WO2022012282A1 - Marqueur de tcr de sang périphérique pour le cancer du foie, et son kit de détection et son utilisation - Google Patents

Marqueur de tcr de sang périphérique pour le cancer du foie, et son kit de détection et son utilisation Download PDF

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WO2022012282A1
WO2022012282A1 PCT/CN2021/101601 CN2021101601W WO2022012282A1 WO 2022012282 A1 WO2022012282 A1 WO 2022012282A1 CN 2021101601 W CN2021101601 W CN 2021101601W WO 2022012282 A1 WO2022012282 A1 WO 2022012282A1
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liver cancer
marker
tcr
sequence
peripheral blood
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PCT/CN2021/101601
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Chinese (zh)
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张志新
卓越
杨鑫
文学平
何彭铭
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成都益安博生物技术有限公司
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001111—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/7051—T-cell receptor (TcR)-CD3 complex

Definitions

  • the invention belongs to the technical field of gene detection, and in particular relates to a peripheral blood TCR marker of liver cancer and a detection kit and application thereof.
  • liver cancer is one of the most common malignant tumors in the world, ranking first in the incidence of various types of cancer (4.7%) and fourth in the proportion of cancer deaths (8.2%). ).
  • China is a big country with liver cancer, and its incidence ranks fourth among malignant tumors in the country, and its mortality ranks second among malignant tumors.
  • a large-scale domestic study included 1330 patients with hepatocellular carcinoma. The 5-year survival rate after surgery was 36.9%, and the recurrence rate was 61.5%. Even small liver cancer had a 5-year recurrence rate of 43.5%.
  • Chemotherapy, intervention, ablation, molecular targeted drugs and other methods are mainly aimed at patients with inoperable or postoperative recurrence and metastasis, but due to the low sensitivity of most liver cancer itself to chemotherapy drugs, and the consumption and failure of liver function in the background of long-term chronic liver disease , which greatly limits the applicability and effectiveness of these methods.
  • Early diagnosis and early treatment are urgent needs to improve the treatment effect of liver cancer, improve the prognosis of patients, and save social resources.
  • the diagnostic methods for liver cancer are mainly divided into four categories: biochemical methods, molecular biological methods, cytological methods and imaging methods.
  • the patient's tissue samples (usually blood, serum) are examined for tumor markers by methods such as enzyme-linked immunoassay (ELISA).
  • ELISA enzyme-linked immunoassay
  • Alpha-fetoprotein is the most commonly used liver cancer tumor marker, with a diagnostic sensitivity of 39% to 65% and a specificity of 76% to 94%. However, its sensitivity and specificity are unsatisfactory, especially in the early stage of liver cancer with small masses, 80% of the patients did not see a significant increase in serum AFP. The detection sensitivities of AFP were 25% and 52%, respectively.
  • Alpha-fetoprotein variant 3 (AFP-L3) is unique to liver cancer cells, so the percentage of AFP-L3 and AFP is often used as a marker for early diagnosis of liver cancer. AFP-L3 is of great significance in the evaluation of the malignant degree, treatment effect and prognosis of liver cancer, especially for the early diagnosis of low-level AFP liver cancer or small liver cancer.
  • Golgi protein 73 has a very low or no expression in normal human hepatocytes, but is significantly increased in serum of patients with liver cancer. Hepatitis and fatty liver can also lead to elevated GP73 levels, although the level of elevation is much lower than in patients with liver cancer. In patients with low-level AFP small hepatocellular carcinoma, the sensitivity and specificity of GP73 detection were 72.0% and 94.0%, respectively. Therefore, GP73 is a good auxiliary diagnostic marker for small hepatocellular carcinoma.
  • Phosphatidyl proteoglycan 3 is a heparan sulfate glycoprotein on the surface of the cell membrane, which is not expressed in the normal human liver.
  • GPC-3 Phosphatidyl proteoglycan 3
  • Osteopontin is a secreted calcium-binding phosphorylated glycoprotein that exists in a variety of human tissue cells, but its expression is particularly high in malignantly transformed epithelial cells.
  • the serum OPN level in patients with liver cancer was significantly higher than that in patients with benign chronic liver disease.
  • the specificity of OPN for diagnosing liver cancer was 26% and the sensitivity was 92.5%.
  • CD166 is a cell surface component of the immune group protein superfamily, and has a certain relationship with the disease progression and prognosis of liver cancer. Therefore, as a serum marker, it is used for the diagnosis and recurrence monitoring of liver cancer with higher sensitivity and specificity than AFP.
