Immune-related adverse event marker and kit

Abstract

The present application provides an immune-related adverse event marker and a kit, which can effectively predict immune-related adverse events caused by the treatment of a programmed death receptor 1 antibody / programmed death ligand antibody. The immune-related adverse event marker includes: CCL20, CXCL11, CXCL10 or CXCL9. The immune-related adverse event marker and kit provided by the technical solution of embodiments of the present application can effectively predict immune-related adverse events, thereby facilitating therapeutic intervention for immune-related adverse events.

Description

Immune related adverse reaction marker and kit

[0001] The present application claims priority to Chinese Patent Application No. 202410978634.8, filed on July 19, 2024, entitled "Immune related adverse reaction marker and kit", the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of biological medicine, and more particularly, to an immune related adverse reaction marker and kit. BACKGROUND

[0003] Immune checkpoint inhibits (ICIs) mainly target antibodies against Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and Programmed cell death protein 1 (PD-1). ICIs activate T cells by blocking CTLA-4, PD-1 and their ligands, promote immune killing of tumor cells, and improve the effect of immunotherapy. Since ICIs rely on activating the body's own immune system to attack tumor cells to achieve the purpose of treatment, it will break the body's immune homeostasis, causing some normal cells of the body to be attacked by the immune system and thus produce immune related adverse reactions (irAEs).

[0004] irAEs can involve all organs of the body and can cause death in severe cases. Existing markers for immune related adverse reactions are based on immunohistochemical detection of tumor tissue sections from patients, which has a high dependence on samples, causes trauma to patients during sampling, and cannot be used to detect patients who cannot obtain tumor samples. At the same time, the immunohistochemical detection test has a long cycle and is subject to personal factors of the operator, and cannot form a standardized detection method and system. Therefore, how to effectively predict immune related adverse reactions is a technical problem that needs to be solved. SUMMARY

[0005] The present application provides an immune related adverse reaction marker and kit, which can effectively predict immune related adverse reactions.

[0006] In a first aspect, an immune related adverse reaction marker is provided, comprising: CCL20, CXCL11, CXCL10 or CXCL9. The immune related adverse reaction is an immune related adverse reaction caused by Programmed death receptor 1 antibody / Programmed death ligand antibody treatment.

[0007] In a second aspect, there is provided use of CCL20, CXCL11, CXCL10 or CXCL9 in the manufacture of a kit for predicting an immune-related adverse reaction. The immune-related adverse reaction is an immune-related adverse reaction caused by a programmed death receptor 1 antibody / programmed death ligand antibody treatment, and the prediction is a prediction before the treatment.

[0008] In a third aspect, there is provided a kit comprising: a reagent for detecting an expression level of CCL20, CXCL11, CXCL10 or CXCL9, the kit being used for predicting an immune-related adverse reaction, the immune-related adverse reaction being an immune-related adverse reaction caused by a programmed death receptor 1 antibody / programmed death ligand antibody treatment, and the prediction being a prediction before the treatment.

[0009] In certain possible implementations, the expression level of CCL20, CXCL11, CXCL10 or CXCL9 comprises a content of CCL20, CXCL11, CXCL10 or CXCL9 in blood plasma.

[0010] In certain possible implementations, the expression level of CCL20, CXCL11, CXCL10 or CXCL9 comprises a content of CCL20, CXCL11, CXCL10 or CXCL9 in blood serum.

[0011] In certain possible implementations, the programmed death receptor 1 antibody comprises at least one of the following antibodies: tregalizumab, seprableuzumab, sidulizumab, carrezumab, tiragolumab, sasanlimab, pidilizumab, poretumab, cixutumumab, pembrolizumab, nivolumab; and the programmed death ligand antibody comprises at least one of the following antibodies: atezolizumab, durvalumab, avelumab, envafolimab, adecatumumab.

[0012] In certain possible implementations, the immune-related adverse reaction comprises: pneumonitis, myocarditis, colitis, pancreatitis, hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis, type I diabetes, adrenal insufficiency, sarcoidosis, vitiligo, skin toxicity, thrombocytopenia, hepatitis, digestive system toxicity, nervous system disorder, nephritis, uveitis, or local pneumonitis.

