CN110687281A - Application of PD-L1 autoantibody in tumor prognosis evaluation - Google Patents
Application of PD-L1 autoantibody in tumor prognosis evaluation Download PDFInfo
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Abstract
The invention provides application of a reagent for detecting a PD-L1 autoantibody in preparing a product for diagnosing, treating and/or prognostically evaluating tumors and a marker for diagnosing, treating and/or prognostically evaluating tumors, wherein the marker is a PD-L1 autoantibody. The expression level of the marker is detected by a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA), and the curative effect response and long-term benefit condition of the patient to the tumor immunotherapy are judged or assisted.
Description
Technical Field
The invention relates to the field of biomedical detection, in particular to application of a PD-L1 autoantibody in tumor diagnosis, treatment and prognosis evaluation.
Background
Global disease burden studies by the world health organization show that cancer is a high mortality disease next to cardiovascular disease worldwide and china. Immunotherapy has become an emerging means of cancer treatment by enhancing the immune system of patients to combat disease. In many immunotherapeutic strategies, Immune Checkpoint Inhibitors (ICBs) have shown significant benefit in the treatment of a variety of cancers by blocking the intrinsic down-regulation programs of immunity, such as cytotoxic T lymphocyte antigen 4(CTLA-4) and programmed cell death 1(PD-1) or its ligand (PD-L1), increasing anti-tumor immunity. The advent of ICB has increased the overall survival of patients with a variety of cancers, and a number of inhibitor drugs are currently approved by the U.S. food and drug administration and the chinese food and drug administration for the treatment of malignancies, but clinical results indicate that patients receiving ICB monotherapy in the vast majority of unselected solid tumors have an objective effective rate of only 10% to 30%, and that a majority of patients do not benefit from this, i.e. primary resistance, and that disease progression, i.e. secondary resistance, occurs even after a period of treatment for patients who are therapeutically effective. With the advent of more ICB drugs and the gradual increase of drug-taking population, it is crucial to find effective therapeutic effect prediction markers and establish related prediction models, so that the tumor response rate can be improved, the treatment cost and the time cost can be saved for patients, a personalized diagnosis and treatment strategy can be provided for the treatment of tumor patients, and the life cycle and the life quality of the patients can be improved.
At present, it is known that early tumor cells can express and produce some abnormal proteins, and can produce specific antibodies after being recognized by the immune system of the body, these proteins are called tumor-associated antigens, and the antibodies are called autoantibodies, and the antibodies are relatively more researched in autoimmune diseases, and in recent years, the early tumor cell expression has certain research in the aspects of disease screening, early diagnosis, prognosis judgment and curative effect monitoring, and the early tumor cell expression has great potential. Compared with other markers, the serum autoantibody sampling approach is simple, and continuous sampling and monitoring can be performed in the treatment process, so that the ICB curative effect prediction by using the autoantibody in the serum has certain advantages. In the early research, the SEREX (recombinant cDNA expression library serological screening), phage peptide library panning, SERPA (serum proteomics) and other methods are respectively adopted to screen the tumor autoantibodies, and a batch of published tumor autoantibodies are used for tumor diagnosis at present. Wherein autoantibodies such as NY-SEO-1, p53, 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 p53, HSP70, HCC-22-5, peroxiredoxin VI, KM-HN-1, p90 and the like are used for gastric cancer diagnosis; autoantibodies such as p62 and HCC1 are used for liver cancer diagnosis; autoantibodies such as interleukin-29(IL29), Survivin (SUR), growing hormone (GRH), Osteoprotegerin (OPG), and Resistance (RES) are used for diagnosis of breast cancer. Regarding the relationship between autoantibodies and the effect of ICB treatment, studies have reported that the production of autoantibodies is related to the toxic and side effects of ICB treatment, and the level of autoantibodies has some relationship with the effect of ICB treatment.
