CN110687282B - PD-1 and/or p53 autoantibodies as markers for tumor efficacy prediction or prognosis evaluation - Google Patents
PD-1 and/or p53 autoantibodies as markers for tumor efficacy prediction or prognosis evaluation Download PDFInfo
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- CN110687282B CN110687282B CN201910791940.XA CN201910791940A CN110687282B CN 110687282 B CN110687282 B CN 110687282B CN 201910791940 A CN201910791940 A CN 201910791940A CN 110687282 B CN110687282 B CN 110687282B
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- G—PHYSICS
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- 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
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/535—Production of labelled immunochemicals with enzyme label or co-enzymes, co-factors, enzyme inhibitors or enzyme substrates
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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
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
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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
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/533—Production of labelled immunochemicals with fluorescent label
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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
Abstract
The invention provides an application of an autoantibody in preparing a product for predicting or prognosticating tumor, a marker for predicting or prognosticating tumor efficacy, a product for predicting or prognosticating tumor efficacy and a detection method of the autoantibody, wherein the autoantibody is PD-1 and/or p53 autoantibody, and the tumor is the tumor efficacy prediction or prognosis of immune checkpoint inhibitor treatment.
Description
Technical Field
The invention relates to the technical field of biomedical detection, in particular to application of a PD-1 and/or p53 autoantibody in preparing a product for predicting curative effect or evaluating prognosis of a tumor, a marker for predicting curative effect or evaluating prognosis of the tumor, a product for predicting curative effect or evaluating prognosis of the tumor and a detection method of the PD-1 and/or p53 autoantibody.
Background
Currently, for the prediction, treatment and prognosis of tumor treatment diseases, autoantibodies of tumors in serum are mostly used as markers, for example: autoantibodies such as NY-SEO-1, annexin I, 14-3-3 theta, LAMR1, PGP9.5, c-myc, HER2, CAGE, GBU-4-5, SOX2 and the like are used for lung cancer diagnosis; autoantibodies such as HSP70, HCC-22-5, peroxiredoxin VI, KM-HN-1, and p90 are used for diagnosing gastric cancer; autoantibodies such as p62 and HCC1 are used for liver cancer diagnosis; autoantibodies such as Interleukin-29 (IL 29), survivin (SUR), growth horone (GRH), osteoprotegerin (OPG), and Resistin (RES) are used for diagnosis of breast cancer. But efficacy predictions and prognosis evaluations for tumor patients treated by immune checkpoint inhibitors are still under study.
The p53 autoantibody is growth inhibitory protein 3, is a tumor-associated antigen, and can be used for early diagnosis of various tumors and screening tests of tumors. For example, literature: the value of the combined detection of the p53 autoantibody and the Bmi-1 autoantibody in lung cancer diagnosis is shown in journal of Chinese physicians and 2017, the expression levels of the p53 and Bmi-1 autoantibodies in serum of 92 lung cancer patients and 80 normal control patients are detected by adopting an enzyme-linked immunosorbent assay, and the combined diagnosis efficacy of the two autoantibodies is analyzed by adopting a subject working characteristic curve (ROC). The results show that the serum p53 and Bmi-1 autoantibodies of the lung cancer patients are higher than the normal control in level, the difference has statistical significance, the sensitivity is 63 percent, the specificity is 91.2 percent, the area under the ROC curve is 0.881, and the diagnosis efficacy is better than that of a single autoantibody. Patent CN108885208A discloses a method for detecting lung cancer comprising contacting a patient sample with an antigen set, detecting whether a complex is formed, thereby determining the presence of autoantibodies in the patient to diagnose lung cancer, wherein the autoantibodies comprise p53 in serum. Patent CN109342727a discloses detection of esophageal squamous cell carcinoma autoantibody molecular markers for distinguishing esophageal squamous cell carcinoma patients from healthy persons, wherein the markers comprise ALDOA autoantibody, p53 autoantibody, ENO1 autoantibody and NY-ESO-1 autoantibody, and the detection method is an enzyme-linked immunosorbent assay. Patent CN103869086a discloses a detection kit for detecting serum autoantibodies of mammals, including p53, huD, CAGE, etc., which adopts the combination of 5 or more than 5 autoantibodies, thereby improving the sensitivity and accuracy of serum autoantibody detection. None of the above prior art discloses a prediction or prognosis of the efficacy of p53 autoantibodies or genes encoding them in the treatment of tumors with immune checkpoint inhibitors. While the pathological and physiological characteristics of the immune checkpoint inhibitor for treating tumors are different from those of the conventional medicaments for treating tumors.
