WO2020119666A1 - Anticorps 3f12 monoclonal entièrement humain anti-h7n9, son procédé de préparation et application associée - Google Patents

Anticorps 3f12 monoclonal entièrement humain anti-h7n9, son procédé de préparation et application associée Download PDF

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WO2020119666A1
WO2020119666A1 PCT/CN2019/124218 CN2019124218W WO2020119666A1 WO 2020119666 A1 WO2020119666 A1 WO 2020119666A1 CN 2019124218 W CN2019124218 W CN 2019124218W WO 2020119666 A1 WO2020119666 A1 WO 2020119666A1
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seq
monoclonal antibody
gene
amino acid
antibody
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万晓春
李俊鑫
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中国科学院深圳先进技术研究院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • 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
    • 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
    • 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
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL

Definitions

  • the present application belongs to the field of immunology, and specifically relates to anti-H7N9 fully human monoclonal antibody 3F12 and its preparation method and application.
  • Humira an anti-TNFa monoclonal antibody for arthritis, which is a fully human monoclonal antibody. It has been the king of medicine for more than 10 billion sales for three consecutive years. Since the launch of the first monoclonal antibody drug in 1986, monoclonal antibody drugs have undergone murine monoclonal antibody drugs (such as Orthoclone OKT3), chimeric monoclonal antibody drugs (Rituximab), humanized monoclonal antibody drugs (Herceptin) and the whole person Source monoclonal antibody drugs (Humira) and other stages.
  • murine monoclonal antibody drugs such as Orthoclone OKT3
  • Renituximab chimeric monoclonal antibody drugs
  • Herceptin humanized monoclonal antibody drugs
  • Humira the whole person Source monoclonal antibody drugs
  • HAMA anti-mouse antibody reaction
  • the monoclonal antibody drugs currently occupying the market are all humanized monoclonal antibody drugs.
  • Shenzhen and even China have a large gap, mainly manifested in the weak innovation ability in the field of human antibody drugs, the independent research and development varieties are few, there is currently no original humanized monoclonal
  • the huge antibody drug market is occupied by foreign pharmaceutical companies. In order to change the backward situation and compete for the domestic and foreign antibody drug markets with huge consumption potential, it is urgent to overcome the technology of fully human monoclonal antibodies.
  • Human-derived monoclonal antibodies are highly specific and effective in treating inflammation, cancer, and particularly influenza.
  • Influenza is an infectious disease caused by influenza virus, which seriously threatens human health. About 1 billion people worldwide are infected with the seasonal influenza virus each year, and 250,000 to 500,000 of them die.
  • the H7N9 virus is an influenza virus that is resistant to the traditional antiviral drugs amantadine and rimantadine, and there is currently no effective treatment. When the H7N9 virus invades the cell, it needs to rely on the specific molecule expressed by the virus itself to bind to the receptor on the human cell in order to infect the cell and further expand.
  • Human antibodies that neutralize viruses are specific antibodies produced by human B lymphocytes, which can bind to antigens on the surface of the virus, thereby preventing the virus from attaching to target cell receptors, preventing the virus from invading cells, and effectively preventing H7N9 influenza.
  • the present application relates to anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of neutralizing H7N9 virus.
  • the present application relates to a gene encoding the anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9, and a vector or cell containing the gene.
  • the present application relates to a method for producing the anti-H7N9 fully human monoclonal antibody 3F12.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9.