[0013] In certain possible implementations, the programmed death receptor 1 antibody / programmed death ligand antibody treatment is used to treat: lung adenocarcinoma, skin melanoma, prostate cancer, bladder urothelial carcinoma, mesothelioma, breast invasive carcinoma, cervical squamous carcinoma, cervical adenocarcinoma, pancreatic carcinoma, ovarian serous cystadenocarcinoma, head and neck squamous cell carcinoma, gastric adenocarcinoma, thyroid carcinoma, cholangiocarcinoma, adrenal cortical carcinoma, rectal adenocarcinoma, colon carcinoma, hepatocellular carcinoma, brain low-grade glioma, glioblastoma multiforme, uveal melanoma, or uterine carcinosarcoma.

[0014] The immune-related adverse reaction marker and kit provided by the technical scheme of the embodiments of the present application can effectively predict immune-related adverse reactions, thereby facilitating intervention treatment of immune-related adverse reactions. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 is the result of CCL20 predicting irAE in Embodiment 1 of the present application.

[0016] Figure 2 is the result of CXCL9 predicting irAE in Embodiment 1 of the present application.

[0017] Figure 3 is the result of CXCL10 predicting irAE in Embodiment 1 of the present application.

[0018] Figure 4 is the result of CXCL11 predicting irAE in Embodiment 1 of the present application.

[0019] Figure 5 is the result of CCL20 predicting irAE in Embodiment 2 of the present application.

[0020] Figure 6 is the result of CXCL9 predicting irAE in Embodiment 2 of the present application.

[0021] Figure 7 is the result of CXCL10 predicting irAE in Embodiment 2 of the present application.

[0022] Figure 8 is the result of CXCL11 predicting irAE in Embodiment 2 of the present application.

[0023] Figure 9 is the result of CCL20 predicting irAE in Embodiment 3 of the present application.

[0024] Figure 10 is the result of CXCL11 predicting irAE in Embodiment 3 of the present application.

[0025] Figure 11 is the result of CXCL11 predicting irAE in Embodiment 4 of the present application.

[0026] Figure 12 is the result of CXCL11 predicting irAE in Embodiment 5 of the present application. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be described below with reference to the drawings. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present application. Unless otherwise specified, the reagents involved in the embodiments of the present application are all commercially available products, which can be purchased through commercial channels.

[0028] Immune-related adverse reactions (irAEs) refer to adverse reactions against normal self-tissues caused by the immune system being enhanced or reactivated in patients receiving immunotherapy, especially immune checkpoint inhibitors (ICIs). These reactions are due to the fact that immunotherapy changes the body's tolerance to self-antigens, so that the immune system not only attacks tumor cells, but also may mistakenly attack normal body tissues, thereby causing damage to various tissues and organs. Anti-programmed death 1 (PD-1) antibody / anti-programmed death ligand 1 (PD-L1) antibody therapy is a typical ICI, which relies on activating the body's immune response for cancer and tumor treatment.

[0029] Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein 3α (MIP-3α), is a small molecular weight cytokine in the CC chemokine family. CCL20 exerts its effects by binding to the receptor CD196 / CCR6, i.e., CCL20 is a CD196 ligand.

[0030] Leukocyte differentiation antigen 196 (CD196), also known as CCR6 (C-C chemokine receptor type 6), is a G protein-coupled receptor belonging to the chemokine receptor family. CCR6 is mainly expressed on Th17 cells, memory T cells, some γδ T cells, B lymphocytes and other immune cells in T cell subsets. After binding to a specific chemokine CCL20 (also known as MIP-3α), it participates in regulating the migration of these immune cells to inflammatory sites or specific tissues. CCR6 plays an important role in various immune responses and inflammatory diseases, for example, in autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis), infectious diseases and tumor metastasis processes, its expression and functional status can affect the progression of the disease.

[0031] Chemokine (C-X-C motif) ligand 9 (CXCL9), also known as MIG (monokine induced by gamma interferon) or SCYB9 (small-inducible cytokine B9), is a small molecular weight cytokine of the CXC chemokine family. CXCL9 is a CD183 ligand. The main function of CXCL9 is chemotaxis, recruiting CXCR3+ cells (such as effector T cells, regulatory T cells (Tregs), and CD8+ cytotoxic T cells) to the inflammation or tumor site by binding to its receptor CD183 / CXCR3.

