CN105497893A - Application of IL-11 monoclonal antibody in inhabiting PI3K/Akt signal channel - Google Patents
Application of IL-11 monoclonal antibody in inhabiting PI3K/Akt signal channel Download PDFInfo
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Abstract
The invention discloses the application of an IL-11 monoclonal antibody in inhabiting a PI3K/Akt signal channel. The concentration of the IL-11 monoclonal antibody is 8 mug/mL, and the dosage of the IL-11 monoclonal antibody is 10 mug. The safe and efficient PI3K/Akt signal channel inhibitor, namely the IL-11 monoclonal antibody is found, and can be specifically combined with IL-11 secreted by cells to induct PTEN transcription, up-regulate PTEN expression and inhibit the expression of AKT on the downstream portion of the PI3K/Akt signal channel, and then the whole signal channel is inhibited. The inhibitor is a natural antibody, so that toxic and side effects are reduced and safety and efficiency are high.
Description
Technical field
The invention belongs to intracellular signaling pathway technical field, be specifically related to a kind of IL-11 monoclonal antibody and suppressing the application in PI3K/Akt signal path.
Background technology
Colon cancer is one of common malignant tumor, and five-year survival rate is less than 5%.Therefore the research that the molecular mechanism of development occurs relevant colon cancer receives much concern.Occuring as of colon cancer is multifactor, the process of multistage and polygenic variation, relate to the molecular events of multiple proto-oncogene and antioncogene mediation, in recent years, along with the development of Celluar and Molecular Biology, people recognize that the expression product of most oncogene is all the constituent in cell signaling pathway, they from multiple link interference cell intracellular signaling process, can cause tumor cell proliferation and differentiation.The abnormal change of signal transduction pathway is also the important biomolecule feature of tumor cell, directly related with the generation of tumor, development and prognosis.
Recent study shows, PI3K/Akt signal path plays an important role in the developing of kinds of tumors.PI3K/Akt mainly plays its Anti-G value by affecting the wide variety of effector molecules in its downstream.At present, to be knocked out by Gene intervention method or small-molecule drug suppresses PI3K/Akt and related gene, block its activation to the multiple anti-apoptotic effector molecule in downstream.Promote that apoptosis has become the focus of oncotherapy research.Have been found that multiple kinase whose micromolecular inhibitor (smallmoleculeinhibitors.SMIs) in this signal path at present.They have optionally anti-tumor activity.Wortmannin and LY294002 is the PI3K inhibitor of two kinds of extensive uses.Their specificitys suppress the catalytic activity of PI3Kpll0 subunit.Block the activation of PI3K/Akt path, effectively can increase the sensitivity of chemotherapeutics to cancerous cell.But due to the side effect that this two kinds of inhibitor are potential, be also all limited in vitro study at present.
By finding the research of intestinal cancer tissue, when there being cancer to occur, the IL-11 secretion increasing in cancer beside organism, the IL-11 increased can infiltrate cancerous tissue and enter in cancer cell, in this case, cancerous cell can be bred rapidly and be broken up fast, and this is very unfavorable to the treatment of intestinal cancer.Solve the Main way that cancerous cell fast breeding problem is current Therapeutic cancer.The propagation of the effective anticancer of IL-11 monoclonal anti physical ability that the present invention finds is the new breakthrough for the treatment of intestinal cancer.
Summary of the invention
The object of this invention is to provide a kind of IL-11 monoclonal antibody suppressing the application in PI3K/Akt signal path, solving the problem that the signal pathway inhibitor existed in prior art brings side effect.
The technical solution adopted in the present invention is, IL-11 monoclonal antibody is suppressing the application in PI3K/Akt signal path.
Further, the concentration of IL-11 monoclonal antibody is 8ug/mL.
Further, the consumption of IL-11 monoclonal antibody is 10ug.
The invention has the beneficial effects as follows: the present invention has searched out one PI3K/Akt signal pathway inhibitor (IL-11 monoclonal antibody) safely and effectively, the specific IL-11 in conjunction with the secretion of cancer parietal cell of this inhibitor energy, induction PTEN transcribes, raise the expression of PTEN, suppress the expression of the AKT in PI3K/Akt signal path downstream, reach the effect suppressing whole piece signal path.This inhibitor is natural antibody, thus reduces toxic and side effects, safe and effective.