At present, whether ICB drug therapy can be applied or the treatment condition of tumor patients can be diagnosed according to the expression condition of PD-L1. For example: patent CN109311989A discloses screening cancer subjects for susceptibility to immune checkpoint inhibitors by measuring the expression of PD-L1 in tumor cells, and monitoring, treating and diagnosing the effect of the treatment. Wherein the subject selected for expression of PD-L1 in the cells can be treated by administration of an immune checkpoint inhibitor. Patent CN107667119A discloses the expression level of PD-L1 in tumor cells or tumor-infiltrating immune cells, determining whether patients suffering from non-small cell lung cancer are likely to respond to treatment comprising a PD-L1 axis binding antagonist, which invention means that tumor cells have an expression level of PD-L1 of 5% or more, before treatment of tumors can be administered an effective amount of 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 of non-small cell lung cancer (NSCLC) patients using pembrolizumab. Meanwhile, a large number of clinical test results show that the high-expression patient has higher effective rate and longer survival time for the PD-1/PD-L1 pathway inhibitor compared with the low-expression patient of PD-L1. For example: the results of the most recently released KEYNOTE-042 study at the American Society for Clinical Oncology (ASCO) show that patients with high expression of PD-L1 (TPS ≧ 50%) receive a more significant survival benefit and a 31% reduction in the risk of death compared to the population with low expression of PD-L1 (1% ≦ TPS ≦ 49%). However, some patients with low expression of PD-L1 still benefit from ICB therapy, and therefore patient screening relying solely on expression of PD-L1 is far from adequate in clinical practice.
The PD-L1 autoantibody is an antibody generated by a human body and aiming at a PD-L1 molecule, and is a potential curative effect marker of immunotherapy. The current research on PD-L1 autoantibodies is in the prognostic diagnosis of autoimmune disease patients, for example: non-patent literature screening of PD-L1 autoantibodies in patients with autoimmune diseases (tuberculosis and breast tumors, yan zhuohong et al, 2017, stage 1) discloses the use of ELISA and immunoblotting to detect PD-L1 autoantibodies in serum for prognostic diagnosis or assessment of autoimmune diseases, tuberculosis. However, no detection of the PD-L1 autoantibody in serum/plasma as the prediction of the curative effect of immunotherapy is seen at present, so the inventor uses the PD-L1 autoantibody for the diagnosis and prognosis of tumors through creative work.
Disclosure of Invention
The inventor successfully detects the content of the PD-L1 autoantibody in the blood of a tumor or autoimmune disease patient by a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA), and more patients with good curative effect on immunotherapy in a high-PD-L1 autoantibody patient, so that the serum PD-L1 autoantibody can be used as a potential marker for tumor diagnosis, curative effect prediction and prognosis evaluation of immunotherapy.
The invention provides an application of a reagent for detecting PD-L1 autoantibody in preparing a product for diagnosing, treating and/or prognostically evaluating tumors and an application of PD-L1 autoantibody in preparing a product for diagnosing, treating and/or prognostically evaluating tumors.
It is another object of the present invention to provide a marker for tumor diagnosis, treatment and/or prognosis evaluation.
It is a further object of the present invention to provide a product for the diagnosis, treatment and/or prognosis of tumours.
It is a further object of the present invention to provide a method for the diagnosis, treatment and/or prognostic evaluation of tumors.
The first aspect of the invention relates to the application of a reagent for detecting PD-L1 autoantibody in the preparation of products for diagnosing and/or treating tumors or autoimmune diseases.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
Preferably, the detecting of the PD-L1 autoantibody is detecting the existence or expression level of the PD-L1 autoantibody.
Preferably, the method for detecting the PD-L1 autoantibody by the reagent for detecting the PD-L1 autoantibody is one or more of ELISA, immunoblotting, indirect immunofluorescence, enzyme immuno-spot method and immunofluorescence.
In a specific embodiment of the invention, the method for detecting PD-L1 autoantibody by using the reagent for detecting PD-L1 autoantibody is ELISA.
In a second aspect, the invention relates to the use of an autoantibody to PD-L1 in the manufacture of a product for the diagnosis and/or treatment of a tumour or an 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
In a third aspect, the invention relates to the application of a reagent for detecting PD-L1 autoantibody in the preparation of a product for the treatment and prognosis evaluation of tumor 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
Preferably, the tumor treatment prognosis evaluation is a prognosis evaluation after treatment with an immune checkpoint inhibitor.
Further preferably, the immune checkpoint inhibitor is one or a combination of more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitors.
Preferably, the immune checkpoint inhibitor treatment is tumor treatment by administration of an immune checkpoint inhibitor alone or in combination with chemotherapy, radiation therapy or other means.
Preferably, the detecting of the PD-L1 autoantibody is detecting the existence or expression level of the PD-L1 autoantibody.
