WO2019154103A1 - Nouveau polypeptide pour le ciblage tumoral et application de ce polypeptide - Google Patents

Nouveau polypeptide pour le ciblage tumoral et application de ce polypeptide Download PDF

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WO2019154103A1
WO2019154103A1 PCT/CN2019/073096 CN2019073096W WO2019154103A1 WO 2019154103 A1 WO2019154103 A1 WO 2019154103A1 CN 2019073096 W CN2019073096 W CN 2019073096W WO 2019154103 A1 WO2019154103 A1 WO 2019154103A1
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polypeptide
tumor
medicament
targeting
novel
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PCT/CN2019/073096
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English (en)
Chinese (zh)
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魏敏杰
赵琳
卫倩
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中国医科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to a novel polypeptide which has a targeting effect on human ovarian cancer cells and uses thereof.
  • Ovarian cancer is one of the most common tumors in female malignant tumors. Its incidence rate is the second in gynecological tumors, and its mortality rate is the first in gynecological malignancies. Because the ovary is located in the deep pelvic cavity, the onset is more concealed, the early stage of the disease is difficult to find and the disease develops rapidly, and the lack of effective screening and early diagnosis means that more than 70% of patients are in advanced stage. At present, the 5-year survival rate of patients with advanced ovarian cancer is only 20% to 40%, while that of early patients can reach 70% to 90%. Therefore, ovarian cancer is a hot topic in early diagnosis and treatment.
  • the existing anticancer drugs mainly include metal anticancer drugs, anticancer active ingredients extracted from natural products, anticancer drug targeted preparations, genetic engineering drugs, and nano controlled release anticancer drugs.
  • drugs with large toxic side effects, large dosages, and prone to acquired drug resistance which have an impact on the treatment of tumors.
  • molecular targeted therapy and other treatment methods provide new options for patients with advanced ovarian cancer. Therefore, early detection and development of ovarian cancer, sensitive diagnostic techniques, targeted therapy is the focus of research.
  • Phage display technology is an important technique for screening intermolecular interactions in the field of molecular biology.
  • the main principle of phage display technology is that the gene of interest or the gene encoding the protein and polypeptide is cloned into the appropriate position of the phage surface protein gene by genetic engineering technology, and it is expressed on the surface of the phage with the amplification of phage DNA, due to the foreign gene.
  • the expression product polypeptide or protein of the foreign gene can maintain its original spatial structure and corresponding biological activity.
  • the target cells or target molecules to perform meiotic screening on the phage, and finally select the phage that can specifically bind to the target cell or target molecule from the phage peptide library, and sequence the DNA to obtain the corresponding polypeptide.
  • the coding sequence This technology enables the connection between genotypes and phenotypes of proteins or peptides, and has the characteristics of simple operation and high-throughput detection, thus becoming an efficient means for screening tumor cell-specific binding peptides, for early detection of tumors and Targeted vector research in drug therapy offers new directions.
  • the object of the present invention is to provide a tumor-targeting novel polypeptide and a use thereof, which can specifically bind to human ovarian cancer cells and have no effect on human ovarian epithelial cells, which is an early diagnosis and targeted drug for ovarian cancer.
  • R&D and other aspects play an important role.
  • the principle of the present invention is: using human ovarian epithelial cells as a control, using human ovarian cancer cell line SK-OV-3 to perform subtraction screening on phage display peptide library, and selecting blue and white screening test to be specific to human ovarian cancer cells. Binding positive phage clones were tested and the specificity of binding of phage to human ovarian cancer cells was verified by ELISA experiments. Then, using E.
  • the purified phage is amplified and the DNA is extracted for sequencing, thereby obtaining a polypeptide coding sequence capable of specifically binding to human ovarian cancer cells, and synthesizing a fluorescently labeled positive polypeptide for fluorescent labeling-polypeptide and
  • the verification of the binding effect of human ovarian cancer cells and tumor-bearing mice provides an experimental basis for early diagnosis and targeted therapy of ovarian cancer.
  • the present invention adopts the following technical scheme: a novel tumor-targeting polypeptide, wherein the polypeptide has the amino acid sequence of: (W) a polypeptide sequence of: WNPLLLTRLLPA (SEQ ID No. 1), (2) A polypeptide derivative of a polypeptide molecule which has one or more amino acids deleted, inserted or substituted and which has the same biological function as the polypeptide molecule of (1).
  • the polypeptide has a targeting effect on tumor cells and specifically binds to tumor cells.
  • the tumor cells are human ovarian cancer cells.
  • polypeptide in the preparation of a tumor diagnostic kit comprising the polypeptide or polypeptide conjugate.
  • a polypeptide for the preparation of a medicament for the treatment of a tumor comprising the polypeptide and a pharmaceutically active ingredient, or a polypeptide and a delivery vehicle.
  • the medicament is any pharmaceutically therapeutically acceptable dosage form, and the preferred dosage form of the medicament is an injectable preparation.
  • the drug is any pharmacologically acceptable dose.
  • the short peptide small molecule drug has the advantages of relatively low molecular weight, weak immunogenicity, high activity and the like.
