CN112379093A - Application of CST-Cathepsin compound as tumor diagnosis marker - Google Patents
Application of CST-Cathepsin compound as tumor diagnosis marker Download PDFInfo
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- CN112379093A CN112379093A CN202011135626.5A CN202011135626A CN112379093A CN 112379093 A CN112379093 A CN 112379093A CN 202011135626 A CN202011135626 A CN 202011135626A CN 112379093 A CN112379093 A CN 112379093A
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- 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
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- 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
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
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- 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
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/81—Protease inhibitors
- G01N2333/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- G01N2333/8139—Cysteine protease (E.C. 3.4.22) inhibitors, e.g. cystatin
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96466—Cysteine endopeptidases (3.4.22)
Abstract
The invention relates to the field of medical diagnostics, in particular to application of a CST-Cathepsin compound as a tumor diagnosis marker. The tissue specificity of the marker can be effectively improved through the detection of the CST-Cathepsin compound, and the detection rate of the tumor can also be effectively improved.
Description
Technical Field
The invention relates to the field of medical diagnostics, in particular to application of a CST-Cathepsin compound as a tumor diagnosis marker.
Background
Tumorigenesis is a multifactorial, multistage process, tumor invasion and metastasis including adhesion, degradation and penetration, and tumor invasion and metastasis are important features of malignant tumors. The study suggests that proteolytic enzymes are involved in the bonding process during tumor invasion. Cathepsins (cathepsins) are major members of the cysteine protease family, are closely related to human tumors, and are a class of target proteases of interest in recent years. Among them, cysteine cathepsins include cathepsins B, L, H, S, K, F, V, X, W, O and C, of which cathepsins B, L, H and S have been reported to be associated with the development and progression of various cancers.
Cystatin (CST) is a type of protein that has an inhibitory effect on cysteine proteases, and is widely distributed in human body fluids and exudates. The change of Cystatin content in blood is related to the progression of cancer, so Cystatin is also a marker which is often used for screening various cancers. The Cystatin family mainly comprises Cystatin A, B, C, D, E, F, S, SN and SA, each family member comprises at least one Cystatin structural domain which is an active region of Cystatin, and the Cystatin structural domain is a wedge-shaped structure formed by about 100 amino acid residues and can be combined with an active site of the Cystatin so as to inhibit the hydrolytic activity of the Cystatin. Based on its inhibitory effect, proteins of the CST superfamily bind to the form of the Cathepsin-CST complex with cysteine proteases.
The research finds that the specificity of both the Cathepsin family protein and the Cystatin family protein is not good as a marker for cancer screening and cancer progression, on one hand, the Cathepsin family protein is widely distributed in vivo, and on the other hand, the sequence conservation among the 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 compound (CST-Cathepsin compound) in preparing a kit for diagnosis, auxiliary diagnosis or prognosis analysis of tumors;
the cysteine protease inhibitor is 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.
Optionally, the CST-Cathepsin complex is selected from the CST-Cathepsin complexes selected from CST1-Cathepsin L and CST1-Cathepsin B.
Optionally, 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.
Optionally, the quantitative detection agent is an antibody specific for the cystepsin and the Cathepsin, which can be used to perform co-immunoprecipitation or enzyme-linked immunosorbent assay to detect the CST-Cathepsin complex.
Optionally, the quantitative detection agent is an antibody specific for the CST-Cathepsin complex.
Optionally, the specific antibody has a label for indicating signal intensity.
Optionally, the label for indicating signal intensity is selected from any one or more of a chromophore, a digoxigenin-labeled probe, an electron-dense substance, colloidal gold, or an enzyme.
The invention also relates to a kit for the diagnosis, co-diagnosis or prognosis of tumours, characterized in that it comprises specific antibodies as defined above.
Optionally, the kit further comprises at least one of a solid phase carrier, a blocking solution, a color developing agent, a calibrator for the CST-Cathepsin fusion antigen, and a washing buffer.
Optionally, the solid support is a chemiluminescent plate.