Preferably, the method for detecting the PD-L1 autoantibody by the reagent for detecting the PD-L1 autoantibody is one or more of ELISA, immunoblotting, indirect immunofluorescence, enzyme immuno-spot method and immunofluorescence.
In a specific embodiment of the invention, the method for detecting PD-L1 autoantibody by using the reagent for detecting PD-L1 autoantibody is ELISA.
The fourth aspect of the invention relates to the application of the PD-L1 autoantibody in the preparation of a product for the treatment and prognosis evaluation of tumors or autoimmune diseases.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the tumor treatment prognosis evaluation is a prognosis evaluation after treatment with an immune checkpoint inhibitor.
Further preferably, the immune checkpoint inhibitor is one or a combination of more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitors.
Preferably, the immune checkpoint inhibitor treatment is tumor treatment by administration of an immune checkpoint inhibitor alone or in combination with chemotherapy, radiation therapy or other means.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
In a fifth aspect, the invention relates to a marker for diagnosing and/or treating a tumor or an autoimmune disease, said marker comprising a PD-L1 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
In one embodiment of the invention, the marker may further comprise another immune checkpoint protein other than PD-L1 or an autoantibody thereof as a concomitant marker, in combination with the PD-L1 autoantibody for detection of the effect of a tumor therapy. Wherein the concomitant marker is one or the combination of more than two of PD-1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In a sixth aspect, the invention relates to a marker for prognosis evaluation of treatment of tumor or autoimmune disease, said marker comprising PD-L1 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
Preferably, the tumor treatment prognosis evaluation is a prognosis evaluation after treatment with an immune checkpoint inhibitor.
Further preferably, the immune checkpoint inhibitor is one or a combination of more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitors.
Preferably, the immune checkpoint inhibitor treatment is tumor treatment by administration of an immune checkpoint inhibitor alone or in combination with chemotherapy, radiation therapy or other means.
In one embodiment of the invention, the marker may further comprise another immune checkpoint protein other than PD-L1 or an autoantibody thereof as a concomitant marker, in combination with the PD-L1 autoantibody for detection of the effect of a tumor therapy. Wherein the concomitant marker is one or the combination of more than two of PD-1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In a seventh aspect, the invention relates to a product for diagnosing and/or treating a tumor or an autoimmune disease, said product comprising a reagent for detecting an autoantibody to PD-L1.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
Preferably, the detecting of the PD-L1 autoantibody is detecting the existence or expression level of the PD-L1 autoantibody.
Preferably, the method for detecting the PD-L1 autoantibody by the reagent for detecting the PD-L1 autoantibody is one or more of ELISA, immunoblotting, indirect immunofluorescence, enzyme immuno-spot method and immunofluorescence.
In a specific embodiment of the invention, the method for detecting PD-L1 autoantibody by using the reagent for detecting PD-L1 autoantibody is ELISA.
Preferably, the product for diagnosing and/or treating tumor can also comprise other immune checkpoint proteins or autoantibodies thereof except PD-L1 as a concomitant marker, and the detection of the tumor treatment effect is carried out by combining the PD-L1 autoantibodies. Wherein the concomitant marker is one or the combination of more than two of PD-1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In an eighth aspect, the invention relates to a product for prognosis evaluation of treatment of tumor or autoimmune disease, said product comprising a reagent for detecting PD-L1 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the PD-L1 autoantibody is a PD-L1 autoantibody in serum and/or plasma.
Preferably, the detecting of the PD-L1 autoantibody is detecting the existence or expression level of the PD-L1 autoantibody.
Preferably, the tumor treatment prognosis evaluation is a prognosis evaluation after treatment with an immune checkpoint inhibitor.
Further preferably, the immune checkpoint inhibitor is one or a combination of more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitors.
Preferably, the immune checkpoint inhibitor treatment is tumor treatment by administration of an immune checkpoint inhibitor alone or in combination with chemotherapy, radiation therapy or other means.
Preferably, the product for the prognosis evaluation of tumor treatment can also comprise other immune checkpoint proteins except PD-L1 or autoantibodies thereof as concomitant markers, and the detection of the tumor treatment effect is carried out by combining the PD-L1 autoantibodies. Wherein the concomitant marker is one or the combination of more than two of PD-1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
Preferably, the method for detecting the PD-L1 autoantibody by the reagent for detecting the PD-L1 autoantibody is one or more of ELISA, immunoblotting, indirect immunofluorescence, enzyme immuno-spot method and immunofluorescence.