  • It can target in vivo tumors, and has the application prospects of specifically transmitting anticancer drugs, imaging agents, inorganic nanoparticles, liposomes, etc. to tumor tissues.
  • the peptides we screened can specifically bind to human ovarian cancer cells, but have no specific effect on human ovarian epithelial cells.
  • antibody-directed drugs which have the advantages of small molecular mass, high permeability, high specificity and low cost, they have shown unique advantages in tumor targeted diagnosis and treatment.
  • Figure 1 shows the binding of 40 phage clones to human ovarian epithelial cells HOSEpiC and human ovarian cancer cell line SK-OV-3.
  • Figure 2 shows the targeted binding of positive phage to human ovarian epithelial cells HOSEpiC and human ovarian cancer cell line SK-OV-3.
  • Figure 3 shows the sequencing results of positive phage DNA.
  • Figure 4 is a targeted binding effect of FITC-WA12 of the present invention to human ovarian epithelial cells HOSEpiC and human ovarian cancer cell line SK-OV-3.
  • Figure 5 is a targeted binding effect of FITC-WA12 of the present invention to tumor-bearing human ovarian cancer cell line SK-OV-3.
  • Phage 12 peptide library Escherichia coli E. coli ER2738, human ovarian epithelial cells HOSEpiC, human ovarian adenocarcinoma cells SK-OV-3, tumor-bearing mice.
  • McCoy's 5A medium RPMI-1640 medium, trypsin, FITG-labeled rabbit anti-mouse, fetal bovine serum, yeast powder, peptone, agar powder, tetracycline stock solution, Tween-20, bovine serum albumin BSA , HRP-anti-M13 filamentous phage antibody, M13 phage single-stranded DNA extraction kit, IPTG, X-gal, PEG-8000, TMB.
  • Preparing cells Firstly, the 6-well culture plate was pretreated with poly-lysine, and human ovarian epithelial cells HOSEpiC and human ovarian adenocarcinoma cell line SK-OV-3 were taken and treated with trypsin and then cultured into cells. Screening was performed after successful adherence and good growth.
  • Serum-free culture The cell culture medium was aspirated, washed once with PBS, and then added to serum-free medium, and placed in a 37 ° C constant temperature cell incubator with 5% CO 2 for 1 h.
  • Closing the cells Aspirate the cell culture medium, place the plate on a clean paper towel, remove the remaining medium, and seal the human ovarian epithelial cells HOSEpiC and human ovarian adenocarcinoma cells with a medium containing 1% BSA. -OV-3, placed in a 37 ° C constant temperature cell incubator with 5% CO 2 for 1 h.
  • Binding The adsorbed phage supernatant was incubated with human ovarian adenocarcinoma cell line SK-OV-3 for 1 h.
  • Washing Discard the unbound phage, place the microplate on a clean paper towel and pat it vigorously to remove the remaining solution. The plate was washed 5 times with 0.1% TBST as described above.
  • the IPTG/X-gal plate was preheated in an electrothermal incubator at 37 ° C; the appropriate amount of top agar was taken out and heated in a microwave oven, and after it was completely melted, it was taken out, and 3 ml was dispensed in each 10 ml centrifuge tube; After the phage was diluted in a ratio, 10 ⁇ l and 200 ⁇ l of E. coli were mixed and reacted for 5 min, then added to 3 ml of top agar, and then evenly spread on preheated IPTG/X-gal plate, after condensation. The titration results were observed at 37 ° C in an electrothermal incubator overnight.
  • Amplification of phage 20 ml of LB/Tet liquid medium was added to the Erlenmeyer flask, then E. coli bacteria solution and phage to be amplified were added at 1:100, placed at 37 ° C, and shaken vigorously in a constant temperature oscillator 4.5 h, an phage amplification solution is obtained.
  • Blocking Remove the fixed 96-well plate, take the liquid in the dry well, wash it with PBS 3 times, then add 3% hydrogen peroxide, and block it in a constant temperature incubator at 37 °C for 30 min to block Endogenous peroxidase activity.
  • Adding phage sample The blocked 96-well plate was taken out, and the liquid in the dry well was photographed, and the purified positive phage was added and reacted in a constant temperature incubator at 37 ° C for 1 h.
  • Termination The 96-well plate after the reaction was taken out, and the reaction was terminated by adding 2 M sulfuric acid.
  • DAPI staining washing with PBS 3 times, adding DAPI 100 ⁇ l, room temperature, 15 min
  • the positive phage was able to bind to human ovarian adenocarcinoma cell line SK-OV-3, and to human The binding ability of HOSEpiC in ovarian epithelial cells is weak, and there are significant differences between them, indicating that positive phage has a targeting effect on human ovarian cancer cells. Then, the phage clones showing positive binding were further sequenced, and it was confirmed that a total of 20 phage sequencing results showed the same sequence, which were 1, 5, 6, 7, 8, 9, 11, 12, 14, 18, 20, 22, 24, respectively. , 26, 27, 30, 32, 36, 38, 39. As shown in Figure 3, the polypeptide sequence was translated according to the principle of the triplet codon: WNPLLLTRLLPA (SEQ ID No. 1), WA12.
  • immunoglobulin staining assay was used to detect the targeted binding of the polypeptide to human ovarian cancer cells.
  • the fluorescently labeled polypeptide FITC-WA12 was used, and then the polypeptide was tested with human ovarian adenocarcinoma cell line SK-OV-3 by tumor-bearing mice. Targeting.
  • DAPI staining washing with PBS 3 times, adding DAPI 100 ⁇ l, room temperature, 15 min
  • the polypeptide sequence can bind to human ovarian adenocarcinoma cell line SK-OV-3, and the binding ability to human ovarian epithelial cells HOSEpiC is weak, and there is a significant difference between them, suggesting that the polypeptide has Target the role of ovarian cancer cells.
  • Tumor-bearing The nude mice were used for four weeks of age, and the human ovarian cancer cell line SK-OV-3 was inoculated into the tumor.
  • Fig. 5 The experimental results are shown in Fig. 5. After constructing human ovarian cancer-bearing mice, the peptide was fluorescently labeled and injected into the tail vein, and it was found that the fluorescence mainly accumulated in the tumor-bearing tissue, suggesting that the polypeptide may have targeted ovarian cancer tissue in vivo. The role.

