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WO2025023774A1 - Composition pour inhiber l'angiogenèse induite par vegf, comprenant un peptide de liaison à ccl8 - Google Patents

Composition pour inhiber l'angiogenèse induite par vegf, comprenant un peptide de liaison à ccl8 Download PDF

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Publication number
WO2025023774A1
WO2025023774A1 PCT/KR2024/010882 KR2024010882W WO2025023774A1 WO 2025023774 A1 WO2025023774 A1 WO 2025023774A1 KR 2024010882 W KR2024010882 W KR 2024010882W WO 2025023774 A1 WO2025023774 A1 WO 2025023774A1
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WO
WIPO (PCT)
Prior art keywords
ccl8
cancer
peptide
present
composition
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Pending
Application number
PCT/KR2024/010882
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English (en)
Korean (ko)
Inventor
강규태
문애리
조효선
정주희
송경
김은숙
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Industry Academic Cooperation Foundation of Duksung Womens University
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Industry Academic Cooperation Foundation of Duksung Womens University
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Publication of WO2025023774A1 publication Critical patent/WO2025023774A1/fr
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Anticipated expiration legal-status Critical

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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention

Definitions

  • the present invention relates to a composition for inhibiting VEGF-induced angiogenesis comprising a CCL8 binding peptide.
  • Cancer is emerging as the greatest threat to national health, and health threats and deaths due to cancer are expected to increase due to aging and various environmental changes. Cancer is divided into benign tumors and malignant tumors. Benign tumors grow relatively slowly and do not metastasize from the original site of the tumor to other tissues, whereas malignant tumors have the characteristic of rapidly growing by leaving the original site and infiltrating other tissues, thereby threatening life and becoming a very important cause of death.
  • Metastasis is a phenomenon that accompanies the progression of malignant tumors. As malignant tumor cells proliferate and cancer progresses, they acquire new genetic characteristics necessary for metastasis, then infiltrate blood vessels and lymph nodes, circulate through blood and lymph, and settle in other tissues and proliferate. Research is actively being conducted to elucidate the mechanism of this metastasis and suppress it.
  • CCL8 CC Motif Chemokine Ligand 8
  • MCP2 monocyte chemoattractant protein 2
  • the present invention aims to provide a composition for inhibiting angiogenesis comprising a peptide represented by sequence number 1 that effectively inhibits the growth or proliferation and metastasis of cancer cells.
  • the present invention aims to provide a method for inhibiting angiogenesis, comprising the step of administering a composition comprising a peptide represented by the sequence number 1 to a subject other than a human.
  • the present invention provides a composition for inhibiting angiogenesis, comprising a peptide represented by sequence number 1.
  • the above peptide may inhibit the proliferation, migration and invasion of cancer cells.
  • the above peptide may inhibit the expression of vascular endothelial growth factor A in cancer cells.
  • the above cancer may include metastatic cancer.
  • the above cancer may be at least one selected from the group consisting of breast cancer, head and neck cancer, uterine cancer, brain cancer, skin cancer, kidney cancer, lung cancer, colorectal cancer, prostate cancer, liver cancer, bladder cancer, kidney cancer, pancreatic cancer, thyroid cancer, esophageal cancer, eye cancer, stomach cancer, ovarian cancer, cervical cancer, gallbladder cancer, bile duct cancer, and osteosarcoma.
  • the above peptide may bind to CCL8 (C-C Motif Chemokine Ligand 8) and inhibit the function of CCL8.
  • the present invention also provides a method for inhibiting angiogenesis, comprising the step of administering to a subject other than a human a composition comprising a peptide represented by sequence number 1.
  • composition according to the present invention can contribute to the prevention of cancer progression and metastasis by inhibiting the proliferation of cancer cells by inhibiting angiogenesis and the movement and invasion of cancer cells. Based on this, it can be usefully utilized in various pharmaceutical, food, and feed industries for the prevention, improvement, and treatment of cancer.
  • Figure 1 is a diagram showing the sequence of the peptide of the present invention, which is a CCL8-binding peptide and a derivative thereof.
  • Figure 2 is a diagram comparing the changes in cell mobility (left) and invasiveness (right) between the CCL8 treatment group and the CCL8 and peptide treatment group of the present invention in MDA-MB-231 cells.
  • Figure 3 is a diagram comparing the changes in vascular endothelial growth factor in cells treated with CCL8 and the peptide treated with CCL8 and the peptide of the present invention in MDA-MB-231 cells.
  • Figure 4 is a diagram comparing the changes in the binding of c-Jun and Sp-1 transcription factors to the VEGF-A promoter by the peptide of the present invention.
  • FIG. 5 is a diagram showing the effect of the peptide of the present invention (DSP-1) on inhibiting angiogenesis of endothelial colony forming cells (ECFCs) induced by CCL8.
