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WO2023000688A1 - Marqueur de tcr pour la maladie d'alzheimer dans le sang périphérique, kit de détection et application associée - Google Patents

Marqueur de tcr pour la maladie d'alzheimer dans le sang périphérique, kit de détection et application associée Download PDF

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Publication number
WO2023000688A1
WO2023000688A1 PCT/CN2022/080368 CN2022080368W WO2023000688A1 WO 2023000688 A1 WO2023000688 A1 WO 2023000688A1 CN 2022080368 W CN2022080368 W CN 2022080368W WO 2023000688 A1 WO2023000688 A1 WO 2023000688A1
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Prior art keywords
disease
alzheimer
tcr
marker
peripheral blood
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Chinese (zh)
Inventor
张志新
乐卫东
杨鑫
卓越
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Chengdu Exab Biotechnology Co Ltd
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Chengdu Exab Biotechnology Co Ltd
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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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention belongs to the technical field of genetic engineering, and in particular relates to a peripheral blood TCR marker for Alzheimer's disease, a detection kit and application thereof.
  • AD Alzheimer's disease
  • a neurodegenerative disease with insidious onset and progressive development Clinically, it is characterized by comprehensive dementia such as memory impairment, aphasia, apraxia, agnosia, impairment of visuospatial skills, executive dysfunction, and personality and behavior changes.
  • the etiology is still unknown.
  • Those with onset before the age of 65 are called Alzheimer's disease; those with onset after the age of 65 are called senile dementia.
  • Alzheimer's disease With the aging of the population, Alzheimer's disease has become an increasingly significant social problem. According to the "World Alzheimer's Disease 2018 Report" released by the International Alzheimer's Association, there were about 50 million Alzheimer's patients in the world in 2018, and it is estimated that 150 million people will suffer from Alzheimer's by 2050. According to incomplete statistics, there are currently more than 10 million dementia patients in China, of which 60% are Alzheimer's disease, the incidence rate of people over 65 years old is 5%, and the incidence rate of people over 80 years old exceeds 30%. It is estimated that by 2050, there will be more than 20 million dementia patients in China.
  • senile dementia is mainly divided into dementia caused by brain degenerative diseases (including Alzheimer's disease, frontotemporal dementia, Lewy body type, Parkinson's dementia syndrome, etc.), dementia caused by cerebrovascular disease and mixed dementia. kind.
  • the clinical diagnosis of Alzheimer's disease is mainly based on its special clinical evolution process, combined with relevant examinations to exclude other organic diseases that cause dementia, and the final diagnosis requires pathological examination results.
  • NINCDS-ADRDA Alzheimer's Disease and Related Disorders Association
  • Lumbar puncture pressure is normal in laboratory examination
  • the NINCDS-ADRDA diagnostic criteria have a good consistency with the pathological results.
  • the standard emphasizes that "the degree of cognitive impairment must affect the patient's daily life ability and social activity function before the diagnosis can be established", and emphasizes that other related system or brain diseases that may cause dementia must be excluded, and the latter is often the same as Alzheimer's disease.
  • the degree of cognitive impairment must affect the patient's daily life ability and social activity function before the diagnosis can be established
  • other related system or brain diseases that may cause dementia must be excluded, and the latter is often the same as Alzheimer's disease.
  • silent disease there is a lack of clear and easily detectable biomarkers. This brings difficulties to the early identification and diagnosis of Alzheimer's disease patients.
  • MRI nuclear magnetic resonance
  • PET Electron emission tomography
  • MRI shows that the hippocampus, entorhinal cortex, and amygdala shrink in size (compared with the same age group);
  • Abnormal cerebrospinal fluid biomarkers decreased A ⁇ 42, increased total tau or phosphorylated tau protein, or the presence of all three at the same time;
  • PET Special manifestations of PET: such as decreased glucose metabolism in bilateral temporal lobes, pathological changes of AD revealed by the imaging agent 18F-FDDNP*, etc.;
  • Alzheimer's disease caused by proven autosomal dominant inheritance in immediate family members.
  • FDDNP An analogue of the non-steroidal anti-inflammatory drug naproxen, which has a strong affinity for senile plaques in vitro.
  • PET Positron Emission Tomography
  • Glucose metabolism PET can show the metabolic decline of the limbic system in patients with Alzheimer's disease in the early stage, and the diagnostic sensitivity for mild Alzheimer's disease reaches 84%, and the specificity reaches 93%.
  • Amyloid PET Amyloid PET
  • Amyloid PET found that when patients with familial Alzheimer's disease did not have brain atrophy and brain metabolism decreased in the asymptomatic period, amyloid deposition in the brain had already occurred, indicating that amyloid clusters (plaques) Block) may be the earliest biomarker, however, studies have also pointed out that other diseases other than Alzheimer's disease may also lead to amyloid deposition in the brain.
  • CSF markers included A ⁇ 42, total tau (t-tau), and phosphorylated tau (p-tau).
  • a ⁇ 42 reflects the deposition of cortical amyloid protein
  • t-tau protein reflects the density of neurodegeneration
  • p-tau is related to the pathological changes of neurofibrillary tangles.
  • Peripheral blood markers include A ⁇ 42 dimer content in peripheral blood cell membranes, plasma gelsolin (GSN) that can inhibit A ⁇ fibrosis and depolymerize A ⁇ fibers, and GSN main degrading enzyme MMP3, etc.
  • GSN plasma gelsolin
  • MMP3 GSN main degrading enzyme
  • structural magnetic resonance can measure regional or whole brain volume, reflecting structural atrophy caused by cell damage, axonal degeneration, and synaptic dysregulation.
  • the earliest and progressive atrophy of the medial temporal lobe structure may be a characteristic change in the early stage of AD.
  • Functional magnetic resonance fMRI
  • Diffusion tensor imaging (DTI), T2 relaxation time imaging and other nuclear magnetic resonance parameters have also shown potential as early diagnostic criteria for Alzheimer's disease in some recent studies.
  • DTI diffusion tensor imaging
  • T2 relaxation time imaging and other nuclear magnetic resonance parameters have also shown potential as early diagnostic criteria for Alzheimer's disease in some recent studies.
  • MRI detection is still more suitable for measuring and monitoring the disease process of Alzheimer's disease so far, and whether it is suitable for early diagnosis of the disease needs further research and further verification.
  • the present invention provides a peripheral blood TCR marker for Alzheimer's disease and its detection kit and application, which can non-invasively and accurately and quickly determine whether there is a high Alzheimer's disease in the sample to be tested. Patients at risk for Haimer's disease.
  • a peripheral blood TCR marker for Alzheimer's disease includes at least one of the proteins whose sequences are shown in SEQ ID NO.1-50, and the specific sequence is shown in Table 1.
