CN116284363A - Novel coronavirus OmicronBA.2/4/5 mutant strain specific antibody and application thereof - Google Patents
Novel coronavirus OmicronBA.2/4/5 mutant strain specific antibody and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of antibodies, in particular to a novel coronavirus OmicronBA.2/4/5 mutant strain specific antibody and application thereof. The invention provides an antibody specifically combined with a novel coronavirus Omicron BA.2/BA.4/BA.5 mutant strain, which can be used as a specific antibody for detecting an Omicron BA.2/BA.4/BA.5 mutant strain antigen, is used for identifying a novel coronavirus vaccine designed for the Omicron BA.2/BA.4/BA.5 mutant strain, quantitatively detects the Spike RBD protein content expressed by the vaccine, can be used as a convenient and efficient vaccine development tool, and is beneficial to accelerating the development process of a new-generation vaccine.
Description
Technical Field
The invention relates to the technical field of antibodies, in particular to a novel coronavirus OmicronBA.2/4/5 mutant strain specific antibody and application thereof.
Background
The mutant strain of the novel coronavirus variant Omicron mainly comprises BA.1, BA.2, BA.4, BA.5 and the like. Many live and pseudovirus experiments showed that the neutralizing capacity of serum of convalescent patients for Omicron mutant strain was reduced 60-80 times compared to the original strain, while the neutralizing capacity of serum of mRNA vaccinators developed based on the original strain was reduced 20-130 times compared to the original strain. Therefore, to cope with ba.5 and the emerging variants, the development of a new generation of vaccine is considered to be the most effective means against the ever-mutating virus. The development of vaccines has stringent requirements for their immunogenicity and effectiveness, so the detection of antigen content is an essential key step in the development of vaccines. In contrast, for the development of multivalent vaccines, it is also necessary to establish quantitative detection methods for various mutant strain antigens.
Currently, many new coronavirus vaccine research and development enterprises are advancing the research and development work of omacron vaccines. Simplifying the development process of the novel coronavirus vaccine has important significance for promoting the development and progress of the vaccine. However, due to the lack of a long-term monitoring of the evolution history of the novel coronavirus and the immune level of the population, the world health organization has not established a set of strict procedures that can be used for an influenza vaccine to cope with the variation of the novel coronavirus strain. In order to advance the development process of more effective novel coronavirus vaccines, convenient and efficient vaccine development tools are needed. However, the antibodies for detecting the novel coronavirus vaccine are all universal at present, and specific detection and identification cannot be carried out on the vaccine designed by the novel coronavirus Omicron mutant strain, especially the novel coronavirus Omicron BA.2/4/5 mutant strain.
Disclosure of Invention
The invention provides a novel coronavirus OmicronBA.2/4/5 mutant strain specific antibody and application thereof.
The novel coronavirus Omicron BA.2 mutant has 16 mutations on RBD protein, the BA.4 and BA.5 mutant has the same 17 mutations on RBD, wherein 15 mutation sites of BA.2 and BA.4 and BA.5 are the same mutation sites, and the invention develops an Omicron BA.2/4/5 specific antibody aiming at the 15 mutations, which is used for specific detection and identification aiming at the Omicron BA.2/4/5 mutant and vaccine thereof.
The invention uses novel coronavirus OmicronBA.4/5 mutant strain Spike RBD protein as immunogen to perform mouse immunization, and the hybridoma cell strain for expressing the antibody is obtained through cell fusion and screening and hybridoma cell subcloning. Experiments prove that the antibody can specifically identify the antigen recognition site of the novel coronavirus OmicronBA.2/4/5 mutant strain. Further, the invention obtains the amino acid sequence of the antibody and the nucleotide sequence of the encoding gene thereof through hybridoma sequencing.
