CN117924472A - Antibodies against respiratory syncytial virus - Google Patents
Antibodies against respiratory syncytial virus Download PDFInfo
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- CN117924472A CN117924472A CN202410174937.4A CN202410174937A CN117924472A CN 117924472 A CN117924472 A CN 117924472A CN 202410174937 A CN202410174937 A CN 202410174937A CN 117924472 A CN117924472 A CN 117924472A
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Landscapes
- Peptides Or Proteins (AREA)
Abstract
The invention discloses an antibody for respiratory syncytial virus, which has strong affinity activity for respiratory syncytial virus, and has the application value of developing a diagnostic reagent or a kit for detecting RSV-F protein, and the potential value of developing a therapeutic antibody for preventing or treating respiratory syncytial virus infection.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to an antibody for respiratory syncytial virus.
Background
Respiratory syncytial virus (Respiratory Syncytial Virus, RSV) is an enveloped, non-segmented, single negative strand RNA virus, a common infectious virus that causes respiratory infections, mainly lower respiratory infections such as bronchiolitis and pneumonia in infants below 6 months, and upper respiratory infections such as rhinitis, colds in older children and adults.
For RSV virus, no specific therapeutic drugs and preventive vaccines exist at present, and a novel neutralizing antibody applicable to RSV virus prevention and treatment is found to have important application significance and conversion value.
Disclosure of Invention
In order to make up for the defects of the prior art, the invention provides an antibody aiming at respiratory syncytial virus.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect the invention provides an antibody or antigen-binding fragment thereof comprising,
Heavy chain variable region complementarity determining region:
V H CDR1 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO.1,
V H CDR2 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 2,
V H CDR3 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 3,
Light chain variable complementarity determining region:
v L CDR1 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO 9,
V L CDR2 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO 10,
V L CDR3 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 11,
The antibodies or antigen binding fragments thereof specifically bind to the F protein of respiratory syncytial virus and/or neutralize respiratory syncytial virus.
Further, the antibody or antigen binding fragment thereof specifically binds to the pre-fusion conformation of the F protein of respiratory syncytial virus.
Further, the amino acid sequence of the V H CDR1 is shown as SEQ ID NO.1,
The amino acid sequence of the V H CDR2 is shown as SEQ ID NO. 2,
The amino acid sequence of the V H CDR3 is shown as SEQ ID NO. 3,
The amino acid sequence of the V L CDR1 is shown as SEQ ID NO 9,
The amino acid sequence of the V L CDR2 is shown as SEQ ID NO 10,
The amino acid sequence of the V L CDR3 is shown in SEQ ID NO. 11.
Further, the antibody or antigen-binding fragment thereof also includes,
Heavy chain variable region framework regions:
V H FR1 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 4,
V H FR2 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 5,
V H FR3 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 6,
V H FR4 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 7,
Light chain variable region framework regions:
V L FR1 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 12,
V L FR2 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 13,
V L FR3 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 14,
V L FR4 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID No. 15.
Further, the amino acid sequence of V H FR1 is shown as SEQ ID NO. 4,
The amino acid sequence of V H FR2 is shown as SEQ ID NO. 5,
The amino acid sequence of V H FR3 is shown as SEQ ID NO. 6,
The amino acid sequence of V H FR4 is shown as SEQ ID NO. 7,
The amino acid sequence of V L FR1 is shown as SEQ ID NO. 12,
The amino acid sequence of V L FR2 is shown as SEQ ID NO. 13,
The amino acid sequence of V L FR3 is shown as SEQ ID NO. 14,
The amino acid sequence of V L FR4 is shown as SEQ ID NO. 15.
Further, the heavy chain variable region V H of the antibody or antigen-binding fragment thereof has an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence shown in SEQ ID NO. 8,
The light chain variable region V L has an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence shown in SEQ ID NO. 16.
Further, the amino acid sequence of the heavy chain variable region V H is shown as SEQ ID NO. 8,
The amino acid sequence of the light chain variable region V L is shown in SEQ ID NO. 16.
Further, the antibody or antigen-binding fragment thereof also includes a defucosylated antibody or antigen-binding fragment thereof.
Further, the antibody or antigen binding fragment thereof further comprises a detectable label.
The second aspect of the present invention provides any one of the following:
(1) A nucleic acid molecule encoding an antibody or antigen-binding fragment thereof according to the first aspect of the invention;
(2) A vector comprising the nucleic acid molecule of (1);
(3) A host cell comprising the nucleic acid molecule of (1) or the vector of (2);
(4) A product for detecting respiratory syncytial virus, the product comprising an antibody or antigen-binding fragment thereof according to the first aspect of the invention.
Further, the nucleic acid molecule encoding a CDR3 of V H CDR1、VH CDR2、VH of (1) has a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the nucleotide sequences shown in SEQ ID NOS 17, 18, 19, respectively,
The nucleic acid molecules encoding the V L CDR1、VL CDR2、VL CDR3 have a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the nucleotide sequences shown in SEQ ID NOS: 20, 21, 22, respectively.
Further, the nucleotide sequences of the nucleic acid molecules encoding the V H CDR1、VH CDR2、VH CDR3 in (1) are respectively shown as SEQ ID NO. 17, 18 and 19,
The nucleotide sequences of the nucleic acid molecules encoding the V L CDR1、VL CDR2、VL CDR3 are shown in SEQ ID NOS 20, 21 and 22, respectively.
