CN112379093B - Application of CST-Cathepsin complex as tumor diagnosis marker - Google Patents
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Abstract
The invention relates to the field of medical diagnostics, in particular to application of a CST-Cathepsin complex as a tumor diagnosis marker. The detection of CST-Cathepsin complex can effectively improve the tissue specificity of the marker and the detection rate of tumor.
Description
Technical Field
The invention relates to the field of medical diagnostics, in particular to application of a CST-Cathepsin complex as a tumor diagnosis marker.
Background
Tumorigenesis is a multifactorial, multiphasic process, tumor invasion and metastasis including adhesion, degradation, and penetration, and tumor invasion and metastasis are important features of malignant tumors. Proteolytic enzymes are thought to play a key role in the tumor invasion process. Cathepsins (cathepsins) are major members of the cysteine protease family, which are closely related to human tumors, and are a class of target proteases of great interest in recent years. Among them, cysteine cathepsins include cathepsins B, L, H, S, K, F, V, X, W, O and C, with cathepsins B, L, H and S having been reported to be associated with the occurrence and progression of a variety of cancers.
Cysteine protease inhibitors (CSTs) are a class of proteins that have an inhibitory effect on cysteine proteases and are widely distributed in human body fluids and secretions. Changes in the amount of Cystatin in the blood are associated with the progression of cancer, and therefore Cystatin is also a frequent marker for screening various cancers. The family of cysteine protease inhibitors consists essentially of Cystatin a, B, C, D, E, F, S, SN, SA, each of which comprises at least one Cystatin domain, which is the active region of Cystatin, typically consisting of a wedge-shaped structure of about 100 amino acid residues which is capable of binding to the active portion of a cysteine protease, thereby inhibiting the hydrolase activity of the cysteine protease. Based on its inhibitory effect, CST superfamily proteins can bind to the Cathepsin-CST complex form with cysteine proteases.
It was found that the specificity of either Cathepsin or Cystatin family proteins is not very good as a marker for cancer screening and cancer progression, on the one hand because Cathepsin family proteins are widely distributed in vivo, and on the other hand, the sequence conservation between Cystatin family proteins is high.
Disclosure of Invention
The invention relates to the application of a quantitative detection agent of a cysteine protease inhibitor and a Cathepsin complex (CST-Cathepsin complex) in the preparation of a kit for diagnosing, assisting diagnosis or prognosis analysis of tumors;
the cysteine protease inhibitor is selected from any one of Cystatin A, cystatin B, cystatin C, cystatin D, cystatin E, cystatin F, cystatin S, cystatin SA and Cystatin SN (CST 1);
the Cathepsin complex is selected from any one of Cathepsin B, cathepsin H, cathepsin K, cathepsin L and Cathepsin S.
Alternatively, the CST-Cathepsin complex is selected from the group consisting of CST1-Cathepsin L and CST1-Cathepsin B.
Optionally, the tumor is selected from one of lung cancer, liver cancer, gastric cancer, esophageal cancer, intestinal cancer, prostate cancer, cervical cancer, breast cancer and thyroid cancer.
Alternatively, the quantitative detection agent is an antibody specific for the cysteine protease inhibitor and the Cathepsin, which can be used to perform co-immunoprecipitation or enzyme-linked immunosorbent assays to detect the CST-Cathepsin complex.
Alternatively, the quantitative detection agent is an antibody specific for the CST-Cathepsin complex.
Optionally, the specific antibody has a label for indicating the intensity of the signal.
Optionally, the label for indicating signal intensity is selected from any one or more of chromophore, digoxin-labeled probe, electron dense substance, colloidal gold or enzyme.
The invention also relates to a kit for tumour diagnosis, auxiliary diagnosis or prognosis analysis, characterized in that it comprises a specific antibody as defined above.
Optionally, at least one of a solid support, a blocking solution, a chromogenic agent, a calibrator for CST-Cathepsin fusion antigen, and a wash buffer is also included.
Optionally, the solid phase carrier is a chemiluminescent plate.