  • DSP-1 the peptide of the present invention
  • Figure 6 is a diagram comparing the cell growth changes in the CCL8 treatment group and the CCL8 and peptide treatment group of the present invention in MDA-MB-231 cells.
  • the peptide according to the present invention is characterized by comprising an amino acid sequence represented by sequence number 1, and has an excellent effect of inhibiting the proliferation, migration and invasion of cancer cells increased under CCL8 (C-C Motif Chemokine Ligand 8) reaction.
  • the above 'peptide' is used interchangeably with 'protein' and includes reference to a polymer of amino acid residues.
  • the peptide may be synthesized using genetic recombination and a protein expression system, and preferably may be synthesized in vitro using a peptide synthesizer or the like.
  • the peptide according to the present invention is one of the derivatives of the peptide synthesized based on the property of evasin P672, a protein present in ticks, binding to CCL8. Specifically, it includes all homologues, analogs, fragments or derivatives of the CCL8-binding peptide produced after confirming the sequence through sequence analysis of the N-terminal region of evasin P672 protein that binds to CCL8.
  • the peptide of the present invention isolated from the CCL8-binding peptide has an amino acid sequence represented by the following SEQ ID NO: 1, as shown in FIG. 1.
  • CCL8 C-C Motif Chemokine Ligand 8
  • CCL8 C-C Motif Chemokine Ligand 8
  • CCL8 production in peritumoral fibroblasts can be upregulated in response to signals induced by breast cancer cells, especially triple-negative breast cancer cells.
  • CCL8 expressed in fibroblasts is secreted extracellularly to form a CCL8 gradient.
  • the formation of the CCL8 gradient acts as a chemoattractant for breast cancer cells, causing cancer cells to migrate toward fibroblasts.
  • Cancer cells activate surrounding fibroblasts to promote the expression of more CCL8, which in turn promotes cancer cell metastasis.
  • anti-CCL8 therapy should be considered for the management of metastatic breast cancer, and have confirmed the inhibitory ability of the peptide of the present invention, which is a derivative of the CCL8-binding peptide, to inhibit the growth, motility and invasiveness of cancer cells increased by CCL8.
  • the present invention provides a composition for inhibiting angiogenesis, comprising a peptide represented by the above sequence number 1.
  • the peptide of the present invention may inhibit the proliferation, migration and invasion of cancer cells.
  • the peptide of the present invention may inhibit the expression of vascular endothelial growth factor A in cancer cells.
  • composition containing the peptide of the present invention has an excellent effect of inhibiting the growth, mobility, invasiveness, and expression of vascular endothelial growth factor-A (VEGF-A) of cancer cells increased by CCL8, and thus has a preventive or therapeutic effect on cancer.
  • VEGF-A vascular endothelial growth factor-A
  • the peptide represented by the sequence number 1 may be included in an amount of 0.000001 to 30 wt%, preferably 0.0006 to 10 wt%, and more preferably 0.0006 to 1 wt%, based on 100 wt% of the total pharmaceutical composition containing the peptide.
  • VEGF-A vascular endothelial growth factor-A
  • the above cancer may include metastatic cancer.
  • the above cancer may be at least one selected from the group consisting of breast cancer, head and neck cancer, uterine cancer, brain cancer, skin cancer, kidney cancer, lung cancer, colorectal cancer, prostate cancer, liver cancer, bladder cancer, kidney cancer, pancreatic cancer, thyroid cancer, esophageal cancer, eye cancer, stomach cancer, ovarian cancer, cervical cancer, gallbladder cancer, bile duct cancer, and osteosarcoma, and preferably may be breast cancer, and more preferably may be malignant breast cancer.
  • the peptide of the present invention may bind to CCL8 (C-C Motif Chemokine Ligand 8) and inhibit the function of CCL8.
  • the peptide of the present invention can be utilized in the management of metastatic breast cancer as an anti-CCL8 therapy because it interferes with the motility of cancer cells and their invasiveness/metastasis through inhibition of CCL8 activity.
  • the present invention provides a method for inhibiting angiogenesis, comprising the step of administering to a subject other than a human a composition comprising a peptide represented by sequence number 1.
  • composition can be administered to a subject in a pharmaceutically effective amount.
  • the above “individual” may mean all animals including rats, mice, and livestock, and preferably may be mammals including humans.
  • administration means introducing a given substance into an individual by an appropriate method, and may include oral administration or parenteral administration.
  • the route of administration of the pharmaceutical composition may be administered through any general route as long as it can reach the target tissue.
  • parenteral administration include, but are not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing side effects, and the level of the effective dosage can be easily determined by those skilled in the art based on factors including the patient’s sex, age, weight, health condition, type and severity of the disease, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, and excretion rate, treatment period, drugs used in combination or simultaneously, and various other factors well known in the medical field, and it is also possible to estimate the amount used in humans from the effective amount determined through animal testing.
