WO2014204229A2 - Composition pharmaceutique pour la prévention ou le traitement de l'arthrite rhumatoïde, comprenant un peptide en tant que principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de l'arthrite rhumatoïde, comprenant un peptide en tant que principe actif Download PDF

Info

Publication number
WO2014204229A2
WO2014204229A2 PCT/KR2014/005414 KR2014005414W WO2014204229A2 WO 2014204229 A2 WO2014204229 A2 WO 2014204229A2 KR 2014005414 W KR2014005414 W KR 2014005414W WO 2014204229 A2 WO2014204229 A2 WO 2014204229A2
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
rheumatoid arthritis
pharmaceutical composition
wkymvm
cells
Prior art date
Application number
PCT/KR2014/005414
Other languages
English (en)
Korean (ko)
Other versions
WO2014204229A3 (fr
Inventor
배외식
김상두
Original Assignee
성균관대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020140074491A external-priority patent/KR20140148325A/ko
Application filed by 성균관대학교산학협력단 filed Critical 성균관대학교산학협력단
Publication of WO2014204229A2 publication Critical patent/WO2014204229A2/fr
Publication of WO2014204229A3 publication Critical patent/WO2014204229A3/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating rheumatoid arthritis, and more particularly to a pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising a peptide consisting of the sequence of SEQ ID NO: 1 as an active ingredient.
  • Rheumatoid arthritis is a systemic inflammatory disease of unknown origin that is characterized by a number of chronic disease infections, but at the same time causes many organ damages. Rheumatoid arthritis progresses chronically with repeated deterioration of remission and exacerbation, and if left untreated, leads to destruction or deformation of the joints and eventually to dysfunction of the motor. Can be life threatening. Thus, patients with rheumatoid arthritis suffer a great deal of physical and mental pain throughout their lives.
  • Biologic Response Modifier which is mainly a TNF inhibitor and IL-1 inhibitor that can inhibit the action of inflammatory cytokines TNF- ⁇ and IL-1 ⁇ that are excessively produced in the pathology of rheumatoid arthritis.
  • selective B cell inhibitors and selective costimulation modulators have been developed and used as therapeutic agents to inhibit the production of autoimmune antibodies.
  • these therapies are known to cause side effects such as pain, itching, respiratory infections, and edema, and they have a fractional effect that inhibits the action of the resulting inflammatory cytokines, which do not provide the ultimate effective treatment.
  • the production of inflammatory cytokines is important in the pathogenesis of rheumatoid arthritis, but ultimately the production and maturation of osteoclasts, which are important for the regulation of bone production and activity, are important in the pathogenesis of rheumatoid arthritis.
  • There is a limit to the fundamental treatment by not having an inhibitory effect on osteoclast generation and activation.
  • the present invention has been made to solve the above problems in the prior art, an object of the present invention to provide a pharmaceutical composition for preventing or treating rheumatoid arthritis comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 1 as an active ingredient. .
  • the present invention to provide a health functional food composition for preventing or improving rheumatoid arthritis comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 1 as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising as an active ingredient a peptide consisting of the amino acid sequence of SEQ ID NO: 1.
  • the peptide is characterized in that it binds to the formyl peptide receptor (FPR).
  • FPR formyl peptide receptor
  • the peptide is characterized in that binding to formyl peptide receptor 2 (FPR2).
  • FPR2 formyl peptide receptor 2
  • the pharmaceutical composition is characterized by inhibiting the production of osteoclasts.
  • the pharmaceutical composition is characterized by reducing immunoglobulin and / or inflammatory cytokine levels.
  • the inflammatory cytokine is selected from the group consisting of interleukin-17 (IL-17), interleukin-21 (IL-21) and TNF- ⁇ (Tumor necrosis factor-alpha) It is done.
  • IL-17 interleukin-17
  • IL-21 interleukin-21
  • TNF- ⁇ Tumor necrosis factor-alpha
  • the pharmaceutical composition is characterized in that it further comprises a pharmaceutically acceptable carrier.