The tissue specificity of the marker can be effectively improved through the detection of the CST-Cathepsin compound, and the detection rate of the tumor can also be effectively improved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a calibration curve for the CST1-Cathepsin L test kit according to one embodiment of the present invention;
FIG. 2 is a calibration curve for the CST1-Cathepsin B test kit in accordance with one embodiment of the present invention;
FIG. 3 is a sample concentration scatter plot of CST1-Cathepsin L versus different cancer and normal person test results in one embodiment of the present invention;
FIG. 4 is a sample concentration scatter plot of CST1-Cathepsin B versus different cancer and normal human test results in one embodiment of the present invention;
FIG. 5 is a graph showing the sensitivity of CST1-Cathepsin L to different cancer samples in accordance with one embodiment of the present invention;
FIG. 6 is a comparison of the sensitivity of CST1-Cathepsin B to different cancer samples in one embodiment of the invention.
Detailed Description
Reference will now 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. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment, can be used on another embodiment to yield a still further embodiment.
It is therefore intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present invention are disclosed in or are 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 compound (CST-Cathepsin compound) in preparing a kit for diagnosis, auxiliary diagnosis or prognosis analysis of tumors;
the cysteine protease inhibitor is 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: the CST-Cathepsin complex. The tissue specificity of the marker can be effectively improved through the detection of the CST-Cathepsin compound, and the detection rate of the tumor can also be effectively improved.
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 cancer, 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 a histologically or cytologically confirmed diagnosis of advanced, unresectable and/or metastatic relapsed or refractory malignant solid tumor that is ineffective or absent treatment proven effective against standard therapy.
The term "marker" as used herein refers to a molecule to be used as a target for the analysis of a patient test sample. Examples of such molecular targets are proteins or polypeptides. Proteins or polypeptides for use 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 of 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. One 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 an inactive form, which can be subsequently activated by proteolysis. As will be appreciated by the skilled artisan, proteins or fragments thereof may also be present as part of a complex. Such complexes may 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 post-translational modifications. Non-limiting examples of post-translational modifications are glycosylation, acylation and/or phosphorylation. In particular, the marker should be located at the binding site of CST and Cathepsin in the CST-Cathepsin complex, and such "binding" refers to the site where amino acid sequences contact each other when CST and Cathepsin interact, and may be a linear epitope or a steric epitope.
In some embodiments, the quantitative detection reagent is an antibody specific for the cystatin and the Cathepsin, which can be used to perform a co-immunoprecipitation or an enzyme-linked immunosorbent assay to detect the CST-Cathepsin complex.
The detection of the CST-Cathepsin complex by the quantitative detection reagent can be carried out by methods known in the art; methods such as biological mass spectrometry, native polyacrylamide gel electrophoresis, chromatography, enzyme-linked immunosorbent assay, immunofluorescence, immunochemiluminescence, immunoturbidimetry, immunoblotting, and dot blotting can be attempted. Common preferred methods are co-immunoprecipitation and enzyme-linked immunosorbent assays, CST can be captured by antibody A, unbound components can be washed away, and Cathepsin can be detected by antibody B with a signal substance; of course, it is also possible to capture Cathepsin and retest CST, as will be readily apparent to those skilled in the art.
The quantitative detection agent is typically a reagent that specifically detects the CST-Cathepsin complex, for example, a lectin that specifically binds to the CST-Cathepsin complex, an aptamer that specifically binds to the CST-Cathepsin complex, or an antibody and antibody fragment that specifically binds to the CST-Cathepsin complex. The specific binding agent has at least 10 for its corresponding target molecule7Affinity of l/mol. The specific binding agent preferably has 10 to its target molecule8l/mol, or more preferably 109Affinity of l/mol. The skilled person will understand that the term "specific" is used to indicate that other biomolecules present in the sample do not bind significantly to the quantitative detector of the CST-Cathepsin complex, such biomolecules being in particular CST and Cathepsin, which are free alone.
In some embodiments, the quantitative detection agent is an antibody specific for the CST-Cathepsin complex.
In some embodiments, the specific antibody is a monoclonal antibody or a polyclonal antibody.
The antibody immunization may be followed by a screening process, which may be performed by screening the CST-Cathepsin recombinant protein for antibodies that specifically bind to the CST-Cathepsin complex, optionally further including selecting for antibodies with high antibody titers, as will be readily apparent to those skilled in the art.
In some embodiments, the specific antibody has a label for indicating signal intensity.
In some embodiments, the label for indicating signal intensity is selected from any one or more of a chromophore, a digoxigenin-labeled probe, an electron-dense substance, colloidal gold, or an enzyme.
The following non-limiting section lists these markers:
enzymes which produce a detectable signal, e.g.by colorimetry, fluorescence or 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 with electron density that can be detected by electron microscopy or by its electrical properties, such as conductivity, amperometry, voltage measurement and resistance.
