KR20150112584A - Monoclonal Antibody Specific to Influenza A Virus, Methods for the Treatment and Diagnosis of Influenza Infection - Google Patents
Monoclonal Antibody Specific to Influenza A Virus, Methods for the Treatment and Diagnosis of Influenza Infection Download PDFInfo
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- KR20150112584A KR20150112584A KR1020140037066A KR20140037066A KR20150112584A KR 20150112584 A KR20150112584 A KR 20150112584A KR 1020140037066 A KR1020140037066 A KR 1020140037066A KR 20140037066 A KR20140037066 A KR 20140037066A KR 20150112584 A KR20150112584 A KR 20150112584A
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Abstract
Description
The present invention relates to an influenza A virus-specific monoclonal antibody and a method of treating and diagnosing influenza infection using the antibody. More particularly, the present invention relates to a hemagglutinin (HA) specific monoclonal antibody of influenza A virus and influenza A To a method of treating and diagnosing a viral infection.
Influenza viruses are RNA envelope viruses with a particle size of about 125 nm in diameter. The virus consists essentially of a core of ribonucleic acid (RNA) bound to an internal nucleocapsid or nuclear protein surrounded by a lipid bilayer structure and a viral envelope with an exogenous glycoprotein. The inner layer of the viral envelope consists mainly of matrix proteins and the outer layer consists mainly of host-derived lipid material.
Influenza virus is a highly polymorphic particle consisting of two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which binds the virus to host cells It is known that the surface proteins, in particular hemagglutinin, mediate the fusion of virus-cell membranes during the infiltration of the virus into the cell, and thus determine the antigen specificity of the influenza subtype.
Influenza viruses are classified as type A, type B, and type C based on differences in antigen. Influenza A virus infects not only humans but also birds and swine. Influenza C causes only mild illness in humans. Influenza A viruses are described by nomenclature including subtype or type, geographic origin, strain number and isolation date, for example, A / Beijing / 353/89. In addition, subtypes of influenza A are determined by the surface antigens hemagglutanin (H) and neuramidase (N) antigens. H antigens are known to H1-H16, and N antigens are known to N1-N9. The gene for type A influenza is composed of 8 gene fragments, and for this reason, genetic recombination can occur. All subtypes are found in birds, but, H1-H3 and N1-N2 are known to be found in humans, swine and horses (Murphy and Webster, Orthomyxoviruses. Fields , BN And DM Knipe (ed.). Fields Virology , Second Edition , 2: 1091, 1990).
Avian influenza viruses and swine influenza viruses do not infect humans well because of interspecies barriers. However, in rare cases infectious diseases exceed species barriers. In 1976, a case of infection with swine influenza (H1N1) occurred in New Jersey, USA. There were 13 infected patients and one of them died. In 1997 in Hong Kong, an infectious disease caused by avian influenza H5N1 occurred, and infection by the H5N1 influenza virus is still sporadic.
Swine influenza A, also known as swine flu, was first described as 'swine influenza' or 'swine flu', but there is no evidence that it is associated with swine, so the official name of the World Health Organization (WHO) It was unified as 'Swine Influenza A'.
Molecular biology research has shown that the new influenza A virus is a recombination of four influenza virus genes. The four influenza viruses are the North American swine influenza virus, the North American avian influenza virus, the human influenza virus and the Eurasian swine influenza virus, respectively. Although the pathway of the virus has not yet been clearly elucidated, it is not clear whether it is caused by droplet infections, such as seasonal influenza viruses, or by coughing or sneezing of an infected person, Within about 2 m) of the propagation direction. Since it is not propagated by food, it is not infected only by ingesting processed pork or pork. When cooked at over 70 ℃, the virus is killed.
At present, the infection diagnosis of influenza A virus is performed through a virus identification method, a virus nucleic acid detection method and the like. For example, a method for isolating and identifying influenza A virus is carried out by a method of inoculating a patient's sample into a Madin-Darby canine kidney (MDCK) cell to identify a virus having hemagglutination ability , And the detection of viral nucleic acid is performed by real-time PCR (RT-PCR) for rapid and accurate diagnosis for rapid treatment of virus-infected patients.
In addition, SRID (Single Radial Immuno Diffusion), which is currently being tested for influenza vaccine antigen content, is laborious and time-consuming and requires measurement of hemagglutinin (HA) of the culture supernatant , The sensitivity is low and the number of samples that can be measured at one time does not exceed a maximum of 10, and the time required (2 days) is long. Further, the diagnostic unit price is high due to the unit price of the standard antigen and the standard antibody used, and the accuracy is not high in the non-purified sample.
Accordingly, the present inventors have made extensive efforts to solve the above problems and to develop an effective method of treating and diagnosing infection of influenza A virus. As a result, it has been found that hemagglutinin (HA) of Influenza A virus is detected in an antibody obtained by immunizing a new influenza antigen, Specific antibodies were selected and HA antigen of influenza A virus can be detected or quantified more efficiently than the conventional SRID method by using the above-mentioned selected antibodies. Thus, the present invention has been completed.
It is an object of the present invention to provide a method of treating and diagnosing influenza A virus infection using hemagglutinin (HA) -specific mAb of influenza A virus and the antibody.
In order to achieve the above object, the present invention provides an influenza A virus hemagglutinin (HA) specific monoclonal antibody containing a heavy chain variable region and a light chain variable region of any one of the following.
(DYDMS) consisting of the amino acid sequence of SEQ ID NO: 2, a CDR2 region (GILGGGERSYYNDSVKG) consisting of the amino acid sequence of SEQ ID NO: 3, and a CDR3 region (HGSSGYVDYGMDY) consisting of the amino acid sequence of SEQ ID NO: 4. Heavy chain variable region,
(Ii) a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 10, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 11, and a CDR3 region (HSWGAYVQYGMDV) consisting of the amino acid sequence of SEQ ID NO: ,
(Iii) a CDR1 region (LTKYKMT) consisting of the amino acid sequence of SEQ ID NO: 20, a CDR2 region (SISSTSRDVDYADSVKG) consisting of the amino acid sequence of SEQ ID NO: 21, and a CDR3 region (DGWLWGWDVRSNYYYNALDV) consisting of the amino acid sequence of SEQ ID NO: ,
(Iv) a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 24, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 25, and a CDR3 region (HGSPGYTLYAWDY) consisting of the amino acid sequence of SEQ ID NO: ,
(V) a CDR1 region (LTSYGVH) comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 region (VIWTDGSTTYNSALKS) consisting of the amino acid sequence of SEQ ID NO: 29, and a CDR3 region (QDRYDGGIAY) consisting of the amino acid sequence of SEQ ID NO: ;
(Vi) a CDR1 region (LYDIH) consisting of the amino acid sequence of SEQ ID NO: 32, a CDR2 region (WIDTGNGDIKYSQKFQD) consisting of the amino acid sequence of SEQ ID NO: 33, and a CDR3 region (DNWGSRIDYFDY) ; And
(b) a CDR1 region (RASQGIGDNLG) consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2 region (GVSTLDS) consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3 region (LQHSNYPMYT) consisting of the amino acid sequence of SEQ ID NO: ; or
A light chain variable region comprising a CDR1 region (RASESVSNYGINFIN) consisting of the amino acid sequence of SEQ ID NO: 14, a CDR2 region (TASNKGT) consisting of the amino acid sequence of SEQ ID NO: 15, and a CDR3 region (QQTKEVPYT) consisting of the amino acid sequence of SEQ ID NO:
The present invention also provides a gene encoding the influenza A virus hemagglutinin (HA) specific monoclonal antibody.
