WO2021209035A1 - Peptide épitope de lymphocyte t du nouveau coronavirus, et pmhc, et préparation et application associées - Google Patents

Peptide épitope de lymphocyte t du nouveau coronavirus, et pmhc, et préparation et application associées Download PDF

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WO2021209035A1
WO2021209035A1 PCT/CN2021/087739 CN2021087739W WO2021209035A1 WO 2021209035 A1 WO2021209035 A1 WO 2021209035A1 CN 2021087739 W CN2021087739 W CN 2021087739W WO 2021209035 A1 WO2021209035 A1 WO 2021209035A1
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novel coronavirus
pmhc complex
cell epitope
pmhc
epitope peptide
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PCT/CN2021/087739
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Chinese (zh)
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陈国兵
邱聪龄
王鹏程
罗钧洪
高利娟
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暨南大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • 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
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • 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
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to the field of biotechnology, and more specifically, to a novel coronavirus T cell epitope peptide, pMHC, and preparation and application thereof.
  • the new coronavirus is the pathogen of the new infectious pneumonia that occurred at the end of 2019. It has caused a pandemic in more than 160 countries and regions around the world, with more than 15,000 deaths. At present, the source of the virus is not clear. Gene sequencing shows that it is highly homologous with bat SARS-like coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV). There are no reports of specific drugs. The immune response mechanism of the human immune system to the new coronavirus, including antigen recognition, immune clarification mechanism, and immune memory protection mechanism, are unclear.
  • the T cell immune response plays an important role in the body's anti-viral defense and the body's immune pathological damage after virus infection, especially CD8 + T cells Its antigen-specific immune activity still exists after 11 years, which illustrates the important role of CD8 + T cell immune response in anti-coronavirus immune defense and its important position in vaccine development.
  • the first step of CD8 + T cell immune response is that T cells specifically recognize the epitope presented by the virus-infected cell through the antigen recognition receptor on its surface. Therefore, the epitope is an important key molecule for T cells to specifically recognize the virus and exert immune protection, and it is a key target molecule for immune detection, immunotherapy and vaccine development.
  • the virus antigens in virus-infected cells need to be processed and presented by the antigen presentation system. After the virus antigen is degraded by the proteasome, it is combined with the transporter associated with antigen processing (TAP), and the antigen peptide of 8-12 amino acids is selectively transported by the TAP to the endoplasmic reticulum.
  • TAP transporter associated with antigen processing
  • the assembled main histocompatibility complex (MHC)-class I molecule's antigen binding groove is combined to form an antigen peptide-MHC-class I molecular complex (pMHC), and the complex is transported to the cell membrane through the Golgi apparatus.
  • CD8 + T cells recognize pMHC activation through the T cell receptor (TCR), kill virus-infected cells and clear the virus, thereby exerting anti-virus cellular immunity. Therefore, computer simulation technology can be used to predict MHC-I (HLA-A2) epitopes from the parameters of the three key nodes of the proteasome, TAP and MHC, and to find T cells from the huge viral genome encoded proteins. Epitope.
  • the purpose of the present invention is to provide a novel coronavirus T cell epitope peptide, pMHC, and preparation and application thereof.
  • the first objective of the present invention is to provide a novel coronavirus T cell epitope peptide
  • the second objective of the present invention is to provide a pMHC complex monomer containing the novel coronavirus T cell epitope peptide.
  • the third objective of the present invention is to provide a pMHC complex multimer containing the novel coronavirus T cell epitope peptide.
  • the fourth object of the present invention is to provide a method for preparing the pMHC complex monomer containing the novel coronavirus T cell epitope peptide.
  • the fifth object of the present invention is to provide the pMHC complex monomer prepared by the method.
  • the sixth object of the present invention is to provide a method for preparing a pMHC complex multimer containing the novel coronavirus T cell epitope peptide.
  • the seventh objective of the present invention is to provide the pMHC complex multimer prepared by the method.