  • the present invention provides a health functional food composition for preventing or improving rheumatoid arthritis comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 1 as an active ingredient.
  • the peptide is characterized in that it binds to the formyl peptide receptor (FPR).
  • FPR formyl peptide receptor
  • the composition is characterized by inhibiting the production of osteoclasts.
  • the present invention provides a method for preventing or treating rheumatoid arthritis, comprising administering to a subject a peptide consisting of the amino acid sequence of SEQ ID NO: 1.
  • the present invention provides a use of the peptide consisting of the amino acid sequence of SEQ ID NO: 1 in the prevention or treatment of rheumatoid arthritis.
  • a pharmaceutical composition for preventing or treating rheumatoid arthritis comprising the peptide consisting of the amino acid sequence of SEQ ID NO: 1 according to the present invention, osteoclasts, in addition to inhibiting the differentiation and activation of T17 cells and T FH cells important in the pathogenesis of rheumatoid arthritis
  • osteoclasts in addition to inhibiting the production and activation of FPR2 through the effect of reducing the production of IL-17, IL-21 and immunoglobulin, it is expected to be applicable to the fundamental treatment of rheumatoid arthritis.
  • FIG. 1 is a view showing the results of measuring the hind paw thickness using a caliper (caliper) in the mice treated with and without the WKYMVm peptide in Example 1.
  • FIG. 2 shows the results of calculating the clinical scores added after scoring by scoring redness and swelling in each of four feet of mice treated with and without the WKYMVm peptide in Example 1; The figure which shows.
  • Figure 3 is a view showing the results of observing the osteoclasts produced by optical microscopy by H & E staining or TRAP staining bone tissue samples of mice treated with and WKYMVm peptide group in Example 2.
  • Figure 4 is a schematic diagram showing the inhibitory effect verification experiment of the osteoclast generation step of WKYMVm peptide.
  • Figure 5 is a view showing the osteoclast generation inhibitory results of the WKYMVm peptide in the early differentiation in Example 3.
  • Figure 6 is a view showing the osteoclast generation inhibitory results of the WKYMVm peptide in the differentiation stage in Example 3.
  • FIG. 7 shows the results of measuring interleukin-10 (IL-10) levels in mice of the WKYMVm peptide treated group and the untreated group of Example 3.
  • FIG. 7 shows the results of measuring interleukin-10 (IL-10) levels in mice of the WKYMVm peptide treated group and the untreated group of Example 3.
  • Figure 8 shows the results of confirming the expression of FPR2 in Example 4-1 (a) Th0 cells not stimulated with CD3 / CD28 (b) Th0 cells stimulated with CD3 / CD28 beads, Th17 and T FH cells Drawing.
  • Figure 9 is a view showing the results confirmed by the quantitative real-time PCR to change the expression level of ROR ⁇ -t and Bcl-6 in accordance with the treatment of the WKYMVm peptide in Example 4-2.
  • Figure 10 shows the results confirmed by FACS analysis whether Th17 inhibits IL-17 production according to the treatment of the WKYMVm peptide in Example 4-3.
  • Figure 11 shows the results confirmed by FACS analysis whether the inhibition of IL-21 production of T FH in accordance with the treatment of the WKYMVm peptide in Example 4-3.
  • FIG. 12 shows the results of calculating the clinical scores added after scoring by scoring redness and swelling in the CIA mouse model treated with the WKYMVm peptide and the untreated CIA mouse model in Example 5-2.
  • FIG. 13 is a view showing photographs observing the CIA mouse model treated with the WKYMVm peptide and the untreated CIA mouse model in Example 5-2.
  • FIG. 13 is a view showing photographs observing the CIA mouse model treated with the WKYMVm peptide and the untreated CIA mouse model in Example 5-2.
  • FIG. 14 is a diagram showing the results confirmed by ELISA analysis of IL-17, IL-21 and TNF- ⁇ production changes in the CIA mouse model treated with WKYMVm peptide and the untreated CIA mouse model in Example 5-2 .
  • FIG. 15 shows the results obtained by FACS analysis of cytokine production of CD4 T cells in splenocytes of CIA mouse in Example 5-3.