The present invention also relates to a method for producing influenza A virus hemagglutinin (HA), which comprises culturing a recombinant vector containing said gene, said gene or said recombinant vector introduced into said host microorganism, ) Specific < / RTI > monoclonal antibody.
The present invention provides a composition for the treatment or diagnosis of influenza A virus infection, which comprises the above-mentioned influenza A virus hemagglutinin (HA) specific monoclonal antibody.
The present invention also provides a method for the detection or quantification of influenza A virus hemagglutinin (HA) antigen characterized by using the above-mentioned influenza A virus hemagglutinin (HA) specific monoclonal antibody.
The present invention also provides an Influenza A virus hemagglutinin (HA) antigen detection or quantification kit comprising said influenza A virus hemagglutinin (HA) specific monoclonal antibody.
The influenza A virus hemagglutinin (HA) -specific monoclonal antibody of the present invention has high affinity for HA antigen and can be used as a composition for treating or diagnosing influenza A virus. In addition, since viruses can be quantified using an antibody highly sensitive to an antigen when carrying out ELISA for detection or quantitation of HA antigen, since the amount of antibody used is small, the cost is lower than that of the SRID method, The method can be used as a method for quantifying influenza HA antigen for substitution or concurrent use.
1 is a schematic diagram for performing primary and secondary screening, ELISA, of the present invention.
FIG. 2 shows affinity and linearity of cell culture supernatant obtained by infection with the antibody of the present invention and three kinds of H1N1 virus.
FIG. 3 shows the specificity of SF587 antibody and SF757 antibody to HA.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the high specificity invention relates to the influenza A virus HA. In general, the nomenclature used herein is well known and commonly used in the art.
In one aspect, the present invention relates to influenza A virus hemagglutinin (HA) -specific mAb containing a heavy chain variable region and a light chain variable region of any one of the following:
(DYDMS) consisting of the amino acid sequence of SEQ ID NO: 2, a CDR2 region (GILGGGERSYYNDSVKG) consisting of the amino acid sequence of SEQ ID NO: 3, and a CDR3 region (HGSSGYVDYGMDY) consisting of the amino acid sequence of SEQ ID NO: 4. Heavy chain variable region,
(Ii) a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 10, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 11, and a CDR3 region (HSWGAYVQYGMDV) consisting of the amino acid sequence of SEQ ID NO: ,
(Iii) a CDR1 region (LTKYKMT) consisting of the amino acid sequence of SEQ ID NO: 20, a CDR2 region (SISSTSRDVDYADSVKG) consisting of the amino acid sequence of SEQ ID NO: 21, and a CDR3 region (DGWLWGWDVRSNYYYNALDV) consisting of the amino acid sequence of SEQ ID NO: ,
(Iv) a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 24, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 25, and a CDR3 region (HGSPGYTLYAWDY) consisting of the amino acid sequence of SEQ ID NO: ,
(V) a CDR1 region (LTSYGVH) comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 region (VIWTDGSTTYNSALKS) consisting of the amino acid sequence of SEQ ID NO: 29, and a CDR3 region (QDRYDGGIAY) consisting of the amino acid sequence of SEQ ID NO: ;
(Vi) a CDR1 region (LYDIH) consisting of the amino acid sequence of SEQ ID NO: 32, a CDR2 region (WIDTGNGDIKYSQKFQD) consisting of the amino acid sequence of SEQ ID NO: 33, and a CDR3 region (DNWGSRIDYFDY) ; And
(b) a CDR1 region (RASQGIGDNLG) consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2 region (GVSTLDS) consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3 region (LQHSNYPMYT) consisting of the amino acid sequence of SEQ ID NO: ; or
A light chain variable region comprising a CDR1 region (RASESVSNYGINFIN) consisting of the amino acid sequence of SEQ ID NO: 14, a CDR2 region (TASNKGT) consisting of the amino acid sequence of SEQ ID NO: 15, and a CDR3 region (QQTKEVPYT) consisting of the amino acid sequence of SEQ ID NO:
In the present invention, the monoclonal antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 9, 19, 23, 27 and 31, and a light chain variable region comprising the amino acid sequence of SEQ ID NOs: And a variable region.
The influenza A virus HA-specific antibody may further include a constant region in the variable region, and it is obvious to a person skilled in the art that the antibody is included in the scope of the present invention.
In the present invention, the influenza A virus HA-specific monoclonal antibody has high affinity and specificity for HA1, and is preferably characterized by being specific to HA of influenza A virus of H1N1 type.
The term " hemagglutinin (HA) "of the present invention represents envelope glycoprotein of influenza virus. HA mediates the passage of influenza virus through the host cell. So far 16 types of subtypes have been reported.
The "monoclonal antibody" of the present invention is also called a monoclonal antibody or monoclonal antibody, and is an antibody produced by a single antibody-forming cell, and has a primary structure (amino acid sequence) homogeneous. Although it is produced by culturing a hybridoma cell that recognizes only one antigenic determinant and generally fusing cancer cells and antibody-producing cells, it can be produced by using a recombinant protein expression host cell using the obtained antibody gene sequence It can also produce.
The "antibody" may be a complete form having two full-length light chains and two full-length heavy chains, as well as fragments of antibody molecules. A fragment of an antibody molecule refers to a fragment having at least an antigen-binding function and is a single-chain Fv (scFv), Fab, F (ab '), F (ab') 2 , .
The "antigen" of the present invention is a molecule containing a site that binds to an antibody. In the antigen molecule, there exists a stereomolecular structure that determines the antigen specificity, reacts with the antibody corresponding thereto, and its structural site is substituted with an antigenic determinant or epitope .
A "Fab fragment" of the present invention is one of fragments obtained by treating or decomposing an antibody with papain, a protease in the presence of a reducing agent having a low concentration, and comprises an antigen-binding domain and is obtained by light chain and disulfide bond Wherein the Fab fragments have no disulfide bond (s) between the H chains present in the F (ab ') 2 fragment.
The term "antigen-binding portion" (or simply "antibody portion") of an antibody refers to one or more fragments of an antibody having the ability to specifically bind to the antigen. The antigen-binding function of the antibody can be performed by a fragment of full-length antibody. Examples of binding fragments included in the term "antigen-binding portion" of the antibody include (i) Fab fragments that are monovalent fragments consisting of the VL, VH, CL, and CH1 domains; (ii) a F (ab ') 2 fragment that is a divalent fragment comprising two Fab fragments linked by a disulfide bond in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an antibody Fv fragment consisting of the VL and VH domains of a single arm; (v) a dAb fragment consisting of the VH domain (Ward et al ., Nature 341: 544, 1989), and (vi) isolated complementarity determining regions (CDRs).
The 'SRID' of the present invention is a single radial immunodiffusion method in which, when measuring a specific antigen amount or antibody value, an object to be examined is immobilized on an immune diffusion plate using a gel containing the corresponding antibody or antigen And the concentration of the test substance is determined by the diameter of the sedimentation line caused by the sedimentation reaction in the gel.
In another aspect, the present invention relates to a gene encoding an influenza A virus hemagglutinin-specific mAb.
In another aspect of the present invention, there is provided a recombinant vector having the ability to produce influenza A virus hemagglutinin-specific monoclonal antibody, wherein the recombinant vector containing the gene, the gene or the recombinant vector is introduced into a host cell .
