WO2024199312A1 - 靶向冠状病毒的抗体鼻喷剂及其应用 - Google Patents

靶向冠状病毒的抗体鼻喷剂及其应用 Download PDF

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Publication number
WO2024199312A1
WO2024199312A1 PCT/CN2024/084227 CN2024084227W WO2024199312A1 WO 2024199312 A1 WO2024199312 A1 WO 2024199312A1 CN 2024084227 W CN2024084227 W CN 2024084227W WO 2024199312 A1 WO2024199312 A1 WO 2024199312A1
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seq
amino acid
antigen
nasal spray
acid sequence
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PCT/CN2024/084227
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English (en)
French (fr)
Inventor
刘翠华
张卫孝
林燕娜
刘媛媚
梅雄
李胜峰
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百奥泰生物制药股份有限公司
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Publication of WO2024199312A1 publication Critical patent/WO2024199312A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, and in particular relates to an antibody nasal spray targeting coronavirus and an application thereof.
  • Nasal drug delivery preparations refer to a type of preparations that are directly applied to the nasal cavity to exert local or systemic therapeutic effects.
  • Nasal drug delivery has the advantages of rapid absorption, fast onset of action, avoidance of the first-pass effect in the liver, high bioavailability, ease of use, and the ability to bypass the blood-brain barrier and deliver drugs directly to the brain.
  • Nasal sprays are currently one of the most widely used dosage forms of nasal drug delivery preparations. Compared with nasal drops, sprays have more accurate dosing, even drug distribution, rapid absorption, and high bioavailability. Compared with aerosols, no propellant is required in the preparation, avoiding adverse reactions caused by the addition of propellants, and the cost is lower.
  • nasal spray administration determines that its requirements for drugs are different from those for injection. Injections are usually one-time medications, prepared and used immediately, usually used in hospitals, with low-temperature storage conditions, and require professional medical personnel to inject and administer. Nasal sprays are usually one bottle or one can that must be used repeatedly, and are generally used by patients outside the hospital, so they do not have low-temperature storage conditions. Therefore, compared with injections, protein nasal sprays have higher requirements for solution stability and require stability at room temperature, which is also a technical difficulty in developing large molecule nasal sprays. Based on this, the antibody protein injection system cannot be directly used in nasal sprays, so it is necessary to develop a nasal spray formulation system that can be stably stored and used multiple times at room temperature to improve the clinical safety and effectiveness of antibody protein nasal sprays.
  • the present invention provides a nasal spray containing an antibody or antigen-binding fragment targeting coronavirus, which can keep the protein stable at a higher concentration. In addition, it can remain stable and have good binding activity under room temperature, long-term refrigeration and repeated freezing and thawing conditions, thereby improving the safety and effectiveness of clinical use.
  • the present invention provides a nasal spray comprising an antibody or antigen-binding fragment targeting a coronavirus.
  • the present invention provides a nasal spray comprising: (1) an antibody or antigen-binding fragment targeting a coronavirus; (2) a buffer; (3) a stabilizer; (4) a surfactant; and (5) a thickener.
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.5, or 6.0 ⁇ 0.3; for example, the pH is about 3.0, about 4.0, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.1, about 6.2, about 6.4, about 6.6, about 7.0, about 8.0, or a range between any two values (including the endpoints). value).
  • the concentration of the antibody or antigen-binding fragment targeting coronavirus is 1 to 200 mg/mL, or 1 to 150 mg/mL, or 1 to 100 mg/mL, or 10 to 100 mg/mL, or 10 to 80 mg/mL, or 10 to 70 mg/mL, for example, the concentration of the antibody or antigen-binding fragment targeting coronavirus is about 1 mg/mL, about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 50 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 120 mg/mL, about 150 mg/mL, about 180 mg/mL, about 200 mg/mL, or a range between any two values (including the endpoint values).
  • the buffer is selected from one or more of phosphate, citric acid, citrate, acetic acid, acetate, succinate, glutamate, histidine and histidine salts.
  • the buffer is selected from phosphate buffer, citric acid buffer and histidine buffer.