  • FIG. 16 shows the results of confirming collagen-specific T FH cell (CD4 + CXCR5 + PD-1 + ) population by WKYMVm peptide treatment in Example 5-3.
  • FIG. 17 shows the results of confirming germinal center formation using an immunohistochemical analysis in the CIA mouse model treated with the WKYMVm peptide and the untreated CIA mouse model in Example 5-3.
  • FIG. 18 shows the results of confirming immunoglobulin amounts according to germinal center formation in mouse serum in Example 5-3 through ELISA analysis.
  • FIG. 19 shows the results of calculating the clinical scores calculated after scoring by scoring redness and swelling in the CIA mouse model treated with CsH and WRW 4 , which are antagonists of FPR1 and FPR2, in Example 5-4. The figure shown.
  • FIG. 20 is a diagram showing the results confirmed by FACS analysis of the production of IL-17 and IL-21 in collagen-specific CD4 T cells in Example 5-4.
  • Example 21 shows the treatment of CsH and WRW 4 , which are antagonists of FPR1 and FPR2, in Example 5-5, and (a) the population of CXCR5 + PD-1 + CD4 T cells was confirmed by FACS analysis. It is a figure showing the result confirmed the formation using the immunohistochemical analysis (immunohistochemical analysis).
  • FIG. 22 shows the results of confirming the immunoglobulin amount in mouse serum by ELISA analysis in Example 5-5.
  • the present inventors have studied a new composition for solving the side effects of the currently available rheumatoid arthritis therapeutics, it was confirmed that the WKYMVm peptide is effective in rheumatoid arthritis by inhibiting the production of osteoclasts, based on the present invention It was completed.
  • the present invention provides a pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising as an active ingredient a peptide consisting of the amino acid sequence of SEQ ID NO: 1.
  • prevention means any action that inhibits or delays the onset of rheumatoid arthritis by administration of a composition of the present invention.
  • treatment refers to any action in which symptoms caused by rheumatoid arthritis are improved or beneficially altered by administration of a composition of the present invention.
  • the peptide which is an active ingredient of the pharmaceutical composition according to the present invention, consists of an amino acid sequence of tryptophan-lysine-tyrosine-methionine-valine-di-methionine (WKYMVm) (SEQ ID NO: 1, hereinafter referred to as "WKYMVm peptide"), It binds to a formyl peptide receptor (FPR), more preferably formyl peptide receptor 2 (FPR2), and is effective in rheumatoid arthritis by inhibiting the production of osteoclasts.
  • FPR formyl peptide receptor
  • FPR2 formyl peptide receptor 2
  • the hind paw thickness and clinical score of the rheumatoid arthritis pathologic index of the mice induced by rheumatoid arthritis were treated by treating the WKYMVm peptide, and the hind paw thickness and It was confirmed that the clinical score was significantly relieved (see Example 1).
  • treated mice with rheumatoid arthritis WKYMVm peptide and confirmed the production status of osteoclasts by H & E staining or TRAP staining, as compared with mice (control) not treated with WKYMVm peptide It was confirmed that the invasion of polymorphonuclear cells was significantly reduced (see Example 2).
  • the peptide as an active ingredient of the pharmaceutical composition of the present invention reduces the production of IL-17, IL-21 and immunoglobulin by binding to a formyl peptide receptor (FPR), preferably FPR2 to rheumatoid arthritis It works.
  • FPR formyl peptide receptor
  • the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • Pharmaceutically acceptable carriers included in the pharmaceutical compositions according to the present invention include, but are not limited to, saline, buffered saline, water, glycerol, polyethylene glycol, vegetable oils, isopropyl myristate and ethanol, and the like. Suitable formulations known to Remington's Pharmaceutical Science (Recent Edition, Mack Publishing Company, Easton PA) are all available.
  • the invention provides a method of treating rheumatoid arthritis by administering to a subject a peptide having the amino acid sequence of SEQ ID NO: 1.
  • subject means a subject in need of treatment for a disease, and more specifically human, or non-human primates, mice, rats, dogs, cats, horses, and cattle Means such mammals.
