CN115925904B - New coronavirus monoclonal neutralizing antibody and application thereof - Google Patents
New coronavirus monoclonal neutralizing antibody and application thereof Download PDFInfo
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- CN115925904B CN115925904B CN202211020423.0A CN202211020423A CN115925904B CN 115925904 B CN115925904 B CN 115925904B CN 202211020423 A CN202211020423 A CN 202211020423A CN 115925904 B CN115925904 B CN 115925904B
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Abstract
The invention discloses a novel coronavirus monoclonal neutralizing antibody and application thereof, and relates to the field of biotechnology; the monoclonal neutralizing antibody of the novel coronavirus has a light chain amino acid sequence shown as SEQ ID NO.1 and a heavy chain amino acid sequence shown as SEQ ID NO. 2. The invention screens human monoclonal antibody from the healthy person, is used for the treatment of new crown infection or the development of related detection products, and the screened monoclonal antibody W6 has the binding effect on new crown RBD protein, has neutralization activity on multiple mutant pseudoviruses of new crown and has neutralization activity in the detection of wild live viruses of new crown through in vitro test. The monoclonal neutralizing antibody is a humanized antibody, can reduce immunogenicity when being used for treating human infection with new coronavirus, has neutralizing activity on various pseudoviruses, has broad-spectrum neutralizing potential, and can cope with infection caused by mutation of the new coronavirus.
Description
Technical Field
The invention relates to the technical field of biology, in particular to a novel coronavirus monoclonal neutralizing antibody and application thereof.
Background
Antibodies have played an important role in the treatment of new crown infections as new crown-specific therapeutic agents. Currently, new coronaviruses have generated a variety of mutants, and specific monoclonal antibodies are required for both treatment and detection of the new coronaviruses, and in particular antibodies with the ability to neutralize viruses are required for use in new coronavirus treatment.
In most humans, viral infection induces the body to produce neutralizing antibodies, thereby eliminating the virus in the body. In general, in the absence of specific drugs, recovery-stage plasma of a convalescence patient containing neutralizing antibodies can be used for emergency treatment. However, convalescence plasma treatment has obvious disadvantages: 1) The number of recovered patients is small, and the obtained plasma is small; 2) In the natural infection state, the plasma neutralizing antibody titer is very low, and it is difficult to provide sufficient protective effect; 3) The plasma is rich in substances, and serious adverse reactions can be generated. The use of fully human monoclonal neutralizing antibodies is expected to overcome these drawbacks.
Disclosure of Invention
The invention aims to provide a novel coronavirus monoclonal neutralizing antibody and application thereof, which are used for solving the problems in the prior art, and the monoclonal neutralizing antibody provided by the invention has neutralizing activity on pseudoviruses of various mutant strains of the novel coronavirus, has neutralizing activity in detection of wild live viruses of the novel coronavirus, and can be used for treatment of the novel coronavirus infection or development of related detection products.
In order to achieve the above object, the present invention provides the following solutions:
the invention provides a novel coronavirus monoclonal neutralizing antibody, the amino acid sequence of a light chain variable region of which is shown as SEQ ID NO.1, and the amino acid sequence of a heavy chain variable region of which is shown as SEQ ID NO. 2. The invention also provides a DNA molecule for coding the novel coronavirus monoclonal neutralizing antibody, wherein the DNA sequence for coding the light chain variable region is shown as SEQ ID NO.3, and the DNA sequence for coding the heavy chain variable region is shown as SEQ ID NO. 4.
The invention also provides a recombinant vector comprising the DNA molecule.
The invention also provides a recombinant cell comprising the DNA molecule or the recombinant vector.
The invention also provides application of the novel coronavirus monoclonal neutralizing antibody, DNA molecule, recombinant vector or recombinant cell in preparing medicines for resisting the novel coronavirus.
The invention also provides an anti-novel coronavirus drug, which comprises the novel coronavirus monoclonal neutralizing antibody, a recombinant vector or a recombinant cell.
The invention also provides application of the novel coronavirus monoclonal neutralizing antibody, DNA molecule, recombinant vector or recombinant cell in preparing products for detecting the novel coronavirus.
