WO2022098173A1 - 코로나바이러스 스파이크 단백질에 특이적인 항체 및 이의 용도 - Google Patents
코로나바이러스 스파이크 단백질에 특이적인 항체 및 이의 용도 Download PDFInfo
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Definitions
- the present invention relates to antibodies specific for the coronavirus spike (S) protein and uses thereof.
- Coronavirus was first discovered in chickens in 1937, followed by animals such as dogs, pigs, and birds, and then in humans in 1965.
- animals such as dogs, pigs, and birds, and then in humans in 1965.
- corona phenomenon which is a phenomenon that glows white around the moon.
- Coronaviruses are known to mainly cause pneumonia and enteritis in humans and animals, and are also known to occasionally cause nervous system infections and hepatitis.
- Coronavirus belongs to the coronaviridae and is a positive sense RNA virus with a spherical outer membrane, about 100-120 nm in size.
- Coronavirus consists of a total of five structural proteins, including the outermost spike protein (S), hemagglutinin-esterase (HE) protein, transmembrane (M) protein, small membrane (E) protein, and nucleocapsid (N) protein.
- S outermost spike protein
- HE hemagglutinin-esterase
- M transmembrane
- E small membrane
- N nucleocapsid
- the spike protein acts as a ligand that binds to the cell receptor and induces fusion between the host cell and the virus, and is known as the most mutable protein.
- coronavirus has been recognized as a pathogen that rarely infects humans and mainly infects animals such as dogs, pigs, and cattle. It is one of several viruses that cause respiratory symptoms even when infecting humans, and only causes a simple cold or intestinal disease such as diarrhea, which is not very dangerous for children.
- SARS Severe Acute Respiratory Syndrome
- MERS Middle East Respiratory Syndrome
- COVID-19 coronavirus disease 2019
- COVID-19 is an infectious disease caused by SARS-coronavirus-2, a disease that was first identified in Wuhan, the capital of Hubei province, China at the end of 2019, and has spread worldwide, resulting in a progressive pandemic. As of May 7, 2020, more than 3.75 million cases were reported in 187 countries, with 263,000 deaths and 1.24 million recoveries. Common symptoms are fever, cough, fatigue, shortness of breath and loss of smell and taste. In most cases, symptoms are mild, but some progress to viral pneumonia, multi-organ failure, and a cytokine storm. The time from onset of symptoms to onset is usually about 5 days, but can be between 2 and 14 days.
- the virus is spread from person to person primarily during close contact and sometimes through droplets that occur when coughing, sneezing, and talking. It is most contagious during the first 3 days after onset of symptoms and can be spread before symptoms appear or even late in the disease.
- a standard method for diagnosing it is using real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab.
- SARS-coronavirus-2 is known as a variant coronavirus belonging to the genus Beta coronavirus and is believed to have originated from bats, the primary carrier host for various coronaviruses (Antiviral Res., 101:45-56). , the exact route of infection has not yet been fully elucidated.
- One object of the present invention is to provide an antibody or antigen-binding fragment thereof that specifically binds to the coronavirus spike protein.
- Another object of the present invention is to provide a polynucleotide encoding the antibody or antigen-binding fragment, an expression vector comprising the polynucleotide, and a transformant comprising the expression vector.
- Another object of the present invention is to provide a method for preparing the antibody or the binding fragment.
- Another object of the present invention is to provide a composition for diagnosing coronavirus infection comprising the antibody or the binding fragment, and a kit comprising the same.
- Another object of the present invention is to provide an information providing method for diagnosing a coronavirus infection, comprising the step of detecting a coronavirus present in a biological sample using the antibody or the binding fragment.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating coronavirus comprising the antibody or the binding fragment.
- Another object of the present invention is to provide a method for treating coronavirus using the antibody or the binding fragment.
- the antibody of the present invention can be usefully used for detecting and diagnosing coronavirus, as well as having a neutralizing ability of coronavirus and can be usefully used for prevention and treatment of coronavirus-infected diseases.
- Figure 1 shows that the antigen is purified and the size and purity of the product are confirmed by SDS PAGE.
- Figure 2 shows the size and purity of the product through SDS PAGE after expression and purification of the anti SARS-CoV-2 antibody obtained through library screening. Specifically, the overall size of the antibody ( ⁇ 150kDa) was confirmed through Non-reduced PAGE, and the size of the heavy chain ( ⁇ 50kDa) and light chain ( ⁇ 25kDa) of the antibody was confirmed through Reduced PAGE.
- Figure 3 is the result of performing a sandwich ELISA to select antigen-specific anti-COVID-19 antibody, through which the antibody showing specific binding to the antigen was selected.
- 4 shows the results of an experiment on whether the selected Anti-SARS-CoV2 antibody also binds to the S(S1S2) protein of SARS-CoV and MERS-CoV, which are other betacoronaviruses.
- 5 is a result of confirming the results of IgG expression and purification of humanized clones by SDS-PAGE. Specifically, the overall size of the antibody ( ⁇ 150kDa) was confirmed through Non-reduced PAGE, and the size of the heavy chain ( ⁇ 50kDa) and light chain ( ⁇ 25kDa) of the antibody was confirmed through Reduced PAGE.
- Figure 6 is a result of performing a sandwich ELISA to screen antigen-specific anti-COVID-19 humanized antibody. Specifically, it is the result of confirming that all of the humanized clones maintain the same binding force as before.
- Figure 8a is a result of the kinetics among the binding properties of the antibody to the anti-SARS-CoV-2 antigen.
- the humanized antibody M4-4 had a dissociation constant value that was 10 times higher than that of the existing antibody M4.
- Figure 8b is a result of evaluating the binding ability of the antibody to the Alpha, Beta, Gamma mutations among the binding properties of the antibody to the anti-SARA-CoV-2 antigen. Specifically, it was confirmed that M4-4 had a very strong binding force to all mutations.
- Figure 9a is the result of observing the expression of ACE2 in ACE2-HEK293 cells by flow cytometry.
- 9B shows the results of measuring the SARS-Cov-2 pseudovirus neutralizing ability of the candidate antibody using SARS-CoV-2 pseudovirus and ACE2-HEK293 cells.
- 10a is a result of observation of Spike protein expression in HT1080-S cells by flow cytometry.
- Figure 10b is the result of measuring the ADCC efficacy of the candidate antibody using ADCC Effector cells and HT1080-S cells.
- Figure 10c is the result of measuring the ADCP efficacy of the candidate antibody using Fc ⁇ RIIa-H Effector cells and HT1080-S cells.
- FIG. 11 shows the neutralizing activity of anti-SARS-CoV-2 antibodies against authentic, wild type antigens, alpha, beta, and gamma mutant antigens. Specifically, the M4-4 antibody was observed to have a neutralizing effect equal to or greater than that of the comparative antibody in all cases.
- M4-4 binds to a wide epitope capable of 100% competition with REGN10987, S309, and ACE2 receptors.
- One aspect of the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to the coronavirus spike (S) protein.
- coronavirus refers to a positive-sense single-stranded RNA virus (ssRNA) belonging to the Coronaviridae family and having a spherical outer membrane, with a size of about 80-220 nm.
- Coronaviruses are the outermost spike (S) protein, hemagglutinin-esterase (HE) protein, membrane (M) protein, envelope (E) protein and nucleocapsid ( It is known to contain five structural proteins such as nucleocapsid, NP) protein (Lai and Homes, 2001. Fields Virology).
- the coronavirus may be SARS-CoV, SARS-CoV-2 or MERS-CoV, specifically SARS-CoV-2, but is not limited thereto.
- the coronavirus spike (S) protein may be a spike 1 (spike1, S1) protein in which some domains of the spike (S) protein of SARS-CoV-2 are truncated, but the antibody or antigen-binding fragment thereof of the present invention Coronaviruses capable of specifically binding are included without limitation.
- SARS-CoV-2 SARS-coronavirus-2
- COVID-19 Coronavirus Infectious Disease-19
- SARS-CoV-2 is a positive single-stranded RNA virus.
- SARS-CoV-2 is a taxonomic strain of SARS-CoV, has zoonotic origins, and is considered to have close genetic similarity to bat coronavirus.
- the SARS-CoV-2 is mainly spread through close contact between people and/or through droplets generated during coughing or sneezing, and mainly the receptor angiotensin converting enzyme 2 that has the spike (S) protein of the virus shell on the surface of human cells. It is known to enter human cells by binding to (angiotensin converting enzyme 2, ACE2).
- SARS-CoV-2 is RNA-dependent RNA polymerase, spike (S), membrane (M), envelope (E) and nucleocapsid (NP) proteins and/or genes encoding these proteins may include Among SARS-CoV-2 structural proteins, the spike (S) protein exists on the surface of virus particles and is involved in host cell invasion, and is divided into S1 and S2. The S1 protein interacts with the receptor of the host cell, and the receptor-binding domain (RBD) present in the S1 protein is known as a key site for binding to the ACE2 receptor present on the host cell surface. The S2 protein is involved in fusion with the host cell membrane.
- the antibody or fragment thereof provided in the present invention may specifically bind to the spike 1 (S1) protein, which is a cleaved form of a part of the spike (S) protein of SARS-CoV-2.
- the antibody that specifically binds to the coronavirus spike protein may be a mouse antibody, a chimeric antibody, or a humanized antibody.
- the antigenic determinant region (epitope, epitope) recognized by the antibody or fragment thereof provided in the present invention may be a part of the binding domain (CD) present in the spike 1 (S1) protein of SARS-CoV-2.