  • the buffer is a combination of citric acid and sodium citrate.
  • the buffer is a combination of acetic acid and sodium acetate.
  • the buffer is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • the buffer is a combination of histidine and histidine hydrochloride.
  • the concentration of the buffer is 1-50 mM, or 1-40 mM, or 1-30 mM, or 1-25 mM, or 1-20 mM, or 1-15 mM, for example, the concentration of the buffer is about 1 mM, about 4 mM, about 5 mM, about 10 mM, about 15 mM, about 17 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 50 mM, or a range between any two values (including the endpoints).
  • the stabilizer is selected from polyols, sugars, amino acids, salts, or combinations thereof. In some embodiments, the stabilizer is selected from one or more of mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride, and arginine or its salt (such as arginine hydrochloride). In some embodiments, the stabilizer is sucrose.
  • the concentration of the stabilizer is 1 to 200 mg/mL, or 20 to 200 mg/mL, or 1 to 150 mg/mL, or 20 to 150 mg/mL, or 20 to 120 mg/mL, or 30 to 120 mg/mL, or 50 to 100 mg/mL; for example, the concentration of the stabilizer is about 1 mg/mL, about 10 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL.
  • mL about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 150 mg/mL, about 160 mg/mL, about 180 mg/mL, about 200 mg/mL, or a range between any two values (including the endpoints).
  • the surfactant is selected from poloxamer (e.g., poloxamer 188), Tween (e.g., Tween 20 and Tween 80). In some embodiments, the surfactant is Tween 80. In some embodiments, the concentration of the surfactant is 0.01-10 mg/mL, or 0.05-10 mg/mL, or 0.1-10 mg/mL, or 0.1-5 mg/mL, or 0.2-5 mg/mL, or 0.5-1 mg/mL; for example, the concentration of the surfactant is about 0.01 mg/mL, about 0.05 mg/mL, about 0.5 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 5 mg/mL, about 8 mg/mL. mg/mL, about 10 mg/mL, or a range between any two values (including the endpoints).
  • poloxamer e.g., poloxamer 188
  • Tween e.g., Tween 20
  • the thickener is selected from povidone thickeners, cellulose ether thickeners, mucopolysaccharide thickeners, polyacrylic acid thickeners, polyvinyl alcohol, or combinations thereof. In some embodiments, the thickener is selected from one or more of povidone, polyvinyl alcohol, carbomer, and hydroxypropyl methylcellulose. In some embodiments, the thickener is selected from one or more of PVP-K30, carbomer, PVA1788, HPMC4000, HPMC400, and HPMC100.
  • the concentration of the thickener is 0.01%-30%, or 0.01%-10%, or 0.05%-15%, or 0.05%-10%, or 0.05%-5%, or 0.05%-1%, or 0.05%-0.5%, or 0.1%-0.25%; for example, the concentration of the thickener is about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.25%, about 1%, about 5%, about 10%, about 20%, about 30%, or a range between any two values (including endpoints).
  • the nasal spray further comprises a preservative.
  • the preservative is selected from one or more of benzyl alcohol, phenol, methylparaben, propylparaben, benzalkonium bromide and benzalkonium chloride.
  • the concentration of the preservative is 0.001%-10%, or 0.005%-10%, or 0.005%-2.5%, or 0.001%-2%, or 0.001%-1%, or 0.003%-2%, or 0.006%-2%, or 0.01%-2%, or 0.01%-0.5%, or 0.01%-0.05%, or 0.01%-0.04%; for example, the concentration of the preservative is about 0.001%, about 0.003%, about 0.006%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 5%, about 10%, or a range between any two values (including the endpoint values).
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-150 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-80 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-70 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • thickener 0.01%-30%
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-150 mg/mL;
  • thickener 0.01%-10%
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-80 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-70 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 35 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the buffer is selected from one or more of phosphate, citric acid, citrate, acetic acid, acetate, succinate, glutamate, histidine and histidine salts.
  • the buffer is selected from phosphate buffer, citric acid buffer, histidine buffer.
  • the buffer is selected from a combination of citric acid and sodium citrate, a combination of acetic acid and sodium acetate, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate, and a combination of histidine and histidine hydrochloride.