[0032] Chemokine (C-X-C motif) ligand 10 (CXCL10), also known as IP-10 (interferon gamma-induced protein 10) or SCYB10 (small-inducible cytokine B10), is a small molecular weight cytokine belonging to the CXC chemokine family. CXCL10 is a CD183 ligand. CXCL10 mainly exerts its biological effects by binding to its receptor CD183 / CXCR3.

[0033] Chemokine (C-X-C motif) ligand 11 (CXCL11), also known as I-TAC (IFN-inducible T-cell alpha-chemoattractant), is a member of the CXC chemokine family. CXCL11 is a CD183 ligand. CXCL11 exerts its biological effects by binding to two chemokine receptors, CXCR3 (CD183) and CXCR7.

[0034] Leukocyte differentiation antigen 183 (CD183), also known as CXCR3, is a CXC chemokine receptor widely distributed on the surface of various immune cells, including T helper cells (especially Th1 cells), natural killer cells (NK cells), B lymphocytes, and some monocyte / macrophage subpopulations. CXCR3 mainly interacts with its ligands CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC), which are secreted by activated macrophages, endothelial cells and other cell types during the inflammatory response and immune response process. When CXCR3 binds to the corresponding chemokines, it can guide the above-mentioned immune cells to migrate to the inflammation site or virus infection area, participate in antiviral immunity and antitumor immunity. Under pathological conditions, the CXCR3 and its chemokine system are closely related to various autoimmune diseases (such as multiple sclerosis, rheumatoid arthritis, etc.), allergic reactions, and the occurrence and development of some types of tumors. Therefore, CXCR3 has become one of the important targets for immune regulation and treatment research.

[0035] PD-1 / PD-L1 antibody treatment is a typical ICI, which relies on activating the body's immune response for cancer and tumor treatment. However, PD-1 / PD-L1 antibody treatment breaks the body's immune homeostasis, and the immune-related adverse reactions caused thereby can involve the whole body organs, and even cause death in severe cases. Therefore, the discovery of immune-related adverse reaction biomarkers is of great significance.

[0036] Therefore, the present application provides an immune-related adverse reaction marker and kit, which can effectively predict immune-related adverse reactions, thereby facilitating the intervention treatment of immune-related adverse reactions.

[0037] In the embodiments of the present application, the immune-related adverse reaction marker comprises CCL20, CXCL11, CXCL10 or CXCL9.

[0038] In the embodiments of the present application, the kit for predicting immune-related adverse reactions comprises a reagent for detecting the expression level of CCL20, CXCL11, CXCL10 or CXCL9, and the kit is used for predicting immune-related adverse reactions caused by programmed death receptor 1 antibody / programmed death ligand antibody treatment, and the prediction is a prediction before treatment.

[0039] Optionally, the expression level of CCL20, CXCL11, CXCL10 or CXCL9 comprises the content of CCL20, CXCL11, CXCL10 or CXCL9 in plasma.

[0040] Optionally, the expression level of the CCL20, CXCL11, CXCL10 or CXCL9 comprises the content of the CCL20, CXCL11, CXCL10 or CXCL9 in serum.

[0041] Optionally, the kit of the embodiments of the present application adopts a double antibody one-step sandwich enzyme-linked immunosorbent assay (ELISA) to obtain the content / concentration of the sample.

[0042] ELISA is to detect the concentration of antigen or antibody in the sample by using the specific binding reaction of antigen and antibody and the catalytic reaction of enzyme on substrate. Specifically, the antigen or antibody is combined to the solid carrier (such as polystyrene microporous plate) and keeps its immunological activity. Then, the sample to be tested is added, and the antigen or antibody in the sample specifically binds to the antigen or antibody on the solid carrier. After washing to remove the unbound substances, enzyme-labeled antigen or antibody is added to further bind to the bound antigen or antibody. Finally, the substrate of enzyme reaction is added, and the enzyme catalyzes the substrate to produce visible colored product, and the amount of product is proportional to the amount of the substance to be tested in the sample, so as to carry out qualitative or quantitative analysis.