Accompanying drawing explanation
The selection result of Fig. 1 IL-11 concentration of the present invention;
The selection result of Fig. 2 IL-11 antibody concentration of the present invention;
Fig. 3 IL-11 of the present invention is to the proliferation function of cell;
The testing result of PTEN in Fig. 4 cell conditioned medium of the present invention;
The testing result of AKT in Fig. 5 cell conditioned medium of the present invention;
The testing result of Fig. 6 NF-Κ of the present invention B, wherein, NF-Κ Bp65 subunit result of variations in time after A:IL-11 stimulates, the testing result of NF-Κ B when A1-A4 represents 12h, 24h, 36h and 48h respectively; NF-Κ Bp65 subunit result of variations in time after B:IL-11 antibody blocking, the testing result of NF-Κ B when B1-B4 represents 12h, 24h, 36h and 48h respectively; C: ghost matched group NF-Κ Bp65 subunit result of variations in time, the testing result of NF-Κ B when C1-C4 represents 12h, 24h, 36h and 48h respectively.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is described in detail.
The effect that embodiment 1IL-11 breeds colon-cancer cell
The screening of 1.IL-11 concentration
Postdigestive 3-5 generation HT-29 cell suspension is pressed l0
4the concentration of/ml is inoculated in 12 well culture plates, every hole 2ml, puts 37 DEG C, 5%CO
2cultivate in incubator.After 12h is adherent, discard culture fluid, add final concentration for (2,5,8,10ug/ml) the DMEM complete medium 2ml of IL-11, set up the cell controls that do not add IL-11 simultaneously and repeat contrast.Continue to cultivate, in cell, add 80ulMTT at 6h, 12h, 24h, 36h, 48h, continue to cultivate after 4h and add 150ul dimethyl sulfoxide, vibrate after 10 points, OD490 detection.
The effect of 2.IL-11 on cell proliferation
Cell suspension presses l0
4the concentration of/ml is inoculated in 12 well culture plates, every hole 2ml, puts 37 DEG C, 5%CO
2cultivate in incubator.After 12h is adherent, discarding culture fluid, add the DMEM complete medium 2ml that final concentration is 8ug/mlIL-11, setting up the cell controls not adding IL-11 to contrast with repeating simultaneously.Continue to cultivate, to cell, add 80ulMTT from 6h, 12h, 24h, 36h, 48h, 60h, 72h, continue to cultivate after 4h and add 150ul dimethyl sulfoxide, vibrate after 10 points, OD490 detection.
The screening of 3.IL-11 antibody concentration
IL-11 presses the carbonate buffer solution bag quilt of 8ug/mL concentration PH9.6, every hole 100 μ L, after 4 DEG C of overnight incubation, the skimmed milk with 0.5% close, every hole 300 μ L, 37 DEG C hatch 2h after, wash for subsequent use.Take out bag by good check-out console, every hole adds 4ug, 8ug, 10ug, 15ug monoclonal antibody, hatch 2h, 4h, 6h, 8h for 37 DEG C, wash 3 times afterwards every hole add the sheep anti-mouse igg 100 μ L of the HRP labelling of 1:10000 dilution, hatch 1h for 37 DEG C, carry out TMB colour developing after washing 3 times, hatch 10min for 37 DEG C, after color development stopping, working sample 450nm place light absorption value.
4. the effect of IL-11 on cell proliferation after antibody blocking
Cell suspension presses l0
4the concentration of/ml is inoculated in 12 well culture plates, every hole 2ml, puts 37 DEG C, 5%CO
2cultivate in incubator.After 12h is adherent, discard culture fluid, add the DMEM complete medium 2ml that final concentration is (8ug/ml) IL-11, adding volume after 4h is 10ul (1ug/uL) IL-11 antibody incubation 4h, sets up the cell controls not adding IL-11 antibody to contrast with repeating simultaneously.Continue to cultivate, to cell, add 80uLMTT from 6h, 12h, 24h, 36h, 48h, 60h, 72h, continue to cultivate after 4h and add 150ul dimethyl sulfoxide, vibrate after 10 points, OD490 detection.
