WO2019057024A1 - Composition médicale comprenant un anticorps monoclonal ou un fragment de liaison à l'antigène de celui-ci et son utilisation - Google Patents

Composition médicale comprenant un anticorps monoclonal ou un fragment de liaison à l'antigène de celui-ci et son utilisation Download PDF

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WO2019057024A1
WO2019057024A1 PCT/CN2018/106144 CN2018106144W WO2019057024A1 WO 2019057024 A1 WO2019057024 A1 WO 2019057024A1 CN 2018106144 W CN2018106144 W CN 2018106144W WO 2019057024 A1 WO2019057024 A1 WO 2019057024A1
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ptx3
monoclonal antibody
pharmaceutical composition
antigen
binding fragment
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PCT/CN2018/106144
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English (en)
Chinese (zh)
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王育民
萧郁韦
纪智瑛
杜军毅
郑朝峻
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王育民
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Publication of WO2019057024A1 publication Critical patent/WO2019057024A1/fr
Priority to TW108133090A priority Critical patent/TWI754171B/zh
Priority to PCT/CN2019/105824 priority patent/WO2020052675A1/fr
Priority to CA3112678A priority patent/CA3112678A1/fr
Priority to KR1020217010919A priority patent/KR20210062036A/ko
Priority to BR112021004586-4A priority patent/BR112021004586A2/pt
Priority to JP2021538885A priority patent/JP2022500503A/ja
Priority to CN202311402782.7A priority patent/CN117417443A/zh
Priority to EP19861063.6A priority patent/EP3862363A4/fr
Priority to US17/274,960 priority patent/US20220119507A1/en
Priority to MX2021003032A priority patent/MX2021003032A/es
Priority to AU2019337248A priority patent/AU2019337248A1/en
Priority to CN201980058876.2A priority patent/CN112739714B/zh
Priority to SG11202102514QA priority patent/SG11202102514QA/en
Priority to PH12021550529A priority patent/PH12021550529A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens

Definitions

  • the present invention relates to a pharmaceutical composition and use thereof, and more particularly to a pharmaceutical composition comprising a monoclonal antibody or antigen-binding fragment thereof which specifically inhibits or slows the binding of PTX3 to a PTX3 receptor, and uses thereof.
  • cancer cells stimulate the microenvironment around the tumor to produce various inflammatory factors, white blood cells, hypervascular hyperplasia and proteases.
  • the chronic inflammatory response of cancer is also related to the growth, metastasis and invasion of cancer cells.
  • the cause and details of the formation are detailed. There are still many unclear aspects of the mechanism.
  • the tumor microenvironment In addition to the inflammatory response, the tumor microenvironment also pointed out that the tumor microenvironment is closely related to metastasis and chemoresistance.
  • the tumor microenvironment is composed of a variety of stromal cells and other different types of cells, which not only protects the tumor, but also allows the tumor cells to escape and resist immune cells, resulting in resistance of the tumor cells.
  • Fibroblasts and macrophages in the stromal tissue surrounding the tumor are activated by CEBPD, which induces the secretion of factor-like protein-like protein 3 (PTX3), which has an activity of promoting angiogenesis. And can increase the ability of nasopharyngeal carcinoma cells to migrate and invade tissue (or invasion).
  • PTX3 factor-like protein-like protein 3
  • past studies have also confirmed that CEBPD is activated in peripheral tissues of cancer, which may also promote cancer metastasis, and even promote the development of drug-resistant cancer cells during chemotherapy. These drug-resistant cancer cells grow faster and are easier to metastasize.
  • small molecule anticancer drugs such as cis-diammine dichloroplatinum (II); CDDP; trade name Cisplatin, paclitaxel (trade name Taxol) and 5-fluorouracil (5-FU), but recent studies have found that the above small molecule anticancer drugs not only activate CEBPD expression in cancer cells, but also activate CEBPD in macrophages and fibroblasts. On the contrary, it promotes cancer drug resistance and rapid metastasis, resulting in poor treatment of cancer.
  • II cis-diammine dichloroplatinum
  • CDDP trade name Cisplatin
  • paclitaxel trade name Taxol
  • 5-fluorouracil 5-fluorouracil
  • a pharmaceutical composition comprising an effective amount of a monoclonal antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier, and the above monoclonal antibody or antigen-binding thereof Fragments are used as active ingredients.