Further, the vector described in (2) has a signal peptide operably linked to an antibody.
Further, the vector also includes elements for controlling expression.
Further, the carrier also includes a material that facilitates its entry into the cell.
Further, the host cells described in (3) include prokaryotic cells and eukaryotic cells.
Further, the prokaryotic cell includes a eubacterium.
Further, the eubacteria include gram-negative or gram-positive organisms, escherichia, enterobacter, streptomyces.
Further, the eukaryotic cells include protozoan cells, animal cells, plant cells, or fungal cells.
Further, the animal cells include mammalian cells, avian cells, insect cells.
Further, the mammalian cells include 293F cells, 293T cells, CHO cells, AT1080 cells, a549 cells.
Further, the product described in (5) further comprises a reagent for performing an antigen-antibody reaction or a reagent for detecting a reaction.
Further, reagents for performing antigen-antibody reactions include buffers, salts.
Further, the product comprises a kit and a test strip.
Further, the kit includes a conjugate of an antibody linked to a signal producing compound.
In a third aspect the present invention provides a pharmaceutical composition for use in the treatment or prophylaxis of respiratory syncytial virus infection, the pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to the first aspect of the invention, or a substance according to the second aspect of the invention.
Further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
Further, the pharmaceutical composition further comprises one or more additional antiviral antibodies.
Further, the one or more additional antiviral antibodies are anti-RSV antibodies or antigen-binding fragments thereof.
Further, the one or more additional antiviral antibodies include palivizumab, motavizumab 、AFFF、P12f2、P12f4、P11d4、A1e9、A12a6、A13c4、A17d4、A4B4、A8c7、1X-493L1、FR H3-3F4、M3H9、Y10H6、DG、AFFF(1)、6H8、L1-7E5、L2-15B10、A13a11、A1h5、A4B4(1)、A4B4L1FR-S28R、A4B4-F52S、rsv6、rsv11、rsv13、rsv19、rsv21、rsv22、rsv23、RF-1、RF-2, and antigen-binding fragments thereof.
A fourth aspect of the invention provides any one of the following applications:
(1) Use of an antibody or antigen-binding fragment thereof according to the first aspect of the invention, or a substance according to the second aspect of the invention, for the detection of respiratory syncytial virus;
(2) Use of an antibody or antigen-binding fragment thereof according to the first aspect of the invention, or a substance according to the second aspect of the invention, for the preparation of a product for diagnosing respiratory syncytial virus;
(3) Use of an antibody or antigen binding fragment thereof according to the first aspect of the invention, a substance according to the second aspect of the invention or a pharmaceutical composition according to the third aspect of the invention for the manufacture of a medicament for the prevention and/or treatment of respiratory syncytial virus infection.
Further, the product described in (2) comprises a kit.
In a fifth aspect, the invention provides a method of preparing an antibody or antigen-binding fragment thereof according to the first aspect of the invention, the method comprising: culturing the host cell of the second aspect of the invention and recovering the antibody or antigen-binding fragment thereof.
Further, the method comprises purifying the antibody or antigen binding fragment thereof.
In a sixth aspect, the invention provides a method of detecting respiratory syncytial virus in a sample, the method comprising: contacting the antibody or antigen binding fragment thereof of the first aspect of the invention with a test sample, thereby detecting the level of respiratory syncytial virus in the test sample.
Further, the method is a method for non-diagnostic purposes.
The invention has the advantages and beneficial effects that:
The antibody against the respiratory syncytial virus provided by the invention has strong affinity activity to the respiratory syncytial virus, and has the application value of developing a diagnostic reagent or a kit for detecting RSV-F protein and the potential value of developing a therapeutic antibody for preventing or treating respiratory syncytial virus infection.
Drawings
FIG. 1 is a SDS-PAGE of protein A magnetic beads after purification of antibodies;
FIG. 2 is a graph showing the detection of binding activity of RSV-F antibody to the antigen DS2-strepII-His 6;
FIG. 3 is a graph showing the detection of the neutralizing activity of RSV-F antibody against the live RSV-A2 virus.
Detailed Description
The following provides definitions of some of the terms used in this specification. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The present invention provides an antibody or antigen-binding fragment thereof comprising a heavy chain variable region complementarity determining region: v H CDR1、VH CDR2、VH CDR3 and light chain variable region complementarity determining region: v L CDR1、VLCDR2、VL CDR3, the antibody or antigen-binding fragment thereof further comprises a heavy chain variable region framework region: v H FR1、VH FR2、VHFR3、VH FR4 and light chain variable region framework regions: v L FR1、VL FR2、VL FR3、VL FR4, which antibody or antigen binding fragment thereof specifically binds to the F protein of respiratory syncytial virus (RSV-F) and/or neutralizes respiratory syncytial virus.