Programmed death receptor 1 (PD-1) is an important immunosuppressive molecule, its ligand is PD-L1, and antibody drugs against PD-1 pathway have been approved for treatment of melanoma, lung cancer, lymphoma and other multiple tumor species. PD-1 autoantibodies are antibodies raised by humans against PD-1 molecules and are potential therapeutic markers for immunotherapy. Patent CN107667119a discloses the level of PD-L1 expression in tumor cells or tumor-infiltrating immune cells, determining whether a patient suffering from non-small cell lung cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, which means that tumor cells have 5% or more of the level of PD-L1 expression, and that treatment of the tumor can only be administered an effective amount of the PD-L1 axis binding antagonist. And direct detection of PD-L1 expression on tumor cells has been recommended by the FDA as a concomitant diagnosis in non-small cell lung cancer (NSCLC) patients using pembrolizumab. Meanwhile, a large number of clinical test results show that compared with a patient with low PD-L1 expression, a patient with high expression has higher effective rate and longer lifetime for the PD-1/PD-L1 pathway inhibitor. For example: recent KEYNOTE-042 research results in American Society of Clinical Oncology (ASCO) show that compared with the population with low PD-L1 expression (TPS is more than or equal to 1% and less than or equal to 49%), the patients with high PD-L1 expression (TPS is more than or equal to 50%) obtain more remarkable survival benefit, and the death risk is reduced by 31%. However, none of the above prior art discloses the use of PD-1 autoantibodies in the prediction of efficacy or prognosis of immune checkpoint inhibitors in the treatment of tumors.
Disclosure of Invention
In a first aspect, the invention provides the use of an autoantibody in the preparation of a product for the prediction or prognosis of the efficacy of an immune checkpoint inhibitor for the treatment of a tumour, wherein the autoantibody is a PD-1 and/or p53 autoantibody.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the immune checkpoint inhibitor is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor, or a combination of immune checkpoint inhibitor and other drugs and therapeutic means.
Preferably, the immune checkpoint inhibitor treats the tumor by administering the immune checkpoint inhibitor alone or in combination with a drug, chemotherapy, radiation or other means.
In one embodiment of the invention, the immune checkpoint inhibitor is a PD-1 inhibitor.
In a second aspect of the invention, there is provided the use of an agent for detecting PD-1 and/or p53 autoantibodies in the manufacture of a product for the prediction of efficacy or for the prognostic assessment of a tumour, said prediction of efficacy or prognostic assessment of efficacy of an immune checkpoint inhibitor for the treatment of a tumour.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the detection of the PD-1 and/or p53 autoantibodies is the detection of the presence or absence, or the expression level, of the PD-1 and/or p53 autoantibodies.
Preferably, the method for detecting the PD-1 and/or p53 autoantibody by using the reagent for detecting the PD-1 and/or p53 autoantibody is selected from one or more than two of ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot method or immunoluminescence.
In one embodiment of the invention, the method for detecting PD-1 and/or p53 autoantibodies by using the reagent for detecting PD-1 and/or p53 autoantibodies is ELISA.
Preferably, the immune checkpoint inhibitor is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor, or a combination of immune checkpoint inhibitor and other drugs and therapeutic means.
Preferably, the immune checkpoint inhibitor treats the tumor by administering the immune checkpoint inhibitor alone or in combination with a drug, chemotherapy, radiation or other means.
In one embodiment of the invention, the immune checkpoint inhibitor is a PD-1 inhibitor.
In a third aspect of the invention there is provided the use of a PD-1 and/or p53 autoantibody in the manufacture of a product for the diagnosis and/or treatment of a tumour or autoimmune disease.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD. In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
In a fourth aspect of the invention, there is provided the use of an agent for detecting PD-1 and/or p53 autoantibodies in the manufacture of a product for diagnosis and/or treatment of a tumour or autoimmune disease.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the detection of the PD-1 and/or p53 autoantibodies is the detection of the presence or absence, or the expression level, of the PD-1 and/or p53 autoantibodies.