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Abstract

La présente invention concerne le domaine de la biomédecine, et concerne spécifiquement un nouveau polypeptide ayant un effet de ciblage sur des cellules cancéreuses ovariennes humaines, et une application associée. Le polypeptide est (1) un polypeptide ayant une séquence d'acides aminés: WNPLLLTRLLPA (SEQ ID N ° 1), et (2) un dérivé polypeptidique qui est obtenu par délétion, insertion ou remplacement d'un ou de plusieurs acides aminés dans des molécules de polypeptide dans (1) et a la même fonction biologique que les molécules de polypeptide dans (1). Le polypeptide présente une faible masse moléculaire relative, une perméabilité élevée, une spécificité élevée, de faibles coûts, etc, et présente des avantages uniques dans le diagnostic et le traitement de ciblage de tumeur.
PCT/CN2019/073096 2018-02-09 2019-01-25 Nouveau polypeptide pour le ciblage tumoral et application de ce polypeptide WO2019154103A1 (fr)

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CN108341854B (zh) * 2018-02-09 2020-02-18 中国医科大学 一种肿瘤靶向的新型多肽及其用途
CN112386707B (zh) * 2019-08-19 2023-08-11 辽宁医学诊疗科技研发中心有限公司 一种肿瘤靶向多肽药物偶联物及其制备方法
CN111253472B (zh) * 2020-04-02 2022-05-27 中国医科大学 一种靶向多种肿瘤细胞的新型多肽及其用途
CN113527430B (zh) * 2020-04-15 2024-04-26 沈阳医健生命科技有限责任公司 一种肿瘤细胞特异靶向的新型多肽及其用途

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US20150111227A1 (en) * 2013-10-17 2015-04-23 National Tsing Hua University Peptide specific for ovarian cancer and applications
CN106589066A (zh) * 2016-11-03 2017-04-26 陕西师范大学 人卵巢癌细胞特异性结合的多肽及其应用
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