  • the present application relates to the use of the anti-H7N9 fully human monoclonal antibody 3F12 described in the present application or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9 or the pharmaceutical composition.
  • the present application relates to a kit for detecting H7N9 virus.
  • FIG. 1 is a flow cytometry result diagram of CD40L expression by NTH-3T3 in Example 1.
  • FIG. 1 is a flow cytometry result diagram of CD40L expression by NTH-3T3 in Example 1.
  • FIG. 2 is a graph showing the results of sorting memory B cells by flow cytometry in Example 1.
  • Example 3 is a graph of the ELISA experiment results in Example 1.
  • FIG. 4 is a graph of the neutralization experiment results of Example 3.
  • the present application provides an anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9, wherein the amino acid sequence of the heavy and light chain CDR1, CDR2 and CDR3 regions of the antibody They are as follows:
  • amino acid sequence of the heavy chain variable region of the antibody is shown in SEQ ID NO: 2, or an amino acid sequence with equivalent functions formed by replacing, deleting, or adding one or several amino acids to the sequence; and/ or
  • amino acid sequence of the light chain variable region of the antibody is shown in SEQ ID NO: 4, or an amino acid sequence with equivalent functions formed by replacing, deleting or adding one or several amino acids to the sequence.
  • the heavy chain amino acid sequence of the antibody is shown in SEQ ID NO: 6, or an amino acid sequence with equivalent functions formed by replacing, deleting, or adding one or more amino acids to the sequence; and/or
  • the light chain amino acid sequence of the antibody is shown in SEQ ID NO: 8, or an amino acid sequence with equivalent functions formed by replacing, deleting or adding one or several amino acids to the sequence.
  • the anti-H7N9 fully human monoclonal antibody 3F12 described in this application can target hemagglutinin HA that binds to the H7N9 virus, with an affinity of 3.5 ⁇ 10 -9 M; in a virus-infected cell model, its IC 50 value Only about 14.35uM.
  • the antibodies described in this application are fully human monoclonal antibodies. Compared with murine antibodies, the genes of fully human antibodies are completely derived from human genes, without the components of other species, and no anti-mouse anti-antibodies occur in the human body. Toxic and side effects, with better biocompatibility, more suitable and more potential to become a macromolecular drug for the treatment of influenza virus.
  • the present application provides a gene encoding the anti-H7N9 fully human monoclonal antibody 3F12 described herein.
  • the gene comprises a nucleotide sequence encoding the amino acid shown in SEQ ID NO: 2, in some embodiments, the nucleotide sequence is shown in SEQ ID NO: 1; and/or
  • the gene contains a nucleotide sequence encoding the amino acid shown in SEQ ID NO: 4, and in some embodiments, the nucleotide sequence is shown in SEQ ID NO: 3.
  • the gene comprises a nucleotide sequence encoding an amino acid having SEQ ID NO: 6, in some embodiments, the nucleotide sequence is shown in SEQ ID NO: 5; and/or
  • the gene includes a nucleotide sequence encoding the amino acid shown in SEQ ID NO: 8, and in some embodiments, the nucleotide sequence is shown in SEQ ID NO: 7.
  • sequence of SEQ ID NO: 1 ⁇ 8 in this application is shown in the sequence table, in which:
  • Sequences 1 to 48 in SEQ ID NO: 5 and SEQ ID NO: 7 are sequences used to encode signal peptides.
  • amino acid sequences at positions 26-33 in SEQ ID NO: 2 and SEQ ID NO: 6 are heavy chain CDR1 sequences; the amino acid sequences at positions 51-58 in SEQ ID NO: 2 and SEQ ID NO: 6 are Heavy chain CDR2 sequence; the amino acid sequence at positions 97-115 in SEQ ID NO: 2 and SEQ ID NO: 6 is the heavy chain CDR3 sequence.
  • the amino acid sequence at positions 26-32 in SEQ ID NO: 4 and SEQ ID NO: 8 is the light chain CDR1 sequence; the amino acid sequence at positions 50-52 in SEQ ID NO: 4 and SEQ ID NO: 8 is The light chain CDR2 sequence; the amino acid sequence at positions 89-99 in SEQ ID NO: 4 and SEQ ID NO: 8 is the light chain CDR3 sequence.