Preferably, the method for detecting the PD-1 and/or p53 autoantibody by using the reagent for detecting the PD-1 and/or p53 autoantibody is selected from one or more than two of ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot method or immunoluminescence.
In one embodiment of the invention, the method for detecting PD-1 and/or p53 autoantibodies by using the reagent for detecting PD-1 and/or p53 autoantibodies is ELISA.
In a fifth aspect of the invention, there is provided a marker for the prediction or prognosis of the efficacy of a tumor comprising PD-1 and/or p53 autoantibodies, said prediction or prognosis of the efficacy of a tumor being a prediction or prognosis of the efficacy of an immune checkpoint inhibitor for the treatment of a tumor.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the immune checkpoint inhibitor is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor, or a combination of immune checkpoint inhibitor and other drugs and therapeutic means.
Preferably, the immune checkpoint inhibitor treats the tumor by administering the immune checkpoint inhibitor alone or in combination with a drug, chemotherapy, radiation or other means.
In one embodiment of the invention, the immune checkpoint inhibitor is a PD-1 inhibitor.
Preferably, the marker further comprises a concomitant marker selected from one or more than two of PD-L1 protein or its autoantibody, CTLA-4 protein or its autoantibody, BTLA protein or its autoantibody, TILA protein or its autoantibody, TITIGIT protein or its autoantibody, LAIR1 protein or its autoantibody, 2B4 protein or its autoantibody or CD160 protein or its autoantibody.
In a sixth aspect of the invention, there is provided a marker for diagnosis and/or treatment of a tumour, autoimmune disease, said marker being PD-1 and/or p53 autoantibodies.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the marker further comprises a concomitant marker selected from one or more than two of PD-L1 protein or its autoantibody, CTLA-4 protein or its autoantibody, BTLA protein or its autoantibody, TILA protein or its autoantibody, TITIGIT protein or its autoantibody, LAIR1 protein or its autoantibody, 2B4 protein or its autoantibody or CD160 protein or its autoantibody.
In a seventh aspect of the invention, there is provided a product of a tumor efficacy prediction or prognosis evaluation comprising reagents for detecting PD-1 and/or p53 autoantibodies, said tumor efficacy prediction or prognosis evaluation being a prediction or prognosis evaluation of efficacy of an immune checkpoint inhibitor for treating a tumor.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the product is selected from the group consisting of kits, mass spectrometry.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the detection of the PD-1 and/or p53 autoantibodies is the detection of the presence or absence, or the expression level, of the PD-1 and/or p53 autoantibodies.
Preferably, the method for detecting the PD-1 and/or p53 autoantibody by using the reagent for detecting the PD-1 and/or p53 autoantibody is selected from one or more than two of ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot method or immunoluminescence.
In one embodiment of the invention, the method for detecting PD-1 and/or p53 autoantibodies by using the reagent for detecting PD-1 and/or p53 autoantibodies is ELISA.
Preferably, the immune checkpoint inhibitor is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor, or a combination of immune checkpoint inhibitor and other drugs and therapeutic means.
Preferably, the immune checkpoint inhibitor treats the tumor by administering the immune checkpoint inhibitor alone or in combination with a drug, chemotherapy, radiation or other means.
In one embodiment of the invention, the immune checkpoint inhibitor is a PD-1 inhibitor.
In an eighth aspect of the invention there is provided a product for the diagnosis and/or treatment of a tumour, an autoimmune disease, said product comprising reagents for detecting PD-1 and/or p53 autoantibodies.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the product is selected from the group consisting of kits, mass spectrometry.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
Preferably, the detection of the PD-1 and/or p53 autoantibodies is the detection of the presence or absence, or the expression level, of the PD-1 and/or p53 autoantibodies.
Preferably, the method for detecting the PD-1 and/or p53 autoantibody by using the reagent for detecting the PD-1 and/or p53 autoantibody is selected from one or more than two of ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot method or immunoluminescence.
In one embodiment of the invention, the method for detecting PD-1 and/or p53 autoantibodies by using the reagent for detecting PD-1 and/or p53 autoantibodies is ELISA.