  • the stabilizer is selected from polyols, sugars, amino acids, salts, or combinations thereof. In some embodiments, the stabilizer is selected from one or more of mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride, arginine or its salts (e.g., arginine hydrochloride).
  • the surfactant is selected from poloxamers (eg, poloxamer 188), Tweens (eg, Tween 20 and Tween 80).
  • the thickener is selected from povidone thickeners (e.g., PVP-K30, PVP-K90), cellulose ether thickeners (e.g., microcrystalline cellulose-sodium carboxymethylcellulose complex, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, or hydroxyethyl cellulose), mucopolysaccharide thickeners (e.g., sodium hyaluronate or chondroitin sulfate), polyacrylic acid thickeners (e.g., carbomer), polyvinyl alcohol, or a combination thereof.
  • povidone thickeners e.g., PVP-K30, PVP-K90
  • cellulose ether thickeners e.g., microcrystalline cellulose-sodium carboxymethylcellulose complex, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, or hydroxyethyl cellulose
  • the thickener is selected from one or more of povidone, polyvinyl alcohol, carbomer, and hydroxypropyl methylcellulose. In some embodiments, the thickener is selected from one or more of PVP-K30, carbomer, PVA1788, HPMC4000, HPMC400, and HPMC100.
  • the preservative is selected from one or more of benzyl alcohol, phenol, methylparaben, propylparaben, benzalkonium bromide and benzalkonium chloride.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-150 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-80 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-70 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-200 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-150 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 1-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-100 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-80 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 10-70 mg/mL;
  • the pH of the nasal spray is 3.0-8.0, or 4.0-8.0, or 5.0-7.0, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 35 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the nasal spray comprises:
  • Antibodies or antigen-binding fragments targeting coronavirus 50 mg/mL;
  • the pH of the nasal spray is 5.5 to 6.5, or 6.0 ⁇ 0.3, for example, the pH is about 6.0.
  • the hypromellose is selected from HPMC of different viscosities, preferably HPMC4000, HPMC400 or HPMC100.
  • the antibody or antigen-binding fragment targeting coronavirus is a monospecific antibody or antigen-binding fragment, and the monospecific antibody or antigen-binding fragment can bind to Spike protein.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises one or more of HCDR1 as shown in SEQ ID NO: 1 or 2, HCDR2 as shown in SEQ ID NO: 3 or 4, HCDR3 as shown in any one of SEQ ID NO: 5-42, LCDR1 as shown in SEQ ID NO: 43 or 44, LCDR2 as shown in SEQ ID NO: 45 or 46, and LCDR3 as shown in SEQ ID NO: 47 or 48.
  • the antibody or antigen-binding fragment targeting coronavirus comprises HCDR1 as shown in SEQ ID NO: 1 or 2, HCDR2 as shown in SEQ ID NO: 3 or 4, HCDR3 as shown in any one of SEQ ID NO: 5-42, LCDR1 as shown in SEQ ID NO: 43 or 44, LCDR2 as shown in SEQ ID NO: 45 or 46, and LCDR3 as shown in SEQ ID NO:47 or 48.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:6, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:9, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45, and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:15, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:16, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:18, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:19, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:20, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting coronavirus comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 3, HCDR3 as shown in SEQ ID NO: 21, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:22, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:23, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:24, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:25, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45, and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:28, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:29, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45, and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:30, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting coronavirus comprises SEQ ID NO: 1. , HCDR1 as shown in SEQ ID NO: 3, HCDR2 as shown in SEQ ID NO: 32, LCDR1 as shown in SEQ ID NO: 43, LCDR2 as shown in SEQ ID NO: 45, and LCDR3 as shown in SEQ ID NO: 47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:33, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:34, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:35, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45, and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:36, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:37, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45, and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:39, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting a coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:40, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45, and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:41, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises HCDR1 as shown in SEQ ID NO:2, HCDR2 as shown in SEQ ID NO:4, HCDR3 as shown in SEQ ID NO:42, LCDR1 as shown in SEQ ID NO:44, LCDR2 as shown in SEQ ID NO:46 and LCDR3 as shown in SEQ ID NO:48.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and/or a light chain variable region;
  • the heavy chain variable region comprises the amino acid sequence shown in any one of SEQ ID NOs: 56, 57, 83-105, or an amino acid sequence that has at least 80% identity with the sequence shown in any one of SEQ ID NOs: 56, 57, 83-105, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence shown in any one of SEQ ID NOs: 56, 57, 83-105;
  • the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 58 or 59, or an amino acid sequence that has at least 80% identity with the sequence shown in SEQ ID NO: 58 or 59, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 58 or 59.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:83, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:84, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:85, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:86, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:87, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting coronavirus comprises a heavy chain variable region and a light chain variable region.