The detection of CST-Cathepsin complex can effectively improve the tissue specificity of the marker and the detection rate of tumor.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a calibration curve of a CST1-Cathepsin L detection kit in accordance with one embodiment of the invention;
FIG. 2 is a calibration curve of a CST1-Cathepsin B detection kit in accordance with one embodiment of the invention;
FIG. 3 is a plot of sample concentration scatter of CST1-Cathepsin L for different cancer and normal human detection results in one embodiment of the invention;
FIG. 4 is a plot of sample concentration versus detection results of CST1-Cathepsin B for different cancers and normal persons in one embodiment of the invention;
FIG. 5 is a graph showing the sensitivity of CST1-Cathepsin L versus various cancer samples in accordance with one embodiment of the present invention;
FIG. 6 is a graph showing the sensitivity of CST1-Cathepsin B to different cancer samples in accordance with one embodiment of the present invention.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
Accordingly, it is intended that the present invention cover such modifications and variations as fall within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present invention will be disclosed in or be apparent from the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention.
The invention relates to the application of a quantitative detection agent of a cysteine protease inhibitor and a Cathepsin complex (CST-Cathepsin complex) in the preparation of a kit for diagnosing, assisting diagnosis or prognosis analysis of tumors;
the cysteine protease inhibitor is selected from any one of Cystatin A, cystatin B, cystatin C, cystatin D, cystatin E, cystatin F, cystatin S, cystatin SA and Cystatin SN (CST 1);
the Cathepsin complex is selected from any one of Cathepsin B, cathepsin H, cathepsin K, cathepsin L and Cathepsin S.
The present invention provides a novel marker for diagnosis: CST-Cathepsin complex. The detection of CST-Cathepsin complex can effectively improve the tissue specificity of the marker and the detection rate of tumor.
In some embodiments, the CST-Cathepsin complex is selected from CST1-Cathepsin L and CST1-Cathepsin B.
In some embodiments, the tumor is a solid tumor, which may also be replaced by the term "carcinoma", selected from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor, bone cancer, and soft tissue sarcoma.
Preferably, the tumor is selected from one of lung cancer, liver cancer, stomach cancer, esophageal cancer, intestinal cancer, prostate cancer, cervical cancer, breast cancer and thyroid cancer.
In some embodiments, the solid tumor is benign.
In some embodiments, the solid tumor is selected from advanced or metastatic malignant solid tumors.
The term "advanced or metastatic malignant solid tumor" refers to an advanced, unresectable and/or metastatic recurrent or refractory malignant solid tumor that is histologically or cytologically confirmed diagnosed, which is ineffective or absent of a therapy that has proven effective for standard therapy.
The term "marker" as used herein refers to a molecule to be used as a target for analysis of a patient experimental sample. Examples of such molecular targets are proteins or polypeptides. Proteins or polypeptides used as markers in the present invention are intended to include naturally occurring variants of said proteins as well as fragments, in particular immunologically detectable fragments, of said proteins or said variants. The immunologically detectable fragment preferably comprises at least 5, 6, 7, 8, 9, 10, 11, 12, 15 or 20 consecutive amino acids of the marker polypeptide. Those skilled in the art will recognize that proteins released by cells or present in the extracellular matrix may be damaged (e.g., during inflammation) and may be degraded or cleaved into such fragments. Certain markers are synthesized in inactive form, which can be subsequently activated by proteolysis. As will be appreciated by the skilled artisan, the protein or fragment thereof may also be present as part of a complex. Such complexes can also be used as markers in the sense of the present invention. In addition, or in the alternative, the marker polypeptide or variant thereof may carry a post-translational modification. Non-limiting examples of post-translational modifications are glycosylation, acylation, and/or phosphorylation. In particular, the marker should be located at the site of binding of CST and Cathepsin in the CST-Cathepsin complex, such "binding" referring to the site where the amino acid sequences contact each other when CST and Cathepsin interact, and may be a linear epitope or a spatial epitope.