  • Yet another aspect of the present invention is to provide a monoclonal antibody or antigen-binding fragment thereof for use in the preparation of a pharmaceutical composition for specifically inhibiting or slowing the binding of PTX3 to a PTX3 receptor, wherein the monoclonal antibody or antigen-binding thereof Fragments are active ingredients, and monoclonal antibodies or antigen-binding fragments thereof have an effective amount to inhibit or slow down the disease or condition associated with PTX3 and PTX3 receptor binding.
  • a further aspect of the present invention provides a method for inhibiting or slowing the activity of a tumor cell in vitro comprising administering to the tumor cell an effective amount of the above pharmaceutical composition, thereby inhibiting or slowing down the activity of the tumor cell.
  • a pharmaceutical composition comprising an effective amount of a monoclonal antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier, and the above monoclonal antibody or antigen-binding fragment thereof As an active ingredient.
  • a monoclonal antibody or antigen-binding fragment thereof for the preparation of a medicament for specifically inhibiting or slowing the binding of a pentraxin-related protein (PTX3) to a PTX3 receptor
  • PTX3 pentraxin-related protein
  • the monoclonal antibody or antigen-binding fragment thereof is an active ingredient, and the monoclonal antibody or antigen-binding fragment thereof has an effective amount to inhibit or slow down the disease or condition associated with PTX3 and PTX3 receptor binding.
  • the pharmaceutical composition is for inhibiting or slowing down a disease or a symptom associated with binding of PTX3 to a PTX3 receptor, wherein the disease or symptom includes lung cancer, breast cancer, nasopharyngeal Cancer (nasopharyngeal carcinoma; NPC) and glioblastoma multiforme (GBM).
  • the disease or symptom includes lung cancer, breast cancer, nasopharyngeal Cancer (nasopharyngeal carcinoma; NPC) and glioblastoma multiforme (GBM).
  • a method for inhibiting or slowing down the activity of a tumor cell in vitro comprises administering an effective dose of the above pharmaceutical composition to a tumor cell, thereby inhibiting or slowing down the activity of the tumor cell.
  • the activity comprises proliferation, cancer stemness, migration, invasiveness, metastasis or drug resistance.
  • a pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment thereof of the present invention, which utilizes a specific PTX3 monoclonal antibody or an antigen-binding fragment thereof as an active ingredient, specifically inhibits or slows down the binding of PTX3 to the PTX3 receptor, This in turn inhibits or slows down the disease or condition associated with PTX3 binding to the PTX3 receptor.
  • FIG. 1A] to [Fig. 1C] are diagrams showing that the PTX3 monoclonal antibody inhibits the number of transitional cells of the breast cancer cell line MDA-MB231 (Fig. 1A), the number of invading cells (Fig. 1B), and cell pellets according to an embodiment of the present invention. The result of the number ( Figure 1C).
  • FIGS. 2A to 2C are diagrams showing the number of transitional cells (Fig. 2A), the number of invading cells (Fig. 2B), and the number of cell pellets of the lung cancer cell line A549 inhibited by the PTX3 monoclonal antibody according to an embodiment of the present invention (Fig. 2A). The result of Figure 2C).
  • FIG. 3A] to [Fig. 3C] are diagrams showing that the PTX3 monoclonal antibody inhibits the number of transitional cells of the nasopharyngeal carcinoma cell line HONE1 (Fig. 3A), the number of invading cells (Fig. 3B), and cell pellets according to an embodiment of the present invention. The result of the number ( Figure 3C).
  • FIG. 4A] to [Fig. 4C] are diagrams showing the number of transition cells of the glioblastoma cell line U87MG inhibited by the PTX3 monoclonal antibody (Fig. 4A), the number of invading cells (Fig. 4B), and cells according to an embodiment of the present invention. The result of the number of pellets (Fig. 4C).
  • FIG. 5 is a graph showing the results of binding of a PTX3 monoclonal antibody or a commercially available antibody to different PTX3 recombinant proteins according to an embodiment of the present invention.
  • FIG. 6A] to [Fig. 6B] are diagrams showing the number of transitional cells (Fig. 6A) and the number of invading cells (Fig. 6B) of the PTX3 monoclonal antibody or the commercially available antibody inhibiting the breast cancer cell line MDA-MB231 according to an embodiment of the present invention. the result of.