  • variable region the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:88
  • the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:89, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:90, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:91, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:92, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:93, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:94, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:95, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:96, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:97, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 98, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: The amino acid sequence shown in NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:99, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:100, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:101, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:102, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:103, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:104, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:105, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:56, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:58.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:57, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:59.
  • the antibody or antigen-binding fragment targeting a coronavirus comprises a heavy chain constant region and/or a light chain constant region;
  • the heavy chain constant region comprises an amino acid sequence as shown in SEQ ID NO: 60 or 61, or an amino acid sequence having at least 80% identity to the sequence shown in SEQ ID NO: 60 or 61, or an amino acid sequence having at least 80% identity to the sequence shown in SEQ ID NO: 60 or 61.
  • the light chain constant region comprises the amino acid sequence as shown in SEQ ID NO:62, or an amino acid sequence that has at least 80% identity with the sequence shown in SEQ ID NO:62, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and/or a light chain;
  • the heavy chain comprises a heavy chain variable region as shown in any one of SEQ ID NO: 56, 57, 83-105 and a heavy chain constant region as shown in SEQ ID NO: 60 or 61;
  • the light chain comprises a light chain variable region as shown in SEQ ID NO: 58 or 59 and a light chain constant region as shown in SEQ ID NO: 62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:83 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:84 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:85 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:86 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:87 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:88 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:89 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:90 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:91 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:92 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:93 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:94 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:95 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:96 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:97 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:98 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:99 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:100 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting a coronavirus comprises a heavy chain and a light chain;
  • the chain comprises a heavy chain variable region as shown in SEQ ID NO: 101 and a heavy chain constant region as shown in SEQ ID NO: 61;
  • the light chain comprises a light chain variable region as shown in SEQ ID NO: 58 and a light chain constant region as shown in SEQ ID NO: 62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:102 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:103 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:104 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:105 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:56 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:58 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises a heavy chain variable region as shown in SEQ ID NO:57 and a heavy chain constant region as shown in SEQ ID NO:61; the light chain comprises a light chain variable region as shown in SEQ ID NO:59 and a light chain constant region as shown in SEQ ID NO:62.
  • the antibody or antigen-binding fragment targeting the coronavirus comprises a heavy chain and a light chain;
  • the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:71 or 72, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:71 or 72, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:71 or 72;
  • the light chain comprises an amino acid sequence as shown in SEQ ID NO:73 or 74, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:73 or 74, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:73 or 74.
  • the antibody targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises the amino acid sequence shown in SEQ ID NO:71, and the light chain comprises the amino acid sequence shown in SEQ ID NO:73.
  • the antibody targeting the coronavirus comprises a heavy chain and a light chain; the heavy chain comprises the amino acid sequence shown in SEQ ID NO:72, and the light chain comprises the amino acid sequence shown in SEQ ID NO:74.
  • the antibody targeting coronavirus is a bispecific antibody, which comprises a first binding portion that binds to the Spike protein and a second binding portion that binds to the Spike protein connected by a linker.
  • the first binding moiety that binds to a spike protein comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:1 or 2, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:3 or 4, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in any one of SEQ ID NO:5-42, or a variant thereof having a single or multiple site substitution, deletion or insertion.
  • the first binding moiety comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:1 or 2, or a variant thereof with single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:3 or 4, or a variant thereof with single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in any one of SEQ ID NO:5-42, or a variant thereof with single or multiple site substitution, deletion or insertion.