Specifically, the invention provides the following technical scheme:
the present invention provides an antibody or an antigen-binding fragment thereof, which is any one of the following (1) to (8):
(1) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 1. 2 and 3; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 4. 5 and 6;
(2) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 7. 8 and 9; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 10. 11, 12;
(3) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 13. 14, 15; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 16. 17, 18;
(4) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 19. 20, 21; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 22. 23, 24;
(5) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 25. 26, 27; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 28. 29, 30;
(6) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 31. 32, 33; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 34. 35, 36;
(7) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 37. 38, 39; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 40. 41, 42;
(8) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 43. 44, 45; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 46. 47, 48;
preferably, the antibody or antigen binding fragment thereof is any one of the following (1) - (8):
(1) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: shown at 49; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 50;
(2) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 51; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 52;
(3) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 53; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 54;
(4) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 55; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 56;
(5) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 57; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 58;
(6) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 59; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 60;
(7) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 61; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 62;
(8) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 63; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 64;
preferably, the antibody or antigen binding fragment thereof described above is selected from monoclonal antibodies, fab ', F (ab') 2, fd, fv, dAb, complementarity determining region fragments, single chain antibodies, animal-derived antibodies, chimeric antibodies, humanized antibodies, bispecific antibodies or multispecific antibodies.
In some embodiments of the invention, an antibody clone number 10B1A5 is provided having the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of SEQ ID NO: 1. 2 and 3; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 4. 5 and 6; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: shown at 49; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 50.
In some embodiments of the invention, an antibody clone number 10B3C6 is provided whose amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region are set forth in SEQ ID NOs: 7. 8 and 9; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 10. 11, 12; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 51; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 52.
In some embodiments of the invention, antibodies are provided with clone number 2G7H7, the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of which are set forth in SEQ ID NOs: 13. 14, 15; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 16. 17, 18; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 53; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 54.
In some embodiments of the invention, antibodies are provided having clone number 8C11C8, the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of which are set forth in SEQ ID NOs: 19. 20, 21; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 22. 23, 24; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 55; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 56.
In some embodiments of the invention, an antibody clone number 8E9B6 is provided having the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of SEQ ID NO: 25. 26, 27; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 28. 29, 30; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 57; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 58.
In some embodiments of the invention, antibodies are provided having clone number 7A3C6, the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of which are set forth in SEQ ID NOs: 31. 32, 33; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 34. 35, 36; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 59; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 60.
In some embodiments of the invention, an antibody clone number 9G6C9 is provided having the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of SEQ ID NO: 37. 38, 39; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 40. 41, 42; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 61; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 62.
In some embodiments of the invention, an antibody having clone number 11F9G1 is provided, the amino acid sequences of complementarity determining regions CDR1, CDR2, CDR3 of the heavy chain variable region of which are set forth in SEQ ID NOs: 43. 44, 45; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 46. 47, 48; the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 63; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 64.
In addition to the antibodies or antigen-binding fragments thereof described above, the present invention provides a nucleic acid molecule encoding the antibodies or antigen-binding fragments thereof.
Based on the amino acid sequences of the above antibodies or antigen binding fragments thereof, the skilled artisan can obtain nucleotide sequences of nucleic acid molecules encoding the above antibodies or antigen binding fragments thereof. Because of the degeneracy of the codons, the nucleotide sequences of the nucleic acid molecules encoding the antibodies or antigen binding fragments thereof are not unique, and all nucleic acid molecules capable of encoding the production of the antibodies or antigen binding fragments thereof are within the scope of the invention.
Further, the present invention provides a biological material comprising the nucleic acid molecule; the biological material is a vector or a host cell.
Such vectors include, but are not limited to, plasmid vectors, phage vectors, viral vectors, artificial chromosome vectors, and the like.
The host cells include microbial cells, insect cells, or other animal cells.
The invention also provides an antibody conjugate, which is obtained by coupling the antibody or antigen binding fragment thereof with a marker, wherein the marker is one or more selected from enzyme markers, biotin markers, fluorescent dye markers, chemiluminescent dye markers and radioactive markers.