  • the daily dosage of the pharmaceutical composition can be applied in various ways by those skilled in the art, and is not specifically limited thereto in the present invention.
  • it can be 0.0001 to 100 mg/kg, and preferably 5 to 25 mg/kg.
  • the above administration may be divided into one or several times a day.
  • the above pharmaceutical composition may be in one or more formulations selected from the group consisting of oral, topical, suppository, sterile injectable solution and spray, each according to a conventional method, but is not limited thereto, and preferably may be an external preparation.
  • the above external preparation may be in the form of an external skin preparation, for example, an ointment, lotion, spray, patch, cream, powder, suspension, gel, or gel, but is not limited thereto, and may mean any form applied externally to the skin without any particular limitation.
  • Example 1 Using the peptide of the present invention Inhibition of cell motility and invasion
  • Example 2 Using the peptide of the present invention Inhibition of VEGF-A expression
  • CCL8 C-C Motif Chemokine Ligand 8 increases the expression of vascular endothelial growth factor A (VEGF-A) in MDA-MB-231 cells.
  • VEGF-A vascular endothelial growth factor A
  • CCL8 C-C Motif Chemokine Ligand 8 increases the expression of vascular endothelial growth factor A (VEGF-A) in MDA-MB-231 cells.
  • RT-qPCR and Westren blot analysis were performed in MDA-MB-231 cells.
  • CCL8 100 ng/ml
  • CCL8 100 ng/ml
  • the peptide of the present invention (20 ⁇ M) were treated in MDA-MB-231 cells, and then total RNA was extracted from the cells using Tri-RNA reagent (Tri-RNA reagent).
  • Tri-RNA reagent Tri-RNA reagent
  • cDNA was obtained using the extracted RNA (1.0 ug), d(T) primer, and reverse transcriptase.
  • the synthesized cDNA and SYBR green dye (Takara, Japan) were measured on an ABI StepOne plus Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) machine according to the manufacturer's suggested method. The results were corrected for the relative value of the beta-actin gene.
  • CCL8 100 ng/ml
  • CCL8 100 ng/ml
  • the peptide of the present invention (20 ⁇ M) were treated and cultured in MDA-MB-231 cells, and then 0.18 ml of cell lysis buffer (50 mM Tris.Cl pH 6.8, 2% SDS, 1 mM EDTA, 100 mM DTT, protease inhibitor) was added to lyse the cells.
  • cell lysis buffer 50 mM Tris.Cl pH 6.8, 2% SDS, 1 mM EDTA, 100 mM DTT, protease inhibitor
  • an equal amount of protein was heated to 95°C or higher for 5 minutes, cooled on ice for 5 minutes, and then electrophoresed on a 12% SDS-PAGE gel at 90 V.
  • Example 3 Using the peptide of the present invention c-Jun and Sp-1 transcription factors Inhibition of VEGF-A promoter binding
  • Chromatin Immunoprecipitation Chromatin Immunoprecipitation assay. Extracts from cells treated with CCL8 were collected, and immunoprecipitation was performed using antibodies to transcription factors such as c-Jun, Sp1, c-fos, and C/EBP. Protein-DNA complexes bound to antibodies were collected, and PCR was performed using primers containing the VEGF-A promoter region. The results are shown in Fig. 4.
  • DSP-1 peptide of the present invention affects the promoter binding of transcription factors involved in VEGF-A transcriptional activity, and confirmed that treatment with CCL8 binding peptide (DSP-1) significantly reduced the transcription factor-DNA binding, such as c-Jun and Sp1, increased by CCL8 (right).
  • Example 4 Inhibition of angiogenesis by the peptide of the present invention
  • DSP-1 peptide of the present invention
  • ECFCs endothelial colony forming cells
  • angiogenesis of ECFCs was significantly increased by treatment with the culture medium of cancer cells stimulated with CCL8, whereas treatment with the peptide of the present invention (DSP-1) significantly reduced angiogenesis increased by CCL8.
  • DSP-1 a vascular endothelial growth factor
  • Example 5 Using the peptide of the present invention Cell growth inhibition
  • composition according to the present invention can contribute to the prevention of cancer progression and metastasis by inhibiting the proliferation of cancer cells by inhibiting angiogenesis and by inhibiting the movement and invasion of cancer cells. Based on this, it can be usefully utilized in various pharmaceutical, food, and feed industries for the prevention, improvement, and treatment of cancer, and thus has industrial applicability.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Food Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Animal Husbandry (AREA)
  • Mycology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pour inhiber l'angiogenèse induite par VEGF, la composition comprenant un peptide de liaison à CCL8. La composition selon la présente invention peut contribuer à prévenir la progression et la métastase du cancer par inhibition de la prolifération des cellules cancéreuses et inhibition de la migration et de l'invasion des cellules cancéreuses. Sur la base de celle-ci, la présente invention peut être efficacement utilisée dans divers médicaments et aliments pour prévenir, soulager ou traiter le cancer, ainsi que dans l'industrie alimentaire.
PCT/KR2024/010882 2023-07-26 2024-07-26 Composition pour inhiber l'angiogenèse induite par vegf, comprenant un peptide de liaison à ccl8 Pending WO2025023774A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2023-0097787 2023-07-26
KR1020230097787A KR20250017027A (ko) 2023-07-26 2023-07-26 Ccl8 결합 펩타이드를 포함하는 vegf 유도-혈관신생 억제용 조성물.