  • the eighth object of the present invention is to provide said novel coronavirus T cell epitope peptide, said pMHC complex monomer, said pMHC complex multimer, and said pMHC complex The application of any one or more of the monomers and the pMHC complex multimers in the preparation of detection reagents for detecting new coronavirus.
  • T2-A2 is an antigen-presenting cell line expressing human MHC-I molecule HLA-A2 through recombinant genetic engineering technology. Only effective epitopes can be presented by it, thereby forming a stable pMHC complex on the cell surface, so it is one of the criteria for identifying and screening T cell epitopes.
  • T cell epitopes cannot be used alone, and must be developed in the form of pMHC monomers or multimers.
  • the present invention utilizes genetically engineered recombinant HLA-A2 heavy chain and light chain proteins and the identified novel coronavirus T cell epitope to refold jointly to prepare pMHC monomers, and on this basis, prepare fluorescent markers The tetramer is found to be able to effectively recognize antigen-specific T cells in patients who have recovered from the new coronavirus infection, and effectively activate T cells. It proves that the newly discovered novel coronavirus T cell epitope has complete biological activity and can be used in immunoassays.
  • a novel coronavirus T cell antigen epitope peptide whose amino acid sequence is shown in any one of SEQ ID NOs: 1-9.
  • SEQ ID NO:1 FVFLVLLPLV
  • SEQ ID NO: 2 FQFCNDPFL
  • SEQ ID NO: 3 YQDVNCTEV
  • SEQ ID NO: 4 FTISVTTEI
  • SEQ ID NO: 6 YIWLGFIAGL
  • SEQ ID NO: 7 RLNEVAKNL
  • SEQ ID NO: 8 VMYSEFPAI
  • SEQ ID NO: 9 GMALSHYYV.
  • the pMHC complex monomer of the novel coronavirus T cell epitope peptide is the pMHC complex monomer of the novel coronavirus T cell epitope peptide.
  • the pMHC complex multimer of the novel coronavirus T cell antigen epitope peptide is the novel coronavirus T cell antigen epitope peptide.
  • the pMHC complex multimer is a tetramer.
  • the tetramer is a fluorescently labeled tetramer.
  • the preparation method of the pMHC complex monomer of the novel coronavirus T cell antigen epitope peptide is to combine the HLA-A2 heavy chain protein, HLA-A2 light chain ⁇ 2m protein and the novel coronavirus T cell antigen table Peptides are mixed and renatured and purified.
  • the renaturation is the reassembly of independent single-chain proteins into active protein complexes under specific conditions. This refers to the refolding of the three independent components of the MHC heavy chain, the MHC light chain and the antigen peptide into a pMHC complex.
  • p stands for peptide
  • MHC stands for histocompatibility complex.
  • the molar ratio of HLA-A2 heavy chain protein, HLA-A2 light chain ⁇ 2m protein and said novel coronavirus T cell epitope peptide is 1: (1-5): (1-20).
  • the molar ratio of HLA-A2 heavy chain protein, HLA-A2 light chain ⁇ 2m protein and said novel coronavirus T cell epitope peptide is 1:2:10.
  • the purification is ion exchange column and molecular sieve purification.
  • the pMHC complex monomer prepared by the method.
  • a method for preparing a pMHC complex multimer containing the novel coronavirus T cell antigen epitope peptide, avidin, biotin, and the pMHC complex monomer are mixed and purified.
  • the molar ratio of avidin, biotin and the pMHC complex monomer is 1: (1-8): (1-8).
  • the molar ratio of avidin, biotin and the pMHC complex monomer is 1:4:4.
  • the purification is molecular sieve purification.
  • the pMHC complex multimer prepared by the method.
  • novel coronavirus T cell epitope peptide, the pMHC complex monomer, the pMHC complex multimer, the pMHC complex monomer, the pMHC complex The application of any one or more of the multimers in the preparation of new coronavirus detection reagents.