In the present invention, antibodies refer to immunoglobulins and immunoglobulin fragments, whether naturally occurring or partially or fully synthetically (e.g., recombinantly) produced, which comprise at least any fragment of a portion of the variable region of an immunoglobulin molecule that retains the binding specificity of a full-length immunoglobulin. Thus, antibodies include any protein having a binding domain that is homologous or substantially homologous to an immunoglobulin antigen binding domain (antibody binding site). Antibodies include antibody fragments, such as anti-RSV antibody fragments. As used herein, the term antibody therefore includes synthetic antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, non-human antibodies, humanized antibodies, chimeric antibodies, intracellular antibodies, and antibody fragments, including but not limited to Fab fragments, fab ' fragments, F (ab ') 2 fragments, fv fragments, disulfide-linked Fv (dsFv), fd fragments, fd ' fragments, single chain Fv (scFv), single chain Fab (scFab), diabodies, anti-idiotype (anti-Id) antibodies, or antigen-binding fragments of any of the above. Antibodies provided herein include members of any immunoglobulin class (e.g., igG, igM, igD, igE, igA and IgY), any class (e.g., igG1, igG2, igG3, igG4, igA1, and IgA 2), or subclass (e.g., igG2a and IgG2 b).
An "antibody fragment" or "antigen-binding fragment" of an antibody refers to any portion of a full-length antibody that is less than full length, but that comprises at least a portion of the variable region of the antibody (e.g., one or more CDRs and/or one or more antibody binding sites) that binds an antigen, and thus retains binding specificity as well as at least a portion of the specific binding capacity of the full-length antibody; antibody fragments include antibody derivatives produced by enzymatic treatment of full length antibodies, as well as synthetically produced derivatives, such as recombinantly produced derivatives. Antibodies include antibody fragments. Examples of antibody fragments include, but are not limited to, fab ', F (ab ') 2, single chain Fv (scFv), fv, dsFv, diabodies, fd, and Fd ' fragments, and other fragments, including modified fragments. The fragments may comprise multiple strands linked together, for example by disulfide bonds and/or by peptide linkers. Antibody fragments generally comprise at least or about 50 amino acids, and typically at least or about 200 amino acids.
The antibody or antigen binding fragment thereof specifically binds to the pre-fusion conformation of the F protein of respiratory syncytial virus.
The F protein of respiratory syncytial virus (RSV-F) is responsible for fusion of viral and host cell membranes and syncytial formation between viral particles. Its sequence is highly conserved among strains. The RSV-F protein undergoes a large conformational change during the mediated membrane Fusion process, transitioning from a metastable pre-Fusion conformation (pre-Fusion) to a stable post-Fusion conformation (post-Fusion). Antibodies to the RSV-F protein include antibodies that bind to the Pre-fusion conformation, neutralizing antibodies that bind to both the Pre-fusion conformation and the Post-fusion conformation. The antibodies of the invention bind to the Pre-fusion conformation.
The antibody or antigen-binding fragment thereof also includes a defucosylated antibody or antigen-binding fragment thereof.
In the present invention, defucosylation refers to core fucosylation of an N-glycan that is substantially devoid of direct or indirect covalent attachment to the N-glycosylation site (e.g., amino acid residue position 297 of the human IgG1 Fc region, numbered according to the EU index) or to a corresponding residue in a non-IgG 1 or non-human IgG1 immunoglobulin.
A defucosylated antibody or antigen binding fragment thereof refers to an IgG1 or IgG3 isotype antibody that lacks fucose in its constant region glycosylation. Glycosylation of human IgG1 or IgG3 occurs at Asn297, in the form of core fucosylated double branched complex oligosaccharide glycosylation ending with up to 2 Gal residues. In some embodiments, the defucosylated antibody lacks fucose at Asn 297. These structures are labeled as G0, G1 (α1,6 or α1, 3) or G2 glycan residues, depending on the amount of terminal Gal residues.
The antibody or antigen binding fragment thereof further comprises a detectable label.
In the present invention, a detectable label may be directly or indirectly attached or linked to a molecule (e.g., an anti-RSV antibody or antigen-binding fragment thereof provided herein) or associated therewith and a detectable label (marker) (e.g., a fluorescent molecule, a chemiluminescent molecule, a bioluminescent molecule, a contrast agent (e.g., a metal), a radionuclide, a chromophore, a detectable peptide, or an enzyme that catalyzes the formation of a detectable product) may be detected. The detection method may be any method known in the art.
The invention provides any one of the following substances:
(1) A nucleic acid molecule encoding the above antibody or antigen binding fragment thereof;
(2) A vector comprising the nucleic acid molecule of (1);
(3) A host cell comprising the nucleic acid molecule of (1) or the vector of (2);
(4) A product for detecting respiratory syncytial virus, the product comprising an antibody or antigen-binding fragment thereof as described above.
In the present invention, a nucleic acid molecule or nucleic acid refers to an oligomer or polymer comprising at least two linked nucleotides or nucleotide derivatives, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) that are typically linked together by phosphodiester bonds. Polynucleotides also include DNA and RNA derivatives, which include, for example, nucleotide analogs or "backbone" linkages other than phosphodiester linkages, such as phosphotriester linkages, phosphoramidate linkages, phosphorothioate linkages, thioester linkages, or peptide linkages (peptide nucleic acids). Polynucleotides (nucleic acid molecules) include single-and/or double-stranded polynucleotides, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), as well as analogs or derivatives of RNA or DNA. The term also includes equivalents, derivatives, variants and analogues of RNA or DNA consisting of nucleotide analogues, single-stranded (sense or antisense) and double-stranded polynucleotides. Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine, and deoxythymidine. For RNA, the uracil base is uridine. Polynucleotides may comprise nucleotide analogs, including, for example, mass modified nucleotides, which allow mass discrimination of polynucleotides; including detectably labeled nucleotides, such as fluorescent, radioactive, luminescent or chemiluminescent labels, which allow for detection of the polynucleotide; or nucleotides comprising reactive groups, such as biotin or thiol groups, which facilitate immobilization of the polynucleotide to a solid support. Polynucleotides may also comprise one or more selectively cleavable backbone linkages, e.g., cleavable chemically, enzymatically, or photolytically. For example, a polynucleotide may include one or more deoxyribonucleotides followed by one or more ribonucleotides, followed by one or more deoxyribonucleotides, such a sequence being cleavable by base hydrolysis at the ribonucleotide sequence. Polynucleotides may also include one or more bonds that are relatively tolerant to cleavage, such as chimeric oligonucleotide primers, which may include nucleotides linked by peptide nucleic acid bonds and at least one nucleotide linked at the 3' end by phosphodiester bonds or other suitable bonds, and which are capable of extension by a polymerase. The peptide nucleic acid sequence can be prepared by a known method. Examples of nucleic acid molecules (polynucleotides) provided by the present invention are oligonucleotides, including synthetic oligonucleotides, oligonucleotide duplex, primers (including fill-in primers), and oligonucleotide duplex cassettes.