In a specific embodiment of the invention, the method for detecting PD-L1 autoantibody by using the reagent for detecting PD-L1 autoantibody is ELISA.
In a ninth aspect, the invention relates to a method for diagnosing a tumor or an autoimmune disease, said method comprising detecting the presence or absence or the expression level of an autoantibody to PD-L1 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In a tenth aspect, the present invention relates to a method for prognosis evaluation of treatment of tumor or autoimmune disease, said method comprising detecting the presence or absence or expression level of an autoantibody to PD-L1 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 autoantibody is a PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In an eleventh aspect, the invention relates to a method of treating a tumor or an autoimmune disease, said method comprising administering to a patient having a tumor an effective amount of an inhibitor of PD-L1, wherein expression of PD-L1 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 tumor is a lymphoma.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the PD-L1 inhibitor is a PD-L1 antibody.
Preferably, said detection of expression of PD-L1 autoantibodies from said patient is detection of expression of PD-L1 autoantibodies from serum, plasma, interstitial fluid, cerebrospinal fluid or urine of said patient. Wherein the higher the expression level of the PD-L1 autoantibody, the better the treatment effect of the immunosuppressant.
The twelfth aspect of the invention relates to a method for detecting a PD-L1 autoantibody, which comprises the steps of coating a PD-L1 protein on the surface of a carrier, adding a sample to be detected, adding an enzyme and a substrate, and determining the concentration.
Preferably, the PD-L1 autoantibody comprises one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE or IgD.
Preferably, the sample to be detected is biological serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the present invention, the sample to be tested is biological serum.
Preferably, the sample to be detected is diluted with a dilution buffer at a concentration of 1: 150-.
Preferably, the dilution concentration is 1: 200-400.
In one embodiment of the present 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 method for measuring the concentration is to measure the absorbance value at 450 nm.
In one embodiment of the present invention, the method comprises:
1) coating the PD-L1 protein in a 96-well plate at 4 ℃ overnight; diluting the serum sample with milk to 1: 200-400;
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 a 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 0.5-1 hour;
4) adding a TMB substrate which is prepared temporarily, and developing in a dark place; adding sulfuric acid to terminate the reaction; preferably, the dark color development time is 10-30 minutes;
5) the absorbance value at 450nm was measured to determine the expression level of PD-L1 autoantibodies in the sample.
The reagent for detecting the expression level of the PD-L1 autoantibody is selected from test paper strips, protein chips, magnetic beads, fluorescent reagents and the like. The detection principle adopts antigen-antibody combination, wherein the detection antigen is PD-L1 protein or polypeptide.
The product comprises the reagent for detecting the level of the PD-L1 autoantibody. Preferably, the product is selected from the group consisting of a kit and mass spectrometry.
A kit for detecting PD-L1 autoantibodies comprising reagents to detect the level of PD-L1 autoantibodies.
A chip for detecting PD-L1 autoantibody comprises a reagent for detecting the level of PD-L1 autoantibody.
A kit for the diagnosis and/or treatment of a tumour comprising reagents to detect the level of PD-L1 autoantibodies together with reagents to detect other immune checkpoints. The other immune check points are selected from one or the combination of more than two of PD-1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
A kit for the prognostic assessment of tumour therapy comprising reagents for detecting the level of PD-L1 autoantibodies together with reagents for detecting other immune checkpoints. The other immune check points are selected from one or the combination of more than two of PD-1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
The diagnosis of tumor in the invention refers to the diagnosis of whether tumor is suffered or not, or the prognosis evaluation of tumor patients, or the evaluation of the benefit degree of the tumor patients treated by immune checkpoint inhibitor.
The tumor treatment method provided by the invention is used for determining whether the treatment is carried out by an immune checkpoint inhibitor or not by detecting the expression level of the PD-L1 autoantibody.
The tumor of the invention is selected from 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, kidney cancer, thyroid cancer, head and neck cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, myelodysplastic syndrome, and sarcoma. Wherein the leukemia is selected from acute lymphocytic (lymphoblastic) leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, plasma cell leukemia, and chronic myelogenous leukemia; said 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's 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 tumor is a lymphoma.
