WO2018101398A1 - Procédé de traitement d'affection intestinale inflammatoire, et composition pharmaceutique destinée à être mise en œuvre dans celui-ci - Google Patents

Procédé de traitement d'affection intestinale inflammatoire, et composition pharmaceutique destinée à être mise en œuvre dans celui-ci Download PDF

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WO2018101398A1
WO2018101398A1 PCT/JP2017/043034 JP2017043034W WO2018101398A1 WO 2018101398 A1 WO2018101398 A1 WO 2018101398A1 JP 2017043034 W JP2017043034 W JP 2017043034W WO 2018101398 A1 WO2018101398 A1 WO 2018101398A1
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apelin
pharmaceutical composition
disease
receptor agonist
ibd
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PCT/JP2017/043034
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Japanese (ja)
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宇司 永石
渡辺　守
敬司 久場
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国立大学法人 東京医科歯科大学
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Definitions

  • the present invention relates to a method for treating inflammatory bowel disease (IBD) and a pharmaceutical composition for use therein. More particularly, it relates to a method for treating inflammatory bowel disease (IBD) comprising administering a pharmaceutical composition containing apelin or an apelin receptor agonist.
  • the present invention also relates to a method for treating a disease caused by inflammatory macrophages and a pharmaceutical composition for use therein.
  • IBD Inflammatory bowel disease
  • This IBD is an inflammatory disease that causes intractable inflammation and ulcers in the mucous membrane of the digestive tract such as the large intestine and small intestine and has a chronic course. Details are not known (for example, see Non-Patent Document 1).
  • This IBD is narrowly defined as ulcerative colitis with diffuse non-specific inflammation of unknown origin that mainly forms erosions and ulcers in the colonic mucosa, and all layers with nonspecific granulomas in the entire digestive tract It refers to two diseases of Crohn's disease, which induces sexual inflammation and causes ulceration, abscess, fibrosis, and thereby stenosis and fistula.
  • IBD ulcerative colitis and Crohn's disease. It occurs especially in young people in their 10s and 20s, and relapses and remissions are repeated, greatly affecting growth, schoolwork, employment, pregnancy, childbirth, and so on. In the absence of radical treatment, patients are forced to continue treatment throughout their lives and are intractable diseases that suffer from physical, mental, social and economic burdens.
  • TNF tumor necrosis factor
  • macrophage migration inhibitory factor macrophage migration inhibitory factor
  • the current treatment options for IBD include 5-aminosalicylic acid (simply referred to as “5-ASA”) preparations, steroid preparations, immunomodulators and the like.
  • 5-ASA 5-aminosalicylic acid
  • steroid preparations steroid preparations
  • immunomodulators and the like.
  • anti-TNF monoclonal antibody preparations have been developed as novel therapies (see, for example, Non-Patent Documents 6 and 7). This treatment is expected to suppress TNF activity and rapidly improve inflammation in patients with Crohn's disease and ulcerative colitis.
  • Non-Patent Documents 8 and 9 which makes it difficult to continue treatment with anti-TNF antibodies. Therefore, the development of new treatments for IBD is urgent, but unlike current therapies that suppress systemic immune responses in particular, strategies that select treatment targets specific to the pathological condition are considered essential in the future. .
  • TNF- ⁇ / NF- ⁇ B in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.
  • An object of the present invention is to provide a pharmaceutical composition for use in the treatment or prevention of inflammatory bowel disease (IBD) and a method for treating or preventing inflammatory bowel disease (IBD) using the same.
  • Another object of the present invention is to provide a pharmaceutical composition for use in treating or preventing a disease caused by inflammatory macrophages, and a method for treating or preventing a disease caused by inflammatory macrophages using the same. I will.
  • a pharmaceutical composition for use in the treatment or prevention of inflammatory bowel disease comprising apelin or an apelin receptor agonist.
  • Composition [3] The pharmaceutical composition according to [2], wherein the apelin is [Pyr 1 ] -Apelin-13.
  • An apelin receptor agonist is TODDLER / ELABELA, E339-3D6, MM07, (S) -N- (1- (butylamino) -5-methyl-1-oxohexane-3-yl) -5- ( 2,6-dimethoxyphenyl) -1-isobutyl-1H-pyrazole-3-carboxamide, (S) -3- ⁇ [1- (1-ethyl-propyl) -2-thiophen-2-ylmethyl-1H-benzimidazole -5-carbonyl] -amino ⁇ -5-methyl-hexanoic acid, (S) -3- ⁇ [2-furan-2-ylmethyl-1- (2-methyl-cyclohexyl) -1H-benzimidazole-5-carbonyl ] -Amino ⁇
  • a method for treating or preventing inflammatory bowel disease (IBD) in a subject comprising a step of administering apelin or an apelin receptor agonist to the subject.
  • the apelin is selected from the group consisting of apelin-36, apelin-17, apelin-13, [Pyr 1 ] -apelin-13, apelin-12, and variants thereof Or prevention methods.
  • the apelin receptor agonist is a low molecular compound, a plant extract, or an agonist antibody.