  • the present application provides a vector containing the gene as described above.
  • the present application provides cells containing the gene as described above or the vector as described above.
  • the present application provides a method for producing the anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9, the method comprising culturing The above-mentioned genes of the heavy and light chains of the human monoclonal antibody 3F12 or genetically engineered cells of the above vector or directly culture the above cells, collect and purify the anti-H7N9 fully human monoclonal antibody 3F12.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the anti-H7N9 fully human monoclonal antibody 3F12 described herein or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9.
  • the present application provides the anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9 or the pharmaceutical composition is prepared for treatment by H7N9 Application of drugs for diseases caused by viruses.
  • the present application provides a kit for detecting the level of H7N9 virus, which contains the anti-H7N9 fully human monoclonal antibody 3F12 or a biologically active fragment derived from the monoclonal antibody capable of specifically binding H7N9 ;
  • the kit further contains a second antibody and an enzyme or fluorescent or radioactive marker for detection, and a buffer; the second antibody is, for example, anti-monoclonal antibody 3F12 of the present application Anti-antibody.
  • the anti-H7N9 fully human monoclonal antibody 3F12 described in this application can target hemagglutinin HA that binds to the H7N9 virus, and has significant neutralizing activity against H7N9 virus infection.
  • Lentivirus was used to establish 3T3-CD40L feeder cells.
  • the lentiviral expression vector pLVX-CD40L was constructed, transfected into 293T cells, and the viral supernatant was collected on the fourth day of transfection.
  • Activate NIH-3T3 cells infect with lentivirus after culturing for 3 generations, continue culturing and pass 3 times.
  • Use flow cytometry to sort the cells whose FITC fluorescence intensity is near the MFI, re-add to the culture flask, culture and test at 37°C, 5% CO 2 incubator. The test results are shown in Figure 1.
  • CD40L 3T3 cells and empty vector pLVX (with ZxGreen) transfected 3T3 cells were stained with anti-CD40L with APC, and then analyzed by flow cytometry. As a result, it was found that all 3T3-CD40L feeder cells expressed CD40L.
  • the cells grow to 80% to 90%, the cells are digested and collected at a concentration of 1 ⁇ 10 7 cells per ml. Place in a radiometer for 5000 rads radiation, resuspend the cells in the cryopreservation solution at a concentration of 3.5 ⁇ 10 7 cells per ml, aliquot 1 ml in a frozen vial, and freeze in liquid nitrogen (can be stored for 2 years).
  • Lymph separation solution was used to separate and freeze the PBMC of rehabilitation patients who had been infected with H7N9 virus. Each tube contains 10-50 ⁇ 10 6 cells, and is frozen in a liquid nitrogen tank. Prepare PBMC flow dyeing solution, its composition is shown in Table 1 below
  • the memory B cells were added to the mixed medium. After mixing, the cells were diluted in a 384-well plate with a limit of 1 cell per well and the volume was 50 ⁇ l. The cells were placed in a 37°C, 5% CO 2 incubator and cultured statically. After 13 days, the supernatant was taken for ELISA.
  • Influenza virus hemagglutinin HA is a columnar antigen on the surface of the viral envelope. It can bind to a variety of red blood cell receptors such as humans, chickens, and guinea pigs to cause red blood cell aggregation. It is immunogenic and anti-hemagglutinin antibodies can neutralize influenza viruses.
  • B cells capable of secreting the antibody 3F12 binding to the H7N9 virus were found by ELISA, and the human monoclonal antibody 3F12 secreted by it can target the hemagglutinin HA binding to the H7N9 virus (FIG. 3 ).