In a ninth aspect of the invention, there is provided a method of diagnosing a tumour or an autoimmune disease, said method comprising detecting the presence or level of expression of PD-1 and/or p53 autoantibodies in an organism.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
In a tenth aspect of the invention, there is provided a method for predicting or prognostic evaluation of tumor efficacy, said method comprising detecting the presence or expression level of PD-1 and/or p53 autoantibodies in an organism.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
In an eleventh aspect of the invention there is provided a method of treatment of a tumour or autoimmune disease, the method comprising administering to a patient suffering from a tumour or autoimmune disease an effective dose of an immune checkpoint inhibitor, wherein expression of PD-1 and/or p53 autoantibodies is detected in the patient.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the detection of the expression of the PD-1 and/or p53 autoantibodies from the patient is detected from serum, plasma, interstitial fluid, cerebrospinal fluid or urine of the patient. Wherein the lower the expression level of the PD-1 and/or p53 autoantibodies, the better the therapeutic effect of the immune checkpoint inhibitor.
In a specific embodiment of the invention, the detection of the expression of PD-1 and/or p53 autoantibodies from the patient is detected from the patient's serum and/or plasma.
Preferably, the immune checkpoint inhibitor is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor, or a combination of immune checkpoint inhibitor and other drugs and therapeutic means.
Preferably, the immune checkpoint inhibitor treats the tumor by administering the immune checkpoint inhibitor alone or in combination with a drug, chemotherapy, radiation or other means.
In one embodiment of the invention, the immune checkpoint inhibitor is a PD-1 inhibitor.
In a twelfth aspect of the invention, a method for detecting a PD-1 autoantibody is provided, which comprises the steps of coating a PD-1 protein on the surface of a carrier, adding a sample to be detected, adding an enzyme and a substrate, and measuring the concentration.
Preferably, the PD-1 autoantibody comprises IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the sample to be tested is biological serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the sample to be tested is biological serum.
Preferably, the sample to be tested is diluted with a dilution buffer before addition, the dilution being in the range of 200-1000. Further preferably, the dilution factor is 300-800.
In one embodiment of the present invention, the dilution factor is 400-600.
In one embodiment of the invention, the dilution buffer is milk.
Preferably, the enzyme is an enzyme-labeled antibody. More preferably, the enzyme-labeled antibody is IgG.
In one embodiment of the invention, the substrate is TMB.
Preferably, the concentration measuring method is to measure the absorbance value of 450 nm.
In one embodiment of the invention, the method comprises:
1) PD-1 protein was coated in 96-well plates at 4 ℃ overnight;
diluting the serum sample to 1:200-1000 with milk; preferably, the serum sample is diluted to 1:300-800 with milk;
2) Adding the diluted serum sample into a 96-well plate, incubating and washing; preferably the incubation time is 0.5-2 hours;
3) Adding fresh diluted anti-human IgG HRP enzyme-labeled antibody, incubating and washing; preferably the incubation time is 0.5-2 hours; more preferably, the incubation time is from 0.5 to 1 hour;
4) Adding a temporarily prepared TMB substrate, and developing in a dark place; adding sulfuric acid to terminate the reaction; preferably, the light-shielding color development time is 10-30 minutes;
5) The absorbance value at 450nm was measured to determine the level of PD-1 autoantibody expression in the sample.
In a thirteenth aspect of the present invention, there is provided a method for detecting p53 autoantibodies, comprising coating p53 protein on the surface of a carrier, adding a sample to be detected, adding an enzyme and a substrate, and measuring the concentration.
Preferably, the sample to be detected is biological serum, plasma, interstitial fluid, cerebrospinal fluid or urine; the sample to be detected is diluted by a dilution buffer before being added, and the dilution multiple is 700-1100. More preferably, the dilution factor is 800-1000.
In one embodiment of the invention, the sample to be tested is biological serum.
In one embodiment of the invention, the dilution buffer is milk.
Preferably, the enzyme is an enzyme-labeled antibody. More preferably, the enzyme-labeled antibody is IgG.
In one embodiment of the invention, the substrate is TMB.
Preferably, the concentration measuring method is to measure the absorbance value of 450 nm.
In one embodiment of the invention, the method comprises:
1) Coating p53 protein in a 96-well plate at 4 ℃ overnight;
diluting the serum sample to 1:700-1100 by milk; preferably, the serum sample is diluted to 1:800-1000 with milk;
2) Adding the diluted serum sample into a 96-well plate, incubating and washing; preferably the incubation time is 0.5-2 hours;
3) Adding fresh diluted anti-human IgG HRP enzyme-labeled antibody, incubating and washing; preferably the incubation time is 0.5-2 hours; more preferably, the incubation time is from 0.5 to 1 hour;
4) Adding a temporarily prepared TMB substrate, and developing in a dark place; adding sulfuric acid to terminate the reaction; preferably, the light-shielding color development time is 10-30 minutes;
5) The absorbance at 450nm was measured to determine the level of p53 autoantibody expression in the sample.