  • the apelin receptor agonist is TODDLER / ELABELA, E339-3D6, MM07, (S) -N- (1- (butylamino) -5-methyl-1-oxohexane-3-yl) -5- ( 2,6-dimethoxyphenyl) -1-isobutyl-1H-pyrazole-3-carboxamide, (S) -3- ⁇ [1- (1-ethyl-propyl) -2-thiophen-2-ylmethyl-1H-benzimidazole -5-carbonyl] -amino ⁇ -5-methyl-hexanoic acid, (S) -3- ⁇ [2-furan-2-ylmethyl-1- (2-methyl-cyclohexyl) -1H-benzimidazole-5-carbonyl ] -Amino ⁇ -5-methyl-hexanoic acid, (S) -5-methyl-3- ⁇ [1-((1R, 2R) -2-methyl-cyclo
  • [15] Use of apelin or an apelin receptor agonist in the manufacture of a medicament for treating or preventing inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the apelin is selected from the group consisting of apelin-36, apelin-17, apelin-13, [Pyr 1 ] -apelin-13, apelin-12, and variants thereof .
  • the apelin is [Pyr 1 ] -apelin-13.
  • the apelin receptor agonist is a low molecular compound, a plant extract, or an agonist antibody.
  • An apelin receptor agonist is TODDLER / ELABELA, E339-3D6, MM07, (S) -N- (1- (butylamino) -5-methyl-1-oxohexane-3-yl) -5- ( 2,6-dimethoxyphenyl) -1-isobutyl-1H-pyrazole-3-carboxamide, (S) -3- ⁇ [1- (1-ethyl-propyl) -2-thiophen-2-ylmethyl-1H-benzimidazole -5-carbonyl] -amino ⁇ -5-methyl-hexanoic acid, (S) -3- ⁇ [2-furan-2-ylmethyl-1- (2-methyl-cyclohexyl) -1H-benzimidazole-5-carbonyl ] -Amino ⁇ -5-methyl-hexanoic acid, (S) -5-methyl-3- ⁇ [1-((1R, 2R) -2-methyl-cyclo
  • a pharmaceutical composition for treating or preventing a disease caused by inflammatory macrophages comprising apelin or an apelin receptor agonist.
  • Diseases caused by inflammatory macrophages include systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyarteritis, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease (MCTD) ), Selected from the group consisting of Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, and sarcoidosis, [22] The pharmaceutical composition according to [22].
  • a method for treating or preventing a disease caused by inflammatory macrophages in a subject comprising a step of administering apelin or an apelin receptor agonist to the subject.
  • Diseases caused by inflammatory macrophages are systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyperiarteritis, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease (MCTD) ), Selected from the group consisting of Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, and sarcoidosis, [24] The treatment or prevention method according to [24].
  • Diseases caused by inflammatory macrophages are systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyarteritis, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease (MCTD) ), Selected from the group consisting of Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, and sarcoidosis, [26] Use as described.
  • IBD inflammatory bowel disease
  • a food composition for treatment, symptom improvement or prevention of a disease caused by inflammatory macrophages comprising apelin or an apelin receptor agonist.
  • Diseases caused by inflammatory macrophages are systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyperiartritis, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease (MCTD) ), Selected from the group consisting of Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, and sarcoidosis, [32] The food composition according to [32].
  • a supplement containing apelin or an apelin receptor agonist for use in the treatment, symptom improvement or prevention of a disease caused by inflammatory macrophages are systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyperiartritis, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease (MCTD) ), Selected from the group consisting of Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, and sarcoidosis, [34] The supplement according to [34].
  • [36] A method of controlling the function of inflammatory macrophages and / or T cells by apelin or an apelin receptor agonist.
  • the method according to [36] comprising a step of contacting apelin or an apelin receptor agonist with inflammatory macrophages and / or T cells in vitro or in vivo.
  • the method according to [36] or [37] wherein the control of the function of inflammatory macrophages and / or T cells is suppression of production of cytokines and / or chemokines that induce inflammation.
  • the method according to [36] or [37] wherein the control of inflammatory macrophage and / or T cell function is suppression of production of TNF, CCL2, CCL5 and / or CXCL10.
  • TLR Toll-like receptor 4 expression of (A) F4 / 80 + , CD11b + macrophage population in the lamina intestinal tract of Rag2 ⁇ / ⁇ mice, and (C) of TLR4 high and TLR4 low macrophages It is the figure shown about production of IL-10 and TNF of a culture supernatant. * P ⁇ 0.05. It is the figure which showed about (A) expression of TLR4 of a macrophage in the large intestine mucosa lamina intestinal of a T cell transfer enteritis model, and (B) expression of apelin receptor (APJ) in a macrophage of TLR4 low and TLR4 high .
  • A Toll-like receptor
  • TLR4 expression in macrophages of Rag2 ⁇ / ⁇ mice that did not develop enteritis was used as a control, and TLR4 low and TLR4 high populations were fractionated based on this expression.
  • the present inventors have found that stimulation of the apelin-APJ system can treat inflammatory bowel disease (IBD) and other diseases caused by inflammatory macrophages.
  • IBD inflammatory bowel disease
  • the present invention is described in detail below.
  • Apelin (APL) Apelin-36 is a bioactive peptide consisting of 36 amino acids identified in 1998 in the bovine stomach as an endogenous ligand for APJ, an orphan receptor (Biochem. Biophys. Res. Commun., 251, 471 (1998).
  • the apelin gene has been identified in various species such as humans, dogs, cows, rats, mice, rhesus monkeys, and zebrafish, and encodes a 77-amino acid apelin preproprotein (also called apelin (1-77)).