In some embodiments, the quantitative detection reagent is an antibody specific for the cysteine protease inhibitor and the Cathepsin, which antibody can be used to perform co-immunoprecipitation or enzyme-linked immunosorbent assays to detect the CST-Cathepsin complex.
Detection of the CST-Cathepsin complex by the quantitative detection reagent can be performed by methods well known in the art; methods such as biological mass spectrometry, non-denaturing polyacrylamide gel electrophoresis, chromatography, enzyme-linked immunosorbent assay, immunofluorescence, immunochromatography, immunonephelometry, immunoblotting, and dot blotting may be attempted. Common preferred methods are co-immunoprecipitation and enzyme-linked immunosorbent assays, whereby CST is captured by antibody A and unbound components are washed away, followed by detection of Cathepsin by antibody B with signal material; of course, cathepsin can also be captured for detection of CST, as will be readily apparent to those skilled in the art.
The quantitative detection agent is typically an agent that specifically detects the CST-Cathepsin complex, e.g., lectins that specifically bind to the CST-Cathepsin complex, aptamers that specifically bind to the CST-Cathepsin complex, or antibodies and antibody fragments that specifically bind to the CST-Cathepsin complex. Specific binding agents having at least 10 for their corresponding target molecules 7 l/mol affinity. The specific binding agent preferably has a binding agent of 10 for its target molecule 8 l/mol, or more preferably 10 9 l/mol affinity. The skilled artisan will appreciate that the term "specific" is used to indicate that other biomolecules present in the sample, particularly free CST and Cathepsin alone, do not significantly bind to the quantitative detection agent of the CST-Cathepsin complex.
In some embodiments, the quantitative detection agent is a specific antibody to the CST-Cathepsin complex.
In some embodiments, the specific antibody is a monoclonal antibody or a polyclonal antibody.
Antibodies immunization may be followed by a screening process, as will be readily appreciated by those skilled in the art, by screening antibodies that specifically bind to the CST-Cathepsin complex by way of a CST-Cathepsin recombinant protein, optionally also including selecting antibodies of high antibody titers.
In some embodiments, the specific antibody has a label for indicating signal strength.
In some embodiments, the label for indicating signal intensity is selected from any one or more of a chromophore, a digoxin-labeled probe, an electron dense substance, colloidal gold, or an enzyme.
These labels are listed in the following non-limiting section:
enzymes that produce detectable signals, such as by colorimetry, fluorescence and luminescence, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase and glucose-6-phosphate dehydrogenase.
Chromophores such as fluorescence, quantum dots, fluorescent microspheres, luminescent compounds (such as acridinium esters or derivatives thereof) and dyes.
Groups having electron densities that can be detected by electron microscopy or by their electrical properties, such as conductivity, amperometry, voltage measurement, and resistance.
A detectable group, such as a molecule of sufficient size to induce a modification detectable in its physical and/or chemical properties; such detection may be achieved by optical methods (e.g., diffraction, surface plasmon resonance, surface variation and angle of contact variation) or physical methods (e.g., atomic force spectroscopy and tunneling).
Electronically dense substances, e.g. radioactive molecules (e.g 32 P， 35 S or 125 I)。
According to a further aspect of the invention, the invention also relates to a kit for tumour diagnosis, auxiliary diagnosis or prognosis analysis, comprising a specific antibody as defined above.
In some embodiments, the kit further comprises at least one of a solid support, a blocking solution, a chromogenic agent, a calibrator for a CST-Cathepsin fusion antigen, and a wash buffer.
The blocking solution can be one or more of BSA, bovine serum, skimmed milk, TBST, etc.
The color development solution can be determined based on the substance labeled on the antibody, for example, when the labeled substance is horseradish peroxidase, the color development agent can be luminol.
The wash buffer may be PBS, TBS, or the like.
Wherein, the sealing liquid, the color development liquid and the washing buffer liquid can be packaged in the kit in the form of working concentration, and can also be packaged in the form of concentrated mother liquor (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 and 50 times concentrated mother liquor).