In a fourteenth aspect of the present invention, there is provided a kit for detecting PD-1 and/or p53 autoantibodies comprising reagents for detecting the level of PD-1 and/or p53 autoantibodies.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
In a fifteenth aspect of the present invention, there is provided a chip for detecting PD-1 and/or p53 autoantibodies, comprising reagents for detecting the level of PD-1 and/or p53 autoantibodies.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
In a sixteenth aspect of the invention, there is provided a kit for diagnosing and/or treating a tumour comprising reagents for detecting the level of PD-1 and/or p53 autoantibodies and reagents for detecting other immune checkpoints. The other immune check points are selected from one or more than two of PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160, or the combination of immune check point inhibitor and other drugs and treatment means.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
In a seventeenth aspect of the invention, there is provided a kit for prognostic evaluation of tumour therapy, comprising reagents for detecting the level of PD-1 and/or p53 autoantibodies and reagents for detecting other immune checkpoints. The other immune checkpoints are selected from one or more than two of PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
Preferably, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-1 and/or p53 autoantibodies comprise IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
In one embodiment of the invention, the PD-1 and/or p53 autoantibodies are PD-1 and/or p53 autoantibodies in serum or plasma.
The reagent for detecting the expression level of the PD-1 and/or p53 autoantibodies is selected from test strips, protein chips, magnetic beads, fluorescent reagents and the like. The detection principle adopts antigen-antibody combination, wherein the detection antigen is PD-1 and/or p53 protein, polypeptide or antibody.
The curative effect prediction of the invention is to predict whether the curative effect of the medicine exists, whether the medicine exists or not or whether the medicine has side effects before the treatment of the disease. Preferably, the agent is an immune checkpoint inhibitor.
The prognosis evaluation of the invention is that of tumors treated by immune checkpoint inhibitors.
The invention relates to diagnosing tumor, which is to diagnose whether the tumor is suffered from, or prognosis evaluation of tumor patients, or evaluation of the benefit degree of treatment of tumor patients with immune checkpoint inhibitors.
The treatment of tumors according to the present invention refers to determining whether to be treated by an immune checkpoint inhibitor by detecting the expression level of PD-1 and/or p53 autoantibodies.
The tumor of the present invention is selected from the group consisting of lymphoma, non-small cell lung cancer, leukemia, ovarian cancer, breast cancer, endometrial cancer, colon cancer, rectal cancer, gastric cancer, bladder cancer, lung cancer, bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, liver and bile duct cancer, esophageal cancer, renal cancer, thyroid cancer, head and neck cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, myelodysplastic syndrome, and sarcoma. Wherein the leukemia is selected from acute lymphoblastic (lymphoblastic) leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, plasma cell leukemia, and chronic myelogenous leukemia; the lymphoma is selected from hodgkin's lymphoma and non-hodgkin's lymphoma, including B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, T-cell lymphoma, and waldenstrom's macroglobulinemia; the sarcoma is selected from osteosarcoma, ewing sarcoma, leiomyosarcoma, synovial sarcoma, soft tissue sarcoma, angiosarcoma, liposarcoma, fibrosarcoma, rhabdomyosarcoma, and chondrosarcoma. Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor. In one embodiment of the invention, the neoplasm is a soft tissue sarcoma neoplasm.
The autoimmune disease described in the present invention is selected from organ specific autoimmune diseases and systemic autoimmune diseases. Wherein the organ specific autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia accompanied by chronic atrophic gastritis, lung hemorrhagic nephritis syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, etc. The systemic autoimmune disease is selected from systemic lupus erythematosus, rheumatoid arthritis, cutaneous rheumatoid nodules, arteritis, pericarditis, scleritis, lymphadenitis, hepatosplenomegaly, neuropathy, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease or ulcerative colitis.