In the present invention, a vector refers to a vector into which a polynucleotide encoding a protein can be operably inserted to cause expression of the protein. Vectors may be used to transform, transduce or transfect host cells such that they express the carried genetic element within the host cells. The vector may contain a variety of elements for controlling expression, including promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and reporter genes. In addition, the vector may contain an origin of replication. The term origin of replication refers to a sequence that when present in a vector initiates replication. The origin of replication may be recognized by a replication initiating factor or alternatively by a DNA helicase. The vector may also include materials that facilitate its entry into the cell, including but not limited to viral particles, liposomes, or protein envelopes.
Examples of vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (e.g., herpes simplex viruses), poxviruses, baculoviruses, papillomaviruses, papovaviruses (e.g., SV 40), lambda and M13 phages, plasmids. Specific examples of carriers include, but are not limited to pcDNA3.3、pMD18-T、pOptivec、pCMV、pEGFP、pIRES、pQD-Hyg-GSeu、pALTER、pBAD、pcDNA、pCal、pL、pET、pGEMEX、pGEX、pCI、pEGFT、pSV2、pFUSE、pVITRO、pVIVO、pMAL、pMONO、pSELECT、pUNO、pDUO、Psg5L、pBABE、pWPXL、pBI、p15TV-L、pPro18、pTD、pRS10、pLexA、pACT2.2、pCMV-SCRIPT.RTM.、pCDM8、pCDNA1.1/amp、pcDNA3.1、pRc/RSV、PCR2.1、pEF-1、pFB、pSG5、pXT1、pCDEF3、pSVSPORT、pEF-Bos.
In the present invention, a host cell is a cell that is used to receive, hold, replicate, and amplify a vector. Host cells may also be used to express the polypeptides encoded by the vectors. When the host cell is divided, the nucleic acid contained in the vector replicates, thereby amplifying the nucleic acid. In one embodiment, the host cell is a genetic package (GENETIC PACKAGE) that can induce expression of the variant polypeptide on its surface. In another embodiment, the host cell is infected with the genetic package.
The host cell may be virtually any cell for which an expression vector is useful. Including prokaryotic, eukaryotic cells including, but not limited to, eubacteria such as gram-negative or gram-positive organisms, e.g., enterobacteriaceae (Enterobacteriaceae), such as Escherichia, e.g., escherichia coli (DH 5. Alpha., BL21DE3pLysS, JM109, TOP10, HB101, SCS110, E.coli JM 110); enterobacter (Enterobacter); enterobacteria (Erwinia); klebsiella (Klebsiella); proteus (Proteus); salmonella (Salmonella), such as Salmonella typhimurium (Salmonella typhimurium); serratia (Serratia), such as Serratia marcescens (SERRATIA MARCESCANS); and Shigella (Shigella), and bacillus (bacillus), such as bacillus subtilis and bacillus licheniformis (b.lichenifermis); pseudomonas (Pseudomonas), such as Pseudomonas aeruginosa (P.aeromonas); and Streptomyces (Streptomyces).
Eukaryotic cells include, but are not limited to, protozoan cells, animal cells including mammalian cells, avian cells, insect cells, plant cells, or fungal cells. Wherein the mammalian cells include, but are not limited to, CHO cells, F2N cells, CSO cells, BHK cells, bowes melanoma cells, heLa cells, 911 cells, AT1080 cells, a549 cells, 293T cells, 293F cells.
The present invention provides a pharmaceutical composition for the treatment or prophylaxis of respiratory syncytial virus infection, which comprises the above antibody or antigen-binding fragment thereof, or the above.