[0043] The double antibody sandwich method of ELISA refers to the specific antibody is combined with the solid carrier to form a solid-phase antibody. After adding the sample to be tested, enzyme-labeled antibody is added to be combined on the solid-phase carrier. Finally, the substrate is added to develop color, and quantitative analysis is carried out according to the color depth.

[0044] Optionally, the programmed death receptor 1 antibody comprises at least one of the following antibodies: tislelizumab, spartalizumab, sintilimab, camrelizumab, toripalimab, sasanlimab, pembrolizumab, pidilizumab, cixutumumab, pembrolizumab, nivolumab; the programmed death ligand antibody comprises at least one of the following antibodies: atezolizumab, durvalumab, avelumab, envafolimab, adecatumumab. It should be understood that the embodiments of the present application do not limit the specific types of programmed death receptor 1 antibody or programmed death ligand antibody. That is, the current or future possible programmed death receptor 1 antibody or programmed death ligand antibody can be applicable.

[0045] Optionally, the immune-related adverse reactions include: pneumonia, myocarditis, colitis, pancreatitis, hypothyroidism, hyperthyroidism, thyroiditis, hypophysis inflammation, type I diabetes, adrenal insufficiency, sarcoidosis, vitiligo, skin toxicity, thrombocytopenia, hepatitis, digestive system toxicity, nervous system disorder, nephritis, uveitis or localized pneumonia. It should be understood that the specific types of immune-related adverse reactions are not limited by the embodiments of the present application. That is, immune-related adverse reactions caused by programmed death receptor 1 antibody / programmed death ligand antibody treatment can all be applicable.

[0046] Optionally, the programmed death receptor 1 antibody / programmed death ligand antibody treatment is used for treating: lung adenocarcinoma, skin melanoma, prostate cancer, bladder urothelial carcinoma, mesothelioma, breast invasive carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, pancreatic cancer, ovarian serous cystadenocarcinoma, head and neck squamous cell carcinoma, gastric adenocarcinoma, thyroid cancer, cholangiocarcinoma, adrenal cortex carcinoma, rectal adenocarcinoma, colon cancer, hepatocellular carcinoma, brain low-grade glioma, glioblastoma multiforme, uveal melanoma or uterine carcinosarcoma. It should be understood that the diseases treated by the programmed death receptor 1 antibody / programmed death ligand antibody are not limited by the embodiments of the present application. That is, the diseases that can be treated by the programmed death receptor 1 antibody / programmed death ligand antibody at present or in the future can all be applicable.

[0047] Embodiments

[0048] The kit of the embodiments of the present application uses a double antibody one-step sandwich enzyme-linked immunosorbent assay (ELISA) to obtain the content of the marker. The sample, standard, and horseradish peroxidase (HRP)-labeled detection antibody are sequentially added to the coated microwells pre-coated with the marker capture antibody, incubated, and thoroughly washed. Color development is performed with substrate 3,3',5,5'-tetramethylbenzidine (TMB), which is converted to blue under the catalysis of peroxidase and to the final yellow under the action of acid. The color depth is positively correlated with the content of the marker in the sample. The absorbance (OD value) is measured at 450 nm wavelength by an enzyme-labeled instrument, and the sample concentration / content is calculated.

[0049] Sample collection

[0050] 1. Serum: The whole blood sample collected in a serum separation tube is placed at room temperature for 2 hours or at 4°C overnight, then centrifuged at 1000 x g for 20 minutes, and the supernatant is detected or stored at -20°C or -80°C.

[0051] 2. Plasma: Collect the specimen with ethylenediaminetetraacetic acid (EDTA) or heparin as an anticoagulant, and centrifuge the specimen at 1000 x g for 15 minutes at 2-8°C within 30 minutes after collection, and take the supernatant for detection, or store the supernatant at -20°C or -80°C.

[0052] Kit composition

[0053] 1. The standard concentrations are 480, 240, 120, 60, 30, and 15 pg / mL in order.

[0054] 2. After a large number of normal specimen tests, the normal concentration values of the specimen are within the detection range provided by the kit, and 50 μL of the sample is directly taken for loading during the experiment.