In the present invention, a "vector" means a DNA product containing a DNA sequence operably linked to a suitable regulatory sequence capable of expressing the DNA in an appropriate host. The vector may be a plasmid, phage particle or simply a potential genome insert. Once transformed into the appropriate host, the vector may replicate and function independently of the host genome, or, in some cases, integrate into the genome itself. Since the plasmid is the most commonly used form of the current vector, 'plasmid' and 'vector' are sometimes used interchangeably in the present invention. For the purpose of the present invention, it is preferable to use a plasmid vector. Typical plasmid vectors that can be used for this purpose include (a) a cloning start point that allows replication to be efficiently made to include several hundred plasmid vectors per host cell, (b) a host cell transformed with the plasmid vector And (c) a restriction enzyme cleavage site into which the foreign DNA fragment can be inserted. Even if an appropriate restriction enzyme cleavage site is not present, using a synthetic oligonucleotide adapter or a linker according to a conventional method can easily ligate the vector and the foreign DNA.
The recombinant cell according to the present invention can be produced by inserting the gene on a chromosome of a host cell according to a conventional method, or introducing the recombinant vector onto a plasmid of a host cell.
A variety of expression host / vector combinations may be used to express monoclonal antibodies according to the invention. Suitable expression vectors for eukaryotic hosts include, but are not limited to, expression control sequences derived from SV40, cow papilloma virus, adenovirus, adeno-associated virus, cytomegalovirus and retrovirus. Expression vectors that can be used for bacterial hosts include Escherichia coli such as pET, pRSET, pBluescript, pGEX2T, pUC vector, col E1, pCR1, pBR322, pMB9, coli) bacterial plasmid, a plasmid having a wider host range, such as RP4, gt10 and gt11, phage, which may be exemplified by a wide variety of phage lambda (phage lambda) derivatives such as NM989 DNA, and M13 and filamentous single strand obtained in the And other DNA fingerprints such as DNA fingerprints. An expression vector useful for yeast cells is 2 plasmid and its derivatives. The vector useful for insect cells is pVL941.
The recombinant vector of the present invention may be transformed into an appropriate host cell such as a yeast cell, an animal cell, etc., and then the transformed host cell may be cultured to mass-produce the human antibody or fragment thereof of the present invention.
A suitable host cell of the vector is E. coli, Bacillus subtilis (Bacillus subtilis), genus Streptomyces (Streptomyces sp.), Pseudomonas species (Pseudomonas sp.), Proteus ( Proteus mirabilis ) or Staphylococcus sp.). < / RTI > In addition, the genus Aspergillus sp.), fungi such as Pichia pastoris), Celebi as Saccharomyces My jiae access (Saccharomyces S. cerevisiae , Schizosaccharomyces eukaryotic cells such as yeast such as Neurospora crassa , other lower eukaryotic cells, and cells of higher eukaryotes such as cells from insects. It can also be derived from plants and mammals. Preferably, the cells are selected from the group consisting of monkey kidney cells (COS7), NSO cells, SP2 / 0, Chinese hamster ovary (CHO) cells, W138, baby hamster kidney (BHK) MDCK, myeloma cell line, HuT 78 cell, and HEK293 cell, but are not limited thereto.
As a method of introducing the recombinant vector of the present invention into a host cell and transforming it, a commonly known gene manipulation method can be used. For example, microinjection (direct insertion of DNA into cells), liposome, directed DNA uptake, receptor ~ mediated DNA transfer, or DNA transport using Ca ++ . Is widely used. Examples include retrovirus vectors, adenovirus vectors, adeno-associated viral vectors, herpes simplex virus vectors, poxvirus vectors, or lentiviral vectors. Particularly, retroviruses have a high gene transfer efficiency, gross deletion It can be used in a wide range of cells without binding by host DNA and rearrangement (resulting in alteration of host DNA function by altering the region of the host DNA similar to that of the host DNA).
A nucleic acid is "operably linked" when placed in a functional relationship with another nucleic acid sequence. This may be the gene and regulatory sequence (s) linked in such a way as to enable gene expression when a suitable molecule (e. G., Transcriptional activator protein) is attached to the regulatory sequence (s). For example, DNA for a pre-sequence or secretory leader is operably linked to DNA for a polypeptide when expressed as a whole protein participating in the secretion of the polypeptide; A promoter or enhancer may be operably linked to a coding sequence if it affects the transcription of the sequence; Or the ribosome binding site is operably linked to a coding sequence if it affects the transcription of the sequence; Or a ribosome binding site is operably linked to a coding sequence if positioned to facilitate translation. Generally, " operably linked " means that the linked DNA sequence is in contact, and in the case of a secretory leader, is in contact and present in the reading frame. However, the enhancer need not be in contact. The linkage of these sequences is carried out by ligation (linkage) at convenient restriction sites. If such a site does not exist, a synthetic oligonucleotide adapter or a linker according to a conventional method is used.
In another aspect, the present invention provides a method of producing influenza A virus hemagglutinin-specific monoclonal antibodies, comprising: (a) culturing a recombinant cell having the ability to produce the influenza A virus hemagglutinin-specific mAb to produce influenza A virus hemagglutinin-specific mAb; And (b) recovering the resulting influenza A virus hemagglutinin-specific monoclonal antibody. The present invention also relates to a method for producing an influenza A virus hemagglutinin-specific monoclonal antibody.
The influenza A virus hemagglutinin-specific monoclonal antibody of the present invention is preferably obtained by expression and purification by a recombinant method, and specifically includes a gene sequence encoding the heavy chain variable region or the entire heavy chain region of the antibody and a light chain variable region Alternatively, the gene sequence coding for the whole light chain region may be separately expressed in one or two vectors, but is not limited thereto.
Specifically, the method for producing the influenza A virus hemagglutinin-specific monoclonal antibody comprises the steps of: preparing a recombinant vector by inserting a gene encoding the influenza A virus hemagglutinin-specific mAb of the present invention into a vector; Transforming the recombinant vector into a host cell and culturing it; And isolating and purifying an influenza A virus hemagglutinin-specific monoclonal antibody from the cultured transformant.
Specifically, influenza A virus hemagglutinin-specific mAb can be produced in a large amount by culturing the transformant expressing the recombinant vector in a nutrient medium. The medium and culturing conditions are appropriately selected and used depending on the host cell . The conditions such as the temperature, the pH of the medium and the incubation time can be appropriately adjusted so as to be suitable for cell growth and mass production of the protein at the time of culturing.
Such recombinantly produced peptides or proteins can be recovered from the medium or cell lysate. If membrane bound, it can be liberated from the membrane by using a suitable surfactant solution (e.g., Triton-X 100) or by enzymatic cleavage.
Cells used for antibody expression can be disrupted by various physical or chemical means such as freeze-thawing, sonication, mechanical disruption or cell disruption, and can be isolated and purified by conventional biochemical separation techniques (Sambrook meat al ., Molecular Cloning: A laborarory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press (1989); Deuscher, M., Guide to Protein Purification Methods Enzymology, Vol. 182. Academic Press. Inc., San Diego, Calif. (1990)). Electrophoresis, centrifugation, gel filtration, precipitation, dialysis, chromatography (ion exchange chromatography, affinity chromatography, immuno adsorption chromatography, size exclusion chromatography, etc.), isoelectric focusing and various variations and combinations thereof But are not so limited.
The culture and recovery of the recombinant cells for producing the influenza A virus hemagglutinin-specific mAb of the present invention can be applied to any culture method and separation and purification method of recombinant proteins conventionally known in the art without any particular limitation.