The invention also provides a product for detecting the novel coronavirus, which comprises the monoclonal neutralizing antibody, the recombinant vector or the recombinant cell of the novel coronavirus.
The invention discloses the following technical effects:
the invention screens human monoclonal antibody from the healthy person, is used for the treatment of new crown infection or the development of related detection products, and the screened monoclonal antibody W6 has the binding effect on new crown RBD protein, has neutralization activity on multiple mutant pseudoviruses of new crown and has neutralization activity in the detection of wild live viruses of new crown through in vitro test. The monoclonal neutralizing antibody is a humanized antibody, can reduce immunogenicity when being used for treating human infection with new coronavirus, has neutralizing activity on various pseudoviruses, has broad-spectrum neutralizing potential, and can cope with infection caused by mutation of the new coronavirus.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the detection of the binding activity of serum of a recovered SARS-CoV-2 infection to Spike protein;
FIG. 2 is a flow cytometry sorting S/RBD specific memory B cells; wherein A is a living cell loop gate, B is a B cell loop gate, C is a memory B cell loop gate capable of secreting lgG antibody, and D is an S protein antigen specific memory B cell loop gate;
FIG. 3 is a graph showing the detection of binding activity of antibody expression supernatants to novel crown S and RBD proteins;
FIG. 4 shows the competition of antibodies with the novel coronavirus RBD protein for ACE2 binding assays;
FIG. 5 shows the detection of binding activity of the W6 antibody to the novel crown WT, B.1.1.7 and B.1.351R BD proteins;
FIG. 6 shows the detection of the binding strength of the W6 antibody to RBD protein by SPR experiments; wherein A is a W6-to-WTRBD mutant, B is a W6-to-B.1.1.7RBD mutant, C is a W6-to-B.1.351RBD mutant, and D is a W6-to-B.1.351RBDE 484K mutant;
FIG. 7 is a graph showing the detection of neutralizing activity of W6 antibodies against various novel coronamutant pseudoviruses;
FIG. 8 shows the detection of neutralizing activity of the W6 antibody against the novel coronavirus.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
Example 1
1. Method of
Antigen-specific memory B cells were obtained from multiple new coronavirus infected rehabilitators. Antibody genes were obtained using single B cell cloning techniques and constructed onto expression vectors. Antibody expression was performed using a mammalian cell expression system, and the binding activity of the expressed antibodies to antigens and the neutralizing activity against viruses were studied.
(1) Sorting of antigen-specific B cells
Firstly, anticoagulants of a convalescence patient infected by the new coronavirus are taken, and Peripheral Blood Mononuclear Cells (PBMC) of a human are separated by utilizing lymphocyte separation liquid. The isolated PBMC were stained with fluorescent-labeled antibody by B cell surface marker CD3 - 、CD20 + 、CD27 + 、IgG + Individual memory B cells are sorted and then antigen specific memory B cells are isolated using the principle that B cell surface BCR can bind to viral antigen proteins.
(2) Single cell PCR and antibody clone expression: the single memory B cells are separated by flow cytometry, total RNA is extracted by cleavage, and cDNA is formed after reverse transcription. The antibody heavy and light chain variable region gene sequences were amplified by single cell PCR technique using antibody family mix primers. The amplified antibody heavy and light chain variable region genes are constructed into an expression vector through homologous recombination, and then the antibody is expressed by using mammalian cells.
Isolation of antibody variable region genes from single B cells using RT-PCR:
preparing cell lysate by using a reverse transcription kit produced by Promega corporation, subpackaging the cell lysate into a 96-well plate, centrifuging the cell, adding a reversing reagent, reversing the cell lysate into cDNA, and freezing the cDNA at-80 ℃ after the reverse transcription is completed;
the heavy and light chain variable region genes of the antibody were amplified by nested PCR using human antibody gene specific primers and B cell cDNA as a template, and a 50. Mu.L system containing 5. Mu.L cDNA, hotStarTaq Plus enzyme, dNTPs, and 0.5. Mu.M specific primers was subjected to PCR amplification under the following conditions: pre-denaturation at 94℃for 5min;94℃for 30s,55℃for 30s,72℃for 50s,35 cycles; 7min at 72 ℃; the PCR product obtained was identified by 1% agarose gel electrophoresis.