[0055] Kit performance

[0056] Detection range: 15 pg / mL-480 pg / mL.

[0057] Sensitivity: The minimum detection concentration is less than 1.0 pg / mL.

[0058] Specificity: No cross-reaction with other soluble structural analogs.

[0059] Repeatability: The intra-plate coefficient of variation is less than 10%, and the inter-plate coefficient of variation is less than 15%.

[0060] Reagent preparation

[0061] The kit is taken out of the refrigerated environment and used after equilibration at room temperature.

[0062] Dilution of 20x washing buffer: Dilute with distilled water at a ratio of 1:20, i.e. 1 part of 20x washing buffer plus 19 parts of distilled water.

[0063] Detection operation

[0064] 1. Take out the required strip from the aluminum foil bag equilibrated at room temperature for 60 min, and seal the remaining strips with a self-sealing bag and put them back at 4°C.

[0065] 2. Set the standard wells and sample wells, and add 50 μL of different concentrations of standard to each standard well.

[0066] 3. Add 50 μL of the sample to be tested to the sample well; no addition to the blank well.

[0067] 4. Add 100 μL of horseradish peroxidase (HRP)-labeled detection antibody to each well of the standard well and the sample well except the blank well, seal the reaction well with a sealing film, and incubate in a 37°C water bath or incubator for 60 min.

[0068] 5. Discard the liquid, pat dry the plate with absorbent paper, add full of washing solution (350 μL) to each well, stand for 1 min, shake off the washing solution, pat dry the plate with absorbent paper, repeat the above steps for 5 times (or use a plate washer to wash the plate).

[0069] 6. Add 50 μL of substrate A and B to each well respectively, incubate at 37 °C for 15 min in dark.

[0070] 7. Add 50 μL of stop solution to each well, measure the OD value of each well at 450 nm within 15 min.

[0071] Calculation of experimental results

[0072] Take the OD value of the measured standard as the abscissa, and the concentration value of the standard as the ordinate, draw a standard curve on the coordinate paper or use related software to obtain the linear regression equation, and substitute the OD value of the sample into the equation to calculate the concentration of the sample.

[0073] Example 1

[0074] In order to screen biomarkers of irAE, patient cohort A was collected.

[0075] Cohort A contains 17 patients, and the peripheral blood plasma samples of the 17 patients before treatment were collected and frozen according to the foregoing method.

[0076] After the treatment of the patients, the patients were divided into irAE group (with immune-related adverse reactions group, 9 patients, of which, 3 cases of skin toxicity (rash), 4 cases of lung toxicity (pneumonia), 1 case of digestive system toxicity (diarrhea), and 1 case of cardiac toxicity (myocarditis)) and non-irAE group (without immune-related adverse reactions group, 8 patients).

[0077] After thawing the samples, the content data of CCL20, CXCL9, CXCL10 or CXCL11 were obtained by the foregoing method, see FIG. 1 to FIG. 4.

[0078] As shown in FIG. 1, the content of CCL20 in the irAE group sample was significantly increased compared with the non-irAE group, specifically, for all grades of irAE, and all types were increased. From the receiver operating characteristic curve (ROC), it can be seen that CCL20 has better prediction ability for irAE.

[0079] As shown in FIG. 2, the content of CXCL9 in the irAE group samples was significantly higher than that in the non-irAE group, specifically, for all grades of irAE, and all types of irAE. It can also be seen from the ROC that CXCL9 has better prediction ability for irAE.

[0080] As shown in FIG. 3, the content of CXCL10 in the irAE group samples was significantly higher than that in the non-irAE group, specifically, for all grades of irAE, and all types of irAE. It can also be seen from the ROC that CXCL10 has better prediction ability for irAE.

[0081] As shown in FIG. 4, the content of CXCL11 in the irAE group samples was significantly higher than that in the non-irAE group, specifically, for all grades of irAE, and all types of irAE, wherein the lung toxicity was less increased than other types. It can also be seen from the ROC that CXCL11 has better prediction ability for irAE.

[0082] Therefore, CCL20, CXCL9, CXCL10 or CXCL11 can be used as a biomarker for predicting immune-related adverse reactions.