In one embodiment of the present invention, an antibody pool obtained by immunizing a new influenza antigen in 2009 was prepared to screen for an antibody specific for influenza virus HA, and an antibody having affinity for influenza virus HA was selected from the pool of antibodies Respectively. ELISA using a culture supernatant infected with the standard antibody for SRID and the subtype of H1N1 influenza virus (A / Brisbane / 59/2007 (IVR-148)) showed affinity for IVR-148 virus affinity) were selected first (Table 1).
In another embodiment of the present invention, the first selection of nine antibodies was screened secondarily and the H1N1 subtype ternary virus A / New Caledonia / 20/1999 (IVR-116) was added to the production cell line to establish ELISA conditions, Affinity tests were performed on culture supernatants and virus-specific standard antigens (for SRID) infected with A / Brisbane / 59/2007 (IVR-148) and A / Solomon Islands / 3/2006 (IVR- Antibodies corresponding to the first, second, third, fourth, sixth, and seventh antibodies of Table 1 were found to have higher affinity than the control commercial antibody (Table 2 and Table 3).
In addition, the linearity of the antibody against the H1N1 subtype virus culture supernatants of the above 2, 3, 4, 6 and 7 antibody was confirmed, and the
In order to confirm the specificity of Hemagglutinin (HA), which is a surface glycoprotein of influenza virus, the
Based on the above results, the amino acid sequence and the light chain variable region of the light chain variable region and heavy chain variable region of the antibody No. 2 (SF587) and the antibody No. 3 (SF757) were analyzed in the present invention (see Table 6 and Table 7), SF587 was composed of the heavy chain variable region represented by the amino acid sequence of SEQ ID NO: 1 and the light chain variable region represented by the amino acid sequence of SEQ ID NO: 5, and the heavy chain variable region of SEQ ID NO: (GILGGGERSYYNDSVKG) consisting of the amino acid sequence of SEQ ID NO: 3 and a CDR3 region (HGSSGYVDYGMDY) consisting of the amino acid sequence of SEQ ID NO: 4, and the light chain variable region of SEQ ID NO: 5 comprises the amino acid sequence of SEQ ID NO: A CDR1 region (RASQGIGDNLG) composed of the amino acid sequence of SEQ ID NO: 6, a CDR2 region (GVSTLDS) composed of the amino acid sequence of SEQ ID NO: 7, (LQHSNYPMYT).
In addition, it was confirmed that SF757 was composed of the heavy chain variable region represented by the amino acid sequence of SEQ ID NO: 9 and the light chain variable region represented by the amino acid sequence of SEQ ID NO: 13, and the heavy chain variable region of SEQ ID NO: (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 11, a CDR3 region (HSWGAYVQYGMDV) consisting of the amino acid sequence of SEQ ID NO: 12, and the light chain variable region of SEQ ID NO: 13 comprises SEQ ID NO: (TASNKGT) consisting of the amino acid sequence of SEQ ID NO: 15, and a CDR3 region (QQTKEVPYT) consisting of the amino acid sequence of SEQ ID NO: 16
In the present invention, the amino acid sequences of the heavy chain variable regions of SF587 and SF757 were derived based on the mutation of amino acids to obtain heavy chain variable regions having the amino acid sequences of SEQ ID NOS: 19, 23, 27 and 31 in Table 8, It was confirmed that the antibody consisting of the combination of the variable region and the light chain variable region having the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 13 in Table 6 had affinity and specificity for influenza A virus HA at a level similar to that of SF587 and SF757 antibodies Respectively.
The heavy chain variable region of SEQ ID NO: 19 has a CDR1 region (LTKYKMT) consisting of the amino acid sequence of SEQ ID NO: 20, a CDR2 region (SISSTSRDVDYADSVKG) consisting of the amino acid sequence of SEQ ID NO: 21, (DGWLWGWDVRSNYYYNALDV) consisting of the amino acid sequence of SEQ ID NO: 22, the heavy chain variable region of SEQ ID NO: 23 comprises the CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 24, the CDR2 region consisting of the amino acid sequence of SEQ ID NO: (GILGGSERSYYRDSVKG), and a CDR3 region (HGSPGYTLYAWDY) consisting of the amino acid sequence of SEQ ID NO: 26.
The heavy chain variable region of SEQ ID NO: 27 comprises a CDR1 region (LTSYGVH) consisting of the amino acid sequence of SEQ ID NO: 28, a CDR2 region (VIWTDGSTTYNSALKS) consisting of the amino acid sequence of SEQ ID NO: 29, a CDR3 region (QDRYDGGIAY The heavy chain variable region of SEQ ID NO: 31 comprises a CDR1 region (LYDIH) consisting of the amino acid sequence of SEQ ID NO: 32, a CDR2 region (WIDTGNGDIKYSQKFQD) consisting of the amino acid sequence of SEQ ID NO: 33, a CDR3 (DNWGSRIDYFDY). ≪ / RTI >
A heavy chain variable region comprising one amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 9, 19, 23, 27 and 31 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5 or 13 Twelve antibodies are highly specific for influenza A virus HA.
In another aspect, the present invention relates to a composition for the treatment or diagnosis of influenza A virus infection comprising the above-mentioned influenza A virus hemagglutinin (HA) specific monoclonal antibody.
"Diagnosis" of the present invention means any action that identifies the presence or characteristic of a pathological condition. For the purposes of the present invention, the diagnosis may be interpreted as any action to ascertain the likelihood of developing an influenza A viral infectious disease, but is not limited thereto.
The term "diagnostic composition" of the present invention refers to a main means used for diagnosis of a desired disease, and may include substances for diagnosing influenza A virus according to the purpose of the present invention. Diagnostic methods can include contacting the antibody or antibody fragment with a sample. Such a sample may be obtained from the nostril, sinus ca vity, salivary gland, lung, liver, pancreas, kidney, ear, eye, placenta, digestive tract, heart, ovary, pituitary gland, adrenal gland, It may be a taken tissue sample. Diagnostic methods may also include detection of an antigen / antibody complex.
The present invention provides a method of treating a subject comprising administering an antibody of the invention for the treatment of an influenza A virus infection, wherein the influenza A virus infection of the subject is reduced. The method also prevents influenza A virus infection of the subject and reduces or delays the risk thereof.
The "therapeutic composition" of the present invention may contain a pharmaceutically acceptable carrier which permits administration. The carrier should not itself induce the production of antibodies harmful to the individual receiving the composition, and should not be toxic. Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers and inert viral particles.
Pharmaceutically acceptable salts may be, for example, inorganic acid salts such as hydrochloride, hydrobromide, phosphate and sulfate, or salts of organic acids such as acetate, propionate, malonate and benzoate. The pharmaceutically acceptable carrier in the therapeutic composition may further contain liquids such as water, saline, glycerol and ethanol. In addition, adjuvants such as wetting or emulsifying agents or pH buffering materials may be present in such compositions. Such carriers may be formulated for tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions for ingestion by the subject.
May be included within the scope of the present invention in a form suitable for administration or parenteral administration, for example injection or infusion, such as bolus injection or continuous infusion. When the product is for injection or infusion, it may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulation agents such as suspending, preserving, stabilizing and / or dispersing agents. Alternatively, the antibody molecule may be in a dry form for reconstitution prior to use with a suitable sterile liquid. Once formulated, the compositions of the present invention may be administered directly to the subject. In one embodiment, the composition is adapted for administration to a human subject.