  • apelin and APJ are found in brain, kidney, heart, lung, adipose tissue, gastrointestinal tract, mammary gland and the like.
  • Apelin has a wide range of activities, including effects on cardiac contractility, blood pressure, appetite, drinking behavior, hypothalamic-pituitary-adrenal system, gastric acid secretion, insulin and gallbladder contractor (CCK) secretion.
  • the base and amino acid sequences of apelin are known and can be obtained from databases such as GenBank:
  • APLN apelin [Homo sapiens (human)] Gene ID: 8862, NM_017413.4, NP_059109.3
  • apelin preproprotein In the processing of apelin preproprotein, a signal peptide corresponding to residues 1 to 22 of the apelin preproprotein is cleaved, and as a result, a 55 amino acid (residues from 23 to 77) apelin proprotein (apelin). (Also called (23-77)).
  • Apelin-36 also called apelin-36 (42-77)
  • Apelin-36 is a 36 amino acid long peptide derived from the 55 amino acid long apelin (23-77) proprotein (Tatemoto et al., Biochem. Biophys. Res). Comm., 251: 471-476, 1998), corresponding to residues 42 to 77 of the preproprotein.
  • Apelin-17 and apelin-13 are derived from the carboxyl (C) terminal side of apelin.
  • Apelin-17 corresponds to residues 61-77 of the apelin proprotein and is also referred to as apelin-17 (61-77).
  • Apelin-13 corresponds to residues 65-77 of the apelin proprotein and is also referred to as apelin-13 (65-77).
  • [Pyr 1 ] -apelin-13 in which glutamine (Gln) at the N-terminal of apelin-13 is replaced with pyroglutamic acid (Pyr), is equivalent to apelin-13 and is about 60 times stronger than apelin-36.
  • apelin-12 is also known to exist.
  • apelin-like peptides having agonist activity of the APJ receptor are collectively referred to as apelin.
  • apelin includes apelin-36, apelin-17, apelin-13, [Pyr 1 ] -apelin- 13, apelin-12, and variants thereof.
  • Variants of apelin introduce, for example, 1 to several (for example, within 25%) amino acid substitutions, deletions or insertions into wild-type apelin peptides Can be obtained.
  • a modified apelin can be obtained, for example, by amidating or acetylating the N-terminal of an apelin peptide, or by PEGylating an apelin peptide.
  • the modification can be produced by any method known to those skilled in the art.
  • Apelin receptor The apelin receptor (APJ) was cloned in 1993 as an orphan G protein-coupled receptor (GPCR).
  • the apelin receptor (APJ) is a member of the seven-transmembrane G protein receptor family and is structurally related to the angiotensin II type I receptor (ATIR).
  • APJ receptor gene is present on human chromosome 11, and its transmembrane region has 40-50% homology with the angiotensin (AT1) receptor (Gene, 136, 355 (1993)).
  • AT1 receptor angiotensin
  • the mRNA is expressed in several tissues such as the central nervous system, blood mononuclear cells, lung, heart, and placenta.
  • GenBank The base and amino acid sequences of the apelin receptor (APJ) are known and can be obtained from databases such as GenBank:
  • APLNR apelin receptor [Homo sapiens (human)] Gene ID: 187, NM_005161.4, NP_005152.1
  • Apelin-36 (42-77), apelin-17 (61-77), and apelin-13 (65-77) all have a phenylalanine residue at the C-terminus and can bind to the APJ receptor. it can.
  • apelin-13 a peptide antagonist version of apelin-13 (65-77), the C-terminal phenylalanine is replaced with alanine (LeeLet al.,. Endocrinology, ology146: 231-236,2362005). ).
  • (Ala-13) -Apelin-13 binds to the APJ receptor but does not stimulate the activity of the APJ receptor.
  • APJ has been shown to function as an endogenous antagonist system that inhibits angiotensin II's blood pressure-increasing action by forming a heterodimer with angiotensin II receptor AT1.
  • the apelin-APJ system exhibits a strong proliferative action on vascular endothelial cells and is involved in various physiological angiogenesis and angiogenesis during pathological conditions.
  • Apelin Receptor Agonist Apelin Receptor (APJ) agonists are typically apelin peptides and variants thereof, as long as they can stimulate apelin receptor activity, other agonist antibodies, small molecules, etc. It may be a substance.
  • WO2015188807A1 and WO20140444738A1 disclose an apelin receptor (APJ) agonist compound (eg, (S) -N- (1- (butylamino) -5-methyl-1-oxohexane-3) based on an imidazole skeleton.
  • AJ apelin receptor
  • Desensitization occurs when apelin is allowed to act for a long period of time, but biased agonists are useful as pharmaceuticals because desensitization does not occur.
  • Brame et al. Also reported that the cyclic peptide MM07 of apelin is a biased agonist (Brame et al. Hypertension 2015: 65, 834-840).
  • an apelin biased agonist is also included in the apelin agonist.
  • WO2015147641 discloses apelin cyclic peptides and their use.
  • WO2012125408 discloses PEGylated apelin.
  • EP1903052 and US2014 / 0094450 also disclose APJ receptor ligands.
  • WO2014099944 is an APJ agonist with increased stability compared to wild-type apelin-13, modified with a group that increases half-life at the N-terminus or C-terminus of the agonist, and at least one amino acid has Disclosed are APJ agonists that are substituted by non-standard amino acids. Groups that extend half-life include PEG, Fc domains, IgG, HSA, PE, Ab, peptides, lipids, poly (O-2-hydroxyethyl) starch (HES), and nanostructures. In the present invention, these apelin receptor agonists can also be used.