  • Epitopes can be assembled with HLA-A2 heavy chain and HLA-A2 light chain ⁇ 2m protein into pMHC monomers, and further assembled into tetramers, and labeled with corresponding fluorescence. It can be used to detect T lymphocytes in the peripheral venous blood of the subject that can recognize the neocoronavirus antigen. It can be applied to:
  • the detection of neocoronavirus antigen-specific T cells in the examinee means that the body has developed T cell immune function. According to the ratio, the body can evaluate the body's immune function against neocoronavirus-infected T cells.
  • the present invention has the following beneficial effects:
  • the present invention discovers 9 novel coronavirus T cell epitope peptides, and uses them to prepare pMHC complex monomers, and further prepares pMHC complex multimers, which can be used in the periphery of patients who have recovered from new coronavirus infections.
  • the detection of antigen-specific T cells in the blood is used in in vitro T cell activation experiments.
  • These novel coronavirus T cell epitope peptides can be applied to immunoassays related to the novel coronavirus.
  • Figure 1 shows the T2-A2 identification of nine epitopes on T cells of the novel coronavirus.
  • A Positive and negative control gradient experiment. Negative (black) is a negative irrelevant control, HLA-A2 does not bind; positive is other known positive polypeptides.
  • B T2-A2 identification experiment of new coronavirus antigen polypeptide. Sample 1: n-Sp1,2: n-Sp2, 6: n-Sp6, 7: n-Sp7, 9: n-Sp9, 11: n-Sp11, 13: n-Sp13, 16: o-Sp2, 18 : O-Sp4.
  • C Summary of three experimental repetitions.
  • Figure 2 shows the preparation of the pMHC complex of the novel coronavirus T cell epitope.
  • A Expression and affinity purification of HLA-A2 light chain recombinant protein. M: molecular marker; 1: light chain induced expression product; 2: chitin affinity chromatography washed light chain product; 3: chitin resuspended light chain; 4: DTT washed light chain; 5: light chain final product Eluted.
  • B Expression and affinity purification of HLA-A2 heavy chain recombinant protein.
  • Figure 3 shows the immunodetection effect of the pMHC complex of the novel coronavirus T cell epitope n-Sp1.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp1tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 4 shows the immunodetection effect of the pMHC complex of the new coronavirus T cell epitope n-Sp2.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp2tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 5 shows the immunodetection effect of the pMHC complex of the n-Sp6 epitope of the novel coronavirus T cell antigen.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp6tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 6 shows the immunodetection effect of the pMHC complex of the n-Sp7 epitope of the novel coronavirus T cell antigen.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp7tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 7 shows the immunodetection effect of the pMHC complex of the novel coronavirus T cell epitope n-Sp9.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp9tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 8 shows the immunodetection effect of the pMHC complex of the new coronavirus T cell epitope n-Sp11.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp11tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 9 shows the immunodetection effect of the pMHC complex of the new coronavirus T cell epitope n-Sp13.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared n-Sp13tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • Figure 10 shows the immunodetection effect of the pMHC complex of the novel coronavirus T cell epitope o-Sp2.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared o-Sp2tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • FIG. 11 Immunodetection effects of pMHC complexes of the o-Sp4 epitope of 11 novel coronavirus T cell antigens.
  • the above-prepared pMHC complex tetramers were used for the flow cytometric detection of PBMC in the peripheral blood of HLA-A2-positive patients who had recovered from the novel coronavirus.
  • B A summary of the results shows that the prepared o-Sp4tetramer can detect memory T cells in patients who have recovered from the novel coronavirus infection.
  • test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used, unless otherwise specified, are commercially available reagents and materials.
  • the polypeptide predicted in Example 1 was artificially synthesized and configured into different concentrations, respectively 0.625 ⁇ M, 1.25 ⁇ M, 2.5 ⁇ M, 5 ⁇ M, 10 ⁇ M, and 20 ⁇ M. Take T2-A2 cells in logarithmic growth state, seeded into 96-well plates, 105 per well, the distribution of holes arranged blank, negative control peptide (GLQRLGYVL, from Zika virus gene coding), a positive control peptide (influenza M1 polypeptide , GILGFVFTL) and each synthetic antigen polypeptide, each group has 3 multiple wells, the final volume is 200 ⁇ L.