The therapeutic composition of the present invention can be administered orally, intravenously, intramuscularly, intraarterially, intrathecally, intraperitoneally, intracisternally, intracerebrally, transdermally, percutaneously, topically, subcutaneously, nasally, enterally, sublingually, And may be administered by any number of routes, including, but not limited to, pathways. Hypospray may also be used to administer the pharmaceutical compositions of the present invention. Typically, the therapeutic composition may be prepared as an injectable material, for example as a liquid solution or suspension. Solutions in liquid vehicles before injection, or solid forms suitable for suspensions may also be prepared.
Direct delivery of the composition will generally be by injection, subcutaneous, intraperitoneal, intravenous or intramuscular, or delivered to the space between the cells of the tissue. The composition may also be administered to a lesion. The medication treatment may be a single medication schedule or a multiple medication schedule. Known antibody-bearing limitations provide guidance as to the frequency of administration, for example whether the drug should be administered daily, weekly, monthly or the like. The frequency and dosage may depend on the severity of the symptoms.
In another aspect, the present invention relates to a method for detecting or quantifying an influenza A virus hemagglutinin antigen characterized by using the above-mentioned influenza A virus hemagglutinin (HA) specific monoclonal antibody.
The methods of detection or quantification of the present invention include, but are not limited to, autoradiography, fluorescence microscopy, direct and indirect enzyme reactions, and the like. Detection assays commonly used include radioisotope or non-radioisotope methods. Among them, they include Western blotting, overlay-analysis, RIA (Radioimmunoassay) and IRMA (Immune Radioimmunometric Assay), EIA (Enzyme Immuno Assay), ELISA (Enzyme Linked Immuno Sorbent Assay), FIA (Fluorescent Immuno Assay) ).
In the present invention, an enzyme-linked immunosorbent assay (ELISA) is preferably used, and the influenza A virus hemagglutinin-specific antibody of the present invention can be used as an antibody for capture or an antibody for detection . In the case of the above method, the capture antibody may be used as the influenza A virus-specific HA antibody of the present invention, the detection antibody may be used as the standard antibody for each virus-specific SRID, or both the capture antibody and the detection antibody Influenza A virus HA specific monoclonal antibodies can be used, and those methods are also included in the scope of the present invention.
(A) fixing an influenza A virus HA specific antibody to an ELISA measurement plate with an antibody for capture, (b) contacting the ELISA assay plate of step (a) with influenza A virus HA antigen or influenza A Treating the cell culture supernatant infected with the virus, and then treating the influenza A virus hemagglutinin (HA) -specific monoclonal antibody of the present invention with the detection antibody; And (c) treating the tracer antibody to measure the absorbance and then detecting or quantifying the antigen of influenza A virus hemagglutinin (HA)
(a) fixing an influenza A virus hemagglutinin (HA) specific monoclonal antibody of the present invention to an ELISA measurement plate as an antibody for capture; (b) Treating the cell culture supernatant infected with the influenza A virus HA antigen or the influenza A virus and then treating the influenza A virus HA specific antibody with the detection antibody; And (c) treating the tracer antibody to measure the absorbance, and then detecting or quantifying the influenza A virus hemagglutinin (HA) antigen.
In the present invention, the influenza A virus HA-specific antibody is a standard antibody for SRID, which is known in the art. In the step (b), the antibody for detection is 0.5 to 5 / / ml, / Ml. ≪ / RTI >
In the present invention, the tracer antibody of step (c) is characterized by being Goat anti-mouse IgG-HRP. However, an antibody capable of recognizing the antibody for detection can be used without limitation. Influenza A virus HA A marker for antigen detection or quantitation is attached.
The label is preferably a conventional coloring agent that undergoes a color reaction and may be labeled with a marker such as HRP (horseradish peroxidase), alkaline phosphatase, coloid gold, fluorescein, Body can be used. The chromogenic substrate for inducing color development is preferably used according to a labeling substance which reacts with a color, and TMB (3,3 ', 5,5'-tetramethyl bezidine), ABTS [2,2'-azino-bis -ethylbenzothiazoline-6-sulfonic acid] and OPD (o-phenylenediamine).
In the present invention, an ELISA was performed in combination of Table 10 to find the optimal antibody combination of capture antibody and detection antibody of ELISA. As a result, only the combination of the antibody for the third antibody and the antibody for SRID Taking into consideration the results of Examples 1 and 2 and the points showing high linearity (R 2 ≥0.97) (Table 11 and Table 12), the antibody for SRID was used as a capture antibody and the antibody The most suitable antibody combination was used as a detection antibody.
Based on the above results, in the present invention, antibody selection and HA ELISA conditions capable of quantifying HA antigen more efficiently than the conventional SRID method using Influenza A virus-specific antibody of the present invention were established (Table 13).
Since the antibodies selected in the present invention exhibit high linearity affinity for the standard antigen (H1N1 type influenza virus HA protein), there is an advantage in that the assay cost is low because the amount of antibody used in the HA ELISA is small And SRID, it can be used as an influenza HA antigen-assay (ELISA) method to replace or in parallel with the SRID method. In addition, the H1N1-type influenza virus It can be used for diagnosis of virus.
In another aspect, the present invention provides an ELISA kit comprising (i) an influenza A virus hemagglutinin (HA) specific monoclonal antibody of the present invention, (ii) an influenza A virus hemagglutinin- A hemagglutinin (HA) antigen or a kit for quantification, which is characterized in that it is composed of a plate for use as an antigen and a (iii) tracer antibody.
The kit of the present invention may contain various buffers and reagents necessary for performing an ELISA reaction. The Influenza A virus HA specific antibody can be generally used as a standard antibody for SRID known in the art. Influenza A virus HA specific Plates for ELISA measurement in which the antibody is immobilized may be separately provided with an influenza A virus HA specific antibody and an ELISA assay plate.
Also, the optimal amount of reagent used in a particular reaction in a kit can be readily determined by those skilled in the art having the teachings herein. Typically, the kit of the present invention is fabricated as a separate package or compartment comprising the aforementioned components.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.
Influenza virus HA Antibody detection or diagnosis for primary detection and purification
Methods for producing fusion cell lines known in the art (Kohler, G. and Milstein, C, 1975; Kozbar et < RTI ID = 0.0 > al . 1983), an antibody pool obtained by immunizing a new influenza antigen in 2009 was prepared. To briefly describe the above method, a swine influenza virus was injected into the abdominal cavity of mice at 6-8 weeks of age to immunize the spleen, and the spleen was removed to single cell and then reacted with myeloma cells to prepare a fusion cell line. The thus prepared fusion cell line (hybridoma) was cloned repeatedly until a stable monoclonal cell line was obtained to produce a monoclonal antibody-producing fusion cell line. Among the antibodies produced in the fusion cell line, the affinity for the influenza virus HA Antibodies were selected.
The ELISA method shown in Fig. 1 was used for the primary screening of antibodies for influenza virus HA antigen detection or diagnosis, and the capture antibody was a standard antibody for SRID (A / Brisbane / 59/2007 (IVR-148); NIBSC, Lot. (A / Brisbane / 59/2007 (IVR-148)) were infected with MDCK cells, and the antigen was used as a sample supernatant prepared by infecting MDCK cells with one type of influenza virus (A / Brisbane / 59/2007
Each of the antibodies of the influenza antibody pool was treated on a 96-well plate coated with the standard antibody for SRID and culture supernatant infected with IVR-148 in order to obtain an antibody having affinity to IVR-148 virus , And then each antibody was purified by IgG purification methods known in the art for use in secondary screening and establishing ELISA conditions (Table 1).