  • WO2013 / 146891 teaches pine extract, saffron extract, kina extract and comfrey extract, and crocetin, which is the main component of saffron extract, as a drug having the same function as apelin.
  • extracts can be obtained by any method known to those skilled in the art. It is known that crocetin is also contained in gardenia fruit.
  • Agonist antibodies can be obtained by any method known to those skilled in the art. Methods for producing monoclonal antibodies are known to those skilled in the art, and agonist antibodies can be obtained by selecting anti-APJ monoclonal antibodies having agonist activity.
  • the animal from which the antibody is derived is not particularly limited, and human antibodies, mouse antibodies, rat antibodies, rabbit antibodies, sheep antibodies, and the like can be used.
  • the antibody can be any of a human antibody, a humanized antibody, and a chimeric antibody, but is preferably a human antibody. Any antibody having agonistic activity against APJ need not be full length, and even antibody fragments can be used.
  • Fab, Fab ′, Fab′-SH, F (ab ′) 2 , Fv, V H , V L , Fab-Fv, scFv, minibody, Nanobody, and the like can also be used as agonist antibodies.
  • the antibody or antibody fragment may contain a peptide sequence identified by screening by a phage display method or the like.
  • aptamers composed of nucleic acids can be used in the same manner as ordinary antibodies.
  • the antibody may form a complex with a small molecule.
  • IBD Inflammatory bowel disease
  • IBD Inflammatory bowel disease
  • Crohn's disease (CD) and ulcerative colitis (UC) are the main types of inflammatory bowel disease, but broadly include intestinal tuberculosis and Behcet's disease. Crohn's disease has symptoms not only in the small and large intestines, but also in the mouth, esophagus, stomach, and anus, while ulcerative colitis is primarily observed in the colon and rectum.
  • Crohn's disease is a type of inflammatory bowel disease (IBD) that can cause symptoms in any part of the gastrointestinal tract, from the mouth to the anus.
  • IBD inflammatory bowel disease
  • the signs and symptoms include abdominal pain, diarrhea, fever, and weight loss.
  • Other complications such as anemia, rash, arthritis, redness of eyes, fatigue, etc. may occur outside the gastrointestinal tract. It is not uncommon for bowel obstruction to occur and patients with this disease are at increased risk of intestinal cancer.
  • 5-aminosalicylic acid mealazine
  • corticosteroids anti-TNF receptor antagonists and the like are used.
  • Ulcerative colitis Ulcerative colitis
  • Ulcerative colitis is a chronic relapsing inflammatory bowel disease (IBD) that causes inflammation and ulcers in the colon. Symptoms vary from mild to severe and usually manifest in young adults. The course is unpredictable, but is likely to be a lifetime illness. A prominent symptom of active disease is bloody diarrhea. UC has much in common with Crohn's disease, which is another IBD, but unlike Crohn's disease, UC shows symptoms only in the colon and rectum, not in the entire gastrointestinal tract. UC is an intermittent disease, in which the time when symptoms worsen and the time when there are relatively no symptoms alternately occur. The symptoms of UC sometimes disappear spontaneously, but usually require treatment before remission. As therapeutic agents for ulcerative colitis, 5-aminosalicylic acid (mesalazine), corticosteroids, immunosuppressants, anti-TNF receptor antagonists and the like are used.
  • 5-aminosalicylic acid mealazine
  • corticosteroids cortico
  • Models derived from chemicals include sodium dextran sulfate (DSS), 4-ethoxymethylene-2-phenyloxazol-5-one (oxazolone) and 2,4,6-trinitrobenzenesulfonic acid (TNBS).
  • DSS sodium dextran sulfate
  • oxazolone 4-ethoxymethylene-2-phenyloxazol-5-one
  • TNBS 2,4,6-trinitrobenzenesulfonic acid
  • An induced enteritis model is used (for example, see Non-Patent Documents 10 to 12).
  • Non-patent Document 13 a method in which naive T cells are transferred to immunodeficient mice such as Rag-deficient mice and SCID mice is known (Non-patent Document 13). ).
  • Various models such as IL-7 transgenic (Tg) mice (Non-Patent Document 14) and IL-10-deficient (KO) mice (Non-Patent Document 15) are known as models for spontaneous development of chronic enteritis.
  • Disease macrophages caused by inflammatory macrophages can be broadly classified into tissue-resident macrophages and monocyte-derived macrophages.
  • the inventors have shown that monocyte-derived inflammatory macrophages are increased in the lamina intestinal of the mouse inflammatory bowel disease (IBD) model, and that APJ expression is resident in inflammatory macrophages. It was found to be higher than macrophages.
  • APJ-apelin stimulation suppresses symptoms in animal models of inflammatory bowel disease (IBD).
  • one aspect of the present invention relates to a pharmaceutical composition containing apelin or an apelin receptor agonist for use in the treatment of diseases caused by inflammatory macrophages.
  • Diseases caused by inflammatory macrophages include, for example, systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyarteritis, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease (MCTD) ), Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, sarcoidosis Not.
  • compositions for use in the treatment or prevention of inflammatory bowel disease (IBD) comprising apelin or an apelin receptor agonist.