The autoimmune disease of 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 with chronic atrophic gastritis, goodpasture's syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple 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.
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Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1: ELISA sandwich method and QiaoLian method are used for detecting the content of PD-L1 autoantibody in blood of tumor patients and comparing the content with the relative level, wherein R4 and R12 respectively represent serum samples of 2 patients.
FIG. 2: the ELISA sandwich method detects the comparison of the relative levels of the PD-L1 autoantibody in different serum dilutions, wherein R4, R5, R12, R13, NR12 and NR13 respectively represent serum samples of 6 patients.
FIG. 3: ELISA sandwich method was used to detect the distribution of PD-L1 serum autoantibodies in 117 tumor patients, wherein the tumor patients were lymphoma, non-small cell lung cancer and soft tissue sarcoma.
FIG. 4: the effect of the level of PD-L1 autoantibodies in lymphoma patients on the prediction of the efficacy of immunotherapy was shown, where CR was complete remission, PR was partial remission, SD was stable disease, PD was disease progression, and the mean OD on the ordinate represents the mean of the OD values of each group of samples.
Detailed Description
The technical solutions in 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 obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
1. Sample collection
Serum samples were collected at the national academy of medicine tumor hospital with a median age of 34(18-74) years of age and a male to female ratio of 71:46, 89 of lymphoma patients, 16 of non-small cell lung cancer patients, 12 of soft tissue sarcoma patients, all of whom received informed consent. And (4) confirming the tumor diagnosis result through the pathological result, receiving the PD-1 antibody immunotherapy on all patients, and obtaining the curative effect evaluation information.
2. The detection method comprises the following steps:
the optimization detection method comprises the following steps: autoantibody levels of PD-L1 in sera of 2 patients were measured using sandwich enzyme-linked immunosorbent assay and QiaoLiang enzyme-linked immunosorbent assay, respectively.
Optimizing the dilution concentration: a sandwich enzyme-linked immunosorbent assay is used for detecting the autoantibody level of PD-L1 in the serum of 6 tumor patients, and 6 serum samples are respectively diluted in milk at the concentration of 1:300, 1:600 and 1:900 for detection.
1) Sandwich enzyme-linked immunosorbent assay (ELISA)
PD-L1 protein (1 ng/. mu.l by 50. mu.l) was coated in 96-well plates overnight at 4 ℃, 2 serum samples were diluted in milk at 1:300, 1:600, 1:900 concentrations, respectively, and 50. mu.l of the diluted samples/well were added to 96-well microtiter plates, incubated at 37 ℃ for 1 hour, and then washed. 50. mu.L of a freshly diluted anti-human IgG HRP enzyme-labeled antibody (diluted 1: 8000) was added to each reaction well, incubated at 37 ℃ for 1 hour, and washed. Then, 0.1mL of the temporarily prepared TMB substrate solution was added to each reaction well, and the reaction was quenched by adding 50. mu.L of 0.05M sulfuric acid to each well, and developed in the dark at 37 ℃ for 25 minutes, and the signal was determined by measuring the absorbance at 450 nm.
2) Qiao Ling Fa
PD-L1 protein (1 ng/. mu.l by 50. mu.l) was coated in 96-well plates overnight at 4 ℃, 2 serum samples were diluted in milk at 1:300, 1:600, 1:900 concentrations, respectively, and 50. mu.l of the diluted samples/well were added to 96-well microtiter plates, incubated at 37 ℃ for 1 hour, and then washed. Meanwhile, 10 mu L of PD-L1 diluted protein is taken and diluted to 100 mu L (10 ng/mu L) by 1XPBS, after being mixed evenly, 1 mu L or 2 mu L of biotin labeling reagent (DMSO dissolution) with the concentration of 20mg/mL is added, and the reaction is carried out for 1h under the condition of room temperature oscillation; during the reaction, the Bio-Spin6 column was turned upside down and mixed, the bottom end of the column was removed and placed in a 2mL centrifuge tube, the column cover and the effluent were removed; the column was returned to a 2mL centrifuge tube and centrifuged at 1000g for 2 min; adding 500 μ L of 1xPBS, centrifuging at 1000g for 1min, removing effluent, and repeating for four times; adding the marked 100 mu L PD-L1 protein sample into the center of the gel bed, and centrifuging for 4min at 1000 g; the effluent was a lectin-labeled PD-L1 protein sample. A freshly labeled PD-L1 protein sample was added to each reaction well, washed after one hour at room temperature, 50. mu.L of an enzyme-labeled antibody to biotin HRP (1:8000 dilution) was added, incubated at 37 ℃ for 1 hour, and washed. Then, 0.1mL of the temporarily prepared TMB substrate solution was added to each reaction well, and the reaction was terminated at 37 ℃ for 25 minutes by adding 50. mu.L of 0.05M sulfuric acid per well, and the signal was determined by measuring the absorbance at 450 nm.