Drawings
Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
fig. 1: ELISA sandwich method for detecting the comparison of the relative levels of PD-1 autoantibodies in different serum dilutions, wherein R1, R2, R3, R4, NR1 and NR2 represent six different samples;
fig. 2: ELISA sandwich method detects the distribution of PD-1 serum autoantibodies of 117 cases of 3 different tumor patients, wherein the different tumor patients are 89 cases of lymphoma, 16 cases of lung cancer (non-small cell lung cancer) and 12 cases of soft tissue sarcoma respectively;
fig. 3: the PD-1 autoantibody level has a curative effect prediction effect on the immune treatment of soft tissue sarcoma, wherein the effective group is a tumor immune treatment effective group, namely a response group, and the ineffective group is a tumor immune treatment ineffective group, namely a non-response group;
fig. 4: ROC curve of efficacy prediction of PD-1 autoantibodies on immunotherapy.
Fig. 5: ELISA sandwich assay detects a comparison of the relative levels of p53 autoantibodies in different serum dilutions, where R1, R2, R3, R4 represent four different samples.
Fig. 6: the ELISA sandwich method detects the distribution of p53 serum autoantibodies of 117 cases of 3 different tumor patients, wherein the different tumor patients are 89 cases of lymphoma, 16 cases of lung cancer (non-small cell lung cancer) and 12 cases of soft tissue sarcoma.
Fig. 7: the p53 autoantibody level predicts the effect of immunotherapy against soft tissue sarcoma, wherein the active group is tumor immunotherapy active group, i.e. response group, and the inactive group is tumor immunotherapy inactive group, i.e. non-response group.
Fig. 8: ROC curve of efficacy prediction of p53 autoantibody on immunotherapy.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
1. Sample collection
Serum samples were collected in tumor hospitals of the national academy of medical science, the median age of tumor patients was 34 (18-74) years, the ratio of men and women was 71:46, 89 of lymphoma patients, 16 of non-small cell lung cancer patients, and 12 of soft tissue sarcoma patients, all of which obtained informed consent. And confirming a tumor diagnosis result through a pathological result, and obtaining curative effect evaluation information by receiving PD-1 antibody immunotherapy for all patients.
2. The detection method comprises the following steps: enzyme-linked immunosorbent assay (ELISA)
An enzyme-linked immunosorbent assay was performed to assess the concentration of serum PD-1 and p53 autoantibodies.
PD-1 protein (1 ng/ul. Times.50 ul) was coated in 96-well plates, serum samples were diluted in dilution buffer (dilution concentrations 1:400, 1:600, 1:800) overnight at 4℃and 50. Mu.L of diluted samples/well were added to 96-well microtiter plates, incubated for 1 hour at 37℃and then washed. To each well, 50. Mu.L of freshly diluted anti-human IgG HRP-enzyme-labeled antibody (1:8000 dilution) was added, incubated at 37℃for 1 hour, and washed. Subsequently, 0.1mL of a temporarily prepared TMB substrate solution was added to each reaction well, developed at 37℃in the absence of light for 25 minutes, and the reaction was stopped by adding 50. Mu.L of 0.05M sulfuric acid to each well, and the signal was determined by measuring the absorbance at 450 nm.
P53 protein (1 ng/. Mu.L. Times.50. Mu.L) was coated in 96-well plates at 4℃overnight. Serum samples were diluted in dilution buffer (dilution concentrations 1:300, 1:600, 1:900, 1:1200) and 50 μl of diluted samples/well was added to a 96-well microtiter plate, incubated for 1 hour at 37 ℃ and then washed. To each well, 50. Mu.L of freshly diluted anti-human IgGHRP enzyme-labeled antibody (1:8000 dilution) was added, incubated at 37℃for 1 hour, and washed. Subsequently, 0.1mL of a temporarily prepared TMB substrate solution was added to each reaction well, developed at 37℃in the absence of light for 25 minutes, and the reaction was stopped by adding 50. Mu.L of 0.05M sulfuric acid to each well, and the signal was determined by measuring the absorbance at 450 nm.
3. Statistical analysis
The inter-group variable differences were compared using the Mann-Whitney U Test, with P <0.05 considered statistically significant.