  • FIG. 7A] to [Fig. 7B] are diagrams showing the results of the inhibition of the number of transitional cells (Fig. 7A) and the number of invading cells (Fig. 7B) of the PTX3 monoclonal antibody or the commercially available antibody inhibiting the lung cancer cell line A549 according to an embodiment of the present invention. .
  • FIG. 8A] to [Fig. 8B] are diagrams showing the number of transitional cells (Fig. 8A) and the number of invading cells (Fig. 8B) of the PTX3 monoclonal antibody or the commercially available antibody inhibiting the nasopharyngeal carcinoma cell line HONE1 according to an embodiment of the present invention. the result of.
  • FIG. 9A] to [Fig. 9C] are diagrams showing a PTX3 monoclonal antibody or a commercially available antibody-inhibiting breast cancer cell line MDA-MB231 (Fig. 9A), a lung cancer cell line A549 (Fig. 9B), and a nasopharynx according to an embodiment of the present invention.
  • FIG. 10A] to [Fig. 10B] are diagrams showing that the PTX3 monoclonal antibody or the control group antibody inhibits the tumor volume of mouse xenografted breast cancer cell line MDA-MB231 (Fig. 10A) and tumor metastasis according to an embodiment of the present invention. (Fig. 10B) results.
  • FIG. 11A] to [Fig. 11B] are diagrams showing inhibition of tumor volume (Fig. 11A) and tumor metastasis of mouse orthotopically transplanted breast cancer cell line 4T1 by a PTX3 monoclonal antibody or an isotype control antibody according to an embodiment of the present invention (Fig. 11A) 11B) results.
  • the present invention provides a pharmaceutical composition comprising a monoclonal antibody or an antigen-binding fragment thereof, and a use thereof, which comprises a monoclonal antibody or an antigen-binding fragment thereof as an active ingredient, which can specifically inhibit or slow down positive five The binding of a pentraxin-related protein (PTX3) receptor to PTX3, thereby inhibiting or slowing down the disease or condition associated with PTX3 binding to the PTX3 receptor.
  • PTX3 pentraxin-related protein
  • the monoclonal antibody or antigen-binding fragment thereof referred to herein may comprise a specific sequence of a heavy chain variable region sequence and a light chain variable region sequence, which specifically blocks the C-terminal specific sequence of the PTX3 and PTX3 receptors. Combine.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence and a light chain variable region sequence, wherein the heavy chain variable region sequence can have, for example, the sequence identification number SEQ ID NO
  • the amino acid sequence listed in 1 and the light chain variable region sequence may, for example, be the amino acid sequence set forth in SEQ ID NO: 2.
  • the monoclonal antibody or antigen-binding fragment thereof thereof specifically inhibits or slows the binding of PTX3 to the PTX3 receptor, thereby specifically inhibiting or slowing the interaction of the PTX3 receptor with one or more PTX3 , suppress or slow down PTX3 information transmission, etc.
  • the aforementioned pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means a carrier, diluent, adjuvant, and/or vehicle that is not itself an active ingredient but is used to deliver the active ingredient to the individual, or Addition to the above composition to improve the handling or storage properties of the composition, or to allow or facilitate the dosage unit of the composition to form an excipient or any substance suitable for pharmaceutical compositions and convenient for administration.
  • the aforementioned pharmaceutically acceptable carrier should not destroy the pharmacological activity of the active ingredient and should be non-toxic when delivering a sufficient therapeutic amount of the active ingredient.
  • compositions include, but are not limited to, buffers, diluents, disintegrants, binders, adhesives, humectants.
  • Specific examples of the aforementioned pharmaceutically acceptable carrier may include, but are not limited to, citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, stearic acid, magnesium stearate, oxidation.
  • cellulose Substances such as cellulose esters of alkanoic acids and cellulose alkyl esters), low melting wax
  • the diseases or symptoms referred to herein as inhibiting or slowing down the binding of PTX3 to the PTX3 receptor may include epithelial cell carcinoma and glioblastoma multiforme (GBM), wherein epithelial cell carcinoma may include, for example, lung cancer, breast cancer, and Nasopharyngeal cancer.
  • GBM glioblastoma multiforme
  • the above monoclonal antibody or antigen-binding fragment thereof can be used to administer an effective amount of the above monoclonal antibody or antigen-binding fragment thereof or the above-described pharmaceutical composition to tumor cells, thereby inhibiting or slowing down the activity of tumor cells.