A detectable group, such as one whose molecular size is sufficient to induce a detectable modification in its physical and/or chemical properties; such detection can be achieved by optical methods (e.g., diffraction, surface plasmon resonance, surface variation and angle of contact variation) or physical methods (e.g., atomic spectroscopy and tunneling).
Electron-dense substances, e.g. radioactive molecules (e.g. of the type32P，35S or125I)。
According to a further aspect of the invention, the invention also relates to a kit for the diagnostic, auxiliary diagnostic or prognostic analysis of tumors, comprising specific antibodies as defined above.
In some embodiments, the kit further comprises at least one of a solid support, a blocking solution, a visualization reagent, a calibrator for the CST-Cathepsin fusion antigen, and a wash buffer.
The blocking solution may be one or more of BSA, bovine serum, skimmed milk, TBST, etc.
The color developing solution can be determined according to the substance marked on the antibody, for example, when the marked substance is horseradish peroxidase, the color developing agent can be luminol.
The washing buffer may be PBS, TBS, or the like.
The blocking solution, the developing solution, and the washing buffer solution may be packaged in the kit in the form of working concentrations, or may be packaged in the form of concentrated mother solutions thereof (e.g., mother solutions concentrated 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 times).
The solid phase carrier is usually used for coating the antibody, the solid phase carrier material for coating the antibody can be polystyrene, cellulose, polyacrylamide, polyethylene polypropylene, cross-linked dextran, glass, silicone rubber, agarose gel and other materials, and the form of the carrier can be a test tube, an EP tube, a multi-well plate (especially a chemiluminescent plate), a microplate well, beads (especially magnetic beads), a small disc and the like.
The preferred solid support is a chemiluminescent plate. It may contain 16, 32, 48, 64, 96 or more holes.
According to a further aspect of the present invention, there is also provided a method for the diagnosis, co-diagnosis or prognostic analysis of a tumour, the method comprising: the content of CST-Cathepsin complex was measured using the quantitative detector/kit as described above.
The sample to be tested may be at least one of blood, serum, cerebrospinal fluid, tissue or tissue lysate, semen and saliva sample 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 with reference to examples.
Example 1 Activity verification and antibody pairing of CST1-Cathepsin L/CST1-Cathepsin B recombinant proteins
And (3) activity analysis: the chemiluminescence plate is coated with 1ug/ml of carbonate buffer (pH9.5) of recombinant CST1-Cathepsin L/CST1-Cathepsin B protein at 100ul volume and 4 ℃ overnight, the capture antibody and the enzyme-labeled antibody (the concentration is 0-1 ug/ml) are diluted in a gradient manner, and goat anti-mouse IgG-HRP (100ng/ml) is added. The detection shows that the luminescence values of the capture antibody and the detection antibody are not less than 20 ten thousand at 100ng/ml, and the reaction curve R of the protein and the antibody2>0.99, the reactivity of the protein meets the requirement.
Antibody pairing: the chemiluminescence plate is coated with 1ug/mL capture antibody, 100uL CST1-Cathepsin L/CST1-Cathepsin B calibrator with different concentrations (5-1000 pg/mL) is added, incubation is carried out for 60min at 37 ℃, after washing, 100uL HPR labeled detection antibody with concentration of 100ng/mL is added, incubation is carried out for 60min at 37 ℃, and after washing, chemiluminescence substrate is added and the luminescence intensity of each well is measured. From the result, the capture antibody and the detection antibody are well paired, and can be used for constructing a double-antibody sandwich system.
Example 2, CST1-Cathepsin L/CST1-Cathepsin B calibration curves
And (3) drawing a calibration curve: first, capture antibody was coated overnight on a chemiluminescent plate at 4 ℃ at a concentration of 1. mu.g/mL, 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 at 100. mu.L per well, and horseradish peroxide-labeled detection antibody was added at a concentration of 5ng/mL at 100. mu.L per well and incubated at 37 ℃ for 1 hour. PBST was washed 3 times, a chemiluminescent substrate was added and the luminescence intensity of each well was measured. The CST1-Cathepsin L/CST1-Cathepsin B content of the test sample was calculated from the calibration curve. The linear range of the calibration curve is 10-1500 pg/mL, and the calibration curve of the CST1-Cathepsin L/CST1-Cathepsin B detection kit is shown in attached figures 1 and 2, wherein the Y axis represents the log value of the luminescence value, and the X axis represents the log value of the concentration of the CST1-Cathepsin L/CST1-Cathepsin B calibrator.