The solid phase carrier is usually used for coating the antibody, and the solid phase carrier material used for coating the antibody can be polystyrene, cellulose, polyacrylamide, polyethylene polypropylene, sephadex, glass, silicone rubber, agarose gel and other materials, and the carrier can be in the form of a test tube, an EP tube, a porous plate (especially a chemiluminescent plate), a concave hole of a micro-reaction plate, a small bead (especially a magnetic bead), a small disc and the like.
The preferred solid support is a chemiluminescent plate. It may contain holes of 16, 32, 48, 64, 96 or more.
According to a further aspect of the present invention there is also provided a method for diagnosis, assisted diagnosis or prognostic analysis of a tumour, the method comprising: the content of CST-Cathepsin complex was measured using the quantitative detector/kit described above.
The sample to be tested may be at least one of blood, serum, cerebrospinal fluid, tissue or tissue lysates, semen and saliva samples of the subject.
The subject is typically a mammal, preferably a primate, more preferably a human.
Embodiments of the present invention will be described in detail below with reference to examples.
Example 1, activity verification and antibody pairing of CST1-Cathepsin L/CST1-Cathepsin B recombinant proteins
Activity analysis: a chemiluminescent plate was coated with 1ug/ml of recombinant CST1-Cathepsin L/CST1-Cathepsin B protein in carbonate buffer (pH 9.5), 100ul volume overnight at 4℃and the capture and enzyme-labeled antibodies were diluted in gradient (0-1 ug/ml) and goat anti-mouse IgG-HRP (100 ng/ml) was added. The detection shows that the luminescence values of the capture antibody and the detection antibody at 100ng/ml are not lower than 20 ten thousand, and the reaction curve R of the protein and the antibody 2 >0.99, the reactivity of the protein meets the requirements.
Antibody pairing: coating a chemiluminescent plate with 1ug/mL capture antibody, adding 100uL of CST1-Cathepsin L/CST1-Cathepsin B calibrator at different concentrations (5-1000 pg/mL), incubating at 37 ℃ for 60min, washing, adding 100uL of HPR labeled detection antibody at 100ng/mL, incubating at 37 ℃ for 60min, washing, adding chemiluminescent substrate and measuring the luminous intensity of each well. From the results, the capture antibody and the detection antibody are well paired, and can be used for constructing a double-antibody sandwich system.
Example 2, plot of CST1-Cathepsin L/CST1-Cathepsin B calibration curve
Drawing a calibration curve: the recombinant human CST1-Cathepsin L/CST1-Cathepsin B calibrator protein was diluted with protein stabilizer to 0pg/mL, 10pg/mL, 50pg/mL, 100pg/mL, 200pg/mL, 500pg/mL, 1500pg/mL, 100. Mu.L per well, and then added with horseradish peroxide labeled detection antibody at a concentration of 5ng/mL, and incubated for 1 hour at 37℃on a chemiluminescent plate overnight at 4 ℃. Wash 3 times with PBST, add chemiluminescent substrate and measure the luminous intensity of each well. The CST1-Cathepsin L/CST1-Cathepsin B content of the tested sample is calculated from the calibration curve. The linear range of the calibration curve is 10-1500 pg/mL, and FIGS. 1 and 2 are calibration curves of CST1-Cathepsin L/CST1-Cathepsin B detection kit, wherein the Y axis represents the luminous value logarithmic value, and the X axis represents the concentration logarithmic value of the CST1-Cathepsin L/CST1-Cathepsin B calibrator.