[0083] Example 2

[0084] In order to verify the prediction ability of CCL20, CXCL9, CXCL10 or CXCL11, patient cohort B was collected.

[0085] Cohort B contained 56 patients, of which 24 patients developed irAE (grade 1-2, 13 cases, grade 3-4, 11 cases) after receiving PD-1 / PD-L1 antibody treatment, and 32 patients did not develop irAE after receiving PD-1 / PD-L1 antibody treatment.

[0086] For the queue B, the content of CCL20, CXCL9, CXCL10 or CXCL11 in the sample was detected respectively by using the foregoing method, and irAE prediction verification was carried out, and the results are shown in Figures 5-8 respectively. From which it can be seen that the content of CCL20, CXCL9, CXCL10 or CXCL11 in the sample of the patient who has irAE is higher than that in the sample of the patient who has no irAE, and the content of CCL20, CXCL9, CXCL10 or CXCL11 in the sample of the patient who has high-grade irAE (i.e. grade 3-4) is higher. The area under the curve (AUC) of ROC of CCL20 for predicting irAE and high-grade irAE is 0.7435 and 0.7841 respectively; the AUC of ROC of CXCL9 for predicting irAE and high-grade irAE is 0.7070 and 0.7813 respectively; the AUC of ROC of CXCL10 for predicting irAE and high-grade irAE is 0.8464 and 0.8722 respectively; the AUC of ROC of CXCL11 for predicting irAE and high-grade irAE is 0.7917 and 0.8636 respectively. The results verify the prediction ability of CCL20, CXCL9, CXCL10 or CXCL11 for irAE, especially for high-grade irAE.

[0087] Example 3

[0088] Further, in order to verify the prediction ability of CCL20 or CXCL11, patient queue C was collected.

[0089] Queue C contains 69 patients, of which 30 patients have irAE (grade 1-2, 15 cases, grade 3-4, 15 cases) after receiving PD-1 / PD-L1 antibody treatment, and 39 patients have no irAE after receiving PD-1 / PD-L1 antibody treatment.

[0090] For queue C, the content of CCL20 or CXCL11 in the sample was detected respectively by using the foregoing method, and irAE prediction verification was carried out, and the results are shown in Figures 9-10 respectively. From which it can be seen that the content of CCL20 or CXCL11 in the sample of the patient who has irAE is higher than that in the sample of the patient who has no irAE, and the content of CXCL11 in the sample of the patient who has high-grade irAE (i.e. grade 3-4) is higher. The area under the curve (AUC) of ROC of CCL20 for predicting irAE and high-grade irAE is 0.6701 and 0.6667 respectively; the AUC of ROC of CXCL11 for predicting irAE and high-grade irAE is 0.7453 and 0.7692 respectively. The results verify the prediction ability of CCL20 or CXCL11 for irAE, especially the better prediction ability of CXCL11 for high-grade irAE.

[0091] Example 4

[0092] Further, in order to verify the prediction ability of CXCL11, patient cohort D was collected.

[0093] Cohort D contained 45 patients, of which 9 patients had irAE (grade 3-4) after receiving PD-1 / PD-L1 antibody treatment, and 36 patients had no irAE after receiving PD-1 / PD-L1 antibody treatment. The specific information of cohort D is as follows:

[0094] For cohort D, the content of CXCL11 in the sample was detected by the foregoing method, and the irAE prediction verification was carried out, and the results are shown in Figure 11, respectively. It can be seen that the content of CXCL11 in the sample of the patient with irAE is higher than that in the sample of the patient without irAE. The AUC of the ROC of CXCL11 predicting irAE is 0.8063, the standard error is 0.08103, the P value is 0.0085, and the threshold is set to 1358, the sensitivity is 80%, and the specificity is 75%. The results verify that CXCL11 has better prediction ability for irAE.

[0095] Example 5

[0096] Further, in order to verify the prediction ability of CXCL11, patient cohort E was collected.