Based on the function of the antibodies or antigen binding fragments thereof of the invention, the invention provides for the use of any of the following of the antibodies or antigen binding fragments thereof or the nucleic acid molecules or the biological material or the antibody conjugates:
(1) The application in the identification or immunogenicity detection of novel coronavirus vaccines;
(2) Application in quality control of novel coronavirus vaccines;
(3) Use in the preparation of a reagent for the detection of novel coronaviruses;
(4) Use in the preparation of a reagent for detecting the content of Spike RBD proteins expressed by a novel coronavirus or vaccine thereof;
(5) The application of the antibody in the quality control of the protective antibody detection in serum after immunization of the novel coronavirus vaccine.
In the application, the identification of the novel coronavirus vaccine is specifically to identify whether the novel coronavirus vaccine contains antigens of the novel coronavirus (especially the Spike RBD protein of the novel coronavirus Omicron BA.2/4/5 mutant strain) and the content level thereof or whether the novel coronavirus vaccine is true or false, namely whether the vaccine is a vaccine aiming at the novel coronavirus (especially the novel coronavirus Omicron BA.2/4/5 mutant strain) or not by utilizing the antibody or the antigen binding fragment thereof provided by the invention.
As the method for identification, detection methods such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay, radioimmunoassay, fluorescent immunoassay, immunochromatography and the like can be used.
In the application, the immunogenicity detection is specifically to detect the immune response performance of the novel coronavirus vaccine to the animal organism, including the evaluation of the humoral immune function (such as neutralizing antibody, neutralizing antibody level and antibody affinity) of the immunized animal, etc., and the antibody or the antigen binding fragment thereof provided by the invention can be used as a standard control antibody for the immunogenicity detection of the vaccine.
In the application, the quality control of the novel coronavirus vaccine is specifically to detect whether the quality, the content, the stability and the like of the antigen in the novel coronavirus vaccine are qualified, and the antibody or the antigen binding fragment provided by the invention can be used as a binding antibody of an antigen detection method (detection methods such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay, radioimmunoassay, fluorescent immunoassay, immunochromatography and the like) for detecting the quality, the content and the stability of the antigen in the vaccine.
In the above application, the detection of the novel coronavirus is specifically to detect whether or not the novel coronavirus (especially the novel coronavirus omacron ba.2/4/5 mutant) or its Spike protein or RBD of Spike protein exists or its content level in the sample by using the antibody or antigen binding fragment thereof provided by the present invention. Detection includes diagnostic purposes (the sample is from a subject, including subject's excretions, oral nasal secretions, etc.) or non-diagnostic purposes (the sample is a cell sample cultured in vitro). The detection method can be enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay, radioimmunoassay, fluorescent immunoassay, immunochromatography and the like.
Reagents for the detection of novel coronaviruses include the antibodies or antigen-binding fragments thereof of the invention, preferably the antibodies or antigen-binding fragments thereof further include a detectable label, and may further include a second antibody carrying a detectable label to detect the antibodies or antigen-binding fragments thereof of the invention.
In the above application, the detection of the content of Spike RBD protein expressed by a novel coronavirus or vaccine thereof is specifically to detect the level of Spike protein or RBD of Spike protein in a sample (the sample is derived from a subject, including excreta of the subject, oronasal secretions, etc.) or non-diagnostic (the sample is a cell sample cultured in vitro) using the antibody or antigen binding fragment thereof provided by the present invention. As the detection method, enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay, radioimmunoassay, fluorescent immunoassay, immunochromatography, competition method and the like can be used.
In the above application, the antibody or the antigen binding fragment thereof provided by the invention can also be used as a quality control antibody for detecting protective antibodies in serum after immunization of a novel coronavirus vaccine, in particular to be used as a standard control antibody in the process of detecting protective antibodies by using detection methods such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay, radioimmunoassay, fluorescent immunoassay, immunochromatography and the like.
Preferably, in the above application, the novel coronavirus is a novel coronavirus Omicron ba.2, omicron ba.4 and/or Omicron ba.5 mutant.
The invention provides a novel detection kit for coronaviruses or vaccines thereof, comprising the antibodies or antigen binding fragments thereof, or comprising the antibody conjugates.