Example 3 clinical Performance verification of CST1-Cathepsin L/CST1-Cathepsin B kit
CST1-Cathepsin L/CST1-Cathepsin B assay kits for cancer diagnosis: collecting 20 cases of preoperative serum of patients with lung cancer, liver cancer, gastric cancer, esophageal cancer, intestinal cancer, prostatic cancer, cervical cancer, breast cancer and thyroid cancer from a hospital; at the same time, 50 healthy donor sera were collected from the blood station. CST1-Cathepsin L/CST1-Cathepsin B assay kit was used to detect CST1-Cathepsin L/CST1-Cathepsin B concentrations in gastric cancer, normal human serum. The sample concentration scatter plot shows that CST1-Cathepsin L/CST1-Cathepsin B has statistical significance for distinguishing gastric cancer/intestinal cancer from normal human detection results, and is shown in figures 3 and 4. The sensitivity of CST1-Cathepsin L and CST1-Cathepsin B in the detection of different cancers and normal persons at a specificity of 100% was calculated by ROC analysis with reference to normal human samples, and plotted as a bar graph, see FIGS. 5 and 6. Wherein, the detection sensitivity of CST1-Cathepsin L to gastric cancer is up to 85% when the specificity is 100%, the detection sensitivity of CST1-Cathepsin B to intestinal cancer is up to 80%,
the technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (11)
1. The use of a quantitative detection agent of a cysteine protease inhibitor and Cathepsin complex, i.e. CST-Cathepsin complex, in the preparation of a kit for the diagnosis, auxiliary diagnosis or prognosis analysis of a tumor;
the CST-Cathepsin complex is selected from CST1-Cathepsin L and CST1-Cathepsin B;
the tumor is selected from one of lung cancer, liver cancer, gastric cancer, esophageal cancer, intestinal cancer, prostatic cancer, cervical cancer, breast cancer and thyroid cancer.
2. The use according to claim 1, wherein the quantitative detection agent is an antibody specific for the cysteine protease inhibitor and the Cathepsin, said antibody being useful for performing co-immunoprecipitation or enzyme-linked immunosorbent assay to detect the CST-Cathepsin complex.
3. The use according to claim 1, wherein the quantitative detection agent is an antibody specific for the CST-Cathepsin complex.
4. The use according to claim 2 or 3, wherein the specific antibody has a label for indicating the intensity of the signal.
5. The use of claim 4, wherein the label for indicating signal strength comprises a chromophore.
6. The use of claim 4, wherein the label for indicating signal strength comprises a digoxin-labeled probe.
7. The use of claim 4, wherein the indicia for indicating signal strength comprises an electronically dense substance.
8. The use according to claim 4, wherein the label for indicating the signal strength comprises colloidal gold or an enzyme.
9. A kit for tumor diagnosis, auxiliary diagnosis or prognosis analysis, comprising the specific antibody according to any one of claims 2 to 8.
10. The kit of claim 9, further comprising at least one of a solid support, a blocking solution, a color reagent, a calibrator for a CST-Cathepsin fusion antigen, and a wash buffer.
11. The kit of claim 10, wherein the solid support is a chemiluminescent plate.
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| CN202011135626.5A CN112379093B (en) | 2020-10-22 | 2020-10-22 | Application of CST-Cathepsin complex as tumor diagnosis marker |
| PCT/CN2021/124817 WO2022083603A1 (en) | 2020-10-22 | 2021-10-20 | Use of complex of cysteine protease inhibitor and cathepsin as tumor diagnostic marker |
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| CN112014578B (en) * | 2020-10-22 | 2021-01-22 | 上海良润生物医药科技有限公司 | Application of cystatin SN and Cathepsin L1 complex as gastric cancer diagnostic marker |
| CN112379094B (en) * | 2020-10-22 | 2022-07-26 | 上海良润生物医药科技有限公司 | Application of CST1-CTSH compound as esophageal cancer diagnosis marker |
| CN112379097B (en) * | 2020-10-22 | 2022-07-26 | 上海良润生物医药科技有限公司 | Application of CST1-CTSB complex as colorectal cancer diagnosis marker |
| CN112379093B (en) * | 2020-10-22 | 2023-06-16 | 上海良润生物医药科技有限公司 | Application of CST-Cathepsin complex as tumor diagnosis marker |
| CN115806623B (en) * | 2023-01-05 | 2023-11-21 | 营龄(武汉)生物科技有限公司 | Application of Cathepsin L inhibition composition in cell expansion |
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