  • Ultrasonic break for 50 minutes 300W work for 3 seconds and stop for 5 seconds
  • centrifuge at 3000*g at 4°C for 15 minutes and collect the supernatant.
  • the centrifugal product filtered through a 0.45 ⁇ m pore filter membrane passes through a chitin affinity chromatography column at low speed, and the chromatography is cleaned with 15 column volumes of loading buffer (20mM Tris-Hcl, 0.5M NaCl, pH8.5) Then quickly rinse the column with 2 times the column volume of elution buffer (50mM DTT loading buffer), and put the column in a refrigerator at 4°C. After 36 hours, the elution buffer is eluted and Collect the protein according to the OD 280 nm ultraviolet absorption peak.
  • HLA-A2 heavy chain and light chain proteins were obtained ( Figure 2A, B).
  • the HLA-A2 heavy chain, HLA-A2 light chain ⁇ 2m and each epitope polypeptide in Example 2 were gradually added dropwise to the refolding solution (5M urea, 0.4M arginine) at a molar ratio of 1:2:10.
  • Acid, 100mM Tris, 3.7mM cystamine, 6.3mM cysteamine, 2mM EDTA) were renatured to obtain the pMHC complex monomer of the epitope peptide.
  • the pMHC complex monomer is further purified by a DEAE ion exchange column, eluted with 0.5M NaCl, and the protein is collected based on the OD280nm ultraviolet absorption peak.
  • the protein purified by DEAE ion exchange column was purified by Superdex 75pg molecular sieve according to the molecular weight, eluted with PBS, and collected different molecular weight proteins according to the OD280nm ultraviolet absorption peak.
  • the fluorescently labeled avidin PE-streptavidin
  • biotin and pMHC complex monomers are in accordance with 1:4:4
  • the molar ratio is mixed at 4°C and incubated in the dark for 16-18 hours to prepare fluorescently labeled neocoronavirus T cell epitope tetramer. Purified by Superdex 75pg molecular sieve, eluted with PBS, and collected different molecular weight proteins according to the OD280nm ultraviolet absorption peak.
  • Peripheral venous blood was collected from patients who recovered from the novel coronavirus infection during the reexamination, and peripheral blood mononuclear cells (PBMC) were isolated, and their HLA subtypes were identified. A total of 5 HLA-A2-positive recovered PBMC samples were obtained.
  • the above-mentioned neocoronavirus T cell epitope polypeptide and the negative control polypeptide (GLQRLGYVL, coded from Zika virus gene) were selected separately by constructing their corresponding tetramers for detection.

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Abstract

L'invention concerne un peptide épitope de lymphocyte T du nouveau coronavirus, et pMHC, ainsi que la préparation et l'application associées. La séquence d'acides aminés du peptide épitope de lymphocyte T du nouveau coronavirus est telle que représentée dans l'une quelconque des SEQ ID NO : 1 à 9. Neuf peptides épitopes de lymphocytes T du nouveau coronavirus sont découverts, et un monomère de composé pMHC est préparé à l'aide de ceux-ci ; un polymère de composé pMHC est en outre préparé, peut être utilisé pour détecter des lymphocytes T spécifiques d'un antigène dans le sang périphérique d'une personne en réadaptation infectée par le nouveau coronavirus, et est utilisé pour une expérience d'activation de lymphocytes T in vitro ; les peptides épitopes de lymphocytes T du nouveau coronavirus peuvent être appliqués à une immunodétection associée à de nouveaux coronavirus.
PCT/CN2021/087739 2020-04-17 2021-04-16 Peptide épitope de lymphocyte t du nouveau coronavirus, et pmhc, et préparation et application associées WO2021209035A1 (fr)

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