  • TGF ⁇ 1 transforming growth factor ⁇ 1
  • IGF-II Insulin-like growth factor II
  • the serum level of IGF-II in patients with liver cancer is significantly increased, which has certain auxiliary diagnosis and prognostic value for liver cancer.
  • Tumor-specific growth factor is a substance produced by tumor cells and surrounding blood vessels as tumors grow. TSGF can be used for early diagnosis of liver cancer, and also has certain application value in monitoring curative effect, metastasis and recurrence. Some studies reported that the sensitivity of TSGF for liver cancer detection was 82.4%, and the specificity was 75.3%.
  • DCP Abnormal prothrombin
  • ⁇ -L-fucosidase has a sensitivity of 72.4% and a specificity of 63.8% for the diagnosis of liver cancer.
  • AFU also increases to a certain extent in diabetes, pancreatitis, and hypothyroidism. Therefore, the specificity of AFU for the early diagnosis of liver cancer is not high, and it needs to be combined with other tumor markers to effectively detect liver cancer.
  • MMPs Matrix metalloproteinases
  • AFP and OPN are major mediators of changes in the tumor development microenvironment and can be used as biomarkers for early diagnosis of liver cancer.
  • MMP1 has higher sensitivity and specificity than AFP and OPN in distinguishing liver cancer patients from liver cirrhosis patients, and MMP1 can distinguish liver cancer patients with AFP level below 20ng/ml.
  • Squamous cell carcinoma antigen (Squamous Cell Carcinoma Antigen, SCCA) is a member of the serine protease inhibitor family, SCCA is overexpressed in the tissue and serum of liver cancer patients. Studies have found that the sensitivity of serum SCCA in the diagnosis of liver cancer is 18% to 84%, and the specificity is 27% to 73%. Serum SCCA-IgM may be a more promising biomarker for the diagnosis of liver cancer.
  • Antigens commonly used in the diagnosis of liver cancer include carcinoembryonic antigen (CEA), carbohydrate antigens (CA19-9, CA12-5, CA50, CA15-3), etc., but the specificity of detecting a single antigen for the diagnosis of liver cancer is low, and multiple antigens are detected. The combined detection of antigen and antibody may improve the diagnostic efficiency of liver cancer.
  • CDH17 Hepato-gut-cadherin
  • CDH17 is a new member of the cadherin superfamily. In normal tissues, the expression of CDH17 is limited to the epithelial cells of the small intestine and colon; it is involved in the process of intercellular recognition and adhesion, and maintains its shape during tissue development There are irreplaceable functions. CDH17 is a useful immunohistochemical marker for the diagnosis of adenocarcinoma of the digestive system.
  • liver cancer tumor markers are often difficult to be satisfactory in both sensitivity and specificity.
  • multiple markers When applied to the diagnosis of liver cancer, multiple markers must be comprehensively evaluated. This will inevitably increase the detection cost, and the comprehensive evaluation of various indicators makes it difficult to interpret the final detection results.
  • tumor markers are:
  • the peripheral blood tumor circulating genetic markers of liver cancer patients are used to monitor distant metastasis or postoperative recurrence of liver cancer.
  • AFP-mRNA is derived from shedding liver cancer cells into the blood, can be detected in the peripheral serum of liver cancer patients, and can be used as a serum tumor marker for liver cancer.
  • AFP-mRNA can be used for the diagnosis of early metastasis of liver cancer, and its specificity is higher than that of biochemical detection of AFP, which can effectively exclude false positive patients.
  • liver cancer R Human cervical oncogene (liver cancer R) is mainly expressed in the plasma membrane and cytoplasm of liver cancer cells, and negative in normal tissues; in the disease process from liver cirrhosis to liver cancer, liver cancer R is better than AFP as a diagnostic marker, especially in the diagnosis of Patients with early stage liver cancer and small liver cancer.
  • AFP a diagnostic marker
  • liver cancer R is closely related to the early occurrence of liver cancer, and has a certain relationship with the invasion and metastasis of liver cancer.
  • the expression of liver cancer R in poorly differentiated liver cancer cells is significantly higher than that in well differentiated liver cancer cells.
  • P53 is an important anti-cancer gene, which is related to biological functions such as cell cycle regulation, repair, cell differentiation, and apoptosis. Abnormal functions can lead to abnormal cell growth. P53 mutation is most common in patients with liver cancer. P53 regulates EMT by affecting the beta-catenin signaling pathway. Reducing the expression of P53 can promote the nuclear accumulation and transcriptional activity of betacatenin. P53 mutation in liver cancer cells predicts poor prognosis in EMT, cell migration and tumor metastasis.