  • Example 1 The B cells obtained in Example 1 capable of secreting the 3F12 antibody that binds to the H7N9 virus were lysed, and the lysate was taken for reverse transcription of RNA to obtain the PCR template cDNA of the human antibody gene.
  • Reverse transcription system 150ng random primer (invitrogen, 48190-011), 0.5 ⁇ l 10mM dNTP (Invitrogen, 18427-088), 1 ⁇ l 0.1M DTT (Invitrogen, 18080-044), 0.5% v/v Igepal CA -630 (Sigma, I3021-50ML), 4U RNAsin (Promega), 6U Prime RNAse Inhibitor (Eppendorf) and 50U III reverse transcriptase (Invitrogen, 18080-044), supplemented with DEPC water to 14 ⁇ l/well.
  • the sequencing result of the PCR product of the variable region of the heavy chain of the antibody gene is shown in the sequence shown in SEQ ID NO: 1, and the corresponding amino acid sequence is shown in the sequence shown in SEQ ID NO: 2.
  • the sequencing result of the PCR product of the light chain variable region of the antibody gene is shown in the sequence shown in SEQ ID NO: 3, and the corresponding amino acid sequence is shown in the sequence shown in SEQ ID NO: 4.
  • the supernatant contains antibodies capable of binding to the H7N9 virus.
  • virus-infected cell model canine kidney cell MDCK
  • the inhibitory effect and effect of the 3F12 antibody against the H7N9 influenza virus were evaluated by a micro-neutralization-ELISA experiment, and the antibody anti-influenza virus activity was detected.
  • MDCK canine kidney cells in logarithmic growth phase after termination, centrifugal collection, evenly disperse, prepare single cell suspension; adjust cell concentration to 5 ⁇ 10 4 cells/ml with cell culture solution, and inoculate in 96-well cell culture Plates, cells were incubated overnight at 37°C in a 5% CO 2 incubator.
  • the 3F12 antibody was established with 10 concentration gradients, which were sequentially diluted 10 to 10 times, and 3 parallel wells were set for each concentration of each group.
  • step (2.1) Discard the cell culture supernatant cultured in step (2.1) and wash 3 times with PBS.
  • the antibody premixed - virus mixed solution (10-fold serially diluted to 10-10 monoclonal antibody 3F12 10 2 ⁇ g / ml, and the concentration of each antibody 3F12 respectively equal volume of virus 100TCID 50 mixing the mixture obtained ).
  • TPCK-Trypsin (maintenance solution) with a final concentration of 2 ⁇ g/ml was added to serum-free DMEM.
  • the PBS in the 96-well plate was discarded, 100 ⁇ l of maintenance solution was added to each well, and incubated at 37° C. in a 5% CO 2 incubator for 20 h.
  • Inhibition rate [(OD virus well-OD negative cell control well)-(OD drug well-OD negative cell control well)]/(OD virus well-OD negative cell control well) ⁇ 100%.
  • the instrument of affinity detection is Fortebio of PALL. Prepare 200 ⁇ l 50 ⁇ g/ml 3F12 antibody, bind proteinA sensor for 120 seconds, HA antigen prepare 100nM, 50nM, 2.5nM, 12.5nM and 6.25nM and 0nM concentration solutions, bind antibody for 120 seconds, dissociation time is 5 minutes, display 3F12 pair

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Abstract

L'invention porte sur un anticorps 3f12 monoclonal entièrement humain anti-H7N9, un procédé de préparation et une utilisation de celui-ci. Ledit anticorps peut cibler l'hémagglutinine HA se liant au virus H7N9, et présente une activité de neutralisation significative contre l'infection virale H7N9. L'anticorps n'a pas d'effets secondaires toxiques tels qu'une réaction d'anticorps anti-murins et présente une meilleure biocompatibilité, est plus approprié et est plus susceptible d'être un médicament macromoléculaire pour le traitement du virus de la grippe.
PCT/CN2019/124218 2018-12-13 2019-12-10 Anticorps 3f12 monoclonal entièrement humain anti-h7n9, son procédé de préparation et application associée WO2020119666A1 (fr)

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CN201811526028.3 2018-12-13

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CN112079918B (zh) * 2020-09-01 2021-05-18 武汉珈创生物技术股份有限公司 一种h7n9病毒特异性识别抗体p51c05及检测试剂盒

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CN111320685B (zh) * 2018-12-13 2022-03-08 中国科学院深圳先进技术研究院 抗h7n9全人源单克隆抗体3f12及其制备方法与应用

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