And (3) recovering the target fragment, carrying out sample feeding and sequencing, and comparing the sequencing result with an IMGT database (http:// www.imgt.org/IMGT_vquest/vquest) to obtain the antibody variable region gene fragment.
Construction of expression vectors for monoclonal antibodies:
homologous recombination primers are used for respectively adding homologous recombination arms at two ends of an antibody heavy chain variable region gene and two ends of a light variable region gene, and expression plasmids containing human antibody heavy and light chain IgG1 constant regions are linearized by using double enzymes to generate homologous recombination arms; the variable region gene fragment added with the homologous recombination arm and the linearized plasmid are connected in a homologous recombination mode to form a complete expression vector, the recombinant product is transformed into TOP10 escherichia coli competence, and the plasmid is amplified.
Expression and purification of monoclonal antibodies:
adding the obtained monoclonal antibody heavy and light chain expression plasmids into an Opti-Mem transfection medium according to the proportion of 1:1, fully mixing, adding a transfection reagent PEI with the mass of 4 times that of DNA, mixing, standing for 30min at room temperature in a dark place, and then adding into 293T cells;
after 6h incubation, the transfection system was removed and FreeStyle was added TM 293 expression medium, using AKTA Protein purification system, purifying the expressed antibody supernatant by affinity purification (Protein A) method to obtain monoclonal antibody, comprising the following steps:
1) Centrifuging the expressed antibody supernatant at 2500 Xg at room temperature for 10min, and removing precipitate;
2) Washing the affinity purification column filled with Protein A with 10 times of Binding Buffer;
3) Passing the expression supernatant through a purification column at a flow rate of 5 mL/min;
4) The purification column was washed thoroughly with 20 volumes of Binding Buffer (Binding Buffer);
5) Eluting the purification column with 0.1M ph=3.0-3.5 citric acid buffer until the elution peak falls to equilibrium, and adjusting the pH to 7.0 with 1M ph=9.0 Tris-HCl buffer;
6) The purified monoclonal antibody was concentrated using a concentration column, PBS was used as a buffer for antibody preservation, and finally the concentration of the concentrated antibody was measured by a BSA protein concentration detection method.
(3) Antibody function verification: the expressed antibodies were validated for their binding activity to viral antigens using ELISA experiments. The validation of antibody neutralization activity was then performed using a pseudo-virus reporter system and a new coronavirus. The suspension cell expression system is used for carrying out mass expression of the antibody, and the AKTA protein purification system is used for purifying the antibody. After obtaining high purity antibodies, the EC50 for antigen binding and the IC50 for virus neutralization were quantitatively detected by the antibodies.
2. Results
(1) After the serum of a virus infection healer is inactivated, ELISA experiments are used for detecting the binding activity of the virus infection healer to S protein, and the results show that 11 healers generate the binding antibody to the novel coronal S protein in vivo, wherein the serum titer of 6 healers is higher. The results are shown in FIG. 1.
(2) Peripheral blood of the infected convalescence person is collected, and PBMC are separated. Using cell surface Marker CD3 - 、CD20 + 、CD27 + 、IgG + Sorting out memory B cells; antigen-specific memory B cells were sorted using S/RBD his+ (fig. 2).
(3) The selected memory B cells are amplified to obtain antibody variable region genes by using a single cell PCR technology. The antibody variable region genes are cloned into antibody expression vectors. Secretory expression of antibodies was performed using the 293 cell line. ELISA experiments on antibody expression supernatants showed that 7 antibody expression supernatants had binding activity to both the novel coronavirus RBD and Spike (FIG. 3).
(4) The ability of the screened antibodies to compete with the novel crown RBD protein for binding to the receptor ACE2 was tested by ELISA competition experiments. The results show that the W6 antibody can compete with the new coronavirus RBD protein for ACE2 binding (fig. 4).
(5) After purification of the W6 antibody by large amounts, ELISA experiments were used to detect the RBD of the W6 antibody against the novel crown wild type, british (B.1.1.7, N501Y) and south Africa (B.1.351, K417N, E484K, N501Y) mutants, W6 EC50 (206.4 ng/mL,203.9ng/mL,200 ng/mL). The results are shown in FIG. 5.