The pharmaceutical composition also includes a pharmaceutically acceptable carrier, typically such pharmaceutical compositions employ components that do not significantly disrupt the biological properties of the antibody or antigen binding fragment thereof, such as binding to a specific epitope thereof (e.g., binding to an epitope on the RSV F protein). Each component is pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injuring the patient. The pharmaceutical compositions may be conveniently presented in unit dosage form and may be prepared by any of a variety of methods well known in the pharmaceutical arts including, but not limited to, tablets, pills, powders, liquid solutions or suspensions (e.g., including injectable, absorbable and topical preparations (e.g., eye drops, gels or ointments), aerosols (e.g., nasal sprays), liposomes, suppositories, injectable and pourable solutions, and sustained release forms, pharmaceutically acceptable carriers including, but not limited to, water, buffers, aqueous saline solutions, phosphate buffered saline solutions, various types of wetting agents, sterile solutions, alcohols, gum arabic, vegetable oils, benzyl alcohol, gelatin, glycerin, carbohydrates (e.g., lactose, sucrose, amylose or starch), magnesium stearate, talc, silicic acid, viscous paraffin, aromatic oils, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl cellulose, powders, and the like, the pharmaceutical compositions provided herein may contain other additives including, for example, antioxidants, preservatives, antimicrobial agents, analgesics, binders, disintegrants, colorants, diluents, flow aids, phosphate buffered saline solutions, various types of wetting agents, sterile solutions, alcohols, gum, vegetable oils, benzyl alcohol, gelatin, glycerin, carbohydrates (e.g., lactose, sucrose, amylose or starch), magnesium stearate, silicic acid, viscous paraffin, aromatic oils, fatty acid monoglycerides, and diglycerol esters, pentaerythritol fatty acid esters, hydroxymethyl cellulose, powder, and the like, propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanth, xanthan gum and derivatives thereof), solvents, and various ingredients, for example crystalline cellulose, microcrystalline cellulose, citric acid, dextrin, dextrose, liquid glucose, lactic acid, lactose, magnesium chloride, potassium metaphosphate, starch. Such carriers and/or additives may be formulated by conventional methods and may be administered to a subject in appropriate dosages.
In some embodiments, the pharmaceutical composition may be administered with one or more additional anti-viral antibodies selected from anti-RSV antibodies or antigen-binding fragments thereof, such as palivizumab, motavizumab 、AFFF、P12f2、P12f4、P11d4、A1e9、A12a6、A13c4、A17d4、A4B4、A8c7、1X-493L1、FR H3-3F4、M3H9、Y10H6、DG、AFFF(1)、6H8、L1-7E5、L2-15B10、A13a11、A1h5、A4B4(1)、A4B4L1FR-S28R、A4B4-F52S、rsv6、rsv11、rsv13、rsv19、rsv21、rsv22、rsv23、RF-1、RF-2, or antigen-binding fragments thereof.
The pharmaceutical compositions of the invention may also be used in combination with one or more additional drugs to treat respiratory syncytial virus infections, including but not limited to immunomodulators, anti-inflammatory agents (e.g., adrenocorticoids, corticosteroids (e.g., beclomethasone (beclomethasone), budesonide, flunisolide, fluticasone, triamcinolone, methylprednisolone, prednisolone, prednisone, hydrocortisone), glucocorticoids, steroids, non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, diclofenac, and COX-2 inhibitors)), analgesics, leukotriene antagonists (e.g., montelukast, methylxanthine, zafirlukant, and zileuton), bronchodilators (e.g., bambuterol, bitolterol, clenbuterol, fenoterol, formoterol, indacaterol, isoperide, oxacillin, pibuterol, procaterol, salmeterol, salbutamol (e.g., 35), and other drugs (e.g., ambrox), antimuscarin, 35, and other drugs (e.g., ambrox, 35, and other drugs).
The invention provides application of the antibody or antigen binding fragment thereof, the substance or the pharmaceutical composition in preparing medicines for preventing and/or treating respiratory syncytial virus infection.
In the present invention, respiratory syncytial virus infection or RSV infection refers to all stages of the RSV life cycle in a host (including but not limited to infection and replication of RSV in a cell or body tissue), as well as pathological conditions resulting from infection and replication of RSV. Infection and proliferation of RSV includes, but is not limited to, the following steps: the RSV particles dock to the cell, the virus fuses with the cell membrane, viral genetic information is introduced into the cell, the RSV protein is expressed, new RSV particles are produced and the RSV particles are released from the cell. The RSV infection may be an upper respiratory RSV infection (URI), a lower respiratory RSV infection (LRI), or a combination thereof. Including bronchiolitis and pneumonia, for example.
The invention is further illustrated below in connection with specific embodiments. It should be understood that the particular embodiments described herein are presented by way of example and not limitation. The principal features of the invention may be used in various embodiments without departing from the scope of the invention.
Examples
1 Experimental materials
Nupraise mouse single cell BCR IgG H/K amplification kit: mouse SINGLE CELL BCR IgG H/K Amplification Kit, vazyme, DD5101;
293F cells and 293T cells are commercially available human embryonic kidney epithelial cells;
pcDNA3.1 (+) vector: invitrogen, cat# V790-20;
HRP anti-Respiratory Syncytial virus antibody：Abcam,Cat:ab20686；
KPL Trueblue color development liquid: sera care, cat:5510-0030.
2 Experimental methods
2.1 Flow sorting of mouse RSV-F antigen specific binding to B cells
Mice were immunized with the pre-fusion conformation of the RSV-F antigen DS2-strep II-His6, and after 3 weeks, secondary immunization was performed, and the spleen of the mice 15 weeks after secondary immunization was taken, and lymphocytes from the mice were obtained using lymphocyte isolates. Lymphocytes were resuspended in 80 μl of 1% BSA in PBS, added to 20 μl l Fc blocking reagent, and blocked for 20min. Adjusting the density of lymphocytes to 1x10e7/ml, adding 200nM of antigen DS2-strepII-His6 and fluorescent antibody of memory B cells, and incubating for 30min in ice and in the absence of light; 1ml of PBS containing 1% BSA was added for resuspension and the cells were washed 3 times. Adding APC-streptavidine, and incubating for 30min in ice in dark place; 1ml of PBS containing 1% BSA was added for resuspension and the cells were washed 3 times. 400 μl of PBS containing 1% BSA was added to resuspend the cells, filtered to flow tubes, and antigen-specific binding memory B cells were collected by sorting using FACS ARIA III flow cytometer.