  • the first binding moiety comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:1 or 2
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:3 or 4
  • HCDR3 which comprises the amino acid sequence shown in any one of SEQ ID NO:5-42.
  • the first binding moiety comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:1 or 2, or a variant thereof with a single or multiple substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:3 or 4, or a variant thereof with a single or multiple substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in any one of SEQ ID NO:5-42, or a variant thereof with a single or multiple substitution, deletion or insertion
  • LCDR1 which comprises the amino acid sequence shown in SEQ ID NO:43 or 44, or a variant thereof with a single or multiple substitution, deletion or insertion
  • e LCDR2, which comprises the amino acid sequence shown in SEQ ID NO:45 or 46, or a variant thereof with a single or multiple substitution, deletion or insertion
  • LCDR3 which comprises the amino acid sequence shown in SEQ ID NO:47 or 48, or a variant thereof with a single or multiple substitution, deletion or insertion.
  • the first binding moiety comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO: 1 or 2, or a variant thereof having single or multiple site substitutions, deletions or insertions
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO: 3 or 4, or variants thereof with single or multiple site substitutions, deletions or insertions
  • HCDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 5-42, or variants thereof with single or multiple site substitutions, deletions or insertions
  • LCDR1 comprising an amino acid sequence as shown in SEQ ID NOs: 43 or 44, or variants thereof with single or multiple site substitutions, deletions or insertions
  • LCDR2 comprising an amino acid sequence as shown in SEQ ID NOs: 45 or 46, or variants thereof with single or multiple site substitutions, deletions or insertions
  • LCDR3 comprising an amino acid sequence as shown in SEQ ID NOs: 47 or 48, or variants thereof with single or multiple site
  • the variants are conservative amino acid substitution variants.
  • the first binding portion comprises one, two, three, four, five or all of HCDR1 as shown in SEQ ID NO:1 or 2, HCDR2 as shown in SEQ ID NO:3 or 4, HCDR3 as shown in any one of SEQ ID NO:5-42, LCDR1 as shown in SEQ ID NO:43 or 44, LCDR2 as shown in SEQ ID NO:45 or 46 and LCDR3 as shown in SEQ ID NO:47 or 48.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1 or 2, HCDR2 as shown in SEQ ID NO:3 or 4, HCDR3 as shown in any one of SEQ ID NO:5-42, LCDR1 as shown in SEQ ID NO:43 or 44, LCDR2 as shown in SEQ ID NO:45 or 46, and LCDR3 as shown in SEQ ID NO:47 or 48.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:6, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:9, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:15, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:16, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:18, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding moiety comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:19, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:20, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:21, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:22, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:23, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:24, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:25, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:28, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:29, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:30, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding moiety comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 3, HCDR3 as shown in SEQ ID NO: 32, HCDR4 as shown in SEQ ID NO: 43, LCDR1, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:33, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:34, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:35, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:36, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:37, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:39, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:40, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:1, HCDR2 as shown in SEQ ID NO:3, HCDR3 as shown in SEQ ID NO:41, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:45 and LCDR3 as shown in SEQ ID NO:47.
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO:2, HCDR2 as shown in SEQ ID NO:4, HCDR3 as shown in SEQ ID NO:42, LCDR1 as shown in SEQ ID NO:44, LCDR2 as shown in SEQ ID NO:46 and LCDR3 as shown in SEQ ID NO:48.
  • the first binding moiety comprises a heavy chain variable region and/or a light chain variable region.
  • the heavy chain variable region of the first binding moiety comprises an amino acid sequence as shown in any one of SEQ ID NOs: 56, 57, 83-105, or has at least one amino acid sequence similar to that shown in any one of SEQ ID NOs: 56, 57, 83-105.
  • the light chain variable region of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO:58 or 59, or an amino acid sequence that has at least 80% identity with the sequence shown in SEQ ID NO:58 or 59, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:58 or 59.