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WO2025023774A1 true WO2025023774A1 (fr) 2025-01-30

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120134940A (ko) * 2011-06-03 2012-12-12 전남대학교산학협력단 골 형성 또는 혈관신생 촉진용 펩타이드 ｂｆｐ 4 및 이의 용도
US20200247855A1 (en) * 2017-08-18 2020-08-06 Oxford University Innovation Limited Therapy and diagnostics
US20200299374A1 (en) * 2015-03-18 2020-09-24 University Of South Carolina Anti-CCL8 Antibodies and Uses Thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120134940A (ko) * 2011-06-03 2012-12-12 전남대학교산학협력단 골 형성 또는 혈관신생 촉진용 펩타이드 ｂｆｐ 4 및 이의 용도
US20200299374A1 (en) * 2015-03-18 2020-09-24 University Of South Carolina Anti-CCL8 Antibodies and Uses Thereof
US20200247855A1 (en) * 2017-08-18 2020-08-06 Oxford University Innovation Limited Therapy and diagnostics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIM, E.-S. ET AL.: "CCL8 mediates crosstalk between endothelial colony forming cells and triple-negative breast cancer cells through IL -8, aggravating invasion and tumorigenicity", ONCOGENE, vol. 40, 2021, pages 3245 - 3259, XP037444967, DOI: 10.1038/s41388-021-01758-w *

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