Embodiment 2IL-11 is to the effect of PTEN, AKT, NF-Κ B in PI3K cell-signaling pathways
Cell suspension presses 5xl0
4the concentration of/ml is inoculated in 12 well culture plates (band creep plate), every hole 2ml, puts 37 DEG C, 5%CO
2cultivate in incubator.After 12h is adherent, discard culture fluid, experiment is divided into two groups, one group of DMEM complete medium 2ml adding final concentration and be (8ug/ml) IL-11, adding volume after 4h is 10ulIL-11 antibody incubation 4h, another group only adds the DMEM complete medium 2ml of final concentration for (8ug/ml) IL-11, sets up signal suppressing agent matched group and repeating groups simultaneously.Continue to cultivate, collect cell conditioned medium from 4h, 6h, 8h, 12h, detect PTEN, AKT by ELISA kit; 12h, 24h, 36h, 48h collect the change of the operating procedure detection NF-Κ B of cell by specification.
Embodiment 3 detects the content of PTEN in above-mentioned cell conditioned medium
One, method:
One) ELISA kit is utilized to detect the content of PTEN in above-mentioned cell conditioned medium.
1. application of sample: establish blank well, gauge orifice, testing sample hole respectively.Blank well adds sample diluting liquid 100ul, and remaining hole adds standard substance or testing sample 100ul respectively, notes not having bubble, sample is added on bottom ELISA Plate hole by application of sample, does not touch hole wall as far as possible, rocks mixing gently, ELISA Plate adds upper cover or overlay film, and 37 DEG C are reacted 120 minutes.
2. discard liquid, dry, need not wash.Every hole adds detects solution A working solution 100ul (get 1ul detection solution A and add the proportions that 99ul detects diluent A, mix gently, prepare in a hour before use), 37 DEG C, 60 minutes.
3. incubation is after 60 minutes, discards liquid in hole, dries, washes plate 3 times, and each immersion every hole of 1-2 minute, 350ul/, dries.
4. every hole adds detection solution B working solution (with detecting A working solution) 100ul, 37 DEG C, 60 minutes.
5. incubation is after 60 minutes, discards liquid in hole, dries, washes plate 5 times, and each immersion every hole of 1-2 minute, 350ul/, dries.
6. sequentially every hole adds substrate solution 90ul, 37 DEG C of lucifuge colour developings (within 30 minutes, now there is the blue color of obvious gradient in the front 3-4 hole of naked eyes visual standard product, and rear 3-4 gradient pores is not obvious, can stop).
7. sequentially every hole adds stop bath 50ul, cessation reaction (now blue vertical turn of yellow).The addition sequence of stop buffer should be as far as possible identical with the addition sequence of substrate solution.In order to ensure the accuracy of experimental result, the substrate reactions time to after should add stop buffer as early as possible.
8. sequentially measure the optical density (OD value) in each hole at 450nm wavelength with enzyme connection instrument.Detect within 15 minutes after adding stop buffer.
Two), utilize ELISA kit to detect the content of AKT in above-mentioned cell conditioned medium, operate the same.
Three) test kit, is utilized to detect the change of NF-Κ B.
Two, experimental result:
One), IL-11 is to the proliferation function of cell
1, the selection result of IL-11 concentration:
As can be seen from Figure 1, to urge the proliferation function of colon-cancer cell the most remarkable for the IL-11 of 8ug/mL.
The screening of IL-11 antibody concentration: as can be seen from Figure 2,10ug antibody incubation 4h is the strongest in conjunction with the ability of IL-11.
2, the effect of IL-11 on cell proliferation:
As can be seen from Figure 3, at the 48h of IL-11 irritation cell, cell quantity reaches maximum, occurs growth stable phase afterwards, and after 60h, cell starts decline.After IL-11 antibody blocking, the proliferation function that IL-11 urgees cell is not remarkable.It can thus be appreciated that IL-11 has the effect promoting propagation to colon-cancer cell.
Two) IL-11 is to the exercising result of PTEN, AKT, NF-Κ B in PI3K cell-signaling pathways
1, the testing result of 1.PTEN
As can be seen from Figure 4, IL-11 suppresses the generation of PTEN, and when after IL-11 antibody blocking, the generation of PTEN is sharply risen, significant difference between two groups of data.And because the action target spot of inhibitor is not at PTEN, so facilitation be there is no to the generation of PTEN.