Example 3 clinical Performance validation of CST 1-Capsule L/CST 1-Capsule B kit
CST1-Cathepsin L/CST1-Cathepsin B test kit for cancer diagnosis: 20 cases of serum before operation of patients with lung cancer, liver cancer, stomach cancer, esophageal cancer, intestinal cancer, prostatic cancer, cervical cancer, breast cancer and thyroid cancer are collected from a hospital; serum was collected from 50 healthy blood donors at the same time. The kit CST1-Cathepsin L/CST1-Cathepsin B is used for detecting the concentration of CST1-Cathepsin L/CST1-Cathepsin B in the serum of gastric cancer and normal human. The sample concentration scattergram shows that CST1-Cathepsin L/CST1-Cathepsin B has statistical significance for the differentiation of the detection results of gastric cancer/intestinal cancer and normal persons, as shown in the attached figures 3 and 4. The sensitivity of CST1-Cathepsin L and CST1-Cathepsin B in the detection of different cancers and normal persons at 100% specificity was calculated by ROC analysis with reference to normal human samples and plotted as histograms, see FIGS. 5 and 6. Wherein the detection sensitivity of CST1-Cathepsin L to gastric cancer reaches 85% when the specificity is 100%, the detection sensitivity of CST1-Cathepsin B to intestinal cancer reaches 80%,
the technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. Use of a quantitative detection agent for a cysteine protease inhibitor and a Cathepsin complex (CST-Cathepsin complex) in the manufacture of a kit for the diagnosis, co-diagnosis or prognostic analysis of a tumour;
the cysteine protease inhibitor is 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.
2. The use of claim 1, wherein the CST-Cathepsin compound is selected from CST1-Cathepsin L and CST1-Cathepsin B.
3. The use of claim 1, wherein the tumor is selected from the group consisting of lung cancer, liver cancer, stomach cancer, esophageal cancer, intestinal cancer, prostate cancer, cervical cancer, breast cancer, and thyroid cancer.
4. The use of claim 1, wherein the quantitative detection agent is an antibody specific for the cystatin and the Cathepsin, which antibody can be used to perform co-immunoprecipitation or enzyme-linked immunosorbent assay to detect the CST-Cathepsin complex.
5. The use of claim 1, wherein the quantitative detection agent is an antibody specific for the CST-Cathepsin complex.
6. Use according to claim 4 or 5, wherein the specific antibody is provided with a label for indicating the intensity of the signal.
7. The use according to claim 6, wherein the label for indicating signal intensity is selected from any one or more of a chromophore, a digoxigenin-labeled probe, an electron-dense substance, colloidal gold, or an enzyme.
8. Kit for the diagnosis, co-diagnosis or prognosis of tumours, characterized in that it comprises a specific antibody as defined in any one of claims 4 or 5.
9. The kit of claim 8, further comprising at least one of a solid support, a blocking solution, a visualization reagent, a calibrator for the CST-Cathepsin fusion antigen, and a wash buffer.
10. The kit of claim 9, wherein the solid support is a chemiluminescent plate.
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| 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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Cited By (4)
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| WO2022083603A1 (en) * | 2020-10-22 | 2022-04-28 | 上海良润生物医药科技有限公司 | Use of complex of cysteine protease inhibitor and cathepsin as tumor diagnostic marker |
| WO2022083586A1 (en) * | 2020-10-22 | 2022-04-28 | 上海良润生物医药科技有限公司 | Application of cysteine protease inhibitor sn and cathepsin l1 complex as gastric cancer diagnostic marker |
| WO2022083580A1 (en) * | 2020-10-22 | 2022-04-28 | 上海良润生物医药科技有限公司 | Use of complex of cysteine protease inhibitor sn and cathepsin h as esophageal cancer diagnostic marker |
| WO2022083582A1 (en) * | 2020-10-22 | 2022-04-28 | 上海良润生物医药科技有限公司 | Use of cystatins sn and cathepsin b complex as marker for diagnosis of colorectal cancer |
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| 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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| WO2022083580A1 (en) * | 2020-10-22 | 2022-04-28 | 上海良润生物医药科技有限公司 | Use of complex of cysteine protease inhibitor sn and cathepsin h as esophageal cancer diagnostic marker |
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| CN112379093B (en) | 2023-06-16 |
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