- the term "antibody” refers to a protein molecule serving as a ligand that specifically recognizes an antigen, including immunoglobulin molecules having immunological reactivity with a specific antigen, polyclonal antibody, monoclonal antibody, Includes both whole antibodies and antibody fragments.
- the term also includes chimeric antibodies (eg, humanized murine antibodies) and bivalent or bispecific molecules (eg, bispecific antibodies), diabodies, triabodies and tetrabodies.
- the term further includes single-chain antibodies having a binding function for neonatal Fc receptor (FcRn), scaps, derivatives of antibody constant regions, and artificial antibodies based on protein scaffolds.
- the whole antibody has a structure having two full-length light chains (LC) and two full-length heavy chains (HC), and each light chain is connected to the heavy chain by a disulfide bond.
- the whole antibody includes IgA, IgD, IgE, IgM and IgG, and IgG is a subtype, including IgG1, IgG2, IgG3 and IgG4.
- the antibody provided by the present invention may be an IgG antibody.
- fragment binding fragment of a polypeptide
- antibody fragment refers to any fragment of an antibody of the invention that retains the antigen-binding activity of the antibody.
- Exemplary antibody fragments include, but are not limited to, single chain antibodies, Fd, Fab, Fab', F(ab')2, dsFv or scFv.
- the Fd refers to the heavy chain portion included in the Fab fragment.
- the Fab has a structure having a light chain and a heavy chain variable region (variable region), a light chain constant region (framework region, FR), and a heavy chain first constant region (CH1 domain), and has one antigen-binding site.
- Fab' differs from Fab in that it has a hinge region comprising one or more cysteine residues at the C-terminus of the heavy chain CH1 domain.
- the F(ab')2 antibody is produced by forming a disulfide bond with a cysteine residue in the hinge region of Fab'.
- Fv (variable fragment) refers to a minimal antibody fragment having only a heavy chain variable region and a light chain variable region.
- dsFv double disulfide Fv
- scFv single chain Fv
- the heavy chain variable region and the light chain variable region are covalently linked through a peptide linker.
- Such antibody fragments can be obtained using proteolytic enzymes (for example, Fab can be obtained by restriction digestion of the entire antibody with papain, and F(ab')2 fragments can be obtained by digestion with pepsin), For example, it can be produced through genetic recombination technology.
- proteolytic enzymes for example, Fab can be obtained by restriction digestion of the entire antibody with papain, and F(ab')2 fragments can be obtained by digestion with pepsin
- epitopic determinant is also referred to as “epitope”, and refers to a region or region of an antigen to which an antibody or antibody fragment specifically binds to an antigen.
- the antibody or antigen-binding fragment thereof may be one that competitively binds to an epitope derived from a coronavirus spike to which casirivimab (REGN10933), imdevimab (REGN10987), and/or S309 binds.
- casirivimab casirivimab
- REGN10987 imdevimab
- S309 binds to an epitope derived from a coronavirus spike to which casirivimab (REGN10933), imdevimab (REGN10987), and/or S309 binds.
- the present invention is not limited thereto.
- the antibody provided in the present invention may be a monoclonal antibody.
- the term "monoclonal antibody” refers to an antibody molecule of a single molecular composition obtained from substantially the same antibody population, and such monoclonal antibody exhibits a single binding specificity and affinity for a specific epitope.
- immunoglobulins typically have heavy and light chains, each heavy and light chain comprising a constant region and a variable region (these regions are also known as domains).
- the variable regions of the light and heavy chains comprise three variable regions and four framework regions called complementarity-determining regions (hereinafter referred to as "CDRs").
- the CDRs mainly serve to bind to an epitope of an antigen.
- the CDRs of each chain are called sequentially CDR1, CDR2, CDR3, typically starting from the N-terminus, and are also identified by the chain in which the specific CDR is located.
- an immunoglobulin has a heavy chain and a light chain, each heavy and light chain comprising a constant region and a variable region.
- the variable regions of the light and heavy chains include three complementarity-determining regions (hereinafter referred to as "CDRs") and four framework regions (hereinafter referred to as "FRs”) called complementarity determining regions.
- CDRs complementarity-determining regions
- FRs framework regions
- the CDRs of each chain mainly play a role in binding to an epitope of an antigen, and are typically named CDR1, CDR2, and CDR3 sequentially, starting from the N-terminus.
- the FR of each chain may be sequentially named FR1, FR2, FR3, FR4 starting from the N-terminus.
- variable region of the heavy chain may be named 'V H ', the variable region of the light chain as 'V L ', and the CDRs of the heavy chain are 'V H -CDR1', 'V H -CDR2', 'V', respectively.
- the CDRs of the light chain are respectively 'V L -CDR1', 'V L -CDR2', 'V L -CDR3'
- the FRs of the heavy chain are 'V H -FR1', 'V H -FR2, respectively ', 'V H -FR3', 'V H -FR4'
- the FR of the light chain is named 'V L -FR1', 'V L -FR2', 'V L -FR3', 'V L -FR4' can be
- the antibody or binding fragment thereof that specifically binds to the coronavirus spike protein of the present invention comprises any one of SEQ ID NOs: 5 to 45, SEQ ID NOs: 87 to 91, SEQ ID NOs: 97 to 115 any one or more heavy chain variable regions selected from the group; and SEQ ID NOs: 46 to 86, SEQ ID NOs: 92 to 96, and SEQ ID NOs: 116 to 131 may include any one or more light chain variable regions selected from the group comprising any one of the sequences.
- the antibody or antigen-binding fragment thereof may have a cross-reactivity with two or more types of coronaviruses.
- the coronavirus may be SARS-CoV, SARS-CoV-2 or MERS-CoV, but is not limited thereto as long as it has a cross-reactivity.
- the antibody or antigen-binding fragment thereof having a cross-reactivity to the two or more coronaviruses is SEQ ID NO: 6 to 12, SEQ ID NO: 14 to 22, SEQ ID NO: 24, 25, 32, 37, 45, SEQ ID NO: 87 to 91 , and any one or more heavy chain variable regions selected from the group comprising any one of SEQ ID NOs: 97 to 99; And any one or more light chain variable regions selected from the group comprising any one of SEQ ID NOs: 47 to 53, SEQ ID NOs: 55 to 63, SEQ ID NOs: 65, 66, 73, 78, 86, and SEQ ID NOs: 92 to 96 It may include, but is not limited to.
- human antibody refers to a molecule derived from human immunoglobulin, wherein the entire amino acid sequence constituting the antibody, including the complementarity determining region and structural region, is composed of the amino acid sequence of human immunoglobulin.
- Human antibodies are commonly used for the treatment of human diseases, which may have three or more potential advantages. First, it interacts better with the human immune system, for example in complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). Thus, it is possible to more efficiently destroy the target cells. Second, it has the advantage that the human immune system does not recognize the antibody as foreign.
- the human antibodies according to the present invention have a preventive or therapeutic effect on coronavirus, particularly SARS-CoV-2, and thus can be usefully used in the treatment of SARS-CoV-2.
- the human monoclonal antibody of the present invention may include a constant region derived from IgG, IgA, IgD, IgE, IgM, a combination thereof, or a hybrid thereof.
- dimer or multimers may be formed from two or more constant regions selected from the group consisting of constant regions of IgG, IgA, IgD, IgE and IgM.
- hybrid means that sequences corresponding to the constant regions of immunoglobulin heavy chains of two or more different origins exist in the constant regions of single-chain immunoglobulin heavy chains, for example, IgG, IgA, IgD, IgE And hybridization of domains consisting of 1 to 4 domains selected from the group consisting of CH1, CH2, CH3 and CH4 of IgM is possible.
- binding to an antibody or antigen fragment thereof may have the same or different origins of the variable region and the constant region, and may have the same or different origins of the CDR, variable regions and constant regions excluding them.
- the antibody or antigen fragment binding thereof of the present invention is a heavy chain CDR1 of SEQ ID NO: 139; heavy chain CDR2 of SEQ ID NO: 140; and a heavy chain variable region comprising a heavy chain CDR3 of SEQ ID NO: 141 and a light chain CDR1 of SEQ ID NO: 142 or 148; light chain CDR2 of SEQ ID NO: 143 or 146; and a light chain variable region comprising the light chain CDR3 of SEQ ID NO: 144 or 147, but is not limited thereto.
- antibody or antigen fragment binding thereof is a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 103; and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 119, but is not limited thereto.
- an antibody comprising a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 103 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 119 was named "M4-4" or "MG1141A”.
- the antibody of the present invention is a heavy chain FR (Framework region) 1 of SEQ ID NO: 148, 152 or 155; heavy chain FR2 of SEQ ID NO: 149 or 156; heavy chain FR3 of SEQ ID NO: 150, 153 or 157; and a heavy chain variable region comprising a heavy chain FR4 of SEQ ID NO: 151, 154 or 158 and a light chain FR1 of SEQ ID NO: 159, 163 or 166; light chain FR2 of SEQ ID NO: 160 or 167; light chain FR3 of SEQ ID NO: 161, 164 or 168; and a light chain variable region comprising a light chain FR4 of SEQ ID NO: 162, 165 or 169, but is not limited thereto.
- FR Framework region 1 of SEQ ID NO: 148, 152 or 155
- heavy chain FR2 of SEQ ID NO: 149 or 156 heavy chain FR3 of SEQ ID NO: 150, 153 or 157
- the present invention provides a method for preparing the novel antibody or antigen-binding fragment thereof.