The present invention provides a pharmaceutical composition comprising said antibody or antigen-binding fragment thereof.
The pharmaceutical composition is used for preventing or treating novel coronavirus infection or diseases related to the novel coronavirus infection. The antibodies or antigen binding fragments thereof provided herein may be used as the sole active ingredient of a pharmaceutical composition, or in combination with other pharmaceutically active ingredients. The pharmaceutical composition may further comprise pharmaceutically acceptable excipients.
The beneficial effects of the invention at least comprise: the invention provides an antibody specifically binding to a novel coronavirus Omicroba.2/4/5 mutant strain, the antibody binds to a special spatial epitope, only specifically binds to Spike RBD of the novel coronavirus Omicroba.2/4/5 mutant strain, has higher affinity, does not bind to wild type and other mutant antigens (Alpha, beta, gamma, delta, omicroba.1/3), is an ideal Omicroba.2/4/5 mutant strain antigen detection antibody, can be used for detecting and identifying the Omicroba.2/4/5 mutant strain or a novel coronavirus vaccine or multivalent vaccine designed for the Omicroba.2/4/5 mutant strain, quantitatively detects the content of Spike RBD protein expressed by the vaccine, or is used for quality control of the novel coronavirus vaccine or multivalent vaccine and immunogenicity detection in clinical and preclinical research, can also be used as a quality control antibody for detecting protective antibodies in serum after vaccination, and can be used as a high-efficiency accelerated development tool for developing a new generation vaccine.
Drawings
In order to more clearly illustrate the invention or the technical solutions of the prior art, the following description will briefly explain the drawings used in the embodiments or the description of the prior art, and it is obvious that the drawings in the following description are some embodiments of the invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the result of SDS-PAGE identification of novel coronavirus OmicronBA.2/4/5 mutant specific antibodies in example 3 of the present invention, wherein protein molecular weight marker bands were 116.0, 66.2, 45.0, 35.0, 25.0, 18.4, 14.4kDa in order from top to bottom.
FIG. 2 shows the results of SEC-MALS identification of novel coronavirus OmicronBA.2/4/5 mutant specific antibodies in example 3 of the present invention.
FIG. 3 shows the results of ELISA specific binding assay for novel coronavirus OmicronBA.2/4/5 mutant specific antibodies in example 3 of the present invention.
FIG. 4 shows the results of BLI analysis of novel coronavirus OmicronBA.4/5 mutant specific antibodies in example 3 of the present invention.
FIG. 5 shows the results of quantitative analysis of the vaccine Spike RBD protein using the novel coronavirus OmicronBA.2/4/5 mutant specific antibody in example 3 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
EXAMPLE 1 preparation of novel coronavirus OmicronBA.2/4/5 mutant specific antibodies
In this example, novel coronavirus omicronba.2/4/5 mutant specific antibodies were prepared as follows:
1. immunization of mice: the novel coronavirus OmicronBA.4/5 mutant Spike RBD protein (from Acrobiosystems) was used as an immunogen to immunize mice with the novel coronavirus OmicronBA.4/5 mutant Spike RBD protein. After the immunization, the serum of the immunized animal is detected by ELISA method. After immunization, if the immunized animal is able to reach the level of immune response against the immunogen, cell fusion is performed.
2. Screening: the supernatant of the fused cells was screened by ELISA to select cell clones positive for specific binding to the novel coronavirus OmicronBA.2/4/5 mutant Spike RBD protein and binding to none of the wild type, alpha, beta, gamma, delta, omicron BA.1, omocronBA.3 Spike RBD proteins.
3. Cloning and expanding culture: positive master clone cells were transferred to 24 well plates for expansion culture. Supernatants were collected from each of the expanded clones and tested by ELISA.
4. Subcloning: subcloning positive parent clone by limiting dilution method and subcloning screening by ELISA method.
5. Hybridoma cell antibody gene sequencing: total RNA of the hybridoma cells is extracted, and the RNA is reversely transcribed into cDNA through an RT-PCR reaction. Cloning antibody light chain and heavy chain sequences, constructing the antibody light chain and heavy chain sequences on a T vector, and then carrying out DNA sequencing analysis to obtain antibody gene sequences.