  • the "effective dose” as referred to in the present invention means that 2 mg to 10 mg of the PTX3 monoclonal antibody or antigen-binding fragment thereof is administered per kilogram of body weight, and the dose is administered once a week.
  • an effective dose of the aforementioned PTX3 monoclonal antibody or antigen-binding fragment thereof may be, for example, 5 mg/kg body weight to 10 mg/kg body weight, and preferably 6 mg/kg body weight to 9 mg/kg body weight.
  • the effective dose of the PTX3 monoclonal antibody is less than 2 mg/kg body weight, it is not possible to effectively reduce or inhibit or slow the binding of PTX3 to the PTX3 receptor within a preset time.
  • the activity of the tumor cells referred to herein is not limited, but may be, for example, proliferation, cancer stemness, migration, invasion, metastasis, tumor volume or drug resistance. (drug resistance).
  • the above pharmaceutical composition can be administered by subcutaneous injection, intramuscular injection, intravenous injection, intraperitoneal injection, orthotopic injection, oral administration, oral and nasal inhalation, etc., thereby specifically inhibiting Endogenous PTX3 activity, which in turn inhibits or slows the activity of cancer cells.
  • the monoclonal antibody or antigen-binding fragment thereof of the present invention and the pharmaceutical composition containing the same can inhibit or slow down the cancer cells after being used for a predetermined period of time, for example, from 4 weeks to 11 weeks. active.
  • a PTX3 monoclonal antibody that specifically recognizes the C-terminal amino acid sequence of the PTX3 recombinant protein is prepared by a conventional fusion tumor method or recombinant protein expression method.
  • the recombinant PTX3 protein of the non-denatured amino acid sequence set forth in SEQ ID NO: 3 was used as an immunogen, and Balb/C mice or PTX3 were injected intraperitoneally (ip) at a dose of 50 ⁇ g per mouse.
  • the knockout (PTX3knockout) mice were intraperitoneally, and after 2 weeks, the mice were boosted with a dose of 50 ⁇ g per mouse, twice a week for four times.
  • the activated splenocytes are fused with melanoma cells to produce a fusion tumor cell line.
  • the culture supernatant of the fusion tumor cell strain obtained above was collected to purify the PTX3 monoclonal antibody via a commercially available column, and then the complementation decision of the heavy chain variable region and the light chain variable region was analyzed by Taiwan Weiqiao Biomedical Co., Ltd.
  • the above PTX3 monoclonal antibody was analyzed by a commercially available monoclonal antibody typing kit, and it was confirmed that the antibody was classified into IgG1k.
  • Example 2 Assessing the effect of PTX3 monoclonal antibody on cancer cell activity
  • Breast cancer, lung cancer, nasopharyngeal carcinoma, glioblastoma multiforme (GBM) are malignant tumors, and the above cancer cells have activities such as migration, invasion, and cancer stemness.
  • This example utilizes a human breast cancer cell line (MDA-MB231, accession number: BCRC 60425, ATCC HTB-26; triple negative breast cancer cell line, hereinafter referred to as MB231), human lung cancer cell line A549 (registration number: BCRC 60074; ATCC) CCL-185), human nasopharyngeal carcinoma cell line HONE1 (Int. J. Cancer. 1990 Jan 15; 45(1): 83-9; Proc. Natl. Acad. Sci. USA, Vol. 86, pp.
  • the above cancer cells were seeded at a cell density of 1 ⁇ 10 5 cells/well in an upper layer (bottom pore diameter of 8 ⁇ m) of a 24-well Boyden cell transitioner (8 ⁇ m), and cultured for 3 hours.
  • Denatured amino acid sequence 2 ⁇ g/mL of PTX3 monoclonal antibody or 2 ⁇ g/mL of control group antibody (IgG1k).
  • FIG. 1A, FIG. 2A, FIG. 3A and FIG. 4A respectively illustrate the inhibition of breast cancer cell line MB231 ( FIG. 1A ), lung cancer cell A549 ( FIG. 2A ) and nasopharyngeal carcinoma by using PTX3 monoclonal antibody of Example 1 of the present invention.
  • the data of the above embodiments are obtained by comparing the three repeated experimental data of each time point and each sample with the mean standard deviation, and all the values are analyzed by one way ANOVA. .