  • the preferred dosage of the pharmaceutical composition according to the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by those skilled in the art.
  • the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight is administered daily or every other day. It may be administered by dividing 1 to 3 times a day. However, the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes.
  • the method of administration is not limited and may be administered, for example, by oral, rectal, or intravenous, intramuscular, subcutaneous, intrauterine dural, or intra cerbroventricular injection.
  • the present invention provides a nutraceutical composition for preventing or improving rheumatoid arthritis comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 1 as an active ingredient. That is, the nutraceutical composition according to the present invention may be used simultaneously or separately with a medicament for the treatment of rheumatoid arthritis before or after the onset of rheumatoid arthritis in order to prevent or improve rheumatoid arthritis.
  • the term “improvement” refers to any action that at least reduces the parameters associated with the condition being treated, such as the extent of symptoms.
  • the health functional food composition according to the present invention binds to the formyl peptide receptor (FPR) and inhibits the production of osteoclasts, and thus can be added to food supplements such as foods and beverages for the purpose of preventing or improving rheumatoid arthritis.
  • FPR formyl peptide receptor
  • foods to which the active ingredient may be added include drink, meat, sausage, bread, biscuit, rice cake, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups , Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, etc., and includes all the health functional foods in the conventional sense.
  • WKYMVm peptide as an active ingredient in the nutraceutical composition according to the present invention can be added to food as it is or used with other foods or food ingredients, and can be suitably used according to conventional methods.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • composition for health drinks of the present invention is not particularly limited to other ingredients except for containing the active ingredient as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the nutraceutical composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors such as synthetic and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • these components can be used independently or in combination.
  • the proportion of such additives may also be appropriately selected by those skilled in the art.
  • mice 7-week-old BALB / c male mice were diluted 1/2 in PBS at 0 and 2 days, respectively.
  • Rheumatoid arthritis was induced by intraperitoneal injection of 100 ⁇ l of K / BxN rheumatoid arthritis serum.
  • 4 mg / kg of WKYMVm peptide was intraperitoneal and subcutaneous injection six times at 12 hour intervals, respectively, and none of the control groups were treated.
  • the hind paw thickness which is one of the rheumatoid arthritis pathology tables, was measured using a caliper, and the results are shown in FIG. 1.
  • the statistical analysis in the experiment was analyzed through Dunnett's Multiple Comparison Test (* P ⁇ 0.05; ** P ⁇ 0.01; *** P ⁇ 0.001 (versus control group)).
  • each mouse's paw with ankle joint was fixed in 10% Normal Buffered Formaldehyde (NBF) for 24-48 hours, followed by two weeks of replacement with 14% EDTA solution daily and demineralized. (decalcified). Then, washed with PBS, dehydrated with ethanol series, and embedded in paraffin to prepare a bone tissue sample. After obtaining 5 ⁇ m thick sections from the prepared bone tissue samples, it was confirmed by H & E staining or TRAP staining to generate osteoclasts, and the results are shown in FIG. 3.
  • NAF Normal Buffered Formaldehyde
  • the control group was confirmed that the exudation of osteoclasts (polymorphonuclear cells) (trap positive cells) in the joint space (joint space) is significantly increased, while bone tissue of the mouse treated with WKYMVm peptide In, the invasion of polymorphonuclear cells was significantly reduced. From the above results, it was found that the WKYMVm peptide according to the present invention is effective in inhibiting the production of osteoclasts.