2.2 Single B cell antibody sequence acquisition, sequence analysis
The sequences of the heavy and light chains of BCR were obtained using a nupraise Mouse single cell BCR IgG H/K amplification kit (Mouse SINGLE CELL BCR IgG H/K Amplification Kit, vazyme, DD 5101).
The method mainly comprises the following steps: (1) reverse transcription, first strand cDNA synthesis was performed. (2) And (3) amplifying by using the first chain cDNA synthesis product as a template to obtain the full-length cDNA of the IgG heavy chain and the light chain. (3) And (3) using the full-length cDNA amplification products of the IgG heavy chain and the light chain as templates to amplify the variable region genes of the heavy chain and the light chain of the antibody. (4) And (3) using the amplified products of the variable regions of the IgG heavy chain and the light chain as templates to amplify the spliced products of the expression frames of the IgG heavy chain and the light chain.
2.3 Detection of antigen-specific binding Activity of antibodies
The heavy and light chain expression cassette splice products were co-transfected into 293T cells. After 48 hours of transfection, the transfection supernatants were collected and assayed for antigen-specific binding activity.
ELISA plates were coated with 1. Mu.g/ml of the RSV-F antigen DS2-strepII-His6, incubated overnight at 4℃and blocked with PBS containing 3% BSA for 1 hour. The 293T supernatant transfected with the linear expression cassette was diluted 1:3 in PBS, added to a 96-well ELISA plate, incubated for 1 hour, and washed 3 times with 200. Mu.l/well by adding PBST (0.05% Tween-80). HRP-Goat-anti-mouse IgG was added, and after 45min incubation, PBST (0.05% Tween-80) was added for 3 washes, 200. Mu.l/well. And constructing heavy chain and light chain sequences of the antibodies into pcDNA3.1 (+) vectors for the antigen specific binding samples obtained by screening, sequencing to obtain variable region sequences of the IgG heavy chain and the light chain, and analyzing sequencing results by utilizing Igblast websites.
2.4 Expression and purification of antibodies
Expression of antibodies: transfection was performed at a density of 2.5X10e6/ml for 293F cells, and 1. Mu.g of antibody heavy chain plasmid and 1. Mu.g of antibody light chain plasmid were added to 20. Mu.l of medium per 2.5X10e6/ml of cells. Mu.g PEI was added to 20. Mu.l medium, after 5min, the dilutions of plasmid and PEI were mixed, left at room temperature for 15min and added to 293F cells. After transfection, the cell supernatants were collected by centrifugation after incubation in a shaker incubator at 37℃and 220rpm at 5% carbon dioxide concentration for 72 hours.
Purification of the antibodies: antibody 293F cell transfection supernatant was incubated with Protein A magnetic beads equilibrated with PBS for 2 hours, the magnetic beads were adsorbed by a magnetic rack, and the supernatant was discarded. And adding 20CV PBS to clean the magnetic beads, repeatedly reversing and uniformly mixing, adsorbing the magnetic beads by using a magnetic frame, discarding the supernatant, and cleaning for 3 times. The antibody was eluted by adding 10CV 0.1M Glycine (ph=3.0), the beads were adsorbed using a magnetic rack, the supernatant was aspirated, and 1M Tris (ph=8.5) was added to neutralize to ph=7. PBS was added to replace buffer.
2.5 Binding Activity of antibodies to Pre-fusion conformational RSV-F protein DS2-strepII-His6
The binding activity of RSV-F antibody to pre-fusion conformation RSV-F protein DS2-strepII-His6 was detected by means of an enzyme-linked adsorption reaction.
The pre-fusion RSV-F protein DS2-strepII-His6 was used as a coating at a concentration of 1. Mu.g/ml, 100. Mu.l/well, coated overnight and the supernatant was discarded. Blocking was performed for 1 hour with 3% BSA in PBS and the blocking solution was discarded. The antibody LV21 to be tested was diluted 11 times with a 3-fold gradient, the initial well concentration was 100. Mu.g/ml, and a multiplex well was set at 37℃and incubated for 1 hour. Mu.l of PBST (0.05% Tween) was added and the plate was washed 3 times. HRP-coat-anti-mouse IgG diluted 1:5K was added, incubated for 45min, 200. Mu.l PBST (0.05% Tween) was added, and the plate was washed 3 times. Adding TMB color development liquid, and after developing for 10min, stopping developing, and reading by an enzyme-labeling instrument.
2.6 Detection of neutralizing Activity of antibodies
1. Vero cells were plated in 96-well plates, 3 x 10e4 per well, and incubated overnight at 37 ℃ in a 5% co 2 incubator using 200 μl of complete medium containing 10% serum.
2. The antibodies were diluted in 96-well plates using a three-fold gradient of complete medium with 2% serum at a initial well concentration of 100 ng/. Mu.l, ensuring a final volume of 100. Mu.l per well.