- novel antibody or antigen-binding fragment thereof of the present invention can be easily prepared by known antibody production techniques. For example, this can be done by preparing hybridomas using B lymphocytes obtained from immunized animals (Koeher and Milstein, 1976, Nature, 256:495), or by using phage display technology.
- the present invention is not limited thereto.
- An antibody library using phage display technology is a method of expressing an antibody on the surface of a phage by directly obtaining an antibody gene from B lymphocytes without producing a hybridoma.
- phage display technology many existing difficulties related to the generation of monoclonal antibodies by B-cell immortalization can be overcome.
- the phage display technology comprises the steps of 1) inserting an oligonucleotide of a random sequence into a gene region corresponding to the N-terminus of the coat protein pIII (or pIV) of the phage; 2) expressing a fusion protein of a portion of a native envelope protein and a polypeptide encoded by the random sequence oligonucleotide; 3) treating a receptor material capable of binding to the polypeptide encoded by the oligonucleotide; 4) eluting the peptide-phage particles bound to the receptor using a low pH or binding competitive molecule; 5) amplifying the eluted phage in a host cell by panning; 6) repeating the method to obtain the desired amount; and 7) determining the sequence of the active peptide from the DNA sequence of the phage clones selected by panning.
- the present invention provides a polynucleotide encoding the novel antibody, an expression vector comprising the polynucleotide, and a transformant comprising the expression vector.
- Another aspect of the present invention provides an expression vector comprising the antibody or antigen-binding fragment thereof provided in the present invention and a host cell into which the vector is introduced.
- the antibody is the same as described above.
- the expression vector comprising the polynucleotide encoding the antibody provided in the present invention is not particularly limited thereto, but mammalian cells (eg, human, monkey, rabbit, rat, hamster, mouse cell, etc.), plant cell, yeast It may be a vector capable of replicating and/or expressing the polynucleotide in a eukaryotic or prokaryotic cell, including a cell, insect cell or bacterial cell (eg, E. coli, etc.), specifically, in a host cell, the nucleotide is It may be a vector that is operably linked to an appropriate promoter for expression and contains at least one selectable marker.
- the polynucleotide may be introduced into a phage, a plasmid, a cosmid, a mini-chromosome, a virus, or a retroviral vector.
- the expression vector comprising the polynucleotide encoding the antibody may be an expression vector comprising a polynucleotide encoding a heavy chain or a light chain of the antibody, respectively, or an expression vector comprising both a polynucleotide encoding a heavy chain or a light chain.
- the transformant introduced with the expression vector provided in the present invention is not particularly limited thereto, but bacterial cells such as Escherichia coli, Streptomyces, Salmonella typhimurium, etc. transformed by introducing the expression vector; yeast cells; Fungal cells such as Pichia pastoris; insect cells such as Drosophila and Spodoptera Sf9 cells; CHO (chinese hamster ovary cells), SP2/0 (mouse myeloma), human lymphoblastoid, COS, NSO (mouse myeloma), 293T, Bow melanoma cells, HT-1080, BHK ( animal cells such as baby hamster kidney cells, HEK (human embryonic kidney cells), and PERC.6 (human retinal cells); or plant cells.
- yeast cells Fungal cells such as Pichia pastoris
- insect cells such as Drosophila and Spodoptera Sf9 cells
- CHO chinese hamster ovary cells
- SP2/0 mouse my
- introduction refers to a method of delivering a vector including a polynucleotide encoding the antibody to a host cell.
- introduction may include calcium phosphate-DNA co-precipitation, DEAE-dextran-mediated transfection, polybrene-mediated transfection, electroshock method, microinjection method, liposome fusion method, lipofectamine and protoplast fusion method, etc. It can be carried out by several methods known in the art.
- transduction means the delivery of a target object into a cell using virus particles by means of infection.
- the vector can be introduced into the host cell by gene bombardment or the like. In the present invention, introduction may be used in combination with transformation.
- Another aspect of the present invention provides a composition for diagnosing coronavirus infection, comprising the antibody or antigen-binding fragment thereof provided in the present invention.
- Another aspect of the present invention provides a kit for diagnosing coronavirus infection, comprising the antibody or antigen-binding fragment thereof provided in the present invention.
- Another aspect of the present invention is an antibody or antigen-binding fragment thereof provided in the present invention; or a composition for diagnosing infection comprising the same; Or, by using a kit comprising the composition, it provides a method for diagnosing a coronavirus infection or an information providing method for diagnosis, comprising the step of detecting a coronavirus present in a biological sample isolated from an individual suspected of having a coronavirus infection.
- diagnosis refers to determining the susceptibility of an individual to a specific disease or disorder, determining whether the individual currently has a specific disease or disorder, or providing information on the efficacy of treatment This includes monitoring the condition of an object for harm.
- the diagnosis may be to confirm whether or not a coronavirus-infected disease occurs.
- coronavirus infection disease refers to a disease caused by an infection in which a coronavirus enters the body of a host organism.
- the coronavirus may be SARS-CoV-2 (SARS-coronavirus-2).
- the coronavirus-infected disease may be COVID-19.
- composition for diagnosing coronavirus infection of the present invention may include an antibody or antigen-binding fragment thereof other than the antibody or antigen-binding fragment thereof of the present invention.
- substances necessary for the antigen-binding reaction of the antibody or antigen-binding fragment thereof of the present invention for example, reagents may be further included.
- substances necessary for detecting this binding, substances for stabilizing the antibody or antigen-binding fragment thereof of the present invention, etc. may be further included.
- the antibody or antigen-binding fragment thereof included in the diagnostic composition of the present invention may be labeled for detection.
- the various methods available for molecular labeling are well known to those skilled in the art and are contemplated within the scope of the present invention.
- label types examples include enzymes, radioactive isotopes, colloidal metals, fluorescent compounds, chemiluminescent compounds and bioluminescent compounds.
- markers include fluorescent substances (eg, fluorescein, rhodamine, Texas red, etc.), enzymes (eg, horseradish peroxidase, beta-galactosidase, alkaline phosphatase), radioactive isotopes (eg, 32P or 125I), biotin, digoxigenin, colloidal metals, chemiluminescent or bioluminescent compounds (eg, dioxetane, luminol or acridinium). Labeling methods such as covalent bonding of enzymes or biotinyl groups, iodination, phosphorylation, and biotinylation are also well known.
- the kit of the present invention may further include reagents and instruments necessary for detecting the binding of the antibody or antigen-binding fragment thereof to the antigen of the present invention.
- kit container of the present invention may contain a solid carrier.
- Antibodies of the invention may be attached to a solid carrier, which may be porous or non-porous, planar or non-planar.
- the kit comprises a solid carrier; a sample pad receiving a sample to be analyzed and having a buffer input unit and a sample input unit; a conjugate pad comprising an antibody that specifically binds to the coronavirus contained in the sample introduced from the sample pad; a signal detection pad including a signal detection unit for detecting whether the coronavirus is present in the sample and a control unit for checking whether the sample has moved to the absorbent pad regardless of the presence or absence of an analyte; and an absorbent pad that absorbs the sample on which the signal detection reaction has been completed, but is not limited thereto.
- the kit of the present invention may be in the form of an enzyme-linked immunosorbent assay (ELISA) kit.
- ELISA enzyme-linked immunosorbent assay
- the term "ELISA" of the present invention is also referred to as an enzyme immunoassay method, and is a method of quantifying using absorbance through the reaction of an enzyme with a substrate by binding an enzyme to an antibody to form an antigen-antibody complex.
- the ELISA is a direct ELISA using a labeled antibody recognizing an antigen attached to a solid support, an indirect ELISA using a labeled secondary antibody recognizing a capture antibody in a complex of an antibody recognizing an antigen attached to a solid support, and a solid support.
- Direct sandwich ELISA using another labeled antibody that recognizes an antigen in a complex of an attached antibody and antigen reacts with another antibody that recognizes an antigen in a complex of an antibody attached to a solid support and an antigen and indirect sandwich ELISA using labeled secondary antibodies.
- the antibody or fragment thereof of the present invention may be used to detect the presence of coronavirus in the biological sample by contacting the biological sample and confirming the reaction.
- the biological sample may be any one selected from the group consisting of sputum, saliva, blood, sweat, lung cells, lung tissue mucus, respiratory tissue, and saliva, but is not limited thereto and can be prepared by a conventional method known to those skilled in the art. It is possible.
- the information providing method for the diagnosis of coronavirus infection of the present invention comprises the steps of (a) contacting the antibody or antigen-binding fragment thereof provided in the present invention with a biological sample; and (b) detecting the complex of the antibody or antigen-binding fragment thereof of the present invention and the coronavirus spike protein formed by the contact.
- the complex of the antibody or fragment thereof and the coronavirus spike protein in step (b) may be a binding domain (CD) site conjugate of the SARS-CoV-2 spike protein.
- the term “antigen-antibody complex” refers to a combination of a corresponding protein antigen in a sample and an antibody that recognizes it.
- the detection of the antigen-antibody complex can be detected using methods known in the art, for example, spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, chemical and other methods, specifically colormetric method, electrochemical method, fluorimetric method, luminometry, particle counting method, visual assessment and scintillation counting method It can be detected by any method selected from the group consisting of, western blotting, ELISA, radioimmunoassay, radioimmunodiffusion, ouchterlony immunodiffusion method, rocket Immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complete fixation assay, fluorescence-activated cell sorting (FACS), protein chip, etc. can be used. It is not limited thereto.