  • the apelin can be apelin-36, apelin-17, apelin-13, apelin-12, or a variant thereof, but is preferably [Pyr 1 ] -apelin-13.
  • the apelin receptor agonist can be a small molecule compound, a plant extract, or an agonist antibody. Also, as an apelin receptor agonist, pine extract, saffron extract, kina extract, comfrey extract, gardenia extract, or crocetin can be used.
  • the content ratio of apelin or apelin receptor agonist in 100% by weight of the pharmaceutical composition can be appropriately set within the range of 0.001 to 99.99% by weight.
  • IBD Inflammatory bowel disease
  • a pharmaceutical composition for use in the treatment of diseases caused by inflammatory macrophages comprising apelin or an apelin receptor agonist.
  • the other components in the pharmaceutical composition according to the present invention are not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples thereof include pharmaceutically acceptable carriers and additives.
  • the carrier or additive is not particularly limited and can be appropriately selected depending on, for example, the dosage form. Any carrier, diluent, excipient, suspension, lubricant, adjuvant, vehicle, delivery system, Emulsifiers, tablet disintegrants, absorbents, preservatives, surfactants, colorants, flavorings, or sweeteners may be included.
  • Any carrier, diluent, excipient, suspension, lubricant, adjuvant, vehicle, delivery system, Emulsifiers, tablet disintegrants, absorbents, preservatives, surfactants, colorants, flavorings, or sweeteners may be included.
  • a dosage form of the pharmaceutical composition based on this invention there is no restriction
  • an injection for example, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the composition, and subcutaneous, intramuscular, intravenous, etc. are added by a conventional method. Injectables can be produced.
  • the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like.
  • Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • Examples of the isotonic agent include sodium chloride and glucose.
  • Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the solid agent may be provided with an enteric coating.
  • the administration method of the pharmaceutical composition according to the present invention is not particularly limited, and for example, either local administration or systemic administration can be selected according to the dosage form of the pharmaceutical composition, the patient's condition, and the like.
  • Administration can be performed by, for example, intravenous administration, subcutaneous administration, intramuscular administration, oral administration, enteral administration, enema administration, tube feeding, and the like.
  • Enteral administration is not limited to administration via the anus, but also includes administration via a tube inserted into the digestive tract from outside the individual, such as a gastric fistula.
  • the insertion position is not limited to the intestine, but includes the esophagus, stomach, small intestine, large intestine and the like.
  • the subject of administration of the pharmaceutical composition according to the present invention is not particularly limited and may be appropriately selected depending on the purpose. Examples thereof include humans, mice, rats, cows, pigs, monkeys, dogs, cats and the like. Is preferably a human patient, particularly a human patient who develops IBD.
  • the pharmaceutical composition according to the present invention may be administered for the purpose of preventing the onset of IBD, and particularly for the purpose of preventing recurrence.
  • the dosage of the pharmaceutical composition according to the present invention is not particularly limited, and can be appropriately selected depending on the dosage form, the age and weight of the administration subject, the degree of desired effect, and the like.
  • the dose of apelin is, for example, 100 to 1,000,000 nmol per day, preferably 150 to 100,000 nmol, and the frequency of administration can be, for example, 1 to 100 times per month.
  • the administration time of the pharmaceutical composition according to the present invention is not particularly limited and may be appropriately selected depending on the purpose. For example, it may be administered prophylactically to a patient susceptible to the above-mentioned diseases, It may be administered therapeutically to patients presenting with symptoms. Moreover, there is no restriction
  • One aspect of the present invention relates to a method of treating or preventing inflammatory bowel disease (IBD) in a patient.
  • Such methods include the step of administering apelin or an apelin receptor agonist to the subject.
  • the apelin can be apelin-36, apelin-17, apelin-13, apelin-12, or a variant thereof, but is preferably [Pyr 1 ] -apelin-13.
  • the apelin receptor agonist can be a small molecule compound, a plant extract, or an agonist antibody. Also, as an apelin receptor agonist, pine extract, saffron extract, kina extract, comfrey extract, gardenia extract, or crocetin can be used.
  • IBD Inflammatory bowel disease
  • Another aspect of the present invention relates to a method for treating or preventing a disease caused by inflammatory macrophages in a patient. Such methods include the step of administering apelin or an apelin receptor agonist to the subject.
  • the apelin can be apelin-36, apelin-17, apelin-13, apelin-12, or a variant thereof, but is preferably [Pyr 1 ] -apelin-13.
  • the apelin receptor agonist can be a small molecule compound, a plant extract, or an agonist antibody. Also, as an apelin receptor agonist, pine extract, saffron extract, kina extract, comfrey extract, gardenia extract, or crocetin can be used. Inflammatory bowel disease (IBD) can be ulcerative colitis or Crohn's disease.
  • Another aspect of the present invention relates to the use of apelin or an apelin receptor agonist in the manufacture of a medicament for use in the treatment or prevention of diseases caused by inflammatory macrophages.
  • Diseases caused by inflammatory macrophages are collagen disease, more specifically systemic lupus erythematosus, rheumatic fever, scleroderma, dermatomyositis and polymyositis, nodular polyarteritis, rheumatoid arthritis, Sjogren's syndrome, mixed Sexual connective tissue disease (MCTD), Wegener's granulomatosis, Takayasu arteritis, temporal arteritis, eosinophilic fasciitis, adult Still's disease, ankylosing spondylitis, psoriatic arthritis, Behcet's disease, or sarcoidosis sell.