[0097] Cohort E contained 30 patients, of which 15 patients had irAE after receiving PD-1 / PD-L1 antibody treatment, and 15 patients had no irAE after receiving PD-1 / PD-L1 antibody treatment. The specific information of cohort E is as follows:

[0098] For cohort E, the content of CXCL11 in the sample was detected by the foregoing method, and the irAE prediction verification was carried out, and the results are shown in Figure 12, respectively. It can be seen that the content of CXCL11 in the sample of the patient with irAE is higher than that in the sample of the patient without irAE. The AUC of the ROC of CXCL11 predicting irAE is 0.6944, the standard error is 0.08836, and the P value is 0.0462. The results also verify that CXCL11 has better prediction ability for irAE.

[0099] As can be seen from the above examples, CCL20, CXCL9, CXCL10 or CXCL11 has good prediction ability for irAE, and CXCL11 has better prediction ability for high-grade irAE, and can be used as a biomarker for predicting immune-related adverse reactions.

[0100] In addition, from the sample acquisition point of view, the present application can only use a blood sample, and by detecting the content of CCL20, CXCL9, CXCL10 or CXCL11, the immune-related adverse reactions caused by PD-1 / PD-L1 antibody treatment can be judged, so that early prediction and active intervention can be carried out, and the prognosis of the patient can be improved, and the dependence on tumor tissue detection of the patient in the past can be eliminated.

[0101] Moreover, from the experimental cycle point of view, the present application can obtain the detection result in a short time after collecting the sample, greatly improving the detection efficiency, and can quickly and accurately provide the doctor with diagnosis and treatment auxiliary information in the first time.

[0102] The above is only a specific embodiment of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can easily think of various equivalent modifications or replacements within the technical scope disclosed by the present application, and these modifications or replacements should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. Use of CCL20, CXCL11, CXCL10 or CXCL9 in the manufacture of a kit for predicting an immune-related adverse reaction caused by a treatment with a programmed death receptor 1 antibody / programmed death ligand antibody, the prediction being a prediction prior to the treatment.

2. A kit comprising:

2. A kit for predicting an immune-related adverse reaction caused by a treatment with a programmed death receptor 1 antibody / programmed death ligand antibody, the prediction being a prediction prior to the treatment, comprising a reagent for detecting the expression level of CCL20, CXCL11, CXCL10 or CXCL9.

3. The kit according to claim 2, wherein the expression level of CCL20, CXCL11, CXCL10 or CXCL9 comprises the content of CCL20, CXCL11, CXCL10 or CXCL9 in plasma.

4. The kit according to claim 2, wherein the expression level of CCL20, CXCL11, CXCL10 or CXCL9 comprises the content of CCL20, CXCL11, CXCL10 or CXCL9 in serum.

5. The kit according to any one of claims 2 to 4, wherein the programmed death receptor 1 antibody comprises at least one of the following antibodies: tislelizumab, seviprotmab, sintyrosimab, camrelizumab, toripalimab, sasanlimab, pembrolizumab, pidilizumab, cixutumumab, pembrolizumab, nivolumab; and the programmed death ligand antibody comprises at least one of the following antibodies: atezolizumab, durvalumab, avelumab, enfortumab vedotin.

6. The kit of any one of claims 2 to 4, the immune-related adverse reactions comprising:

6. The kit according to any one of claims 2 to 5, wherein the immune-related adverse reaction is pneumonitis, myocarditis, colitis, pancreatitis, hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis, type I diabetes, adrenal insufficiency, sarcoidosis, vitiligo, skin toxicity, thrombocytopenia, hepatitis, digestive system toxicity, nervous system disorder, nephritis, uveitis or local pneumonitis.

7. The kit according to any one of claims 2 to 6, wherein the treatment with a programmed death receptor 1 antibody / programmed death ligand antibody is for treating lung adenocarcinoma, skin melanoma, prostate cancer, urothelial carcinoma of the bladder, mesothelioma, breast invasive carcinoma, cervical squamous carcinoma, cervical adenocarcinoma, pancreatic carcinoma, ovarian serous cystadenocarcinoma, head and neck squamous cell carcinoma, gastric adenocarcinoma, thyroid carcinoma, cholangiocarcinoma, adrenocortical carcinoma, rectal adenocarcinoma, colon cancer, hepatocellular carcinoma, brain low-grade glioma, glioblastoma multiforme, uveal melanoma or uterine carcinosarcoma.

Images