  • the figure number "**" of the above embodiment represents data having statistical significance (P ⁇ 0.01), and the figure number "***" represents data having statistical significance (P ⁇ 0.001).
  • the PTX3 monoclonal antibody significantly inhibited or slowed down breast cancer cell line MB231, lung cancer cell line A549, nasopharyngeal carcinoma cell line HONE1 and gliacin compared to the control group antibody IgG1k.
  • the upper layer (bottom pore size of 8 ⁇ m) of the 24-well Bodenden cell transition chamber was previously coated with a basement membrane matrix (matrigel, purchased from BD Bioscience), and the above cancer cells were 1 ⁇ .
  • the cell density of 10 5 cells/well was seeded in the upper layer of a 24-well Borden cell transferer and cultured for 3 hours.
  • Denatured amino acid sequence 2 ⁇ g/mL of PTX3 monoclonal antibody or 2 ⁇ g/mL of control group antibody (IgG1k).
  • the cells on the inner side of the upper layer were scraped with a cotton swab and transferred to the cells outside the bottom of the upper layer using 4',6-diamidino-2-phenylindole (4',6-diamidino-2-phenylindole DAPI; Invitrogen) was stained, and the number of cells moving to the outer side of the upper layer was calculated under a field of magnification of 200 times the magnification of the fluorescence microscope, and the results are shown in FIGS. 1B, 2B, 3B, and 4B.
  • FIG. 1B, FIG. 2B, FIG. 3B and FIG. 4B respectively illustrate the inhibition of breast cancer cell line MB231 ( FIG. 1B ), lung cancer cell A549 ( FIG. 2B ) and nasopharyngeal carcinoma by using PTX3 monoclonal antibody of Example 1 of the present invention.
  • the PTX3 monoclonal antibody significantly inhibited or slowed down breast cancer cell line MB231, lung cancer cell line A549, nasopharyngeal carcinoma cell line HONE1 and gliacin compared to the control group antibody IgG1k.
  • the above cancer cells have cancer stemness, and the addition of the PTX3 monoclonal antibody causes the aforementioned cancer cells to form cell globules.
  • the above cancer cells were added to a 10% fetal bovine serum containing 2.5 ⁇ g/mL of PTX3 recombinant protein, 2 ⁇ g/mL of PTX3 monoclonal antibody or 2 ⁇ g/mL of control group antibody (IgG1k).
  • Fetal Bovine Serum; FBS Fetal Bovine Serum
  • FBS Fetal Bovine Serum
  • RPMI-1640 cell culture medium containing 10% fetal bovine serum (FBS), 50-100 ⁇ g/mL streptomycin and 50-100 U/mL penicillin]
  • Incubation at a concentration of 5% carbon dioxide at 37 ° C to maintain humidity, which is generally known in the art to which the present invention pertains, and therefore will not be further described.
  • the above-mentioned differently treated cancer cells were seeded at a cell density of 5 ⁇ 10 3 cells/well in a multi-well plate with ultra-low attachment surface (Corning Inc.) to Serum-free cell culture medium DMEM/F12 (Gibco) [B27 (Invitrogen), 20 ng/mL epidermal growth factor (EGF; Abcam) and 10 ng/mL basic fibroblasts) Growth factor (basic Fibroblast Growth Factor (bFGF; Peprotech)] was co-cultured. After 2 weeks of culture, the number of cell pellets was observed by an optical microscope, and the results are shown in Fig. 1C, Fig. 2C, Fig. 3C, and Fig. 4C.
  • FIG. 1C, FIG. 2C, FIG. 3C and FIG. 4C respectively illustrate the inhibition of breast cancer cell line MB231 (FIG. 1C), lung cancer cell A549 (FIG. 2C), nasopharyngeal carcinoma by using PTX3 monoclonal antibody of Example 1 of the present invention.
  • the PTX3 monoclonal antibody of Example 1 can significantly inhibit or slow down breast cancer cell line MB231, lung cancer cell A549, nasopharyngeal carcinoma cell line HONE1 and the control group antibody IgG1k.
  • Example 5 the epitope localization region of the PTX3 monoclonal antibody of Example 1 and the commercially available PTX3 monoclonal antibody (model: ab90806; abcam plc., UK) for PTX3 binding was evaluated in the same manner as in Example 3. The result is shown in Figure 5. Each value is three repetitions.
  • PTX3/FL represents SEQ ID NO according to an embodiment of the present invention.