  • Bone marrow cells (BMC) of mice were treated with macrophage colony-stimulating factor (M-CSF) to differentiate into macrophage, and then a combination of receptor activator of NF- ⁇ B Ligand (RANKL) and M-CSF While the osteoclasts were generated by the treatment, the WKYMVm peptide was treated at the early and middle stages of differentiation to verify the inhibitory effect of the osteoclast generation at each stage.
  • M-CSF macrophage colony-stimulating factor
  • RTKL NF- ⁇ B Ligand
  • BMC cells (5x10 3 cells / well) into 96 well plates using ⁇ -MEM medium, RANKL (100 ng / ml), M-CSF (30 ng / ml) and Various concentrations of WKYMVm peptides (0, 1, 10, 100 and 1000 nM) were treated, with media being replaced on day 3.
  • RANKL 100 ng / ml
  • M-CSF 30 ng / ml
  • WKYMVm peptides Various concentrations of WKYMVm peptides (0, 1, 10, 100 and 1000 nM) were treated, with media being replaced on day 3.
  • the number of trap positive cells was determined by optical microscopy to confirm the osteoclast generation inhibitory ability of the WKYMVm peptide at the beginning of differentiation, and the results are shown in FIG. 5. .
  • the ⁇ -MEM medium was replaced and RANKL (100 ng / ml), M-CSF (30 ng / ml) and various concentrations of WKYMVm peptides (0) for 1 day. , 1, 10, 100 and 1000 nM).
  • RANKL 100 ng / ml
  • M-CSF 30 ng / ml
  • various concentrations of WKYMVm peptides (0) for 1 day. , 1, 10, 100 and 1000 nM.
  • the number of trap positive cells was determined by optical microscopy to confirm the osteoclast generation inhibitory ability of the WKYMVm peptide during differentiation, and the results are shown in FIG. 6. .
  • BMC cells were differentiated into TRAP positive polymorphonuclear cells, and WKYMVm peptide was confirmed to inhibit the production of osteoclasts.
  • WKYMVm peptide was confirmed to inhibit the production of osteoclasts.
  • the inhibitory ability of osteoclast production was not large, it was confirmed that when 1 ⁇ M of WKYMVm peptide was treated, it significantly inhibited the production of osteoclasts.
  • the IL-10 levels of the K / BxN treated mice did not increase significantly, whereas the mice treated with the WKYMVm peptide showed a significant increase in IL-10 levels.
  • CD4 + CD62L hi CD44 lo CD25 neg cells were isolated from mouse spleen and cultured in polarizing reagent.
  • the isolated cells were treated with Th0 or IL-6 30ng / ml, TGF ⁇ 5ng / ml, IL-23 50ng / ml, anti-IL-4 10 ⁇ g / ml and anti-IFN ⁇ 10 ⁇ g / ml to differentiate into Th17, Differentiated into follicular helper T (T FH ) cells by treatment with 30ng / ml IL-6, 10 ⁇ g / ml anti-IFN ⁇ , 10 ⁇ g / ml anti-IL-4 and 20 ⁇ g / ml anti-TGF- ⁇ (1D11) neutralizing Abs Thereafter, FACS analysis was performed using mouse FPR2 antibody with stimulation with CD3 / CD28 Dynabeads, and the results are shown in FIG. 8.
  • mouse FPR2 was not expressed in Th0 cells that did not stimulate CD3 / CD28 (see FIG. 8A), while Th0 cells, Th17, and T FH stimulated with CD3 / CD28 beads. It was confirmed that the expression of mouse FPR2 in the cells (see Fig. 8 (b)).
  • Gene expression was analyzed using the Qiagen Rotor-Gene Q System (Qiagen, Inc.) using a SYBR green real-time PCR kit. Specific information of the primers used at this time is shown in Table 1 below.
  • Relative quantitation values was 2 - means the difference between ⁇ were expressed as Ct, where ⁇ Ct is conducted three times sample and endogenous ⁇ -actin Ct average value of the control group.
  • IL-17 derived from Th17 cells is known to induce various inflammatory diseases and chronic inflammatory diseases.
  • T FH cells produce IL-21 to stimulate B cells, thereby inducing maturation of B cells and differentiation into plasma cells.
  • IL-17 production is reduced when the WKYMVm peptide is treated (see FIG. 10 (b)) than in the case of Th17 cells not treated with the WKYMVm peptide (see FIG. 10 (a)).
  • IL-21 is treated more when treated with WKYMVm peptide (see FIG. 11 (b)) than when T FH cells not treated with WKYMVm peptide (see FIG. 11 (a)). It was confirmed that the production was reduced more than three times.
  • Example 4 the result was that WKYMVm peptide, a FPR2 agonist, reduced the function of Th17 and T FH through FPR2, and based on this, whether the same result was observed even in actual rheumatoid arthritis using a CIA mouse model. Confirmed.