  • SALL4 has a close clinical relationship with liver cancer and has certain clinical value in judging the prognosis of patients.
  • liver cancer tumor markers also has the problem that it is difficult to be satisfactory in both sensitivity and specificity.
  • multiple markers When applied to the diagnosis of liver cancer, multiple markers must be comprehensively evaluated. This will inevitably increase the detection cost, and the comprehensive evaluation of various indicators makes it difficult to interpret the final detection results.
  • liver cancer exfoliated cell detection can be performed, which has a high sensitivity for tumor detection, but there are some problems: some benign cells may be misinterpreted as cancer cells when they are abnormal; The tumor is located; in order to ensure reliability, the detection requires a large workload; the extraction of ascites is more painful and harmful to the patient, and so on.
  • Circulating tumor cells have emerged as promising candidate markers for predicting tumor recurrence and metastasis.
  • Some studies have shown that epithelial cell adhesion molecule-positive CTCs can be used as prognostic indicators after liver cancer surgery, but their clinical effectiveness still needs to be verified.
  • Abdominal ultrasound (Ultrasonography, US) is the most commonly used clinical imaging method for liver because of its simple operation, flexible and intuitive, non-invasive and other characteristics. Routine ultrasound screening can detect suspicious intrahepatic lesions early and sensitively, accurately identify cystic or solid lesions, and observe whether there are other related metastases in the liver or abdomen. Color Doppler flow imaging can not only observe the blood supply in the lesion, but also clarify the adjacent relationship between the lesion and the important blood vessels in the liver, which provides important information for the selection of clinical treatment methods and the formulation of surgical plans. Real-time contrast-enhanced ultrasound technology can reveal the hemodynamic changes of liver tumors, help to identify and diagnose different types of liver tumors.
  • the disadvantage is that the resolution is low, the detection of early tumors, and the relatively difficult qualitative diagnosis of tumors.
  • CT X-ray computed tomography
  • Nuclear medicine imaging examination such as Positron Emission Tomography/CT (PET/CT)
  • PET/CT Positron Emission Tomography/CT
  • PET/CT Positron Emission Tomography/CT
  • Staging because PET functional images are not affected by the anatomical structure, it can accurately display the recurrence and metastasis after the anatomical structure changes or the complex anatomical structure
  • the efficacy evaluation for the targeted drugs that inhibit tumor activity, the efficacy evaluation is more sensitive and accurate.
  • the disadvantage is that the equipment is expensive and the detection cost is high.
  • Magnetic Resonance Imaging with no radiation effects, high tissue resolution, multi-directional, multi-sequence parameter imaging, and morphological combination functions (including diffusion-weighted imaging, perfusion-weighted imaging and spectral analysis)
  • MRI Magnetic Resonance Imaging
  • morphological combination functions including diffusion-weighted imaging, perfusion-weighted imaging and spectral analysis
  • Gd-EOB-DTPA hepatocyte-specific contrast agent
  • NMR detection has the disadvantages of expensive equipment, huge volume, large space occupation, and high detection cost.
  • DSA Digital Subtraction Angiography
  • This technology is more used for local treatment of liver cancer or Treatment of acute hepatocellular carcinoma with rupture and hemorrhage.
  • the main manifestations of liver cancer in DSA are tumor blood vessels and tumor staining, and the number, size and blood supply of liver tumors can also be clearly displayed.
  • DSA can provide accurate and objective information for vascular anatomical variation and important vascular anatomical relationships, as well as portal vein infiltration, which is of great value for judging the possibility and thoroughness of surgical resection and determining a reasonable treatment plan.
  • this method is more suitable for the guidance of treatment, and has considerable limitations in the diagnosis of early-stage tumors.
  • the purpose of the present invention is to provide a peripheral blood TCR marker of liver cancer and a detection kit and application thereof in view of the deficiencies in the above-mentioned prior art.
  • a peripheral blood TCR marker of liver cancer comprising at least one of the proteins shown in the sequence SpecSeq1-100, and the specific sequence is shown in Table 1:
  • protein sequence of the marker is the sequence shown in SpecSeq1-100, after one or more bases are substituted, deleted and/or replaced, a protein with the same function can be expressed.
  • the preparation includes a plasmid, viral vector or nucleic acid fragment of the T cell receptor containing the marker.
  • a kit for liver cancer detection includes antibodies that can specifically bind to the above markers.
  • a preparation includes antibodies that can specifically bind to the above markers; the preparation can be used for diagnosis, prediction, detection or screening of liver cancer.