  • protein sequence of the marker is a protein that can achieve the same function after the sequence shown in SEQ ID NO.1-50 is substituted, deleted and/or replaced by one or more amino acids.
  • the marker is peripheral blood TCR CDR3 sequence.
  • the preparation includes the T cell receptor containing the marker, or a plasmid, virus vector or nucleic acid fragment capable of expressing the T cell receptor producing the marker.
  • a reagent kit for detecting Alzheimer's disease including an antibody capable of specifically binding to the above-mentioned marker.
  • a preparation including an antibody capable of specifically binding to the above-mentioned marker; the preparation can be used for diagnosing, predicting, detecting or screening Alzheimer's disease.
  • the protein chip for detecting Alzheimer's disease.
  • the protein chip includes a substrate and a specific antibody spotted on the substrate.
  • the specific antibody is an antibody that can specifically combine with the above-mentioned markers.
  • 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.
  • BCR B cell receptor
  • TCR T cell receptor
  • the diversity of BCR and TCR is the basis for establishing the acquired immune system.
  • the theoretical value of BCR diversity is 10 18
  • the theoretical value of TCR diversity is 10 14 .
  • antigenic determinant 3 (CDR3) is the most important part to determine the antigenic specificity, so the sequence of CDR3 is considered to represent the characteristics of BCR and TCR sequences.
  • BCR and TCR will change with different antigen stimulation. Therefore, the occurrence and development of diseases can be tracked by using the results of high-throughput sequencing of BCR or TCR.
  • MCHII histocompatibility antigen II
  • Antigen fragments presented by normal cells will 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 or other diseases.
  • a large data analysis model was first established using 1725 non-Alzheimer's disease control samples and TCR high-throughput sequencing data of 11 Alzheimer's disease patients.
  • the comparison of TCR sequences specific to Alzheimer's disease can clearly determine whether there is a person with a higher risk of Alzheimer's disease in the sample to be tested.
  • TCR changes through high-throughput sequencing can detect very early Alzheimer's disease, using the unique TCR CDR3 sequence of Alzheimer's disease to analyze the response of T cells in the human immune system to Alzheimer's disease, It is a new detection method.
  • the present invention uses high-throughput sequencing technology to simultaneously compare a large number of specific TCR sequences, which has higher specificity and accuracy than detecting one or several markers alone.
  • the cost of high-throughput sequencing equipment used in the present invention is lower than that of large-scale imaging equipment, and can be outsourced to third parties.
  • the labor cost of sampling and processing is lower than that of simultaneous detection of multiple markers, and 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, and it is a non-invasive testing method.
  • TCR CDR3 sequence described in the present invention can be used for immunotherapy of Alzheimer's disease.
  • Figure 1 shows the discovery of the characteristic TCR sequence of Alzheimer's disease using the immune-based big data analysis system in the present invention.
  • the abscissa represents the order in which the CDR3 sequence of a specific amino acid combination is added to the control sequence set or the Alzheimer's disease characteristic sequence set, and the ordinate represents the logarithmic value of the sequence's repeated occurrence times C X in a sample;
  • the immune map of patients with Alzheimer's disease has multiple types and high repetitions of Alzheimer's disease characteristic sequences, while healthy people have very few Alzheimer's disease characteristic sequences, and the comparison of Alzheimer's disease characteristics in unknown subjects Obviously, the risk of Alzheimer's disease is higher.
  • Fig. 2 is a comparative analysis of Alzheimer's disease and other diseases using Alzheimer's disease characteristic index in the present invention.
  • the Alzheimer's disease characteristic index of healthy people, non-neurological disease patients, and non-Alzheimer's disease patients with other neurological diseases is significantly different from that of Alzheimer's disease patients, which proves the characteristic sequence of Alzheimer's disease Set specificity. Based on this, it can be determined whether the unknown subject suffers from Alzheimer's disease.
  • Example 1 Obtaining the sequence set of Alzheimer's disease TCR marker CDR3 through immunographic analysis
  • Collect 1726 control groups including healthy people and non-nervous disease patients, 1725 people for model building, 1 healthy person for verification), 12 Alzheimer's disease patients (11 people for model building, 1 person for for verification) and the peripheral blood of a subject with unknown health status (10mL per person), the amino acid sequence of the TCR epitope 3 (CDR3) of the subject and the control group was obtained by high-throughput sequencing, ensuring that each sample The total number of CDR3 sequences of the functional TCR is not less than 25,000;
  • the immune map of a healthy person, a patient with Alzheimer's disease and a subject with unknown health status are compared with reference to the control sequence set and the Alzheimer's disease characteristic sequence set.
  • Figures see Figures 1B-D. It can be seen from the figure that the immune profiles of patients with Alzheimer's disease contain more types of Alzheimer's disease characteristic sequences with a high number of repetitions (Figure 1B); in the immune profiles of healthy people, only a very small amount of Al The characteristic sequence of Alzheimer's disease (Fig. 1C); while the subject with unknown health status has a higher characteristic sequence of Alzheimer's disease than the healthy person, indicating that this person has a higher risk of suffering from Alzheimer's disease (Fig. 1D) .
  • the antigenic determinant 3 (CDR3) amino acid sequence of the TCR of the patients and the control group to ensure that the total number of functional TCR CDR3 sequences of each sample is not less than 25,000; the total number of CDR3 sequences of each functional TCR is higher than 30,000
  • the sequence of the sample is randomly sampled without replacement, so that the total number of CDR3 sequences of the sample is 30,000. So far, the total number of functional TCR CDR3 sequences contained in all samples is 25,000-30,000.
  • Example 2 According to the 11 Alzheimer's patients from Example 1, and 97 healthy people, 44 non-nervous disease patients, 26 epilepsy patients, 20 Parkinson's patients, and 5 newly acquired patients from Example 2 Immune profiles of subjects with unknown health status analyzed for Alzheimer's disease characteristic indices.
  • the characteristic index of Alzheimer's disease is defined as: in a certain sample, the sum of the repeated times C X of all CDR3 sequences belonging to the characteristic sequence set of Alzheimer's disease in the sample.
  • the analysis results are shown in Table 2 and accompanying drawing 2 below.
  • the Alzheimer's disease TCR marker CDR3 sequence described in the present invention does have significant Alzheimer's disease specificity, and can not only be used for Alzheimer's disease to predict subjects suffering from Alzheimer's disease It can also be used in the biological immunotherapy of Alzheimer's disease in the future.