- Another aspect of the present invention provides a pharmaceutical composition for preventing or treating coronavirus infection comprising the antibody or binding fragment thereof.
- the coronavirus may be SARS-CoV-2.
- the composition may be for prevention or treatment of COVID-19.
- COVID-19 refers to a disease caused by infection with SARS-CoV-2. Since the antibody of the present invention exhibits neutralizing ability and infection inhibition ability for SARS-CoV-2, it can be used for prevention or treatment of COVID-19.
- prevention may mean any action that suppresses or delays the onset of coronavirus infection by administration of the composition
- treatment refers to symptoms caused by coronavirus infection by administration of the composition can mean any action that is improved or is changed for the better.
- the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
- the term "pharmaceutically acceptable carrier” refers to a carrier or diluent that does not stimulate the organism and does not inhibit the biological activity and properties of the administered compound.
- acceptable pharmaceutical carriers for compositions formulated as liquid solutions are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostats may be added as needed.
- diluents such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
- the pharmaceutical composition may be in various oral or parenteral formulations.
- formulation it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc.
- lubricants such as magnesium stearate and talc are also used.
- Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
- Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
- the pharmaceutical composition is selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories It may have any one formulation.
- composition of the present invention is administered in a pharmaceutically effective amount.
- the term "pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is dependent on the type and severity of the subject, age, sex, and cancer. It may be determined according to the type, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs, and other factors well known in the medical field.
- the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art.
- Another aspect of the present invention provides a method for preventing or treating a coronavirus infection using the antibody.
- the coronavirus may be SARS-CoV-2.
- the method may include administering the antibody to a subject suspected of being infected with SARS-CoV-2.
- the method may be a method comprising administering a pharmaceutical composition further comprising an antibody and a pharmaceutically acceptable carrier to a subject infected with or infected with a coronavirus, wherein the pharmaceutically acceptable carrier is as described above. same as bar
- the subject includes mammals, birds, etc. including cattle, pigs, sheep, chickens, dogs, humans, and the like, and includes, without limitation, individuals whose coronavirus infection is treated by administration of the composition of the present invention.
- the antibody may be administered single or multiple in a pharmaceutically effective amount.
- the antibody may be administered in the form of a liquid, powder, aerosol, capsule, enteric-coated tablet or capsule or suppository.
- Routes of administration include, but are not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, endothelial administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, and the like.
- the method may also be used for preventing or treating a coronavirus infectious disease, specifically, preventing or treating an infectious disease of SARS-CoV-2.
- a coronavirus infectious disease specifically, preventing or treating an infectious disease of SARS-CoV-2.
- it may be used for the prevention or treatment of COVID-19, but is not limited thereto.
- Another aspect of the present invention is the use of the antibody for the manufacture of a medicament for the prevention or treatment of a coronavirus infection.
- the drug may be used for the prevention or treatment of SARS-CoV-2 infectious disease, for example, COVID-19, but is not limited thereto.
- the antibody and the prevention or treatment of SARS-CoV-2 infection are the same as described above.
- Genes encoding the outer domain (spike-ECD) and RBD (RBD-his) of the SARS-CoV-2 spike glycoprotein were synthesized and cloned into the pCIW mammalian expression vector with a C-terminal 6x histidine tag.
- Genes encoding RBD-Fc and human ACE2-Fc were cloned into the pCIW vector.
- the pCIW mammalian vector was transformed into Expi293F TM cells (Cat. No. A1435101). All steps for the analysis of expression were performed according to the manufacturer's instructions. After 5-6 days of cell culture, cells were harvested by centrifugation, and the supernatant was passed through a 0.22 ⁇ m filter to remove cell debris.
- Ni-NTA resin was added to the supernatant for His-tag purification of the recombinant protein.
- MabSelect Xtra Cat. no. 17-5269-02, GE Healthcare
- PBS phosphate-buffered saline
- Zeba Spin Desalting Columns Protein concentration was quantified using a Nanodrop 2000C spectrophotometer (Thermo Scientific) (Fig. 1).
- a human B cell-derived library, a mouse immune library, and a human domain antibody synthesis library were constructed and screened.
- a commonly used single clone ELISA method was used.
- the monoclonal ELISA screening method is a method to check whether the antibody is specific to the spike protein by mixing the spike protein with the antibody expressed from a single clone. 5 (clones M1-M5), 3 (clones 5E9, 6D9, 6H10) spike protein-specific clones were obtained from the human domain antibody synthesis library.
- the heavy chain and light chain sequences of the antibody obtained through sequence analysis were confirmed (FIG. 3, Table 1, Table 2, Table 3).
- the clones obtained from the human domain antibody synthesis library included only heavy chain sequence information because the synthetic library itself is a library consisting only of heavy chain sequences.
- the anti-SARS-CoV-2 scFv was converted to human IgG1 format by subcloning into pCIW.
- Expi293F TM cells were prepared in 30 mL Expi293 TM expression medium at a concentration of 2.5 ⁇ 10 6 cells/mL (37° C., 8% CO 2 , 125 rpm, viability ⁇ 95%). These cells were transfected with a DNA mixture consisting of 30 ⁇ g of DNA (pCLW-anti-SARS-CoV-2 heavy chain: 15 ⁇ g, pcIw-anti-SARS-CoV-2 light chain: 15 ⁇ g), OptiProTM SEM medium and ExpiFectamineTM 293 reagent. converted.
- the desalting column was centrifuged at 1000 g for 2 min to filter the preservation solution. After adding PBS buffer to the volume of the column, centrifugation was performed at 1000 g for 2 min, and column washing was repeated 3 times. After adding the sample, centrifugation was performed for 1000 g and 2 min, and the concentration was measured again using a 280 nm wavelength.
- Antigens are Recombinant SARS (1-1190) (Beta Lifescience, BLIT-0210), SARS-CoV-2 (2019-nCoV) Spike Protein (S1+S2 ECD, His tag) (Sino Biological., 40589-V08B1), MERS -CoV Spike Protein (ECD, aa 1-1297, His Tag) (Sino Biological., 40069-V08B) was used.
- the antigen was removed from the ELISA plate and washed 3 times with PBS + tween20 0.05%. Each well coated with the antigen was blocked with 200 ⁇ l of PBS + BSA 5% at room temperature for 1 hour. After 1 hour, wash 3 times with PBS + tween 20 0.05%. 35 antibody concentrations were measured by dilution to 300 nM. 50 ⁇ l of the diluted antibody was put into each well and allowed to bind at room temperature for 1 hour. It was again washed 3 times with PBS + tween 20 0.05%. 50 ⁇ l of Anti-human Fc-HRP (3000: 1) was put into each well and incubated at room temperature for 1 hour.
- Humanization was performed on M4 and M5 clones among mouse immune clones.
- the framework region sequences of the M4 and M5 antibodies were identified as mouse germline sequences IGHV5-6 and IGKV6-32, respectively.
- M4 and M5 clones have the same HCDR sequence and different LCDR sequences.
- CDR-grafting a general method, CDR-grafting, was used. Igblast search was performed to search for human frameworks with the highest homology to M4 and M5. As a result of the search, it was confirmed that the homology was the highest with IGHV3-21 and IGKV1-39, and the CDRs of M4 and M5 were grafted with human antibody skeletons IGHV3-21 and IGKV1-39, respectively.
- a variant was designed by introducing additional mutations after identifying core residues that play an important role in determining antibody structure stability and canonical structure of CDRs (Table 5).
- the gene sequences of the M4 and M5 antibodies of which the design was completed were synthesized and used as inserts (SEQ ID NOs: 132 to 138).
- the synthesized gene was cloned by the infusion cloning method, and the culture and purification of the chimeric antibody were performed as previously described (FIG. 5).
- ELISA was performed to confirm that each humanized antibody specifically binds to the SARS-CoV2 spike protein.
- Spike protein was coated on an ELISA plate at 3 ⁇ g/ml and 100 ⁇ l per well at 4°C overnight. The next day, the spike protein of the ELISA plate was removed and blocked with 200 ⁇ l of PBS + BSA 2% in each well at 37° C. for 1 hour. Washed 3 times with PBS + tween 20 0.05%. M4, M5, and each humanized antibody was diluted 11 times with PBS from the initial concentration (100 nM) to a final concentration of 0.5 pM. 100 ⁇ l of the diluted antibody solution was placed in each well and bound at 37° C. for 1 hour.
- both M4-4 and M5-4 were confirmed to have a binding force greater than or equal to the WT RBD level for the mutant.
- REGN10933 and REGN10987 used as comparative antibodies when treated alone, it was confirmed that the binding force to Y453F and N439K mutant was reduced by 50% or more, respectively (FIG. 7).
- Anti-SARS-CoV-2 spike protein antibodies showed different binding properties to the spike protein and its variants, alpha (UK), beta (South Africa) and gamma (Brazil), antigen-antibody binding properties were checked. .
- the kinetics were determined using a Biacore T-200 biosensor (Cytiva). The antibody was diluted with HBS-EP buffer to a concentration of 10 ⁇ g/mL and immobilized on the SA chip at a flow rate of 10 ⁇ L/min until Rmax reached 200Ru.
- the RBM-targeting neutralizing antibody REGN10933 showed similar binding affinity to the alpha variant as in the original RBD, but it was confirmed that the binding of REGN10933 was significantly reduced in the beta and gamma variants. In contrast, M4 and M4-4 exhibited similar binding affinities for pre-existing RBDs and all variants (Fig. 8b).
- the antibody of the present invention maintains the ability to bind to the newly generated SARS-CoV-2 mutant, and has binding ability to neutralize various mutant viruses.