2, the testing result of AKT
As can be seen from Figure 5, IL-11 promotes the generation of AKT, and when after IL-11 antibody blocking, the generation of AKT sharply declines, significant difference between two groups of data.Inhibitor produces inhibitory action to the activation of signal path, so AKT content declines.
3, the testing result of NF-Κ B:
As can be seen from Figure 6, after IL-11 antibody blocking, the p65 subunit of NF-Κ B is in endochylema always, do not shift to karyon, illustrate that NF-Κ B does not change, when stimulating rear 12h with IL-11, p65 subunit starts to nuclear translocation, 24hp65 subunit shifts and increases in nucleus, NF-Κ B changes in time, shows that IL-11 is relevant to intracellular PI3K signal path, and the existence of IL-11 determines the change of PI3K signal path in cell.
PI3K/AKT signal path is signal path important in cell, with the propagation of cell with regulate and control relevant.PTEN is negative regulation albumen important in PI3K/AKT signal path, can suppress the activation of PI3K/AKT signal path; AKT is the important functional protein in PI3K/AKT signal path downstream, and the generation of AKT can point out the activation of PI3K/AKT signal path.PTEN and AKT is test point important in PI3K/AKT signal path.Therefore from above result, IL-11 can suppress the expression of PI3K/AKT signal path negative regulation albumen PTEN, raise the generation of PI3K/AKT signal path downstream AKT, and then promote the activation of PI3K/AKT signal path, promote the propagation of cancerous cell, and add IL-11 antibody in cell after, in conjunction with the IL-11 in cell, reduce the combination of IL-11 and cell membrane surface receptors, make the expression of receptor deactivation and then rise PI3K/AKT signal path negative regulation albumen PTEN, suppress the generation of PI3K/AKT signal path downstream AKT, thus reach the effect suppressing PI3K/AKT signal path.The inhibitory action of IL-11 antibody treatment group to PI3K/AKT signal path is better than PI3K/AKT signal pathway inhibitor group, and significant difference.
The present invention sets up a kind of cell model in vitro, demonstrating IL-11 can stimulate colon-cancer cell to breed really, and after add IL-11 monoclonal antibody in cell, antibody can in conjunction with IL-11, and cause the IL-11 be combined with cell membrane surface receptors to leave away, receptor deactivation causes cell proliferation to slow down, and the change of the PI3K signal path relevant with propagation can be caused, suppress signal path, effect is stronger than signal pathway inhibitor, is the medicine of natural anti-IL-11 target spot.
This research is by the colon-cancer cell model set up in vitro, by the amount (2-10ug/mL) of the IL-11 of normal cell secretion as the consumption of cancerous cell, in the time period of Growth of Cells, choose most representative 0h, 6h, 12h, 24h, 36h, 48h is as time point, detect the effect of IL-11 on cell proliferation, these 6 time points, it is the exponential phase drawing growth curve, cell was formed with logarithm and increased in period this, most scientific in the effect of this time detecting IL-11 various dose on cell proliferation, to draw in IL-11 concentration be the proliferation of 8ug/mL with 10ug/mL to cell is consistent in research, so select the stimulation consumption of IL-11 concentration as cell model of 8ug/mL, after having measured IL-11 concentration, with 8ug/mL as standard, determine IL-11 monoclonal antibody and IL-11 in conjunction with concentration, invention draws can to greatest extent in conjunction with IL-11 with 10ug antibody, therefore, the volume of the IL-11 monoclonal antibody that research adopts is 10uL, irritation cell is removed with the IL-11 of fixed concentration (8ug/mL), to the time 72h of cell ageing death from 0h, do the growth curve of cell, draw compared with normal cell, IL-11 stimulates hindgut cancer cell multiplication significantly to accelerate, and 48h is the peak of Growth of Cells, show that 48h normal cell is 60,000/mL in the present invention, and IL-11 stimulates rear 48h cell to be 80,000/mL, be significantly higher than normal cell.After IL-11 antibody (10uL) blocks, the proliferation function that IL-11 urgees cell is remarkable, during the peak of 48h intracellular growth, normal cell is 60,000/mL, be 20,000/mL after IL-11 antibody blocking, significant difference, illustrates the stimulation that IL-11 antibody capable reduction IL-11 breeds colon-cancer cell.