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Abstract

La présente invention concerne un marqueur de TCR pour la maladie d'Alzheimer dans le sang périphérique, un kit de détection et une application associée. Le marqueur de TCR pour la maladie d'Alzheimer dans le sang périphérique comprend au moins l'une des protéines dont les séquences sont telles que représentées dans les SEQ ID NO: 1 à 50. Sur la base d'une méthode de séquençage à haut débit, seule une petite quantité de sang périphérique doit être recueillie pour extraire l'ARN, une banque de cartes immunitaires est établie par traitement d'échantillons, puis lors d'un séquençage à haut débit et d'une analyse des données de TCR, une séquence de TCR dans le sang périphérique caractéristique de la maladie d'Alzheimer est d'abord déterminée, puis un résultat de test d'un échantillon à tester est comparé à la séquence de TCR caractéristique, de façon à déterminer si une personne souffre de la maladie d'Alzheimer. Selon la méthode, un très grand nombre de séquences de TCR spécifiques de la maladie d'Alzheimer peut être comparé simultanément, et par comparaison avec la détection d'un ou de plusieurs marqueurs seuls, le marqueur présente une spécificité et une exactitude supérieures, et l'efficacité de diagnostic est améliorée.
PCT/CN2022/080368 2021-07-23 2022-03-11 Marqueur de tcr pour la maladie d'alzheimer dans le sang périphérique, kit de détection et application associée Ceased WO2023000688A1 (fr)

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CN202110835011.1A CN113567682A (zh) 2021-07-23 2021-07-23 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
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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

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