- Pseudoviruses carrying the full-length spike protein of SARS-CoV-2 and variants carrying the firefly luciferase reporter gene were produced in Lenti-X 293T cells (Takara). That is, 10 ⁇ g of psPAX2 (Addgene), 10 ⁇ g of pLVX-Luciferase, and 10 ⁇ g of SARS-CoV-2 S (codon-optimized) expression plasmid were injected with polyethylenimine (mass ratio 1:2) into Lenti-X 293T cells.
- the ACE2-HEK293 stable cell line was maintained in DMEM medium containing 10% fetal bovine serum and an antibiotic-antifungal cocktail.
- 96-well flat-bottom plates were coated with 10 ⁇ g/mL collagen I and incubated at 37 °C in an atmosphere containing 5% CO 2 for 4 h.
- ACE2-HEK293 cells were suspended in DMEM and aliquoted in a collagen-coated 96-well flat bottom plate at 1 ⁇ 10 5 cells/well and cultured for 24 hours.
- Antibodies were serially diluted 3-fold from 10 ⁇ g/mL (66.67 nM) with DMEM containing 2% FBS and antibiotic-antifungal cocktail.
- Antibody dilutions were mixed 1:1 with pseudovirus and incubated at 37 °C in an atmosphere containing 5% CO 2 for 1 h.
- the supernatant was removed from ACE2-HEK293 cells and replaced with 50 ⁇ L of antibody-pseudovirus mixture. Then, the cells were incubated for 1 h at 37 °C in an atmosphere containing 5% CO 2 . 50 ⁇ L of infection medium was added to the cells, and the cells were further incubated at 37 °C in an atmosphere containing 5% CO 2 for 48 h.
- Cells were lysed with 5X reporter lysis buffer (Promega) and relative luciferase activity was determined using a luciferase assay system and a luminometer.
- Relative luciferase units were converted to percent neutralization and plotted as a nonlinear regression curve fitted to Prism Software (GraphPad, Prism 8.0). As a result, it was confirmed that the M4 and M5 chimeric antibodies and the humanized candidate antibodies M4-4,5,7,8 and M5-4,5,7,8 showed a neutralizing ability similar to that of REGN10933 (Fig. 9a, b).
- pcDNA3.1-spike cDNA of SARS-CoV-2 was transfected into a cell line expressing the SARS-CoV-2 S protein. was selected with 1.5 mg/mL Geneticin. Expression of SARS-CoV-2 S protein was confirmed by flow cytometry (FACS LSR Fortessa, BD Biosciences) using the anti-SARS-CoV-2 antibody REGN10933 (FIG. 10a).
- ADCC and ADCP effects were assayed to determine whether anti-SARS-CoV-2 antibody exhibits Fc-mediated antibody-dependent phagocytosis.
- HT1080-S cells were used as target cells and Jurkat-NFAT-Luc/Fc ⁇ RIIIa were used as effector cells.
- HT1080-S cells were cultured in an appropriate medium for 18 hours, and ADCC assay buffer was added thereto. Thereafter, the antibody was diluted and added, followed by reaction for 15 minutes. After adding effector cells and culturing for 18 hours, Bio-Glo luciferase assay reagent was added and luminescence was measured according to the manufacturer's instructions.
- the humanized SARS-CoV-2 antibody, M4-4 can neutralize WT and selected spike mutant SARS-CoV-2 pseudovirus particles, and it was confirmed that the neutralization efficacy was similar to that of the Regeneron cocktail ( FIG. 11 ).
- Epitope binning was performed in three steps using the BLI system (Octet Qke). Step 1 involves antigen immobilization; Step 2 involved primary antibody binding and Step 3 involved secondary antibody binding. A baseline signal was confirmed by setting a reference step of 60 seconds between each step.
- step 1 20 ⁇ g/mL purified recombinant SARS-CoV-2 spike protein or RBD His was immobilized on a pre-hydrated antipenta-His biosensor at 1000 rpm for 200 seconds.
- step 2 37.5 ⁇ g/mL of different primary binding Abs were bound for 300 seconds.
- one type of secondary antibody (18.75 ⁇ g/mL) was bound for 150 seconds to confirm the degree of self-binding and competition. The degree of competition was defined as a percentage.
- M4-4 can bind to a wider epitope than REGN10933, REGN10987, and S309.
- BioLuminate in Schrodinger Suite was used for scFv homology modeling of M4-4 using the structures of anti-PD1 (PDB code: 6JJP) and anti-SIRP ⁇ antibody (PDB code: 6 NMR) as templates for heavy and light chains, respectively.
- Docking the scFv structure of M4-4 to RBD (PDB code: 6M0J) was performed using PIPER in BioLuminate56.
- the distance between Lys440 and Thr500 of the RBD and CDR loops was limited to between 2 ⁇ and 10 ⁇ based on the results of epitope binning.
- BioLuminate proposed 30 best complexes with 70,000 possible protein-protein configurations.
- the final complex for M4-4 was selected according to cluster size and conformance with epitope binning results, followed by energy minimization.
- the predicted binding site of M4-4 to RBD was found to be a position capable of interfering with the binding of REGN10933, REGN10987, S309 and ACE2 receptors.
- the epitope of M4-4 FOG. 13
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Abstract
Description
클론 | 가변영역 | 아미노산서열 | 서열번호 |
1 | 중쇄 | EVQLVQSGAEVQKPGSSVKVSCKASGGTFSSYPISWVRQAPGQGLEWMGKIIPILGIPNYAQRFQGRVTITADKSTGTAYLDLSSLSSEDTAVYYCARAGGYSGYGAHYYMDVWGKGTLVTVSS | 5 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSVFGGGTKLTVLG | 46 | |
2 | 중쇄 | EVQLVESGGGLIQPGGSLRLSCAASGFTFSNFAMSWVRQAPGKGLEWVSGISGSGGSTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVFYCAKDLYGGPGSSTFDYWGQGTLVTVSS | 6 |
경쇄 | DIVMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPLTFGPGTKVDIKR | 47 | |
3 | 중쇄 | QVQLVQSGGGLIQPGGSLRLSCAASGFTFSNFAMSWVRQAPGKGLEWVSGISGSGGSTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVFYCAKDLYGGPGSSTFDYWGQGTLVTVSS | 7 |
경쇄 | AIWMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGNGSGTDFTLTISSLQPEDFAIYYCQQSYSTPLTFGGGTKVEIKR | 48 | |
4 | 중쇄 | EDQLVESGGGLIQPGGSLRLSCAASGFTFSNFAMSWVRQAPGKGLEWVSGISGSGGSTSYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVFYCAKDLYGGPGSSTFDYWGQGTLVTVSS | 8 |
경쇄 | DIVMTQTPSSLSASVGDRVTITCQASQDISIYLNWYQQKPGKAPKLLIYDASILETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYFSYPITFGGGTKVEIKR | 49 | |
5 | 중쇄 | EDQLVESGGGLIQPGGSLRLSCAASGFTFSNFAMSWVRQAPGKGLEWVSGISGSGGSTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVFYCAKDLYGGPGSSTFDYWGQGTLVTVSS | 9 |
경쇄 | DIQMTQSPSSLSASVGDRVTITCQASEDITDYLNWYQQKPGKAPKLLIYDASILETGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYDGLPLFGPGTKVDIKR | 50 | |
6 | 중쇄 | QLQLQESGGGWVQPGRSLRLTCATSGFTFDDYAMHWVRQAPGKGLEWVSGITWNSDSIGYADSVKGRFTISRDDAKNSLYLQMDNLRPEDTALYYCVKDSAYRILPYWYFDLWGRGTTVTVSS | 10 |
경쇄 | DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQIPGKAPKLLMYAATRLHSGVPSRFSGSGSGTDFTLTIYSLQPEDFATYYCQQSFGSPYTFGQGTKLEIKR | 51 | |
7 | 중쇄 | EVQLVESGGDLVQPGGSLRISCAASGFAVSNNYMSWVRQAPGKGLEWVSVIHTDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGFGELLGSDAFDIWGQGTMVTVSS | 11 |
경쇄 | AIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPHTFGPGTKVDIKR | 52 | |
8 | 중쇄 | QVQLVQSGGGLVQPGGSLRLSCVASGFTFRTFEMNWVRQAPGKGLEWVSYISPSGSSIYNADSVKGRFTISRDNARNSLYLQMNSLRAEDTAVYYCAREGGSYYGGSAFDIWGQGTMVTVSS | 12 |