4. Experimental results
1) Optimization of conditions for detecting levels of PD-1 and p53 autoantibodies in serum of tumor patient
Using the detection method described above: ELISA (enzyme-Linked immunosorbent assay) for detecting the level of autoantibodies to PD-1 in the serum of 6 tumor patients, 6 serum samples were diluted in milk at 1:400, 1:600, and 1:800 concentrations, respectively, and the results showed that the antibody level detected by the serum concentration of 1:400 was the highest (see FIG. 1, wherein R1, R2, R3, R4, NR1, NR2 represent six different samples).
Using the detection method described above: ELISA (enzyme-Linked immunosorbent assay) for detecting the level of p53 autoantibodies in the serum of 4 tumor patients, 4 serum samples are respectively diluted in milk at the concentrations of 1:300, 1:600, 1:900 and 1:1200, and the results show that the detected antibody level of the serum concentrations of 1:300 and 1:600 is the highest, but the OD value is close to 3, precipitation is generated in a titration plate, the optimal serum dilution concentration of 1:900 is determined according to the OD value of ELISA (slightly more than 1) as the optimal detection value, and the subsequent test is carried out at the optimal dilution concentration (see FIG. 5, R1, R2, R3 and R4 represent four different samples).
2) The method can successfully detect the level of PD-1 and p53 autoantibodies in the serum of tumor patients
Using the detection method described above: the conditions of the ELISA (dilution concentration of serum sample is 1:400) detect the expression level of PD-1 autoantibodies in serum samples of 89 cases of lymphomas, 16 cases of non-small cell lung cancers and 12 cases of soft tissue sarcoma tumor patients, and the results are shown in figure 2, and the relative level of PD-1 autoantibodies in serum of tumor patients can be successfully detected by using the ELISA method, and the levels of PD-1 autoantibodies in serum of patients among different tumors are different.
Using the detection method described above: the conditions of ELISA (dilution concentration of serum sample is 1:900) detect the p53 autoantibody expression level of 89 cases of lymphomas, 16 cases of non-small cell lung cancer and 12 cases of soft tissue sarcoma tumor patient serum samples, and the results of FIG. 6 show that the relative level of p53 autoantibody in tumor patient serum can be successfully detected by using the ELISA method, and the p53 autoantibody levels in patient serum are different among different tumors.
3) Relation between serum PD-1 and p53 autoantibody levels in tumor patients and therapeutic effects of immunotherapy
How to more effectively distinguish effective and ineffective patients in tumor immunotherapy is a major problem to be solved in clinical urgent need, and the OD value is firstly standardized, and the relation between the serum PD-1 and p53 autoantibody levels in soft tissue sarcoma and PD-1 immunotherapy is confirmed. The results show that in patients with good treatment effect, the level of PD-1 autoantibody is lower than that of the non-response group (figure 3), the level of p53 autoantibody is lower than that of the non-response group (figure 7), and the two indexes are used for distinguishing patients with different treatment effects, the area under the curve can reach 0.77 (PD-1 is shown in figure 4) and 0.83 (p 53 is shown in figure 8), so that the level of serum PD-1 and/or p53 autoantibody is a potential tumor immunotherapy marker.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (5)
1. The application of an autoantibody serving as a marker in preparing a product for predicting or prognosticating a tumor, wherein the tumor is an immune checkpoint inhibitor for predicting or prognosticating the tumor, the autoantibody is PD-1 or PD-1 and p53 autoantibodies, and the tumor is a soft tissue sarcoma.
2. The use according to claim 1, wherein said PD-1 autoantibody or said p53 autoantibody is a PD-1 autoantibody or a p53 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine; the PD-1 autoantibody or the p53 autoantibody comprises IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
3. The use of claim 1, wherein the immune checkpoint inhibitor is selected from one or more of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4, or CD160 inhibitor, or wherein the immune checkpoint inhibitor treats a tumor by administering the immune checkpoint inhibitor alone or in combination with chemotherapy, radiation therapy, or other means.
4. The use of claim 1, wherein the marker further comprises a concomitant marker selected from one or more than two of PD-L1 protein or its autoantibody, CTLA-4 protein or its autoantibody, BTLA protein or its autoantibody, TIM-3 protein or its autoantibody, LAG-3 protein or its autoantibody, TIGIT protein or its autoantibody, LAIR1 protein or its autoantibody, 2B4 protein or its autoantibody, or CD160 protein or its autoantibody.
5. The use according to claim 1, wherein the product comprises reagents for detecting PD-1 autoantibodies, or PD-1 autoantibodies and p53 autoantibodies.
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