  • a protein chip for detecting liver cancer the protein chip comprises a substrate and a specific antibody spotted on the substrate, and the specific antibody is an antibody that can specifically bind to the above marker.
  • B lymphocytes and T lymphocytes in the human body are two important types of cells in the acquired immune system.
  • B cells recognize antigens through the B cell receptor (BCR) on the cell surface. Later, when B cells differentiate into plasma cells, BCR is expressed as an antibody and secreted outside the cell.
  • T cells recognize antigens through T cell receptors (TCRs) on the cell surface.
  • BCR and TCR The diversity of BCR and TCR is the basis for the establishment of the adaptive immune system.
  • the theoretical value of BCR diversity is 10 18 and the theoretical value of TCR diversity is 10 14 .
  • antigenic determinant 3 CDR3
  • CDR3 antigenic determinant 3
  • BCR and TCR will change with different antigenic stimulation. Therefore, the occurrence and development of diseases can be tracked by using BCR or TCR high-throughput sequencing results.
  • human cells after degraded senescent proteins, their fragments are transported to the cell surface and presented to T cells in the immune system through histocompatibility antigen II (MCHII).
  • MCHII histocompatibility antigen II
  • Antigen fragments presented by normal cells do not cause an immune response due to immune tolerance.
  • the abnormal protein expressed by the mutated gene and its fragments are presented on the cell surface, which will cause the human immune system to produce a targeted immune response. Therefore, analyzing the changes of BCR or TCR can detect the occurrence and development of tumors.
  • a method for analyzing peripheral blood TCR sequence based on high-throughput sequencing is used to detect whether there is liver cancer, and the specific steps are as follows:
  • CDR3 antigenic determinant 3
  • TCR CDR3 data analysis Determine the sequence of liver cancer TCR marker CDR3 by analysis:
  • the liver cancer characteristic index is defined as: in a certain sample, the sum of the repeated occurrence times C X of all CDR3 sequences belonging to the liver cancer characteristic sequence set in the sample.
  • liver cancer characteristic index of a subject with unknown health status is higher than or close to the mean value of the "other tumors" group + 2 ⁇ SD, this person has a higher risk of developing liver cancer; if the liver cancer characteristic index is close to that of healthy people or non- The mean value of the tumor disease group indicates a low risk of liver cancer.
  • an artificial intelligence analysis model is first established by using the non-HCC control group samples and the TCR high-throughput sequencing data of liver cancer patients. Those with a higher risk of liver cancer;
  • the cost of the high-throughput sequencing instrument used in the present invention is lower than that of large-scale imaging equipment, and it can be outsourced to a third party.
  • the labor cost of sampling and processing is lower than the simultaneous detection of multiple markers, and it is also lower than that of a large number of cytology detection, therefore, the present invention greatly reduces the detection cost;
  • the present invention only needs to take a small amount of peripheral blood, and the sampling is simple and safe;
  • TCR CDR3 sequence described in the present invention can be used for immunotherapy of liver cancer.
  • Figure 1 shows the CDR3 sequence and the characteristic sequence of liver cancer in the control group in the present invention.
  • Abscissa represents a particular combination of amino acid sequences are added to the control sequence of CDR3 sequences or a set of signature sequences set liver, the ordinate represents the logarithm of the number of times C X duplication sequence in a sample; immunogram having liver cancer patients
  • liver cancer feature sequences There are many types of liver cancer feature sequences with high repetitions, and healthy people rarely have liver cancer feature sequences, while unknown subjects have more obvious liver cancer features, indicating a higher risk of liver cancer.
  • Fig. 2 is the liver cancer characteristic index of healthy people, non-tumor patients, non-cancerous tumor patients and liver cancer patients, and the liver cancer characteristic index of healthy people, non-tumor patients, and non-cancerous cancer patients according to the liver cancer characteristic sequence set in the present invention. All of them were significantly different from liver cancer patients, which proved the specificity of the liver cancer feature sequence set. Based on this, it can be determined whether the unknown subject suffers from liver cancer.
  • Collected 1301 controls including healthy and non-tumor disease patients, 1300 were used for model establishment, 1 healthy person was used for validation), 11 liver cancer patients (10 were used for model establishment, 1 was used for validation) and Peripheral blood (10 mL per person) of 1 subject with unknown health status, the antigenic determinant 3 (CDR3) amino acid sequence of TCR of the subject and the control group was obtained by high-throughput sequencing to ensure the functional TCR of each sample
  • the total number of CDR3 sequences is not less than 30000;
  • the abscissa represents the sequence in which the CDR3 sequence of a specific amino acid combination is added to the control sequence set or the liver cancer characteristic sequence set, and the ordinate represents the logarithm value of the number of times the sequence repeats in a certain sample C X .