경쇄 | SYELTQPSSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVLG | 53 | |
9 | 중쇄 | EVQLVESGGGVVQPGRSLRLSCVASGFTFRTFEMNWVRQAPGKGLEWVSYISPSGSSIYNADSVKGRFTISRDNARNSLYLQMNSLRAEDTAVYYCAREGGSYYGGSAFDIWGQGTTVTVSS | 13 |
경쇄 | SYELTQPPSASGTPGQRVTISCSGSSSNIERNIVNWYQQVPGTAPKLLIYTNSHRPSGVPDRFSGSKSGSAASLAISGLQSEDEADYYCAAWDDTLNGWVFGGGTKLTVLG | 54 | |
10 | 중쇄 | EVQLVQSGGGSVQPGGSLRLSCAASGFTFRTFEMNWVRQAPGKGLEWVSYISPSGSSIYNADSVKGRFTISRDNARNSLYLQMNSLRAEDTAVYYCAREGGSYYGGSAFDIWGQGTMVTVSS | 14 |
경쇄 | QSVPTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGRWVFGGGTKLTVLG | 55 | |
11 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDHWGQGTLVTVSS | 15 |
경쇄 | QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTWVFGGGTKLTVLG | 56 | |
12 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGLEWVSAISGNGGSTSYAASVQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 16 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGYVFGTGTKVTVLG | 57 | |
13 | 중쇄 | QVQLVESGGGVVQPGRSLRLSCAASGFTFRGYAMHWVRQAPGKGLEWVAVISEDGSDEYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 17 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGYVFGTGTELTVLG | 58 | |
14 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 18 |
경쇄 | SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGYVFGTGTKVTVLG | 59 | |
15 | 중쇄 | QVQLVESGGTLVQPGGSLRLSCAASGFTFSGYAMNWVRQAPGKGLEWVSSVSGRGDTTHYADSVKGRFTISRDNRENKLYLQMHSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 19 |
경쇄 | QAGLTQPPSVSGAPGQRVTMSCTGTTSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGYVFGTGTKVTVLG | 60 | |
16 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFRTYAMSWVRQAPGKGLEWVSAISSSDDTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 20 |
경쇄 | SYELTQPLSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGTKLTVLG | 61 | |
17 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFSSSYYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 21 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGTKLTVLG | 62 | |
18 | 중쇄 | EVQLVQSGGGLVQPGGSLRLSCAASGFTFRTYAMSWVRQAPGKGLEWVSAISSSDDTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 22 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQDEDEADYYCQSYDSSLSEYVFGTGTKVTVLG | 63 | |
19 | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 23 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNFGAGYDVHWYQQLPGTAPKLLIYGNDNRPSGVPDRFSGSKSGTSASLAITGLQDEDEADYYCQSYDSSLSEYVFGTGTQLTDLG | 64 | |
20 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFRTYAMSWVRQAPGKGLEWVSAISSSDDTTYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTTVTVSS | 24 |
경쇄 | QSALIQPRSVSGSPGQSVTISCTGTSSNVGVYNYVSWYQQHPGKAPKLIIYDVTKRPSGVPDRFSGSKSGNTGSLTISGLQAEDEADYYSCSYAGSYTWVFGPGTKVTVLS | 65 | |
21 | 중쇄 | QVQLLESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 25 |
경쇄 | QTVVTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSGVFGGGTKLTVLG | 66 | |
22 | 중쇄 | EVQLVESGGGLAQSGGSLRLSCEASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 26 |
경쇄 | SYELTQPPSASGTPGQRVTISCSGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDYNLSGYVSGTGTKVTVLG | 67 | |
23 | 중쇄 | QVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 27 |
경쇄 | TYELSQPPSVSGAPGQRVTISCTGSSSNIGADYDVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSGTSGSLAITGLRSEDEADYYCAAWDDSLSGYVFGTGTKVTVLG | 68 | |
24 | 중쇄 | EVQLVESGGAMVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 28 |
경쇄 | QPVLTQPPSVSGAPGQRVTITCTGSGSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGAPDRVSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLRTYVFGTGTKVTVLG | 69 | |
25 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISKDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 29 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGRVFGGGTKLTVLG | 70 | |
26 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 30 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSNLSGYVFGTGTKVTVLG | 71 | |
27 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 31 |
경쇄 | SYELMQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLRAYVFGTGTKVTDLG | 72 | |
28 | 중쇄 | QVQLVQSGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 32 |
경쇄 | DVVMTQSPSSLSASVGDRVTITCRASQGITNDLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDTPPYTFGQGTKLEIKR | 73 | |
29 | 중쇄 | QVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 33 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSTVFGGGTELTVLG | 74 | |
30 | 중쇄 | EVQLVETGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 34 |
경쇄 | SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDNSLSGVFGGGTKLTVLG | 75 | |
31 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMSWVRQAPGKGLEWVANIKQEGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 35 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQVPGTAPKLLIYGNINRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGSYVFGTGTKVTVLG | 76 | |
32 | 중쇄 | QVQLVQSGGGVVQPGGSLRLSCAASGFTFSGYGMNWVRQAPGKGLEWVADIEKDGGERNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGYYYGSGSYYKPKVVFDYWGQGTLVTVSS | 36 |
경쇄 | QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQHLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDGSLSGWVFGGGTKLTVLG | 77 | |
33 | 중쇄 | EVQLVESGGGLIQPGGSLRLSCAASGFTFSSFWMSWVRQAPGKGLEWVANIKQDGSEKYSVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHGIYCSGDNCYYFAPTLSSHAFDIWGQGTMVTVSS | 37 |
경쇄 | AIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKR | 78 | |
34 | 중쇄 | QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGSSWNSGTIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAIIPGDGYNYPGASDFDYWGQGTLVTVSS | 38 |
경쇄 | QPVLTQPPSASGTPGQRVIISCSGSSSNIGSHTVNWYQQLPGTAPKLLIYNNNQRPSGVPDRFSGSKSGTSASLAISGLQSADEADYSCAAWDDSLNGYVFGTGTKVTVLG | 79 | |
35 | 중쇄 | EVQLLESGGGLVQPGRSLKLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGSSWNSGTIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAIIPGDGYNYPGASDFDYWGQGTLVTVSS | 39 |
경쇄 | QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVGQRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSSYVFGTGTKVTVLG | 80 | |
36 | 중쇄 | QVTLKESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGSSWNSGTIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAIIPGDGYNYPGASDFDYWGQGTLVTVSS | 40 |
경쇄 | SYELTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHVVFGGGTQLIILG | 81 | |
37 | 중쇄 | QVQLVESGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGSSWNSGTIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAIIPGDGYNYPGASDFDYWGQGTTVTVSS | 41 |
경쇄 | RPVLTQPPSASGTPGQRATISCSGSSSNIGSNTVNWYRQLPGTAPKLLIHSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCATWDDSLDGWVFGGGTKLTVLG | 82 | |
38 | 중쇄 | QVQLVQSGAEVKKPGASVRVSCKASGYTFSSYYTHWVRQAPGQGLEWMGIINPSGGSTIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLPRDGVHASDIWGQGTTVTVSS | 42 |
경쇄 | QTVVTQEPSVSAAPEQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAYVFGTGTKVTVLG | 83 | |
39 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYYMGWVRQAPGKGLEWVSLISGSGGSTYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPPYSFDSMSESDYWGQGTLVTVSS | 43 |