  • MCTD mixed Sexual connective tissue disease
  • One aspect of the present invention relates to food compositions or supplements containing apelin or an apelin receptor agonist, particularly for use in the treatment, symptom improvement or prevention of inflammatory bowel disease (IBD).
  • the present invention relates to a food composition or supplement, or a food composition or supplement (also referred to as nutritional supplement or health supplement) for intestinal regulation, intestinal environment improvement, intestinal inflammation suppression or intestinal inflammation prevention.
  • One embodiment of the present invention also relates to a food composition or supplement containing apelin or an apelin receptor agonist for use in the treatment, symptom improvement or prevention of a disease caused by inflammatory macrophages.
  • animal organ extracts eg, kidney, heart, lung, adipose tissue, gastrointestinal tract
  • apelin receptor agonist for example, pine extract, saffron extract, kina extract, comfrey extract, gardenia extract, crocetin and the like can be used, but are not limited thereto.
  • Examples of the food composition include general foods, foods for specified health including conditionally specified foods for specified health, nutritional supplements, functional foods, foods for the sick, and the like.
  • the specific form of the food composition is not particularly limited.
  • dietary supplement In the case of food for specified health use, dietary supplement, functional food, etc., forms such as powder, granule, capsule, troche, tablet, syrup and the like can be mentioned.
  • the supplement according to the present invention can take any form such as a tablet, powder, liquid and the like.
  • the supplement can be prepared, for example, to be taken orally 1 to 3 times a day before, during, or after a meal.
  • One aspect of the present invention relates to a method of controlling the function of inflammatory macrophages with apelin or an apelin receptor agonist.
  • Such methods can include contacting apelin or an apelin receptor agonist with inflammatory macrophages in vitro or in vivo.
  • the control of the function of inflammatory macrophages is, for example, suppression of production of cytokines and / or chemokines that induce inflammation, and preferably suppression of production of TNF, CCL2, CCL5 and / or CXCL10.
  • Such control of the function of inflammatory macrophages can be useful in the treatment and / or prevention of diseases involving inflammatory macrophages.
  • mice C57BL / 6 (Claire Japan) as wild type (WT) mice, donated by Rag2 deficient (Rag2 ⁇ / ⁇ ) mice (Taconic), apelin deficient (APL ⁇ / ⁇ ) mice (Vienna, IMBA) ) was used for cell preparation and DSS enterocolitis and T cell transfer enterocolitis models.
  • apelin / Rag2 double deficient (APL ⁇ / ⁇ Rag2 ⁇ / ⁇ ) mice were created by crossing Rag2 ⁇ / ⁇ and APL ⁇ / ⁇ mice.
  • female mice aged 8 to 12 weeks were used.
  • anti-F4 / 80 antibody BM8: eBioscience
  • anti-CD11b antibody M1 / 70: BD Biosciences or eBioscience
  • anti-CD11c antibody HL3: BD Biosciences
  • anti-TLR4 Antibody MRS510: abcam or BioLegend
  • anti-CD4 antibody RM4-5: BD Biosciences, eBioscience, or BioLegend
  • anti-CD62L antibody MEL-14: BD Biosciences, eBioscience or BioLegend
  • anti-CD44 antibody IM7: BD Biosciences) Or BioLegend
  • anti-apelin receptor (APJ) antibody H-300: Santa Cruz
  • anti-CCR2 antibody 475301: R & D Systems
  • FACSCalibur BD Biosciences
  • FACSCanto FACSCanto for flow cytometry analysis (FACS) II (BD Biosciences)
  • FA for cell isolation by FACS method Saria II a (BD Biosciences)
  • Cell If necessary
  • T cell transfer enteritis model The preparation of T cell transfer enteritis model was performed by Nagaishi et al (Takashi Nagaishi et al. SHP1 Phosphatase-Dependent T Cell Inhibition by CEACAM1 Adhesion Molecule Isoforms. Immunity. 2006 Nov; 25 (5): 769-81.). Specifically, spleen cells were collected from WT mice, hemolyzed using ACK buffer, and CD4-positive T cells were isolated using Pan T CELL Isolation Kit II (Miltenyi Biotec) and CD8 microbead beads (Miltenyi Biotec).
  • naive T cell fraction of CD4 + CD44 ⁇ CD62L + was isolated using FACSAria II. 2 ⁇ 10 5 isolated naive T cells were suspended in PBS and transferred into the abdominal cavity of Rag2 ⁇ / ⁇ or APL ⁇ / ⁇ Rag2 ⁇ / ⁇ mice. These mice are known to develop enteritis 6 to 8 weeks after transfer.
  • Tissues other than the supernatant were collected as pellets, washed with PBS, immersed in HBSS containing 10% FCS, 0.2 mg / ml collagenase type IV (Sigma), and 10 ⁇ g / ml DNase I (Sigma), and treated with The supernatant was recovered and filtered through a 40 ⁇ m cell strainer, and then centrifuged again to recover the pellet. The leukocyte fraction was recovered from this by specific gravity centrifugation using Percoll (GE).
  • GE Percoll
  • the collected cells were stained with anti-F4 / 80 antibody, anti-CD11b antibody, and anti-CD11c antibody, and the F4 / 80 + CD11b + CD11c ⁇ macrophage fraction was isolated and cultured using FACSAria II.
