based myocardial infarction prevention or treatment recombinant protein (NP-011) of the present invention was confirmed weight change during cardiac function improvement.
  • each of the second experimental group and the fifth experimental group, which were previously set up, is measured and graphed over a total of three times on the first day (Day1), the 28th (Day28), and the 56th (Day56) for 8 weeks. Did.
  • the recombinant protein for preventing or treating myocardial infarction (NP-011) of the present invention was compared to a rat in which acute myocardial infarction (AMI) was induced compared to a rat in which acute myocardial infarction (AMI) was induced.
  • AMI acute myocardial infarction
  • AMD acute myocardial infarction
  • AMI acute myocardial infarction
  • NP-011 rat myocardial infarction prevention or treatment recombinant protein
  • NP-011 recombinant protein
  • MFG-E8 milk fat globule-EGF factor 8
  • Paraffin block is prepared and excised to a thickness of 4 ⁇ m to analyze the degree of fibrosis of the heart tissue through H & E staining and Masson's trichrome (MT) staining.
  • Hematoxylin and Eosin purchased from Sigma were used for H & E staining
  • Trichrome Stain Kit purchased from Sigma was used for MT staining.
  • FIG. 11 a photograph of a heart tissue sample for each experimental group was obtained as shown in FIG. 11 through MT and H & E staining to calculate the area value of the locally fibrous portion compared to the total area of the left ventricle.
  • the recombinant protein for preventing or treating myocardial infarction of the present invention prevents the fibrosis of various cardiac tissues including myocardial cell tissues that have undergone fibrosis by necrosis by myocardial infarction through providing an overwhelmingly excellent antifibrotic ability.
  • the abnormality of the heartbeat function due to tissue fibrosis and the cardiac hypertrophy phenomenon can be solved and essential treatment of myocardial infarction can be achieved.

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Abstract

La présente invention concerne une protéine recombinante pour la prévention ou le traitement de l'infarctus du myocarde, qui est recombinée sur la base de la protéine du facteur 8 EGF du globule gras du lait (MFG-E8) et qui présente la séquence d'acides aminés de séquence SEQ ID NO : 1. La protéine recombinante peut fournir un excellent effet antifibrotique sur le tissu cardiaque d'un sujet à traiter, dans lequel le remodelage progresse avec une fibrose induite par un infarctus du myocarde, ce qui permet de restaurer la dimension du cœur et la fonction de rythme cardiaque à des niveaux normaux. De plus, la présente invention concerne une composition pharmaceutique comprenant en tant que principe actif une protéine recombinante pour la prévention ou le traitement de l'infarctus du myocarde, qui est recombinée sur la base d'une protéine du facteur 8 EGF du globule gras du lait (MFG-E8) et qui présente la séquence d'acides aminés de séquence SEQ ID NO : 1.
PCT/KR2018/012780 2018-10-25 2018-10-26 Protéine recombinante pour la prévention ou le traitement de l'infarctus du myocarde et composition la comprenant pour la prévention ou le traitement de l'infarctus du myocarde WO2020085545A1 (fr)

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KR1020180128033A KR102129178B1 (ko) 2018-10-25 2018-10-25 심근경색 예방 또는 치료용 재조합 단백질을 포함하는 심근경색 예방 또는 치료용 조성물

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WO2017118764A1 (fr) * 2016-01-07 2017-07-13 Thomas Brocker Nouvelles approches pour la visualisation in vivo et in vitro de cellules mourantes

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DATABASE Protein 25 July 2016 (2016-07-25), "Homo sapiens milk fat globule-EGF factor 8 protein, partial [synthetic construct", XP055709054, retrieved from NCBI Database accession no. AAP36434.1 *
DENG, KE -QIONG: "Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway", HYPERTENSION, October 2017 (2017-10-01), pages 770 - 779, XP055709051 *
NAKAYA, M.: "Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction", THE JOURNAL OF CLINICAL INVESTIGATION, January 2017 (2017-01-01), pages 383 - 401, XP055709056 *

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