경쇄 | QSVLTQPPSVSAAPGQKVTISCSGSGSNVENNYVSWYQQLPGTAPKLLIYENNNRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGVWDDSLNHVIFGGGTKLTVLG | 84 | |
40 | 중쇄 | QVQLQDSGPGLVKPSETLSLTCTVSGGSISSYDWSWIRQPPGKGLEWIGDIYNSGSTKYNPSLKSRVTISVDTSKNQLSLKLSSVTAADTAVYYCARRGLGNYDILTGYFENAFDIWGQGTTVTVSS | 44 |
경쇄 | EIVLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPRTFGQGTRLEIKR | 85 | |
41 | 중쇄 | ETQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSTSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARTRLTQLAMIGRGGNAFDIWGQGTMVTVSS | 45 |
경쇄 | SYELTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSVVFGGGTKLTVLG | 86 |
클론 | 가변영역 | 아미노산서열 | 서열번호 |
M1 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYYMGWVRQAPGKGLEWVSLISGSGGSTYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPPYSFDSMSESDYWGQGTLVTVS | 87 |
경쇄 | QSVLTQPPSVSAAPGQKVTISCSGSGSNVENNYVSWYQQLPGTAPKLLIYENNNRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGVWDDSLNHVIFGGGTKLTVLG | 92 | |
M2 | 중쇄 | QAYLQQSGAELVRSGASVKLSCTASGFNIKDYYMHWVKQRPEQGLEWIGWIDPENGDTEYAPKFQGKATMTADTSSNTAYLQLSSLTSEDTAVYYCNEDGNYDYWGQGTTLTVSS | 88 |
경쇄 | DVVVTQSPASLAVSLGQRATISCKASQSVDYAGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIKR | 93 | |
M3 | 중쇄 | EVQLLESGGGLVKPGGSLKLSCAASGFTFSSYDMSWVRQTPEKRLDWVASISSSGGTYYPDSVKGRFTISRDIARNILYLQMNSLRSEDTAMYYCVRGDYWGQGTTLTVSS | 89 |
경쇄 | DIVMTQSHKFMSASVGDRVNITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYTRYSNTFGGGTKLEIKR | 94 | |
M4 | 중쇄 | DVMLVESGGDLVKPGGSLKLSCAASGFTFSSRGMSWVRQTPDKRLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCVRPNDGYFDYWGQGTTLTVSA | 90 |
경쇄 | DIVMTQSHKFMSTSVGDRVSITCKASQDVSTDVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTINSVQAEDLALYYCQQHYSTPWTFGGGTKLEIKR | 95 | |
M5 | 중쇄 | EVKLVESGGDLVKPGGSLKLSCAASGFTFSSRGMSWVRQTPDKRLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCARPNDGYFDYWGQGTTLTVSS | 91 |
경쇄 | DVVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYASNRYTGVPDRFTGSGYGTDFTLTINSVQAEDLAVYYCQQSYSAPYTFGGGTKLEMK | 96 |
클론 | 가변영역 | 아미노산서열 | 서열번호 |
5E9 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFTTYDMGWVRQAPGKGPEWVSLISSGGSNTWYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK EKYPYSDCDY WGQGTLVTVSS | 97 |
6D9 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYDMGWVRQAPGKGPEWVSLISGDSGNTWYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK YRGTTKDY WGQGTLVTVSS | 98 |
6H10 | 중쇄 | EVQLVESGGGLVQPGGSLRLSCAASGFTFTNYYMGWVRQAPGKGPEWVSLISYDGSSTWYDDSVKGRFAISRDNSKNTLYLQMNTLRAEDTAVYYCAK PDY WGQGTLVTVSS | 99 |
Clone | SARS-CoV-S1S2 | SARS-CoV2-S1S2 | MERS-CoV-S1S2 | |||
2 | 2.446 | 2.4908 | 2.027 | 2.027 | 0.0732 | 0.0721 |
3 | 2.4794 | 2.5186 | 1.9015 | 1.8947 | 0.07 | 0.0765 |
4 | 2.4746 | 2.5391 | 1.9973 | 1.9937 | 0.0769 | 0.0719 |
5 | 2.481 | 2.5269 | 1.9471 | 1.9842 | 0.0773 | 0.0743 |
6 | 0.0838 | 0.081 | 0.2018 | 0.1948 | 0.0816 | 0.0842 |
7 | 0.7374 | 0.7917 | 2.2017 | 2.2618 | 0.0759 | 0.0758 |
8 | 1.5787 | 1.6213 | 2.2563 | 2.3055 | 0.0811 | 0.0743 |
10 | 1.4732 | 1.6543 | 2.2592 | 2.322 | 0.0824 | 0.0718 |
11 | 1.6712 | 1.7502 | 2.189 | 2.243 | 0.0896 | 0.0937 |
12 | 1.5002 | 1.5042 | 2.2436 | 2.2271 | 0.0851 | 0.0862 |
13 | 1.5442 | 1.5971 | 2.1301 | 2.2009 | 0.0763 | 0.0754 |
14 | 1.7089 | 1.6739 | 2.3198 | 2.2674 | 0.0795 | 0.0801 |
15 | 1.6942 | 1.6906 | 2.2577 | 2.2371 | 0.0945 | 0.0899 |
16 | 1.6185 | 1.6898 | 2.2151 | 2.2353 | 0.072 | 0.0721 |
17 | 1.5754 | 1.6017 | 2.1343 | 2.2118 | 0.0837 | 0.087 |
18 | 1.6126 | 1.5299 | 2.1413 | 2.2009 | 0.0814 | 0.0772 |
20 | 1.2254 | 1.2087 | 2.375 | 2.3156 | 0.1114 | 0.0909 |
21 | 1.7254 | 1.7082 | 2.3127 | 2.2976 | 0.0822 | 0.0809 |
28 | 0.8419 | 0.8235 | 2.2509 | 2.2324 | 0.0759 | 0.0736 |
33 | 1.589 | 1.6232 | 2.081 | 2.128 | 0.1097 | 0.1014 |
41 | 1.8776 | 1.9265 | 2.2973 | 2.3247 | 0.0892 | 0.0893 |
5E9 | 0.2944 | 0.2779 | 0.8921 | 0.9043 | 0.4069 | 0.3855 |
6D9 | 0.3894 | 0.3859 | 0.9972 | 0.9911 | 0.4242 | 0.3948 |
6H10 | 0.4795 | 0.4939 | 2.0931 | 2.0575 | 0.5794 | 0.5073 |
M1 | 0.2098 | 0.1506 | 0.9114 | 0.8545 | 0.3014 | 0.2892 |
M2 | 0.2735 | 0.2355 | 1.2127 | 1.1994 | 0.5101 | 0.53 |
M3 | 2.6159 | 2.6175 | 2.2611 | 2.285 | 0.0799 | 0.0732 |
M4 | 0.1178 | 0.1186 | 1.953 | 1.9824 | 0.0779 | 0.0751 |
M5 | 0.0773 | 0.0777 | 1.9465 | 1.9842 | 0.0837 | 0.0814 |
huCCM1 ab | 0.0689 | 0.0709 | 0.1381 | 0.1178 | 0.0698 | 0.0716 |
클론 | 가변영역 | 아미노산 서열 | 서열번호 |
M4-1 | 중쇄 (H original) |
DVMLVESGGDLVKPGGSLKLSCAASGFTFSSRGMSWVRQTPDKRLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCVRPNDGYFDYWGQGTTLTVSA | 100 |
경쇄 (hM4-k2) |
DIVMTQSPATLSVSPGERATLSCKASQDVSTDVAWYQQKPGQAPRLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQSEDFAVYYCQQHYSTPWTFGGGTKVEIKR | 116 | |
M4-2 | 중쇄 (H original) |
DVMLVESGGDLVKPGGSLKLSCAASGFTFSSRGMSWVRQTPDKRLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCVRPNDGYFDYWGQGTTLTVSA | 101 |
경쇄 (hM4-k3) |
DIVMTQSPATLSVSPGDRVSISCRASQDVSTDVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSLQPEDFAVYYCQQHYSTPWTFGGGTKVEIKR | 117 | |
M4-3 | 중쇄 (H1) |
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSRGMSWVRQAPGKGLEWVSTISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPNDGYFDYWGQGTLVTVSS | 102 |
경쇄 (4k original) |
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTDVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTINSVQAEDLALYYCQQHYSTPWTFGGGTKLEIKR | 118 | |
M4-4 | 중쇄 (H1) |
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSRGMSWVRQAPGKGLEWVSTISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPNDGYFDYWGQGTLVTVSS | 103 |
경쇄 (hM4-k2) |
DIVMTQSPATLSVSPGERATLSCKASQDVSTDVAWYQQKPGQAPRLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQSEDFAVYYCQQHYSTPWTFGGGTKVEIKR | 119 | |
M4-5 | 중쇄 (H1) |
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSRGMSWVRQAPGKGLEWVSTISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPNDGYFDYWGQGTLVTVSS | 104 |
경쇄 (hM4-k3) |
DIVMTQSPATLSVSPGDRVSISCRASQDVSTDVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSLQPEDFAVYYCQQHYSTPWTFGGGTKVEIKR | 120 | |
M4-6 | 중쇄 (H2) |
EVQLVESGGGLVKPGGSLKLSCAASGFTFSSRGMSWVRQAPGKGLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLKAEDTAIYYCARPNDGYFDYWGQGTLVTVSS | 105 |
경쇄 (4k original) |
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTDVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTINSVQAEDLALYYCQQHYSTPWTFGGGTKLEIKR | 121 | |
M4-7 | 중쇄 (H2) |
EVQLVESGGGLVKPGGSLKLSCAASGFTFSSRGMSWVRQAPGKGLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLKAEDTAIYYCARPNDGYFDYWGQGTLVTVSS | 106 |
경쇄 (hM4-k2) |
DIVMTQSPATLSVSPGERATLSCKASQDVSTDVAWYQQKPGQAPRLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQSEDFAVYYCQQHYSTPWTFGGGTKVEIKR | 122 | |
M4-8 | 중쇄 (H2) |
EVQLVESGGGLVKPGGSLKLSCAASGFTFSSRGMSWVRQAPGKGLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLKAEDTAIYYCARPNDGYFDYWGQGTLVTVSS | 107 |
경쇄 (hM4-k3) |
DIVMTQSPATLSVSPGDRVSISCRASQDVSTDVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSLQPEDFAVYYCQQHYSTPWTFGGGTKVEIKR | 123 | |