6. Antibody production and purification: cloning the antibody gene sequence obtained in the step 5 into an expression vector, and transferring the expression vector into HEK293 cells, performing amplification culture, purifying the antibody by adopting a protein A/G affinity chromatography method, and storing the purified antibody in Phosphate Buffer (PBS) by adopting a dialysis method.
EXAMPLE 2 specificity analysis of novel coronavirus OmicronBA.2/4/5 mutant antibodies
In this example, 8 monoclonal antibodies of different sequences were obtained according to the method described in example 1 above, and the novel coronavirus omicronba.2/4/5 mutant antibodies described above were specifically analyzed by enzyme-linked immunosorbent assay as follows:
1. with CBS (0.015 mol/L Na 2 CO 3 ， 0.035mol/L NaHCO 3 , 0.0077mol/L NaN 3 pH 9.59) the novel coronavirus wild type, alpha, beta, gamma, delta and the SPIKE RBD proteins of Omicron BA.1, BA.2, BA.3, BA.4, BA.5 were diluted to 2. Mu.g/mL and added to the microplate wells at 100. Mu.L per well. Sealing with sealing plate film, and standing at 4deg.CAnd (5) at night.
2. The wells were discarded, the ELISA plates were dried, washed with PBST wash solution, 300. Mu.L/Kong Jinpao, and the ELISA plates were dried and washed 3 times.
3. mu.L of blocking agent (PBST wash containing 1.5% BSA) was added to each well, membrane-sealed with a sealing plate, incubated at 37℃and then washed.
4. The novel coronavirus Omacron mutant antibody was diluted to 1. Mu.g/mL with a sample dilution (PBST wash containing 0.5% BSA). Add to the elisa plate 100 μl per well. And (5) sealing the plates by using sealing plates, placing the plates at 37 ℃ for incubation, and then cleaning.
5. HRP-Anti-Human IgG was diluted to 0.05. Mu.g/mL with sample dilution, 100. Mu.L was added to each well, membrane sealed with sealing plate, incubated at 37℃and then washed.
6. The wells were then filled with 100. Mu.L of color development solution, and the wells were covered with a plate membrane, and incubated at 37℃in the absence of light.
7. 50 mu L of stop solution is added into each hole, and the ELISA plate is gently shaken until color development is uniform.
8. The absorbance values of 450 nm and 630nm were read by an ELISA reader, and the absorbance values were read by OD 450 Knot subtracts OD 630 The values give absorbance values (OD values).
The absorbance (OD) of each monoclonal antibody is shown in table 1.
TABLE 1 ELISA detection of different antibodies OD values
The above experimental results show that among the 8 novel coronavirus antibodies, clone numbers: 10B1A5, 10B3C6, 11F9G1 showed high specificity for the novel coronavirus OmicronBA.2/BA.4/BA.5 mutant strain and did not cross-react with other mutants.
EXAMPLE 3 analytical identification and functional analysis of novel coronavirus OmicronBA.2/4/5 mutant specific antibodies
In this example, the novel coronavirus omicronba.2/4/5 mutant specific antibodies screened in example 2 (clone No. 10B1 A5) were identified analytically and functionally analyzed using methods known in the art, as follows:
1. SDS-PAGE identification result (figure 1) shows that the molecular weight of two bands of the 10B1A5 clone number antibody through reduction electrophoresis is about 25kDa and 50kDa respectively, and the purity is more than 95%.
2. The SEC-MALS assay (FIG. 2) showed that the antibody clone number 10B1A5 had a purity of greater than 99% and a molecular weight of 143kDa.
3. ELISA binding experiments (FIG. 3) showed that antibody clone No. 10B1A5 was able to specifically recognize the novel coronavirus Omicron BA.2/4/5 mutant antigen (the Spike RBD protein of the novel coronavirus Omicron BA.2/4/5 mutant strain), but did not bind to the novel coronavirus wild type and Alpha, beta, gamma, delta, omicron BA.1/3 mutant Spike RBD proteins.