(6) Results of the SPR test antibody W6 on the WT RBD, B.1.1.7RBD, B.1.351RBD, and B.1.351RBD E484K mutants showed that the binding activity of W6 on the B.1.7 mutant RBD was enhanced 1.5-2.6 times, especially on the B.1.351 mutant E484K site mutant RBD protein (FIG. 6).
(7) Antibody W6 has neutralizing activity against various mutant pseudoviruses, and IC 50's were 0.35, 3.4, 2.2, 2.6, 11.1. Mu.g/mL, respectively, indicating that the W6 antibody has a broad spectrum of neutralizing activity (FIG. 7).
(8) The purified antibody is diluted in a gradient and then added to 1000PFU living virus for co-incubation, and then added to susceptible cells. The results show that the neutralizing IC50 of the antibody W6 to the live virus is 0.003mg/mL, and the neutralizing activity is very good, and particularly the W6 antibody has complete neutralizing effect to the wild-type live virus (figure 8).
Light and heavy chain variable region amino acid and nucleic acid sequences of W6 antibodies:
the light chain variable region amino acid sequence (SEQ ID NO. 1) is:
NFMLTQPHSVSESPGKTVTISCTGSSGSIASNYVQWYQQRPGSAPTTVIYEDNQRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYDSSNWVFGGGTKLTVL；
the heavy chain variable region amino acid sequence (SEQ ID NO. 2) is:
EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGQLGPWVGVDYWGQGTLVTVSS；
the light chain variable region nucleic acid sequence (SEQ ID NO. 3) is:
aattttatgctgactcagccccactctgtgtcggagtctccggggaagacggtaaccatctcctgcaccggcagcagtggcagcattgccagcaactatgtgcagtggtaccagcagcgcccgggcagtgcccccaccactgtgatctatgaggataaccaaagaccctctggggtccctgatcggttctctggctccatcgacagctcctccaactctgcctccctcaccatctctggactgaagactgaggacgaggctgactactactgtcagtcttatgatagcagcaattgggtgttcggcggagggaccaagctgaccgtcctag；
the heavy chain variable region nucleic acid sequence (SEQ ID NO. 4) is:
gaggtgcagctggtgcagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcacctttagtagctattggatgagctgggtccgccaggctccagggaaggggctggagtgggtggccaacataaagcaagatggaagtgagaaatactatgtggactctgtgaagggccgattcaccatctccagagacaacgccaagaactcactgtatctgcaaatgaacagcctgagagccgaggacacggccgtgtattactgtgcgagaggtcagctcggcccttgggtgggtgttgactactggggccagggaaccctggtcaccgtctcctcag。
the new crown neutralizing antibody obtained by the invention is used for treating new crown infection and developing related detection products thereof.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (8)
1. A monoclonal neutralizing antibody of new coronavirus features that the amino acid sequence of light chain variable region is shown in SEQ ID NO.1 and the amino acid sequence of heavy chain variable region is shown in SEQ ID NO. 2.
2. A DNA molecule encoding the novel coronavirus monoclonal neutralizing antibody of claim 1, wherein the DNA sequence encoding the light chain variable region is shown in SEQ ID No.3 and the DNA sequence encoding the heavy chain variable region is shown in SEQ ID No. 4.
3. A recombinant vector comprising the DNA molecule of claim 2.
4. A recombinant cell comprising the DNA molecule of claim 2 or the recombinant vector of claim 3.
5. Use of a novel coronavirus monoclonal neutralizing antibody according to claim 1, a DNA molecule according to claim 2, a recombinant vector according to claim 3 or a recombinant cell according to claim 4 for the preparation of an anti-novel coronavirus medicament.
6. An anti-novel coronavirus drug comprising the novel coronavirus monoclonal neutralizing antibody of claim 1.
7. Use of a novel coronavirus monoclonal neutralizing antibody according to claim 1, a DNA molecule according to claim 2, a recombinant vector according to claim 3 or a recombinant cell according to claim 4 for the preparation of a product for detecting a novel coronavirus.
8. A product for detecting a novel coronavirus comprising the monoclonal neutralizing antibody of claim 1.
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