  • a PTX3 recombinant protein fragment listed in 4 RI37 represents a PTX3 recombinant protein fragment as set forth in SEQ ID NO: 5
  • KT37 represents a PTX3 recombinant protein fragment as set forth in SEQ ID NO: 6
  • GI40 represents SEQ ID NO: 7
  • the PTX3 monoclonal antibody of Example 1 and the commercially available PTX3 monoclonal antibody (ab90806) have higher affinity for PTX3/FL (SEQ ID NO: 4), but the PTX3 monoclonal of Example 1.
  • the antibody PTX3 monoclonal antibody has higher affinity for the PTX3 recombinant protein fragment of RI37 (SEQ ID NO: 5) than the commercially available PTX3 monoclonal antibody (ab90806), and is statistically significant, representing the PTX3 monoclonal antibody and the commercially available PTX3 monoclonal
  • the antibody (ab90806) does have a difference in the epitope localization region for PTX3 binding.
  • FIG. 6A, FIG. 7A and FIG. 8A respectively illustrate the inhibition of breast cancer cell line MB231 ( FIG. 6A ) and lung cancer cell A549 by using the PTX3 monoclonal antibody of the first embodiment of the present invention or with the commercially available PTX3 monoclonal antibody ( FIG. 7A ).
  • the nasopharyngeal carcinoma cell line HONE1 (Fig. 8A)
  • the transition cell number bar graph wherein the figure number "**" represents statistically significant (P ⁇ 0.01) data, and the figure number "***” represents statistically significant Sexual (P ⁇ 0.001) data.
  • the PTX3 monoclonal antibody of Example 1 and the commercially available PTX3 monoclonal antibody (ab90806) significantly inhibited or slowed down breast cancer cell line MB231 and lung cancer cells compared to the control group antibody IgG1k.
  • the number of transitional cells of A549 and nasopharyngeal carcinoma cell line HONE1 was significantly higher than that of the commercially available PTX3 monoclonal antibody (ab90806), and was statistically significant.
  • FIG. 6B, FIG. 7B and FIG. 8B respectively illustrate the inhibition of breast cancer cell line MB231 ( FIG. 7B ) and lung cancer cell A549 by using the PTX3 monoclonal antibody of the first embodiment of the present invention or with the commercially available PTX3 monoclonal antibody ( FIG. 8B ).
  • the nasopharyngeal carcinoma cell line HONE1 (Fig. 9B)
  • the number of invading cells is a bar graph, wherein the figure number "**" represents statistically significant (P ⁇ 0.01) data, and the figure number "***" represents statistically significant Sexual (P ⁇ 0.001) data.
  • the PTX3 monoclonal antibody of Example 1 and the commercially available PTX3 monoclonal antibody (ab90806) significantly inhibited or slowed down breast cancer cell line MB231 and lung cancer cells compared to the control group antibody IgG1k.
  • FIG. 9A, FIG. 9B and FIG. 9C respectively illustrate the inhibition of breast cancer cell line MB231 ( FIG. 9A ) and lung cancer cell A549 by using the PTX3 monoclonal antibody of Example 1 of the present invention or with a commercially available PTX3 monoclonal antibody ( FIG. 9B ).
  • the cell pellet number of the nasopharyngeal carcinoma cell line HONE1 (Fig. 9C), wherein the figure number "**” represents statistically significant (P ⁇ 0.01) data, and the figure number "***” represents statistical Significant (P ⁇ 0.001) data.
  • the PTX3 monoclonal antibody of Example 1 and the commercially available PTX3 monoclonal antibody (ab90806) significantly inhibited or slowed down breast cancer cell line MB231 and lung cancer cells compared to the control group antibody IgG1k.
  • the number of cell pellets of A549 and nasopharyngeal carcinoma cell line HONE1 was still significantly higher than that of the commercially available PTX3 monoclonal antibody (ab90806), and was statistically significant. Sex.
  • Example 3 Assessing the effect of PTX3 monoclonal antibody on tumor growth and metastasis in vivo
  • the human cancer cell line is injected into the mammary fat pad of the immunodeficient mouse in situ, and after the tumor is formed, the PTX3 monoclonal antibody of Example 1 is administered, thereby evaluating the PTX monoclonal of the first embodiment.
  • Antibodies inhibit or slow the effects of tumors.