4. BLI analysis data (FIG. 4) shows that the fitted line represents the time-dependent change in affinity and dissociation between Omacron mutant antigen and antibody of clone 10B1A5 at a concentration of 1000nM, and the results indicate that antibody of clone 10B1A5 binds to novel coronavirus Omacron BA.4/5 mutant antigen with an affinity as high as 2.38 nM.
5. The quantitative detection experimental result (figure 5) of the novel coronavirus Omicron mutant antigen shows that the antibody of clone number 10B1A5 can quantitatively detect the novel coronavirus Omicron BA.4/5 mutant antigen by adopting a double antibody sandwich method, so that the content of vaccine Spike RBD protein is obtained, and the sensitivity reaches 0.39ng/mL.
6. Subtype identification of the antibody of clone No. 10B1A5 showed that the antibody was subtype IgG1 kappa by Ig Isotyping Mouse Instant ELISA Kit (cat. No.: 88-50660, invitrogen).
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. An antibody or antigen-binding fragment thereof, characterized in that the antibody or antigen-binding fragment thereof is any one of the following (1) - (8):
(1) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 1. 2 and 3; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 4. 5 and 6;
(2) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 7. 8 and 9; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 10. 11, 12;
(3) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 13. 14, 15; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 16. 17, 18;
(4) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 19. 20, 21; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 22. 23, 24;
(5) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 25. 26, 27; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 28. 29, 30;
(6) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 31. 32, 33; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 34. 35, 36;
(7) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 37. 38, 39; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 40. 41, 42;
(8) The amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the heavy chain variable region are shown in SEQ ID NO: 43. 44, 45; the amino acid sequences of complementarity determining regions CDR1, CDR2 and CDR3 of the light chain variable region are shown in SEQ ID NO: 46. 47, 48.
2. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof is any one of the following (1) - (8):
(1) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: shown at 49; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 50;
(2) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 51; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 52;
(3) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 53; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 54;
(4) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 55; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 56;
(5) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 57; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 58;
(6) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 59; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 60;
(7) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 61; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: indicated at 62;
(8) The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: indicated at 63; the amino acid sequence of the light chain variable region is shown in SEQ ID NO: shown at 64.
3. The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of monoclonal antibodies, fab ', F (ab') 2, fd, fv, dAb, complementarity determining region fragments, single chain antibodies, animal-derived antibodies, chimeric antibodies, humanized antibodies, bispecific antibodies, or multispecific antibodies.
4. A nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of any one of claims 1-3.
5. A biological material comprising the nucleic acid molecule of claim 4, wherein the biological material is a vector or a host cell.
6. An antibody conjugate, which is characterized in that the antibody or the antigen binding fragment thereof according to any one of claims 1 to 3 is conjugated with a label, wherein the label is one or more selected from the group consisting of an enzyme label, a biotin label, a fluorescent dye label, a chemiluminescent dye label and a radioactive label.
7. Use of the antibody or antigen binding fragment thereof of any one of claims 1-3 or the nucleic acid molecule of claim 4 or the biological material of claim 5 or the antibody conjugate of claim 6, as follows:
(1) The application in the identification or immunogenicity detection of novel coronavirus vaccines;
(2) Application in quality control of novel coronavirus vaccines;
(3) Use in the preparation of a reagent for the detection of novel coronaviruses;
(4) Use in the preparation of a reagent for detecting the content of Spike RBD proteins expressed by a novel coronavirus or vaccine thereof;
(5) The application of the antibody in the quality control of the protective antibody detection in serum after immunization of the novel coronavirus vaccine.
8. The use according to claim 7, characterized in that the novel coronavirus is a novel coronavirus Omicron ba.2, omicron ba.4 and/or Omicron ba.5 mutant.
9. A kit for detecting a novel coronavirus or vaccine thereof, comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, or the antibody conjugate according to claim 6.
10. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1-3.
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