  • TNF- ⁇ a representative cytokine of IL-17, IL-21 and rheumatoid arthritis, was markedly reduced in serum of the CIA model treated with the WKYMVm peptide, rather than the CIA model without the WKYMVm peptide.
  • the WKYMVm peptide according to the present invention is effective in inhibiting rheumatoid arthritis, and more specifically, the WKYMVm peptide decreases the function of Th17 and T FH through FPR2, thereby inhibiting rheumatoid arthritis.
  • cytokine production of CD4 T cells in splenocytes of CIA mice was confirmed by FACS analysis, and the results are shown in FIG. 15. As shown in FIG. 15, IL-17 and IL-21 generated in collagen-specific CD4 T cells of the CIA model were increased, but significantly decreased in the CIA model (CIA + WKYMVm) treated with the WKYMVm peptide. there was.
  • T FH cells are immune cells that mainly produce IL-21, and the collagen-specific T FH cells (CD4 + CXCR 5+ PD-1 + ) population by WKYMVm peptide treatment were identified, and the results are shown in FIG. 16. Shown in As shown in FIG. 16, CD4 + CXCR 5+ PD-1 + cells were significantly reduced in the CIA model (CIA + WKYMVm) treated with the WKYMVm peptide, rather than the CIA model without the WKYMVm peptide.
  • GCs germinal centers
  • PNA peanut agglutinin
  • Biotin-labeled anti-mouse PNA was applied as the primary antibody, followed by avidin and biotinylated alkaline phosphatase complex reagent.
  • PNA and other agents were obtained from Vector Laboratary, and slides for PNA staining were counted after staining with Hematoxlin.
  • GC formation was maintained in the CIA model not treated with the WKYMVm peptide, while GC formation was inhibited in the CIA model (CIA + WKYMVm) treated with the WKYMVm peptide.
  • immunoglobulin immunoglobulin
  • CIA + WKYMVm CIA + WKYMVm treated with the WKYMVm peptide, rather than the CIA model without the WKYMVm peptide.
  • FIG. 20 As shown in FIG. 20, the production of IL-17 and IL-21 was significantly decreased in the CIA + WKYMVm group than the CIA group, and the reduction effect by WKYMVm was inhibited by the injection of WRW 4 .
  • CsH and WRW 4 which are antagonists of FPR1 and FPR2
  • population and PNA formation of CXCR5 + PD-1 + CD4 T cells were confirmed by FACS and immunohistochemical analysis. Is shown in FIG. 21.
  • the population of CXCR5 + PD-1 + CD4 T cells was decreased in the CIA + WKYMVm group than the CIA group, and the reduction effect by WKYMVm was inhibited by the injection of WRW 4 .
  • the amount of immunoglobulins (immunoglobulin) in mouse serum was determined by ELISA analysis, and the results are shown in FIG. 22.
  • IgG1 and IgG2a production were also reduced in the CIA + WKYMVm group than the CIA group, the WKYMVm reduction effect was confirmed that the inhibition by WRW 4 injection.
  • the WKYMVm peptide alleviates the symptoms of rheumatoid arthritis by reducing the production of IL-17, IL-21 and immunoglobulin (immunoglobulin) through FPR2.
  • the peptide consisting of the amino acid sequence of SEQ ID NO: 1 not only inhibits the production and activation of osteoclasts, but also inhibits the production and activation of osteoclasts, as well as inhibits Th17 and T FH cell differentiation and activation, which are important in the pathogenesis of rheumatoid arthritis. It has an effect of reducing the production of IL-21 and immunoglobulin, and is expected to be useful as an active ingredient in pharmaceutical compositions or functional food compositions for the treatment of rheumatoid arthritis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement de l'arthrite rhumatoïde, comprenant, en tant que principe actif, un peptide constitué d'une séquence d'acides aminés comprenant SEQ ID NO: 1. La composition pharmaceutique selon la présente invention possède l'avantage d'inhiber la production et l'activation d'ostéoclastes, ainsi que la différentiation et l'activation de cellules Th17 et TFH, qui sont importantes dans le processus étiologique de l'arthrite rhumatoïde. Ladite composition peut donc être appliquée au traitement fondamental de l'arthrite rhumatoïde.
PCT/KR2014/005414 2013-06-21 2014-06-19 Composition pharmaceutique pour la prévention ou le traitement de l'arthrite rhumatoïde, comprenant un peptide en tant que principe actif WO2014204229A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20130071760 2013-06-21
KR10-2013-0071760 2013-06-21
KR1020140074491A KR20140148325A (ko) 2013-06-21 2014-06-18 펩타이드를 유효성분으로 포함하는 류마티스 관절염 예방 또는 치료용 약학적 조성물
KR10-2014-0074491 2014-06-18