M5-1 | 중쇄 (H original) |
EVKLVESGGDLVKPGGSLKLSCAASGFTFSSRGMSWVRQTPDKRLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCARPNDGYFDYWGQGTTLTVSS | 108 |
경쇄 (hM5-k1) |
DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPYTFGGGTKVEIKR | 124 | |
M5-2 | 중쇄 (H original) |
EVKLVESGGDLVKPGGSLKLSCAASGFTFSSRGMSWVRQTPDKRLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCARPNDGYFDYWGQGTTLTVSS | 109 |
경쇄 (hM5-k2) |
DVVMTQSPATLSVSPGERATLSCKASQSVSNDVAWYQQKPGQAPRLLIYYASNRYTGVPDRFTGSGSGTDFTLTISSLQSEDFAVYYCQQSYSAPYTFGGGTKVEIKR | 125 | |
M5-3 | 중쇄 (H1) |
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSRGMSWVRQAPGKGLEWVSTISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPNDGYFDYWGQGTLVTVSS | 110 |
경쇄 (5k original) |
DVVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYASNRYTGVPDRFTGSGYGTDFTLTINSVQAEDLAVYYCQQSYSAPYTFGGGTKLEMK | 126 | |
M5-4 | 중쇄 (H1) |
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSRGMSWVRQAPGKGLEWVSTISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPNDGYFDYWGQGTLVTVSS | 111 |
경쇄 (hM5-k1) |
DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPYTFGGGTKVEIKR | 127 | |
M5-5 | 중쇄 (H1) |
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSRGMSWVRQAPGKGLEWVSTISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPNDGYFDYWGQGTLVTVSS | 112 |
경쇄 (hM5-k2) |
DVVMTQSPATLSVSPGERATLSCKASQSVSNDVAWYQQKPGQAPRLLIYYASNRYTGVPDRFTGSGSGTDFTLTISSLQSEDFAVYYCQQSYSAPYTFGGGTKVEIKR | 128 | |
M5-6 | 중쇄 (H2) |
EVQLVESGGGLVKPGGSLKLSCAASGFTFSSRGMSWVRQAPGKGLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLKAEDTAIYYCARPNDGYFDYWGQGTLVTVSS | 113 |
경쇄 (5k original) |
DVVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYASNRYTGVPDRFTGSGYGTDFTLTINSVQAEDLAVYYCQQSYSAPYTFGGGTKLEMK | 129 | |
M5-7 | 중쇄 (H2) |
EVQLVESGGGLVKPGGSLKLSCAASGFTFSSRGMSWVRQAPGKGLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLKAEDTAIYYCARPNDGYFDYWGQGTLVTVSS | 114 |
경쇄 (hM5-k1) |
DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPYTFGGGTKVEIKR | 130 | |
M5-8 | 중쇄 (H2) |
EVQLVESGGGLVKPGGSLKLSCAASGFTFSSRGMSWVRQAPGKGLEWVATISFGDIYTYYPDSVKGRFTISRDNAKNSLYLQMNSLKAEDTAIYYCARPNDGYFDYWGQGTLVTVSS | 115 |
경쇄 (hM5-k2) |
DVVMTQSPATLSVSPGERATLSCKASQSVSNDVAWYQQKPGQAPRLLIYYASNRYTGVPDRFTGSGSGTDFTLTISSLQSEDFAVYYCQQSYSAPYTFGGGTKVEIKR | 131 |
Mutant | 회사 명, 제품번호 | Mutant | 회사 명, 제품번호 |
RBD-V367F | Sino biologics, 40592-V08H1 | RBD-N501Y | Sino biologics, 40592-V08H82 |
RBD-N439K | Sino biologics, 40592-V08H14 | RBD-A520S | Sino biologics, 40592-V08H20 |
RBD-S477N | Sino biologics, 40592-V08H46 | RBD-A522S | Sino biologics, 40592-V08H21 |
RBD-T478I | Sino biologics, 40592-V08H30 | Spike-D614G | Sino biologics, 40589-V08B4 |
RBD-P479S | Sino biologics, 40592-V08H57 |
Claims (17)
- 코로나바이러스 스파이크 단백질에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서,상기 항체 또는 이의 항원 결합 단편은 서열번호 5 내지 45, 서열번호 87 내지 91, 서열번호 97 내지 115 중 어느 하나의 서열을 포함하는 군으로부터 선택되는 어느 하나 이상의 중쇄 가변영역; 및 서열번호 46 내지 86, 서열번호 92 내지 96, 및 서열번호 116 내지 131 중 어느 하나의 서열을 포함하는 군으로부터 선택되는 어느 하나 이상의 경쇄 가변영역을 포함하는 것인, 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서,상기 항체 또는 이의 항원 결합 단편은 서열번호 87 내지 91, 및 서열번호 100 내지 115 중 어느 하나의 서열을 포함하는 군으로부터 선택되는 어느 하나 이상의 중쇄 가변영역; 및 서열번호 92 내지 96 및 서열번호 116 내지 131 중 어느 하나의 서열을 포함하는 군으로부터 선택되는 어느 하나 이상의 경쇄 가변영역을 포함하는 것인, 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서,상기 코로나바이러스는 SARS-CoV, SARS-CoV-2 또는 MERS-CoV인, 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서,상기 항체 또는 이의 항원 결합 단편은 2종 이상의 코로나바이러스에 교차반응을 가지는 것인, 항체 또는 이의 항원 결합 단편.
- 제5항에 있어서,상기 2종 이상의 코로나바이러스에 교차반응을 가지는 항체 또는 이의 항원 결합 단편은 서열번호 6 내지 12, 서열번호 14 내지 22, 서열번호 24, 25, 32, 37, 45, 서열번호 87 내지 91, 및 서열번호 97 내지 99 중 어느 하나의 서열을 포함하는 군으로부터 선택되는 어느 하나 이상의 중쇄 가변영역; 및 서열번호 47 내지 53, 서열번호 55 내지 63, 서열번호 65, 66, 73, 78, 86, 및 서열번호 92 내지 96, 중 어느 하나의 서열을 포함하는 군으로부터 선택되는 어느 하나 이상의 경쇄 가변영역을 포함하는 것인, 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서,상기 항체 또는 이의 항원 결합 단편은서열번호 139의 중쇄 CDR1; 서열번호 140의 중쇄 CDR2; 및 서열번호 141의 중쇄 CDR3을 포함하는 중쇄 가변영역 및서열번호 142 또는 145의 경쇄 CDR1; 서열번호 143 또는 146의 경쇄 CDR2; 및 서열번호 144 또는 147의 경쇄 CDR3을 포함하는 경쇄 가변영역을 포함하는 것인, 항체 또는 이의 항원 결합 단편.
- 제1항에 있어서,상기 중쇄 가변영역은 서열번호 103의 아미노산 서열로 이루어지고;상기 경쇄 가변영역은 서열번호 119의 아미노산 서열로 이루어진 것인, 항체 또는 이의 항원 결합 단편.
- 제1항 내지 제8항 중 어느 한 항의 항체 또는 이의 항원 결합 단편을 코딩하는 폴리뉴클레오티드.
- 제9항의 폴리뉴클레오티드를 포함하는 발현 벡터.
- 제10항의 발현 벡터가 도입된 형질전환체.
- 제1항 내지 제8항 중 어느 한 항의 항체 또는 이의 항원 결합 단편을 포함하는, 코로나바이러스 감염증의 예방 또는 치료용 약학 조성물.
- 제1항 내지 제8항 중 어느 한 항의 항체 또는 이의 항원 결합 단편을 인간을 제외한 개체에 투여하는 단계를 포함하는, 코로나바이러스 감염증의 예방 또는 치료 방법.
- 제1항 내지 제8항 중 어느 한 항의 항체 또는 이의 항원 결합 단편에 약물이 결합된, 항체-약물 결합체.
- 제1항 내지 제8항 중 어느 한 항의 항체 또는 이의 항원 결합 단편을 포함하는, 코로나바이러스 감염 진단용 조성물.
- 제15항의 조성물을 포함하는, 코로나바이러스 감염 진단용 키트.
- 제1항 내지 제8항 중 어느 한 항의 항체 또는 이의 항원 결합 단편; 또는 이를 포함하는 감염 진단용 조성물; 또는 상기 조성물을 포함하는 키트를 이용하여, 코로나바이러스 감염 의심 개체로부터 분리된 생물학적 시료에 존재하는 코로나바이러스를 검출하는 단계를 포함하는, 코로나바이러스 감염 진단을 위한 정보제공방법.
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JP2023524972A JP2023547167A (ja) | 2020-11-06 | 2021-11-05 | コロナウイルススパイクタンパク質に特異的な抗体及びその用途 |
US18/035,235 US20230417748A1 (en) | 2020-11-06 | 2021-11-05 | Coronavirus Spike Protein-Specific Antibody and Use Thereof |
CN202180074379.9A CN117098773A (zh) | 2020-11-06 | 2021-11-05 | 特异于冠状病毒刺突蛋白的抗体及其用途 |
EP21889638.9A EP4242224A1 (en) | 2020-11-06 | 2021-11-05 | Antibody specific to coronavirus spike protein and use thereof |
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KR101895228B1 (ko) * | 2017-08-23 | 2018-10-30 | 대한민국 | 중동호흡기증후군 코로나바이러스의 스파이크 단백질에 대한 단일클론항체 및 이의 용도 |
CN111366734A (zh) * | 2020-03-20 | 2020-07-03 | 广州市康润生物科技有限公司 | 双指标筛选新冠病毒及预判重型肺炎的方法 |
CN111592594A (zh) * | 2020-03-13 | 2020-08-28 | 北京大学 | 一种抗新型冠状病毒的单克隆抗体及其应用 |
US10787501B1 (en) * | 2020-04-02 | 2020-09-29 | Regeneron Pharmaceuticals, Inc. | Anti-SARS-CoV-2-spike glycoprotein antibodies and antigen-binding fragments |
CN111727199A (zh) * | 2018-01-31 | 2020-09-29 | 赛特瑞恩股份有限公司 | 针对中东呼吸综合征-冠状病毒具有中和活性的结合分子 |
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- 2021-11-05 EP EP21889638.9A patent/EP4242224A1/en active Pending
- 2021-11-05 US US18/035,235 patent/US20230417748A1/en active Pending
- 2021-11-05 WO PCT/KR2021/016073 patent/WO2022098173A1/ko active Application Filing
- 2021-11-05 JP JP2023524972A patent/JP2023547167A/ja active Pending
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KR101895228B1 (ko) * | 2017-08-23 | 2018-10-30 | 대한민국 | 중동호흡기증후군 코로나바이러스의 스파이크 단백질에 대한 단일클론항체 및 이의 용도 |
CN111727199A (zh) * | 2018-01-31 | 2020-09-29 | 赛特瑞恩股份有限公司 | 针对中东呼吸综合征-冠状病毒具有中和活性的结合分子 |
CN111592594A (zh) * | 2020-03-13 | 2020-08-28 | 北京大学 | 一种抗新型冠状病毒的单克隆抗体及其应用 |
CN111366734A (zh) * | 2020-03-20 | 2020-07-03 | 广州市康润生物科技有限公司 | 双指标筛选新冠病毒及预判重型肺炎的方法 |
US10787501B1 (en) * | 2020-04-02 | 2020-09-29 | Regeneron Pharmaceuticals, Inc. | Anti-SARS-CoV-2-spike glycoprotein antibodies and antigen-binding fragments |
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US20230417748A1 (en) | 2023-12-28 |
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