3. The RSV A2 live virus was thawed at 4℃and the TCID50 of the live virus was 1.45x10e5 Pfu/ml. Mu.l of the mixture was added to 9.7ml of a complete medium containing 2% serum, and the mixture was mixed and added to 100. Mu.l of the antibody gradient dilution.
4. VC (no antibody, no virus) wells and CC (no antibody, no virus) wells were set in 96-well plates as controls.
5. The overnight medium was discarded, the solution obtained in the 2-4 steps was mixed well, and the mixture was added to Vero cells and cultured in a 5% CO 2 incubator at 37℃for 3 hours.
6. The solution added in step 5 was discarded, and 200. Mu.l of methylcellulose was used for each well, and the mixture was cultured in a 5% CO 2 incubator at 37℃for 72 hours.
7. Mu.l of 4% paraformaldehyde was added to each well, and the mixture was fixed at room temperature for 10 minutes, tapped to discard all the supernatant, and 60. Mu.l of 4% paraformaldehyde was added to each well again, and the mixture was fixed at room temperature for 10 minutes.
8. And 200 mu l of PBS solution is used for each hole, the holes are washed for 5 to 8 times, all the supernatant is removed by tapping, all the residual methylcellulose on the cell surface is washed completely, no viscous liquid or viscous bubbles are ensured in the holes, and the effects of the steps such as subsequent antibody staining and the like are prevented from being influenced.
9. 200 Μl of 5% BSA in PBS was added to each well and blocked for 1 hour at room temperature with a shaker.
10. 1 Diluted with 100. Mu.l PBS per well: 500 RSV polyclonal antibody (Abcam, cat: ab 20686), incubated for 2 hours at room temperature in the absence of light.
11. The wells were washed 5-8 times with 200. Mu.l of PBS solution each.
12. And adding 100 mu l Trueblue KPL of color development liquid (Seracare, cat: 5510-0030) into each hole, incubating for 10-20 minutes at room temperature in a dark place, discarding the color development liquid when obvious blue precipitates are formed in cells observed under a microscope, and directly or after the liquid in the holes is dried, performing photographing counting by using an ELISPot plate reader.
Neutralization activity (%) = [1- (number of spots of test group-number of spots of cell control)/(number of spots of virus control-number of spots of cell control) ] ×100%.
The concentration of antibody at 50% neutralization activity, i.e., the IC50 value of the antibody, was calculated using GRAPHPAD PRISM software.
3 Results of experiments
TABLE 1LV21 antibody sequences
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TABLE 2 heavy chain novel analysis of antibodies
TABLE 3 analysis of antibody light chain novelty
The monoclonal cell sorting technology is used for carrying out single cell sorting on mouse spleen memory B cells immunized with RSV-F pre-fusion conformational immunogen DS2-strep II-His6, thus obtaining a novel neutralizing antibody LV21 (figure 1) of RSV-F protein, the sequences of the antibodies are shown in table 1, and the antibodies have novelty (tables 2 and 3) and have the capability of neutralizing live viruses of RSV-A2 strain.
The half-binding concentration EC50 of LV21 antibody to RSV-F pre-fusion conformational immunogen DS2-strepII-His6 was 0.009237 μg/ml (FIG. 2), indicating that the antibody has higher binding activity to pre-fusion conformational immunogen DS2-strepII-His 6. In addition, the IC50 value of LV21 for neutralizing RSV-A2 strain virus was 0.04082. Mu.g/ml (FIG. 3), indicating that the antibody has a strong neutralizing activity.
The above description of the embodiments is only for the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that several improvements and modifications can be made to the present invention without departing from the principle of the invention, and these improvements and modifications will fall within the scope of the claims of the invention.
Claims (10)
1. An antibody or antigen-binding fragment thereof, characterized in that the antibody or antigen-binding fragment thereof comprises,
Heavy chain variable region complementarity determining region:
V H CDR1 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO.1,
V H CDR2 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 2,
V H CDR3 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 3,
Light chain variable region complementarity determining region:
v L CDR1 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO 9,
V L CDR2 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO 10,
V L CDR3 comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 11,
The antibody or antigen binding fragment thereof specifically binds to the F protein of respiratory syncytial virus and/or neutralizes respiratory syncytial virus;
Preferably, the antibody or antigen binding fragment thereof specifically binds to the pre-fusion conformation of the F protein of respiratory syncytial virus;
Preferably, the amino acid sequence of the V H CDR1 is shown in SEQ ID NO.1,
The amino acid sequence of the V H CDR2 is shown as SEQ ID NO. 2,
The amino acid sequence of the V H CDR3 is shown as SEQ ID NO. 3,
The amino acid sequence of the V L CDR1 is shown as SEQ ID NO 9,
The amino acid sequence of the V L CDR2 is shown as SEQ ID NO 10,
The amino acid sequence of the V L CDR3 is shown in SEQ ID NO. 11.
2. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof further comprises,
Heavy chain variable region framework regions:
V H FR1 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 4,
V H FR2 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 5,
V H FR3 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 6,
V H FR4 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 7,
Light chain variable region framework regions:
V L FR1 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 12,
V L FR2 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 13,
V L FR3 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO. 14,
V L FR4 comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID No. 15;
Preferably, the amino acid sequence of V H FR1 is shown as SEQ ID NO. 4,
The amino acid sequence of V H FR2 is shown as SEQ ID NO. 5,
The amino acid sequence of V H FR3 is shown as SEQ ID NO. 6,
The amino acid sequence of V H FR4 is shown as SEQ ID NO. 7,
The amino acid sequence of V L FR1 is shown as SEQ ID NO. 12,
The amino acid sequence of V L FR2 is shown as SEQ ID NO. 13,
The amino acid sequence of V L FR3 is shown as SEQ ID NO. 14,
The amino acid sequence of V L FR4 is shown as SEQ ID NO. 15;
Preferably, the heavy chain variable region V H of the antibody or antigen-binding fragment thereof has an amino acid sequence which is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence shown in SEQ ID NO. 8,
The light chain variable region V L has an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence shown in SEQ ID NO. 16;
preferably, the amino acid sequence of the heavy chain variable region V H is shown in SEQ ID NO. 8,
The amino acid sequence of the light chain variable region V L is shown as SEQ ID NO. 16;
Preferably, the antibody or antigen-binding fragment thereof further comprises a defucosylated antibody or antigen-binding fragment thereof;
preferably, the antibody or antigen binding fragment thereof further comprises a detectable label.
3. Any of the following:
(1) A nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of claim 1 or 2;
(2) A vector comprising the nucleic acid molecule of (1);
(3) A host cell comprising the nucleic acid molecule of (1) or the vector of (2);
(4) A product for detecting respiratory syncytial virus, comprising the antibody or antigen-binding fragment thereof of claim 1 or 2;
preferably, the nucleic acid molecule encoding a CDR3 of V H CDR1、VH CDR2、VH of (1) has a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the nucleotide sequence shown in SEQ ID NO 17, 18, 19, respectively,
The nucleic acid molecules encoding the V L CDR1、VL CDR2、VL CDR3 have a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the nucleotide sequences shown in SEQ ID NOs 20, 21, 22, respectively;
Preferably, the nucleotide sequences of the nucleic acid molecules encoding the CDR3 of V H CDR1、VH CDR2、VH of (1) are shown in SEQ ID NOS.17, 18, 19, respectively,
The nucleotide sequences of the nucleic acid molecules encoding the V L CDR1、VL CDR2、VL CDR3 are shown in SEQ ID NOS 20, 21 and 22, respectively.
4. A substance according to claim 3, wherein the carrier in (2) has a signal peptide operably linked to an antibody;
Preferably, the vector further comprises an element for controlling expression;
preferably, the carrier further comprises a material that facilitates its entry into the cell.
5. A substance according to claim 3, wherein the host cell in (3) comprises a prokaryotic cell, a eukaryotic cell;
preferably, the prokaryotic cell comprises a eubacterium;
preferably, the eubacteria include gram-negative or gram-positive organisms, escherichia, enterobacter, streptomyces;
preferably, the eukaryotic cell comprises a protozoan cell, an animal cell, a plant cell or a fungal cell;
Preferably, the animal cells include mammalian cells, avian cells, insect cells;
Preferably, the mammalian cells include 293F cells, 293T cells, CHO cells, AT1080 cells, A549 cells.
6. A substance according to claim 3, wherein the product of (5) further comprises reagents for performing an antigen-antibody reaction or reagents for detecting a reaction;
preferably, the reagents for performing an antigen-antibody reaction include buffers, salts;
preferably, the product comprises a kit and a test strip;
Preferably, the kit comprises a conjugate of an antibody linked to a signal generating compound.
7. A pharmaceutical composition for use in the treatment or prophylaxis of respiratory syncytial virus infection, characterized in that the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof according to claim 1 or 2, or a substance according to any one of claims 3-6;
preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier;
preferably, the pharmaceutical composition further comprises one or more additional antiviral antibodies;
Preferably, the one or more additional antiviral antibodies are anti-RSV antibodies or antigen-binding fragments thereof;
Preferably, the one or more additional antiviral antibodies include palivizumab, motavizumab 、AFFF、P12f2、P12f4、P11d4、A1e9、A12a6、A13c4、A17d4、A4B4、A8c7、1X-493L1、FR H3-3F4、M3H9、Y10H6、DG、AFFF(1)、6H8、L1-7E5、L2-15B10、A13a11、A1h5、A4B4(1)、A4B4L1FR-S28R、A4B4-F52S、rsv6、rsv11、rsv13、rsv19、rsv21、rsv22、rsv23、RF-1、RF-2, and antigen-binding fragments thereof.
8. Any of the following applications:
(1) Use of an antibody or antigen-binding fragment thereof according to claim 1 or 2, or a substance according to any one of claims 3-6, for the detection of respiratory syncytial virus;
(2) Use of an antibody or antigen-binding fragment thereof according to claim 1 or 2, or a substance according to any one of claims 3-6, for the preparation of a product for diagnosing respiratory syncytial virus;
(3) Use of an antibody or antigen-binding fragment thereof according to claim 1 or 2, a substance according to any one of claims 3-6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention and/or treatment of respiratory syncytial virus infection;
Preferably, the product described in (2) comprises a kit.
9. A method of making the antibody or antigen-binding fragment thereof of claim 1 or 2, comprising: culturing the host cell of any one of claims 3-5, recovering the antibody or antigen-binding fragment thereof;
preferably, the method further comprises purifying the antibody or antigen binding fragment thereof.
10. A method of detecting respiratory syncytial virus in a sample, the method comprising: contacting the antibody or antigen binding fragment thereof of claim 1 or 2 with a test sample, thereby detecting the level of respiratory syncytial virus in the test sample.
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