Publications (2)

Publication Number Publication Date
WO2014204229A2 true WO2014204229A2 (fr) 2014-12-24
WO2014204229A3 WO2014204229A3 (fr) 2015-04-23

Family

ID=52105446

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2014/005414 WO2014204229A2 (fr) 2013-06-21 2014-06-19 Composition pharmaceutique pour la prévention ou le traitement de l'arthrite rhumatoïde, comprenant un peptide en tant que principe actif

Country Status (1)

Country Link
WO (1) WO2014204229A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017213695A1 (fr) 2016-06-07 2017-12-14 The Brigham And Women's Hospital, Inc. Compositions et méthodes se rapportant aux lymphocytes t auxiliaires périphériques dans des conditions associées aux autoanticorps
CN112368294A (zh) * 2018-07-03 2021-02-12 首尔大学校产学协力团 用于治疗风湿性关节炎的肽以及其用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040012929A (ko) * 2002-01-29 2004-02-11 주식회사 포스코 면역 조절 펩타이드
KR20060130064A (ko) * 2003-11-07 2006-12-18 아카디아 파마슈티칼스 인코포레이티드 통증 및 염증 치료에 효과적인 화합물을 동정하기 위한도구로서의 리폭신 수용체, ｆｐｒｌ1의 용도
US20100210509A1 (en) * 2007-10-09 2010-08-19 Postech Academy-Industry Foundation Long acting hyaluronic acid - peptide conjugate
KR20100091991A (ko) * 2007-11-02 2010-08-19 포항공과대학교 산학협력단 면역 관련 질병을 예방 및 치료하기 위한 조성물 및 방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040012929A (ko) * 2002-01-29 2004-02-11 주식회사 포스코 면역 조절 펩타이드
KR20060130064A (ko) * 2003-11-07 2006-12-18 아카디아 파마슈티칼스 인코포레이티드 통증 및 염증 치료에 효과적인 화합물을 동정하기 위한도구로서의 리폭신 수용체, ｆｐｒｌ1의 용도
US20100210509A1 (en) * 2007-10-09 2010-08-19 Postech Academy-Industry Foundation Long acting hyaluronic acid - peptide conjugate
KR20100091991A (ko) * 2007-11-02 2010-08-19 포항공과대학교 산학협력단 면역 관련 질병을 예방 및 치료하기 위한 조성물 및 방법

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017213695A1 (fr) 2016-06-07 2017-12-14 The Brigham And Women's Hospital, Inc. Compositions et méthodes se rapportant aux lymphocytes t auxiliaires périphériques dans des conditions associées aux autoanticorps
EP3463482A4 (fr) * 2016-06-07 2020-01-15 The Brigham and Women's Hospital, Inc. Compositions et méthodes se rapportant aux lymphocytes t auxiliaires périphériques dans des conditions associées aux autoanticorps
US11534496B2 (en) 2016-06-07 2022-12-27 The Brigham And Women's Hospital, Inc. Compositions and methods relating to T peripheral helper cells in autoantibody-associated conditions
CN112368294A (zh) * 2018-07-03 2021-02-12 首尔大学校产学协力团 用于治疗风湿性关节炎的肽以及其用途
EP3800196A4 (fr) * 2018-07-03 2022-03-30 Seoul National University R & DB Foundation Peptide pour le traitement de la polyarthrite rhumatoïde et son utilisation
CN112368294B (zh) * 2018-07-03 2023-09-29 首尔大学校产学协力团 用于治疗风湿性关节炎的肽以及其用途
US11987645B2 (en) 2018-07-03 2024-05-21 Seoul National University R&Db Foundation Peptide for treating rheumatoid arthritis and use thereof