(Hereinafter referred to as an antibody number)
Influenza virus HA Antibody detection or diagnosis secondary antibody screening
In order to select the ELISA conditions, the 9 kinds of antibodies selected first in Example 1 were screened for
The standard antigens used above were A / Brisbane / 59/2007 (IVR-148; NIBSC, Lot No. 08/100) and A / New Caledonia / 20/1999 (IVR-116; NIBSC, Lot The standard antibodies used as capture antibodies in ELISA were A / Solomon Islands / 3/2006 (IVR-145; NIBSC, Lot No. 07/102) Brisbane / 59/2007 (IVR-148, NIBSC, Lot No. 10/120), A / New Caledonia / 20/1999 (IVR-116; NIBSC, Lot No. 04/260) 2006 (IVR-145; NIBSC, Lot No. 07/104) was used.
2-1: H1N1 subtype Three-cell virus infected cell culture In the supernatant Affinity test for
In the ELISA model of FIG. 1, a capture antibody for capture was used as the standard antibody for SRID, and the same concentration as that for SRID was used. For the detection antibody, the antibody selected first in Example 1 was used at a concentration of 5 μg / ml, and the tracer was labeled with Goat anti-mouse IgG-HRP (KPL, Cat. No. 074-1806) Was used at a concentration of 1: 10,000. As a control, C102 (H1 (H1N1) monoclonal antibody, clone C102; Hytest, Cat. No. 3IH4), a commercialized antibody for Western blotting / ELISA, was used.
In the first test, the antibodies corresponding to 5, 8, 9 and 10 of Table 1 were excluded because their affinity was very low and the affinity measurement for the antibodies corresponding to the remaining 2, 3, 4, 6 and 7 Are shown in Tables 2 and 3 below.
In order to establish a HA antigen assay that can be used in parallel with or substituting with SRID, standard antibodies for SRID were used as capture antibodies, serial dilutions of virus culture supernatant and standard antigen for SRID were confirmed, (Table 2 and Table 3). The results are shown in Table 2 and Table 3.
2-2: Virus culture The supernatant For standard antigens Linearity Confirm
In order to confirm the linearity of the cell culture supernatant and the standard antigen cultured by infection with the three kinds of H1N1 virus, the ELISA assay was carried out in the same manner as the ELISA method of Example 2-1, and the standard antibody for SRID Was used at 0.5 times the concentration used in SRID. The detection antibody was used at a concentration of 1 μg / ml corresponding to 2, 3, 4, 6 and 7 in Table 1, and the measurement was performed at a concentration of 1: 20000 in a tracer .
Serial dilutions of the virus culture supernatant and SRID standard antigen showed that the
2-3: HA Concentration conversion and SRID Measure and match consistency
Based on the results of Example 2-2, it was confirmed that the H3N1 virus was consistent with the HA concentration conversion and the SRID measurement.
-ND (not detected); Low affinity measurement not possible.
- Antibodies with low affinity for viral culture supernatants are excluded from concentration conversions.
Comparison of SRID and HA ELISA measurements of each virus culture supernatant revealed that the antibody was used as a detection antibody for the detection of SRID confidence interval (80 to 125%) and 3 (SF757) (Table 4).
Influenza A virus In hemagglutinin (HA) Identification for specificity
In order to confirm the specificity of the selected SF587 and SF757 antibodies against hemagglutinin (HA), an influenza virus surface glycoprotein, the affinity was confirmed using the viruses shown in Table 5 below.
As a result, as shown in Fig. 3, it was confirmed that the primary screened antibody specifically recognized the new influenza vaccine and H1-55 and H1-85.
Identification of antibody amino acid sequence
In order to analyze the amino acid sequence of the Fab fragments of antibody No. 2 (SF587) and antibody No. 3 (SF757) exhibiting a high binding property with the HA protein of influenza virus, light chains of the antibodies No. 2 and No. 3 purified in Example 2 The amino acid sequences of the variable light chain and the variable heavy chain were analyzed (Table 6 and Table 7).
Variable area
Variable area
Variable area
Variable area
(The underlined and bold lines indicate the CDR portion.)
Light chain variable region
Light chain variable region
The heavy chain variable region of SEQ ID NO: 1 was composed of the heavy chain variable region represented by the amino acid sequence of SEQ ID NO: 1 and the light chain variable region represented by the amino acid sequence of SEQ ID NO: 5, and the heavy chain variable region of SEQ ID NO: CDR1 region (DYDMS), a CDR2 region (GILGGGERSYYNDSVKG) consisting of the amino acid sequence of SEQ ID NO: 3, and a CDR3 region (HGSSGYVDYGMDY) consisting of the amino acid sequence of SEQ ID NO: 4, and the light chain variable region of SEQ ID NO: CDR1 region (RASQGIGDNLG) consisting of the sequence of SEQ ID NO: 7, CDR2 region (GVSTLDS) consisting of the amino acid sequence of SEQ ID NO: 7, and CDR3 region (LQHSNYPMYT) consisting of the amino acid sequence of SEQ ID NO: 8.
In addition, it was confirmed that SF757 was composed of the heavy chain variable region represented by the amino acid sequence of SEQ ID NO: 9 and the light chain variable region represented by the amino acid sequence of SEQ ID NO: 13, and the heavy chain variable region of SEQ ID NO: (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 11, a CDR3 region (HSWGAYVQYGMDV) consisting of the amino acid sequence of SEQ ID NO: 12, and the light chain variable region of SEQ ID NO: 13 comprises SEQ ID NO: (TASNKGT) consisting of the amino acid sequence of SEQ ID NO: 15, and a CDR3 region (QQTKEVPYT) consisting of the amino acid sequence of SEQ ID NO: 16.
In the case of antibodies obtained by mutating the amino acid sequences of the SF587 and SF757 antibodies, the amino acid sequences of the heavy chain variable region and the light chain variable region were mutagenized by a general method known in the art to confirm that the specificity for influenza A virus HA was maintained And HA-specific antibodies were selected in the same manner as in Examples 1 to 3.
Variable area
(The underlined and bold lines indicate the CDR portion.)
As a result, an antibody consisting of a heavy chain variable region having the amino acid sequences of SEQ ID NOS: 19, 23, 27, and 31 shown in Table 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: SF587 and SF757 antibodies with affinity and specificity for influenza A virus HA.
The heavy chain variable region of SEQ ID NO: 19 comprises a CDR1 region (LTKYKMT) consisting of the amino acid sequence of SEQ ID NO: 20, a CDR2 region (SISSTSRDVDYADSVKG) consisting of the amino acid sequence of SEQ ID NO: 21, a CDR3 region (DGWLWGWDVRSNYYYNALDV) consisting of the amino acid sequence of SEQ ID NO: The heavy chain variable region of SEQ ID NO: 23 comprises a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 24, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 25, a CDR3 region consisting of the amino acid sequence of SEQ ID NO: (HGSPGYTLYAWDY).
The heavy chain variable region of SEQ ID NO: 27 comprises a CDR1 region (LTSYGVH) consisting of the amino acid sequence of SEQ ID NO: 28, a CDR2 region (VIWTDGSTTYNSALKS) consisting of the amino acid sequence of SEQ ID NO: 29, a CDR3 region (QDRYDGGIAY The heavy chain variable region of SEQ ID NO: 31 comprises a CDR1 region (LYDIH) consisting of the amino acid sequence of SEQ ID NO: 32, a CDR2 region (WIDTGNGDIKYSQKFQD) consisting of the amino acid sequence of SEQ ID NO: 33, a CDR3 (DNWGSRIDYFDY). ≪ / RTI >
Table 9 below summarizes the CDR regions of antibodies with high specificity for influenza A virus HA by heavy chain variable region and light chain variable region.