  • cytokines and chemokines Macrophages and T cells isolated from the lamina intestinal tract are RPMI1640 medium containing 1% non-essential amino acid, 10 mM HEPES, 500 U / ml penicillin, 100 ⁇ g / ml streptomycin, 10% FCS. And 0 to 1000 nM of synthetic apelin-13 (APL-13) was added as necessary, and cultured at 37 ° C. for 48 hours.
  • the culture supernatant was collected, and IL-6 (BD Biosciences), MIP-2 (BD), TNF (BD Biosciences), CCL2 (BD Biosciences), CCL5 (R & D Systems), CXCL10 (R & D Systems), IFN- ⁇
  • IL-6 BD Biosciences
  • MIP-2 BD
  • TNF BD Biosciences
  • CCL2 BD Biosciences
  • CCL5 R & D Systems
  • CXCL10 R & D Systems
  • IFN- ⁇ IFN- ⁇
  • concentrations of various cytokines and chemokines such as IL-2 were measured by ELISA.
  • Example 2 Expression system of inflammatory macrophages in the lamina propria> Cells were collected from the lamina intestinal of the large intestine of Rag2 ⁇ / ⁇ mice, and the macrophage population of F4 / 80 + CD11b + CD11c ⁇ was analyzed (FIG. 1A). As a result, a group with high expression of TLR4, a marker of inflammatory macrophages ( There were TLR4 high ) and a low group (TLR4 low ) (FIG. 1B). TLR4 high macrophage group and TLR4 low macrophage group were isolated using FACSAria II and cultured for 48 hours. Production of IL-10 and TNF in the culture supernatant was measured by ELISA.
  • TLR4 high macrophage fraction IL-10 production was significantly lower and TNF production was higher than that of the TLR4 low macrophage culture supernatant (FIG. 1C).
  • M1 inflammatory
  • M2 non-inflammatory macrophages
  • Example 3 Expression of apelin receptor in intestinal mucosa macrophage of IBD model> Naive T cells derived from the spleen of WT mice were isolated by FACS method and transferred into the abdominal cavity of Rag2 ⁇ / ⁇ mice. This was used as a T cell transfer group, and a control group was prepared by administering only the solvent (PBS) intraperitoneally without transferring T cells. In mice of the control group and the T cell transfer group, cells in the lamina intestinal of the large intestine were collected 6 to 8 weeks after cell transfer, and TLR4 expression of the macrophage population was analyzed in the same manner as in Example 2 above.
  • PBS solvent
  • the macrophage fraction in the T cell transfer group was identified using the TLR4 expression level of each M1 / M2 macrophage fraction in the control group as an index, and the expression of apelin receptor (APJ) in each fraction was analyzed by the FACS method.
  • APJ apelin receptor
  • Example 4 Action of apelin receptor agonist on inflammatory macrophages>
  • the colonic mucosa lamina limba macrophage of the T cell transfer enteritis model induced by the method described in Example 1 (3) above was isolated using FACSAria II, cultured in the presence of 0 to 1000 nM APL-13 for 48 hours.
  • Production of cytokines and chemokines such as IL-6, MIP-2, TNF, CCL2, CCL5 and CXCL10 in the supernatant was measured by ELISA.
  • the production of TNF, CCL2, CCL5, and CXCL10 was suppressed depending on the addition concentration of APL-13, although the production of IL-6, MIP-2 and the like was not affected (FIG.
  • CCL2 (MCP-1) is known to be associated with diseases associated with onset of monocyte infiltration such as psoriasis, rheumatoid arthritis, and atherosclerosis, and mainly monocytes, memory T cells, dendritic cells It has chemotactic activity against leukocytes such as basophils, and has the effect of attracting leukocytes to the local area of inflammation.
  • References related to CCL2 functions include: -Xia M, Sui Z (Mar 2009). "Recent developments in CCR2 antagonists". Expert Opinion on Therapeutic Patents. 19 (3): 295-303.
  • CCL5 (RANTES) is known to be associated with diseases such as rheumatoid arthritis and has chemotactic activity on leukocytes such as T cells, eosinophils, and basophils, and attracts leukocytes to the inflamed area. It is known to have an action to cause.
  • CXCL10 IP-10 is a chemokine discovered in psoriasis caused by neutrophil infiltration and has an action of enhancing adhesion of T cells to endothelial cells, monocytes, macrophages, NK cells, activated T cells. This contributes to the migration of B cells to the local area of inflammation.
  • CXCL10 is thought to be important in delayed type hypersensitivity reactions, and recently it has been reported that it binds to TLR4 and is also associated with cell damage in diabetes.
  • Example 5 Administration effect of apelin receptor agonist in IBD model animal>
  • T cell transfer enteritis model induced by the method described in Example 1 (3) above, 7.5 ⁇ g of APL-13 per mouse over 9 weeks from 1 week before T cell transfer to 8 weeks after transfer, or A control solution (PBS) was administered intraperitoneally three times a week to serve as an apelin administration group and a control group, respectively.
  • PBS PBS
  • the survival rate of the control group mice at 8 weeks after the transfer was about 60%, compared with about 90% in the apelin-administered group (FIG. 4).
  • mice 8 weeks after transfer was collected, fixed, sliced, and stained with hematoxylin and eosin. Histopathological analysis was performed on evaluation items such as epithelial injury, intestinal wall thickening, lymphocyte infiltration, and granulocyte infiltration.