  • breast cancer cell line MB231-Luc2 [MB231 is a human breast cancer cell, does not exhibit estrogen receptor (ER) ⁇ and ER ⁇ ; Luc2 is a gene exhibiting luciferase] is inoculated in situ to NOD-SCID mice. (purchased from Leko Biotech Co., Ltd., Taiwan) in the breast fat pad. After the average volume of the tumor reached 80 mm 3 , the experimental mice were administered the PTX3 antibody (8 mg/kg body weight) of the first example or the control group antibody (IgG1k, 8 mg/kg body weight) once a week, and the results are shown in Fig. 10A. It is shown in Figure 10B. Fig.
  • 10B is a result of in vivo imaging at week 11 after inoculation of breast cancer cell line MB231-Luc2, wherein the luminescent image represents a tumor having a formation of breast cancer cell line MB231-Luc2 in mice. Then, all mice were sacrificed, the tumor size in vivo was measured, and the tumor volume was calculated using the following formula (I):
  • V (w ⁇ l 2 ) ⁇ 0.52 (I)
  • l represents the length of the tumor and w represents the width of the tumor.
  • FIG. 10A to FIG. 10B respectively show that the PTX3 monoclonal antibody or the control group antibody inhibits the tumor volume of mouse orthotopically transplanted breast cancer cell line MDA-MB231 ( FIG. 10A ) and tumor metastasis, respectively, according to an embodiment of the present invention.
  • Fig. 10B results.
  • the data in Fig. 10A is obtained by taking six replicate experimental data at each time point and each sample, taking the positive and negative mean standard deviations, and the figure number "*" represents statistically significant compared to the control group antibody (IgG1k). Sex (p ⁇ 0.05).
  • the PTX3 monoclonal antibody of Example 1 significantly inhibited or slowed down the tumor volume and tumor metastasis of the xenografted breast cancer cell line MB231 compared to the control group antibody (IgG1k), and this Item differences are statistically significant.
  • the human cancer cell line is injected in situ into the mammary fat pad of the normal normal mouse, and after the tumor is formed, the PTX3 monoclonal antibody of Example 1 is administered, thereby evaluating the PTX of the first embodiment.
  • Monoclonal antibodies inhibit the effects of tumors.
  • breast cancer cells 4T1-Luc2 (4T1 is a mouse breast cancer cell line, showing ER ⁇ but not ER ⁇ ) were inoculated in situ to wild-type BALB/c mice (purchased from Lesco Biotech Co., Ltd., Taiwan). The mammary fat pad. After the average volume of the tumor reached 80 mm 3 , the experimental mice were administered the PTX3 antibody (8 mg/kg body weight) or the control group antibody (IgG1k, 8 mg/kg body weight) of Example 1 once a week, and the results are shown in Fig. 11A. This is shown in Figure 11B. Fig.
  • 11B is the result of in vivo imaging at week 11 after inoculation of breast cancer cells 4T1-Luc2, wherein the luminescent image represents a tumor having a breast cancer cell 4T1-Luc2 formation in mice. Then, all mice were sacrificed, the tumor size in vivo was measured, and the tumor volume was calculated using the above formula (I).
  • FIG. 11A to FIG. 11B respectively show that the PTX3 monoclonal antibody or the control group antibody inhibits the tumor volume of the mouse in situ xenografted breast cancer cell 4T1 ( FIG. 11A ) and tumor metastasis ( FIG. 11A ) according to an embodiment of the present invention.
  • the result of Figure 11B The data in Fig. 11A is obtained by taking six replicate experimental data at each time point and each sample, taking the positive and negative mean standard deviations, and the figure number "**" means having statistics compared to the control group antibody (IgG1k). Significant (p ⁇ 0.01).
  • the PTX3 monoclonal antibody of Example 1 can significantly inhibit or slow down the tumor volume and tumor metastasis of in situ allograft breast cancer cell 4T1 compared to the control group antibody (IgG1k), and This difference is statistically significant.
  • the present invention exemplifies a pharmaceutical composition containing a monoclonal antibody or an antigen-binding fragment thereof of the present invention and a use thereof, using a specific sequence of a PTX3 monoclonal antibody, a specific analysis mode or a specific evaluation mode, and the use thereof.
  • the present invention is not limited thereto, and the pharmaceutical composition containing the monoclonal antibody or antigen-binding fragment thereof of the present invention and use thereof can be used without departing from the spirit and scope of the present invention.