Variable area
Variable area
(SEQ ID NO: 1)
(SEQ ID NO: 2)
(SEQ ID NO: 3)
(SEQ ID NO: 4)
(SEQ ID NO: 9)
(SEQ ID NO: 10)
(SEQ ID NO: 11)
(SEQ ID NO: 12)
(SEQ ID NO: 19)
(SEQ ID NO: 20)
(SEQ ID NO: 21)
(SEQ ID NO: 22)
(SEQ ID NO: 23)
(SEQ ID NO: 24)
(SEQ ID NO: 25)
(SEQ ID NO: 26)
(SEQ ID NO: 27)
(SEQ ID NO: 28)
(SEQ ID NO: 29)
(SEQ ID NO: 30)
(SEQ ID NO: 31)
(SEQ ID NO: 32)
(SEQ ID NO: 33)
(SEQ ID NO: 34)
Variable area
(SEQ ID NO: 5)
(SEQ ID NO: 6)
(SEQ ID NO: 7)
(SEQ ID NO: 8)
(SEQ ID NO: 13)
(SEQ ID NO: 14)
(SEQ ID NO: 15)
(SEQ ID NO: 16)
A heavy chain variable region comprising one amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 9, 19, 23, 27 and 31 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5 or 13 Twelve antibodies are highly specific for influenza A virus HA.
ELISA Antibody combination test
In order to find the optimal combination of capture antibody and detection antibody for ELISA, four antibodies (# 3, 4, 6, 7) with affinity to each virus culture supernatant (# 3, ELISA was performed using 5 kinds of antibodies including antibodies for each SRID. Antibody combining conditions are shown in Table 10, and experiments were performed on 16 virus combinations for each virus culture supernatant.
As a result, it was confirmed that the measurement of the combination of antibodies other than the antibody combination of antibody No. 3 and SRID was a non-linear positive fluorescence absorber, and a highly false-positive absorbance was confirmed in a well not treated with the culture supernatant (Table 11 and Table 12).
Considering the high linearity (R 2 ≥0.97) and the results of Examples 1 and 2, only the combination of
Based on the above results, HA ELISA conditions were established and are shown in Table 12 below.
In the present invention, HA antigen can be quantitatively quantitated more efficiently than a conventional SRID method from a culture sample produced by infecting H1N1 subtype viruses of influenza type A through antibody screening obtained by H1N1 antigen immunization Antibody screening and HA ELISA conditions were established.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments, It will be obvious. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
<110> Green Cross Medical Science <120> Monoclonal Antibody Specific to Influenza A Virus, Methods for Treatment and Diagnosis of Influenza Infection <130> P14-B032 <160> 34 <170> Kopatentin 2.0 <210> 1 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> SF587 heavy chain variable region <400> 1 Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Asp 20 25 30 Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 35 40 45 Gly Ile Leu Gly Gly Gly Glu Arg Ser Tyr Tyr Asn Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Lys Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg His Gly Ser Ser Gly Tyr Val Asp Tyr Gly Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 2 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> SF587 heavy chain variable region CDR1 <400> 2 Asp Tyr Asp Met Ser 1 5 <210> 3 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> SF587 heavy chain variable region CDR2 <400> 3 Gly Ile Leu Gly Gly Gly Glu Arg Ser Tyr Tyr Asn Asp Ser Val Lys 1 5 10 15 Gly <210> 4 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> SF587 heavy chain variable region CDR3 <400> 4 His Gly Ser Ser Gly Tyr Val Asp Tyr Gly Met Asp Tyr 1 5 10 <210> 5 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> SF587 light chain variable region <400> 5 Asp Ile Val Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Asn 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Gly Val Ser Thr Leu Asp Ser Gly Val Ser Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Ser Asn Tyr Pro Met 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 6 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> SF587 light chain variable region CDR1 <400> 6 Arg Ala Ser Gln Gly Ile Gly Asp Asn Leu Gly 1 5 10 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> SF587 light chain variable region CDR2 <400> 7 Gly Val Ser Thr Leu Asp Ser 1 5 <210> 8 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> SF587 light chain variable region CDR3 <400> 8 Gly Val Ser Thr Leu Asp Ser 1 5 <210> 9 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> SF757 heavy chain variable region <400> 9 Val Lys Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Asp 20 25 30 Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 35 40 45 Gly Ile Leu Gly Gly Ser Glu Arg Ser Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Ser Thr Ile Ser Arg Asp Asn Ser Arg Lys Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg His Ser Trp Gly Ala Tyr Val Gln Tyr Gly Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 10 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> SF757 heavy chain variable region CDR1 <400> 10 Asp Tyr Asp Met Ser 1 5 <210> 11 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> SF757 heavy chain variable region CDR2 <400> 11 Gly Ile Leu Gly Gly Ser Glu Arg Ser Tyr Tyr Arg Asp Ser Val Lys 1 5 10 15 Gly <210> 12 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> SF757 heavy chain variable region CDR3 <400> 12 His Ser Trp Gly Ala Tyr Val Gln Tyr Gly Met Asp Val 1 5 10 <210> 13 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> SF757 light chain variable region <400> 13 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly 1 5 10 15 Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Asn Tyr 20 25 30 Gly Ile Asn Phe Ile Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Thr Ala Ser Asn Lys Gly Thr Gly Val Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Phe Cys Gln Gln Thr Lys 85 90 95 Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 <210> 14 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> SF757 light chain variable region CDR1 <400> 14 Arg Ala Ser Glu Ser Val Ser Asn Tyr Gly Ile Asn Phe Ile Asn 1 5 10 15 <210> 15 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> SF757 light chain variable region CDR2 <400> 15 Thr Ala Ser Asn Lys Gly Thr 1 5 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> SF757 light chain variable region CDR3 <400> 16 Gln Gln Thr Lys Glu Val Pro Tyr Thr 1 5 <210> 17 <211> 466 <212> DNA <213> Artificial Sequence <220> <223> SF587 light chain variable region nucleotide <400> 17 tacgactcac tatagggcga attgggcccg acgtcgcatg ctcccggccg ccatggcggc 60 cgcgggaatt cgattgacat tgtgctgacc cagtctccat ccttcctgtc tgcatctgtg 120 ggagacagag tcaccatcac ttgccgggca agtcagggca ttggagataa tttaggctgg 180 tatcaacaga aaccagggaa agcccctaag cgcctgatct atggtgtttc tactttggat 240 agtggcgtcc catcaaggtt cagcggcagt ggatctggga cagaattcac tctcacaatc 300 aacagcctgc agcctgaaga ttttgcaact tattactgtc tacagcacag taattaccct 360 atgtacactt ttggccaggg caccaagctg gaaatcaaac ggaatcacta gtgaattcgc 420 ggccgcctgc aggtcgacca tatgggagag tccnacgcgt gagcag 466 <210> 18 <211> 482 <212> DNA <213> Artificial Sequence <220> <223> SF757 light chain variable region nucleotide <400> 18 tgctcacgcg ttnggagctc tcccatatgg tcgacctgca ggcggccgcg aattcactag 60 tgattgacat ccagatgacg cagtctccag cttctttggc tgtgtctcca gggcagaggg 120 ccaccatcac ctgcagagcc agcgaaagtg ttagtaatta tggcattaac tttattaact 180 ggttccaaca gaaaccagga cagccaccca aactcctcat ctatactgca tccaacaaag 240 gaactggggt ccctgccagg tttagtggca gtgggtctgg gacagacttc accctcacaa 300 tcaatcctgt ggaggctgag