  • the apelin-administered group showed a tendency to improve enteritis pathologically compared to the control group (FIG. 5). From these results, it was shown that an apelin receptor agonist such as APL-13 can be applied to the treatment of inflammatory diseases such as IBD.
  • mice 8 weeks after transfer were administered intraperitoneally three times a week to serve as a MM07 administration group and a control group, respectively. Further, the large intestine of mice 8 weeks after transfer was collected and T cells were isolated, and then the inflammatory cytokines IFN- ⁇ , IL- in the T cell culture supernatant were obtained by the method described in Example 1 (5) above. 2.
  • MM07 administration has an inhibitory effect on inflammatory cytokines in an enteritis model, and that apelin receptor agonists such as MM07 can be applied to the treatment of inflammatory diseases such as IBD.
  • Example 6 IBD exacerbation effect in apelin-deficient mice>
  • APL ⁇ / ⁇ A T cell transfer enteritis model was induced in APL ⁇ / ⁇ Rag2 ⁇ / ⁇ or Rag2 ⁇ / ⁇ mice by the method described in Example 1 (3) above.
  • exacerbation of weight loss at 5 and 6 weeks after cell transfer FOG. 6A
  • exacerbation of clinical symptoms such as diarrhea, bloody stool, glans, and dermatitis 6B
  • a decrease in survival rate FIG. 7
  • deterioration of pathological findings FIG. 8
  • APL ⁇ / ⁇ mice were also evaluated by the DSS enteritis model.
  • 2% DSS solution was administered to WT or APL ⁇ / ⁇ mice with free drinking for 5 days to induce inflammation of the large intestine, and then replaced with normal drinking water to evaluate enteritis.
  • weight loss significantly worsened with APL ⁇ / ⁇ compared to WT mice (FIG. 9).
  • macrophages infiltrating the lamina intestinal tract were isolated from WT or APL ⁇ / ⁇ mice 8 days after replacement with normal drinking water by the method described in Example 1 (4) above, and the expression of TLR4 was compared.
  • TLR4 expression was increased in colon macrophages of APL ⁇ / ⁇ mice compared to WT (FIG. 10).
  • Example 7 Analysis of inflammatory macrophage dynamics in the lamina intestinal mucosa of apelin-deficient mice> After inducing T cell transfer enteritis in APL ⁇ / ⁇ Rag2 ⁇ / ⁇ and Rag2 ⁇ / ⁇ mice by the method described in Example 1 (3) above, the intestinal mucosa lamina basement by the method described in Example 1 (4) above macrophages infiltrating isolated, was compared the number of cells, Rag2 - / - as compared to APL - / - Rag2 - / - significant increase was observed in the number of cells macrophages infiltrating in mice (FIGS. 11A and 11B). Further, Rag2 - / - as compared to APL - / - Rag2 - / - are TLR4 and CCL2 expressed was increased on colonic mucosa murine macrophages (Fig. 11C, D).
  • apelin or an apelin receptor agonist can be used to treat or prevent inflammatory bowel disease (IBD).
  • Apelin or an apelin receptor agonist can also be used to treat diseases such as collagen disease caused by inflammatory macrophages.

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Abstract

L'invention fournit une composition pharmaceutique destinée à être mise en œuvre dans le traitement ou la prévention d'une affection intestinale inflammatoire (AII). Concrètement, l'invention fournit une composition pharmaceutique qui comprend une apeline ou un agoniste de récepteur d'apeline. En outre, cette composition pharmaceutique qui comprend une apeline ou un agoniste de récepteur d'apeline, se révèle avantageuse dans le traitement d'autres affections provoquées par un macrophage inflammatoire, telles qu'une maladie du tissu conjonctif.
PCT/JP2017/043034 2016-12-01 2017-11-30 Procédé de traitement d'affection intestinale inflammatoire, et composition pharmaceutique destinée à être mise en œuvre dans celui-ci WO2018101398A1 (fr)

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WO2022079428A1 (fr) * 2020-10-12 2022-04-21 Heptares Therapeutics Limited Agonistes linéaires du récepteur de l'apeline
WO2022109092A1 (fr) * 2020-11-18 2022-05-27 Howard University Safran utilisé comme agent anti-inflammatoire dans le traitement d'une maladie intestinale inflammatoire
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Publication number Priority date Publication date Assignee Title
US11401244B2 (en) 2014-06-06 2022-08-02 Research Triangle Institute Apelin receptor (APJ) agonists and uses thereof
WO2021041791A1 (fr) * 2019-08-29 2021-03-04 Rti International, Inc. Méthodes et utilisations pour agonistes de récepteur de l'apeline
WO2022079428A1 (fr) * 2020-10-12 2022-04-21 Heptares Therapeutics Limited Agonistes linéaires du récepteur de l'apeline
WO2022109092A1 (fr) * 2020-11-18 2022-05-27 Howard University Safran utilisé comme agent anti-inflammatoire dans le traitement d'une maladie intestinale inflammatoire
CN114177272A (zh) * 2021-12-15 2022-03-15 广东省职业病防治院(广东省职业卫生检测中心) Mm07在制备治疗矽肺的药物中的应用
CN114177272B (zh) * 2021-12-15 2023-07-18 广东省职业病防治院(广东省职业卫生检测中心) Mm07在制备治疗矽肺的药物中的应用

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