Also Published As

Publication number Publication date
WO2014204229A3 (fr) 2015-04-23

Similar Documents

Publication Publication Date Title
RU2423139C2 (ru) КОМПОЗИЦИИ, СОДЕРЖАЩИЕ Actinidia, И СПОСОБЫ ИХ ПРИМЕНЕНИЯ
KR20170010442A (ko) 주사 또는 홍안 관련 피부 질환의 치료를 위한, 베르베린 또는 그의 유사체를 함유하는 조성물
WO2018070854A2 (fr) Composition pour la prévention ou le traitement de l'hépatite contenant un composé de monoacétyldiacylglycérol
WO2011031063A9 (fr) Composition de prévention ou de traitement de troubles métaboliques contenant l'anticorps anti-4-1bb
WO2014204229A2 (fr) Composition pharmaceutique pour la prévention ou le traitement de l'arthrite rhumatoïde, comprenant un peptide en tant que principe actif
Torii et al. Calcitonin gene-related peptide and Langerhans cell function
WO2019225953A2 (fr) Composition comprenant un extrait de sous-produit de pin à pignon et ayant pour effet de lutter contre helicobacter pylori
WO2017073849A1 (fr) Composition pour la prévention ou le traitement de l'arthrite, contenant un extrait de sargassum serratifolium en tant que substance active
WO2015026124A1 (fr) Composition contenant un composé de monoacétyldiacylglycérol en tant que principe actif pour prévenir ou traiter l'asthme
KR101924054B1 (ko) 피뿌리풀 추출물로부터 분리한 신규화합물 스테차몬을 유효성분으로 함유하는 아토피성 피부염 개선 또는 치료용 조성물
KR20150095012A (ko) 코디세핀을 유효성분으로 함유하는 아토피 치료 또는 예방용 피부 외용제 조성물
WO2015034247A1 (fr) Composition contenant un composé de monoacétyldiacylglycérol comme principe actif pour prévenir ou traiter la dermatite atopique
WO2021246755A1 (fr) Composition pour prévenir, soulager ou traiter une maladie métabolique, comprenant un inhibiteur de la phospholipase d2
WO2018030650A1 (fr) Composition anti-obésité contenant un extrait de feuilles de chrysanthème en tant que principe actif
KR101745278B1 (ko) 펩타이드를 유효성분으로 포함하는 류마티스 관절염 예방 또는 치료용 약학적 조성물
KR102174194B1 (ko) 플라본-레스베라트롤 접합체 화합물을 포함하는 아토피 피부염 예방, 치료 및 개선용 조성물
KR101836822B1 (ko) 모노아세틸디아실글리세롤 화합물을 함유하는 건선의 예방 또는 치료용 조성물
Telci et al. Alternative clinical approaches to the treatment of pruritus related with canine atopic dermatitis
WO2019103571A1 (fr) Composition destinée à traiter la dermatite, contenant un extrait et une fraction de parties aériennes de gypsophila oldhamiana miq et utilisation associée
KR20190118919A (ko) 감초 추출물 또는 분획물을 유효성분으로 포함하는 다발성 경화증의 예방, 치료, 또는 개선용 조성물
WO2021182865A1 (fr) Composition topique comprenant un extrait d'herbes combinées comprenant longanae arillus pour l'inhibition de la tlsp et le traitement ou le soulagement d'une maladie cutanée inflammatoire et son utilisation
WO2023033535A1 (fr) Composition comprenant un extrait de marron d'inde
WO2020091485A1 (fr) Composition destinée à être utilisée pour prévenir ou soulager la dermatite, comprenant de la caulophyllogénine, et son utilisation
WO2023033630A1 (fr) Composition pour la prévention ou le traitement de la dermatite atopique comprenant un inhibiteur de la voie de signalisation akt en tant que principe actif
KR101935371B1 (ko) 말톨, 이소소이아말로사이드 i 또는 이들의 혼합물을 유효성분으로 함유하는 아토피성 피부염 예방 또는 치료용 조성물

Legal Events

Date Code Title Description
122 Ep: pct application non-entry in european phase

Ref document number: 14813971

Country of ref document: EP

Kind code of ref document: A2