  • the immune profiles of 1 healthy person, 1 liver cancer patient and 1 subject with unknown health status were mapped with reference to the control sequence set and the liver cancer characteristic sequence set, as shown in Figure 1B-D. It can be seen from the figure that the immune maps of patients with liver cancer contain a large number of liver cancer characteristic sequences with a high number of repetitions; the immune maps of healthy people have only a very small number of liver cancer characteristic sequences; while subjects with unknown health status have The sequence of liver cancer characteristics is higher than that of healthy people, indicating that this person has a higher risk of developing liver cancer.
  • liver cancer feature sequences Collect liver cancer feature sequences, and put all CDR3 sequences that appear in two or more liver cancer samples participating in the modeling, and press the "sum of the number of repetitions C X of this sequence in a single sample of all liver cancer samples participating in the modeling ⁇ including the Sequences involved in modeling liver cancer samples are sorted from high to low, and the top 100 are the TCR marker CDR3 sequences of liver cancer. The specific sequences are shown in SpecSeq1-100.
  • the peripheral blood (10 mL per person) of 335 non-HCC tumor patients and 4 subjects with unknown health status was collected, and the amino acid sequence of the TCR epitope 3 (CDR3) of the subjects and the control group was obtained by high-throughput sequencing , to ensure that the total number of CDR3 sequences of functional TCRs of each sample is not less than 30,000; the CDR3 sequences of TCRs of each sample are randomly sampled without replacement, so that the total number of CDR3 sequences of each sample is 30,000.
  • CDR3 TCR epitope 3
  • Example 3 According to the immune profiles of 100 healthy people, 45 non-tumor disease patients, and 10 liver cancer patients from Example 1, as well as 335 non-liver cancer tumor patients and 4 subjects with unknown health conditions newly obtained in Example 2 , to analyze the characteristic index of liver cancer.
  • the liver cancer characteristic index is defined as: in a certain sample, the sum of the repeated occurrence times C X of all CDR3 sequences belonging to the liver cancer characteristic sequence set in the sample.
  • liver cancer characteristic index of each group (Table 3).
  • the first 2 patients were indeed liver cancer patients, and the latter 2 were healthy people. The feasibility of using the liver cancer feature sequence set and liver cancer feature index to predict the risk of liver cancer in subjects is proved.
  • the CDR3 sequence of the TCR marker for liver cancer of the present invention does have significant liver cancer specificity, and can not only be used for liver cancer to predict the risk of liver cancer in subjects, but can also be used for biological immunotherapy of liver cancer in the future.

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Abstract

Un marqueur de TCR de sang périphérique pour le cancer du foie, et son kit de détection et son utilisation sont divulgués, le marqueur comprenant au moins l'une des protéines présentées dans la séquence SpecSeq1-100. Le marqueur TCR est basé sur un procédé de séquençage à haut débit, dans lequel seule une petite quantité de sang périphérique doit être prise pour extraire l'ARN ; une bibliothèque de cartes immunitaires est établie au moyen d'un traitement d'un échantillon ; puis une séquence de TCR caractéristique dans le sang périphérique du cancer du foie est déterminée d'abord au moyen d'une analyse de séquençage à haut débit et de données de TCR, et ensuite, un résultat de test d'un échantillon à tester est comparé à la séquence de TCR caractéristique, de telle sorte que la présence d'un cancer du foie est déterminée.
PCT/CN2021/101601 2020-07-11 2021-06-22 Marqueur de tcr de sang périphérique pour le cancer du foie, et son kit de détection et son utilisation WO2022012282A1 (fr)

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CN111624339A (zh) * 2020-07-11 2020-09-04 成都益安博生物技术有限公司 一种肝癌的外周血tcr标志物及其检测试剂盒和应用
CN113092761A (zh) * 2021-03-15 2021-07-09 成都益安博生物技术有限公司 一种弥漫大b细胞淋巴瘤的外周血tcr标志物及其检测试剂盒和应用
CN113030473A (zh) * 2021-03-15 2021-06-25 成都益安博生物技术有限公司 一种急性b淋巴细胞白血病的外周血tcr标志物及其检测试剂盒和应用
CN113567682A (zh) * 2021-07-23 2021-10-29 成都益安博生物技术有限公司 一种阿尔茨海默病的外周血tcr标志物及其检测试剂盒和应用
CN113563454A (zh) * 2021-07-23 2021-10-29 成都益安博生物技术有限公司 一种IgA肾病的外周血TCR标志物及其检测试剂盒和应用

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