  • Other analysis modes or other evaluation methods can also be used.
  • the pharmaceutical composition containing the monoclonal antibody or the antigen-binding fragment thereof of the present invention and the use thereof have the advantages of using a specific PTX3 monoclonal antibody or an antigen-binding fragment thereof as an active ingredient, and specifically inhibiting or The binding of PTX3 to the PTX3 receptor is slowed down, thereby inhibiting or slowing the disease or condition associated with PTX3 binding to the PTX3 receptor.

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Abstract

La présente invention concerne une composition médicale comprenant un anticorps monoclonal ou un fragment de liaison à l'antigène de celui-ci et son utilisation. L'anticorps monoclonal ou le fragment de liaison à l'antigène de celui-ci peut être utilisé en tant que principe actif inhibant spécifiquement ou ralentissant la liaison de PTX3 avec le récepteur PTX3 et inhibant en outre ou ralentissant des maladies ou des symptômes associés à la liaison de PTX3 avec le récepteur PTX3.
PCT/CN2018/106144 2017-09-19 2018-09-18 Composition médicale comprenant un anticorps monoclonal ou un fragment de liaison à l'antigène de celui-ci et son utilisation WO2019057024A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
TW108133090A TWI754171B (zh) 2018-09-14 2019-09-12 含單株抗體或其抗原結合片段之醫藥組成物及其用途
SG11202102514QA SG11202102514QA (en) 2018-09-14 2019-09-13 Medicinal composition containing monoclonal antibody or antibody fab fragment thereof, and use thereof
CN202311402782.7A CN117417443A (zh) 2018-09-14 2019-09-13 含单株抗体或其抗原结合片段的医药组合物及其用途
CA3112678A CA3112678A1 (fr) 2018-09-14 2019-09-13 Composition medicale contenant un anticorps monoclonal ou un fragment fab d'anticorps et utilisation associee
KR1020217010919A KR20210062036A (ko) 2018-09-14 2019-09-13 단클론 항체 또는 그의 항원 결합 단편을 포함하는 의약 조성물 및 그의 용도
BR112021004586-4A BR112021004586A2 (pt) 2018-09-14 2019-09-13 composição medicinal incluindo anticorpo monoclonal ou fragmento de ligação ao antígeno e seu uso
JP2021538885A JP2022500503A (ja) 2018-09-14 2019-09-13 モノクローナル抗体又はその抗原結合断片を含む医薬組成物及びその使用
PCT/CN2019/105824 WO2020052675A1 (fr) 2018-09-14 2019-09-13 Composition médicale contenant un anticorps monoclonal ou un fragment fab d'anticorps et utilisation associée
EP19861063.6A EP3862363A4 (fr) 2018-09-14 2019-09-13 Composition médicale contenant un anticorps monoclonal ou un fragment fab d'anticorps et utilisation associée
US17/274,960 US20220119507A1 (en) 2018-09-14 2019-09-13 Medicinal composition containing monoclonal antibody or antibody fab fragment thereof, and use thereof
MX2021003032A MX2021003032A (es) 2018-09-14 2019-09-13 Composicion medicinal que incluye un anticuerpo monoclonal o fragmento de union a antigeno y uso del mismo.
AU2019337248A AU2019337248A1 (en) 2018-09-14 2019-09-13 Medicinal composition containing monoclonal antibody or antibody fab fragment thereof, and use thereof
CN201980058876.2A CN112739714B (zh) 2018-09-14 2019-09-13 含单株抗体或其抗原结合片段的医药组合物及其用途
PH12021550529A PH12021550529A1 (en) 2018-09-14 2021-03-11 Medicinal composition containing monoclonal antibody or antibody fab fragment thereof, and use thereof

Applications Claiming Priority (4)

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US201762560202P 2017-09-19 2017-09-19
US62/560,202 2017-09-19
CNPCT/CN2018/105733 2018-09-14
PCT/CN2018/105733 WO2019056991A1 (fr) 2017-09-19 2018-09-14 Anticorps monoclonal ou fragment de liaison à l'antigène de celui-ci, et son utilisation

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PCT/CN2018/106144 WO2019057024A1 (fr) 2017-09-19 2018-09-18 Composition médicale comprenant un anticorps monoclonal ou un fragment de liaison à l'antigène de celui-ci et son utilisation

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