3. Statistical analysis
Differences in the variables between groups were compared using the Mann-Whitney U Test, and P <0.05 was considered statistically significant.
4. Results of the experiment
The autoantibody level of PD-L1 in the serum of 2 patients was measured by sandwich ELISA and QiaoLieISoSorbent assay, and the results are shown in FIGS. 1-2. The sandwich enzyme-linked immunosorbent assay can detect higher PD-L1 antibody level compared with the QiaoJO assay (FIG. 1, R4 and R12 respectively represent serum samples of 2 patients).
The autoantibody level of PD-L1 in the serum of 6 tumor patients was detected by a sandwich enzyme-linked immunosorbent assay, and the result showed that the antibody level detected by the serum concentration of 1:300 was the highest. (FIG. 2, R4, R5, R12, R13, NR12, NR13 represent serum samples of 6 patients, respectively).
Example 2
The expression levels of PD-L1 autoantibodies in serum samples of 89 lymphoma, 16 non-small cell lung carcinomas and 12 soft tissue sarcoma tumor patients (specimen collection in example 1) were tested using the conditions of the sandwich ELISA assay in example 1 (1:300), and the results showed that the relative levels of autoantibodies in serum of tumor patients could be successfully detected using the sandwich ELISA method (FIG. 3).
Example 3
How to more effectively distinguish effective patients from ineffective patients in tumor immunotherapy is a great problem to be solved urgently in clinic, the relationship between serum PD-L1 autoantibody level and PD-L1 immunotherapy is researched by selecting lymphoma with the largest number of patients, the curative effect of the lymphoma is divided into four grades according to the evaluation standard of the curative effect of solid tumors (RECIST 1.1), CR (complete remission), PR (partial remission), SD (stable disease), PD (disease progression) and the curative effect are reduced in sequence, and the result shows that the higher the mean level of the PD-L1 autoantibody of patients with better curative effect is, so that the higher the level of the serum PD-L1 autoantibody is a potential marker of the tumor immunotherapy (figure 4).
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. The application of the reagent for detecting the PD-L1 autoantibody in the preparation of products for diagnosing and/or treating tumors.
2. The use of claim 1, wherein the PD-L1 autoantibodies comprise one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE, or IgD; the detection of the PD-L1 autoantibody is the detection of the existence or the expression level of the PD-L1 autoantibody; the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
3. The use of claim 2, wherein the reagent for detecting PD-L1 autoantibody detects PD-L1 autoantibody by one or more methods selected from ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot assay, or immunofluorescence.
Use of an autoantibody to PD-L1 in the manufacture of a product for the diagnosis and/or treatment of tumours.
5. The use of any one of claims 1-4, wherein the PD-L1 autoantibodies comprise one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE, or IgD; the PD-L1 autoantibody is PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine; the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
6. A marker for diagnosing and/or treating a tumor, wherein said marker comprises PD-L1 autoantibody.
7. The marker of claim 6, wherein the PD-L1 autoantibodies comprise one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE, or IgD; the PD-L1 autoantibody is PD-L1 autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine; the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
8. A product for the diagnosis and/or treatment of tumours, said product comprising reagents for the detection of autoantibodies to PD-L1.
9. The product of claim 8, wherein the PD-L1 autoantibodies comprise one or a combination of two or more of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgE, or IgD; the method for detecting the PD-L1 autoantibody by the reagent for detecting the PD-L1 autoantibody is selected from one or the combination of more than two of ELISA, immunoblotting, indirect immunofluorescence, enzyme immuno-spot method or immunofluorescence; the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
10. A detection method of PD-L1 autoantibody is characterized in that PD-L1 protein is coated on the surface of a carrier, a sample to be detected is added, enzyme and substrate are added, and the concentration is measured.
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