IL-11 can stimulate colon-cancer cell to breed, must be relevant with participating in the signal path that regulating cell breeds in cell, studies and studies important PI3K signal path.Recent study shows, P13K/Akt signal path plays an important role in the developing of kinds of tumors, and it can the Proliferation and apoptosis of modulate tumor cell, and being signal path important in cell, is also the important target spot of research.PI3K signal path has the research target point protein that 2 generally acknowledged, PTEN, AKT, they are target point proteins that Chinese scholars research PI3K signal path must detect, the activation of their direct reaction signal path and suppression, study by stimulating after colon-cancer cell with IL-11, at 0h-12h, in the prime time at Growth of Cells initial stage, detect IL-11 to the effect of PTEN and AKT in cell pathway, show that IL-11 suppresses the generation of PTEN, promote the generation of AKT, PTEN is the negative regulation albumen of PI3K, it is 4.35ug/mL that normal cell produces PTEN at 12h, IL-11 is 3.76ug/mL after stimulating, PTEN declines and shows that PI3K signal path first half section activates, AKT is the downstream targets of PI3K signal path, it is 3.8ug/mL that normal cell produces AKT at 12h, IL-11 is 6ug/mL after stimulating, the expression of AKT raises the activation of reaction PI3K lower semisection signal path, and when after IL-11 antibody blocking, the generation of PTEN is sharply risen, it is 4.35ug/mL that normal cell produces PTEN at 12h, IL-11 antibody blocking group is 7ug/mL, the generation of AKT sharply declines, and normal cell is 3.8ug/mL, IL-11 antibody blocking group at 12h generation AKT is 2ug/mL, and after showing IL-11 antibody blocking, intracellular signaling pathway is suppressed.
When detecting the end NF-Κ B of signal path, find that NF-Κ B also has corresponding change.NF-Κ B is that cell signal is delivered to nuclear crucial target spot by cell membrane, it is the end of signal path, when signal path changes, NF-Κ B also there will be corresponding change, we detect 4 time points 12h, 24h, 36h, 48h that Intracellular signals transmission is the most active, detect P65 subunit (the generally acknowledged detection subunit of NF-Κ B) the time dependent result of NF-Κ B.After stimulating with IL-11 during 12h, p65 subunit starts to nuclear translocation, and 24hp65 subunit shifts and increases in nucleus, and 48h transfers in nucleus completely, and signal path end activates, and show that IL-11 can promote the activation of PI3K signal path in cell; After IL-11 antibody blocking, the p65 subunit of NF-Κ B is in endochylema always, from 0h-48h not to karyon transfer, illustrates that the end of signal path is suppressed, signal path un-activation, draws the activation of PI3K signal path in IL-11 antibody capable T suppression cell.
Claims (3)
1.IL-11 monoclonal antibody is suppressing the application in P13K/Akt signal path.
2. IL-11 monoclonal antibody according to claim 1 is suppressing the application in P13K/Akt signal path, and it is characterized in that, the concentration of described IL-11 monoclonal antibody is 8ug/mL.
3. IL-11 monoclonal antibody according to claim 1 is suppressing the application in P13K/Akt signal path, and it is characterized in that, the consumption of described IL-11 monoclonal antibody is 10ug.
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| US11078269B2 (en) | 2016-12-16 | 2021-08-03 | Singapore Health Services Pte Ltd | IL-11Rα antibodies |
| US11078268B2 (en) | 2016-12-16 | 2021-08-03 | Singapore Health Services Pte Ltd | IL-11 antibodies |
| US11319368B2 (en) | 2019-01-21 | 2022-05-03 | Singapore Health Services Pte Ltd. | Treatment of hepatotoxicity with IL-11 antibody |
| WO2022033538A1 (en) * | 2020-08-13 | 2022-02-17 | 广东东阳光药业有限公司 | Antibody of il-11 and use thereof |
| WO2023016505A1 (en) * | 2021-08-12 | 2023-02-16 | 广东东阳光药业有限公司 | Il-11 humanized antibody and application thereof |
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