gatactgcaa attatttctg tcagcaaact aaggaggttc 360 cgtacacgtt cggagggggg accaagctgg aaataaaacg gaatcgaatt cccgcggccg 420 ccatggcggc cgggagcatg cgacgtcggg cccaattcgc cctatagtga gtcgtattac 480 aa 482 <210> 19 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 1 heavy chain variable region <400> 19 Val Lys Leu Gln Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 1 5 10 15 Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Ser Leu Thr Lys Tyr Lys 20 25 30 Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 35 40 45 Ser Ile Ser Ser Thr Ser Arg Asp Val Asp Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Val Asp Asp Thr Ala Val Tyr Tyr Cys Thr 85 90 95 Arg Asp Gly Trp Leu Trp Gly Trp Asp Val Arg Ser Asn Tyr Tyr Tyr 100 105 110 Asn Ala Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 20 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 1 heavy chain variable region CDR1 <400> 20 Leu Thr Lys Tyr Lys Met Thr 1 5 <210> 21 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 1 heavy chain variable region CDR2 <400> 21 Ser Ile Ser Ser Thr Ser Arg Asp Val Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 22 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 1 heavy chain variable region CDR3 <400> 22 Asp Gly Trp Leu Trp Gly Trp Asp Val Arg Ser Asn Tyr Tyr Tyr Asn 1 5 10 15 Ala Leu Asp Val 20 <210> 23 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 2 heavy chain variable region <400> 23 Val Lys Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Gly Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Asp 20 25 30 Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 35 40 45 Gly Ile Leu Gly Gly Ser Glu Arg Ser Tyr Tyr Arg Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Lys Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg His Gly Ser Pro Gly Tyr Thr Leu Tyr Ala Trp Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 24 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 2 heavy chain variable region CDR1 <400> 24 Asp Tyr Asp Met Ser 1 5 <210> 25 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 2 heavy chain variable region CDR2 <400> 25 Gly Ile Leu Gly Gly Ser Glu Arg Ser Tyr Tyr Arg Asp Ser Val Lys 1 5 10 15 Gly <210> 26 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> mutatoin 2 heavy chain variable region CDR3 <400> 26 His Gly Ser Pro Gly Tyr Thr Leu Tyr Ala Trp Asp 1 5 10 <210> 27 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> mutation 3 heavy chain variable region <400> 27 Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser 1 5 10 15 Leu Ser Ile Thr Cys Thr Ile Ser Gly Phe Ser Leu Thr Ser Tyr Gly 20 25 30 Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu Val 35 40 45 Val Ile Trp Thr Asp Gly Ser Thr Thr Tyr Asn Ser Ala Leu Lys Ser 50 55 60 Arg Leu Ser Ile Ser Lys Asp Asn Ser Ser Ser Ser Gln Val Phe Leu Lys 65 70 75 80 Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 85 90 95 Gln Asp Arg Tyr Asp Gly Gly Ile Ala Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 <210> 28 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> mutation 3 heavy chain variable region CDR1 <400> 28 Leu Thr Ser Tyr Gly Val His 1 5 <210> 29 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> mutation 3 heavy chain variable region CDR2 <400> 29 Val Ile Trp Thr Asp Gly Ser Thr Thr Tyr Asn Ser Ala Leu Lys Ser 1 5 10 15 <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> mutation 3 heavy chain variable region CDR3 <400> 30 Gln Asp Arg Tyr Asp Gly Gly Ile Ala Tyr 1 5 10 <210> 31 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> mutation 4 heavy chain variable region <400> 31 Val Val Gln Leu Gln Glu Ser Gly Ala Glu Val Met Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Leu Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Pro Glu Trp Met 35 40 45 Gly Trp Ile Asp Thr Gly Asn Gly Asp Ile Lys Tyr Ser Gln Lys Phe 50 55 60 Gln Asp Arg Val Thr Ile Ser Arg Asp Thr Phe Glu Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Asn Trp Gly Ser Arg Ile Asp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 32 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> mutation 4 heavy chain variable region CDR1 <400> 32 Leu Tyr Asp Ile His 1 5 <210> 33 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> mutation 4 heavy chain variable region CDR2 <400> 33 Trp Ile Asp Thr Gly Asn Gly Asp Ile Lys Tyr Ser Gln Lys Phe Gln 1 5 10 15 Asp <210> 34 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> mutation 4 heavy chain variable region CDR3 <400> 34 Asp Asn Trp Gly Ser Arg Ile Asp Tyr Phe Asp Tyr 1 5 10
Claims (14)
(DYDMS) consisting of the amino acid sequence of SEQ ID NO: 2, a CDR2 region (GILGGGERSYYNDSVKG) consisting of the amino acid sequence of SEQ ID NO: 3, and a CDR3 region (HGSSGYVDYGMDY) consisting of the amino acid sequence of SEQ ID NO: 4. Heavy chain variable region,
(Ii) a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 10, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 11, and a CDR3 region (HSWGAYVQYGMDV) consisting of the amino acid sequence of SEQ ID NO: ,
(Iii) a CDR1 region (LTKYKMT) consisting of the amino acid sequence of SEQ ID NO: 20, a CDR2 region (SISSTSRDVDYADSVKG) consisting of the amino acid sequence of SEQ ID NO: 21, and a CDR3 region (DGWLWGWDVRSNYYYNALDV) consisting of the amino acid sequence of SEQ ID NO: ,
(Iv) a CDR1 region (DYDMS) consisting of the amino acid sequence of SEQ ID NO: 24, a CDR2 region (GILGGSERSYYRDSVKG) consisting of the amino acid sequence of SEQ ID NO: 25, and a CDR3 region (HGSPGYTLYAWDY) consisting of the amino acid sequence of SEQ ID NO: ,
(V) a CDR1 region (LTSYGVH) comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 region (VIWTDGSTTYNSALKS) consisting of the amino acid sequence of SEQ ID NO: 29, and a CDR3 region (QDRYDGGIAY) consisting of the amino acid sequence of SEQ ID NO: ;
(Vi) a CDR1 region (LYDIH) consisting of the amino acid sequence of SEQ ID NO: 32, a CDR2 region (WIDTGNGDIKYSQKFQD) consisting of the amino acid sequence of SEQ ID NO: 33, and a CDR3 region (DNWGSRIDYFDY) ; And
(b) a CDR1 region (RASQGIGDNLG) consisting of the amino acid sequence of SEQ ID NO: 6, a CDR2 region (GVSTLDS) consisting of the amino acid sequence of SEQ ID NO: 7, and a CDR3 region (LQHSNYPMYT) consisting of the amino acid sequence of SEQ ID NO: ; or
A light chain variable region comprising a CDR1 region (RASESVSNYGINFIN) consisting of the amino acid sequence of SEQ ID NO: 14, a CDR2 region (TASNKGT) consisting of the amino acid sequence of SEQ ID NO: 15, and a CDR3 region (QQTKEVPYT) consisting of the amino acid sequence of SEQ ID NO:
(a) culturing a recombinant cell having the ability to produce an influenza A virus hemagglutinin (HA) -specific mAb according to claim 5 to generate an influenza A virus hemagglutinin (HA) specific monoclonal antibody step; And
(b) recovering the generated influenza A virus hemagglutinin (HA) specific monoclonal antibody.
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WO2022052781A1 (en) * | 2020-09-14 | 2022-03-17 | 东莞市朋志生物科技有限公司 | Anti-influenza a virus antibody and kit |
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US20110076265A1 (en) * | 2008-05-27 | 2011-03-31 | Roberto Burioni | Monoclonal antibodies having homosubtype cross-neutralization properties against influenza a viruses subtype h1 |
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