  • the heavy chain variable region of the first binding portion comprises an amino acid sequence as shown in any one of SEQ ID NOs: 56, 57, 83-105, or an amino acid sequence that is at least 80% identical to a sequence shown in any one of SEQ ID NOs: 56, 57, 83-105, or an amino acid sequence that has one or more conservative amino acid substitutions compared to a sequence shown in any one of SEQ ID NOs: 56, 57, 83-105;
  • the light chain variable region of the first binding portion comprises an amino acid sequence as shown in SEQ ID NOs: 58 or 59, or an amino acid sequence that is at least 80% identical to a sequence shown in SEQ ID NOs: 58 or 59, or an amino acid sequence that has one or more conservative amino acid substitutions compared to a sequence shown in SEQ ID NOs: 58 or 59.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:83, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:84, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:85, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:86, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:87, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:88, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:89, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:90, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:91, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding moiety comprises an amino acid sequence as shown in SEQ ID NO: 92.
  • the light chain variable region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:93, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:94, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:95, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:96
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:97
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:98
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:99
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:100, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:101, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:102, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:103, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:104, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:105, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:56, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:57
  • the light chain variable region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:59.
  • the first binding portion further comprises a heavy chain constant region, a light chain constant region, an Fc region, or a combination thereof.
  • the light chain constant region is a kappa or lambda chain constant region.
  • the first binding portion is one of the isotypes of IgG, IgM, IgA, IgE, or IgD, or a fragment thereof.
  • the isotype is IgG1, IgG2, IgG3, or IgG4, or a fragment thereof.
  • the C-terminus of the heavy chain constant region in the first binding portion is truncated.
  • the C-terminus of the heavy chain constant region in the first binding portion of IgG1 or IgG4 type lacks amino acid residues G and K.
  • the first binding portion is a chimeric antibody, a humanized antibody, or a fully human antibody. In one aspect, the first binding portion is a fully humanized antibody.
  • the first binding moiety comprises a heavy chain and/or a light chain.
  • the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:71 or 72, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:71 or 72, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:71 or 72; and/or
  • the light chain comprises an amino acid sequence as shown in SEQ ID NO:73 or 74, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:73 or 74, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:73 or 74.
  • the heavy chain of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:71, and the light chain of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:73.
  • the heavy chain of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:72, and the light chain of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:74.
  • the heavy chain of the first binding portion comprises an amino acid sequence as shown in amino acid positions 1 to 450 of SEQ ID NO:71 or amino acid positions 1 to 451 of SEQ ID NO:72, or an amino acid sequence that is at least 80% identical to the sequence shown in amino acid positions 1 to 450 of SEQ ID NO:71 or amino acid positions 1 to 451 of SEQ ID NO:72, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence shown in amino acid positions 1 to 450 of SEQ ID NO:71 or amino acid positions 1 to 451 of SEQ ID NO:72; and/or
  • the light chain of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO:73 or 74, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:73 or 74, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:73 or 74.
  • the heavy chain of the first binding portion comprises the amino acid sequence shown as amino acid position 1 to amino acid position 450 in SEQ ID NO:71 or amino acid position 1 to amino acid position 451 in SEQ ID NO:72, and the light chain of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:73 or 74.
  • the heavy chain of the first binding moiety comprises amino acids 1 to 2 in SEQ ID NO: 71.
  • the amino acid sequence shown at amino acid position 450 of SEQ ID NO: 72, and the light chain of the first binding moiety comprises the amino acid sequence shown at amino acid position 1 to amino acid position 451 of SEQ ID NO: 73.
  • the heavy chain of the first binding moiety comprises the amino acid sequence shown at amino acid position 1 to amino acid position 451 of SEQ ID NO: 72, and the light chain of the first binding moiety comprises the amino acid sequence shown at amino acid position 74.
  • the first binding moiety comprises two sequence-identical heavy chains and two sequence-identical light chains.
  • the linker is a polypeptide comprising glycine and serine.
  • the sequence of the linker is (GmS)n, wherein each m is independently 2, 3, 4 or 5, and n is independently 1, 2, 3, 4 or 5. In some embodiments, the sequence of the linker is (GGGGS)n, wherein each n is independently 1, 2, 3, 4 or 5. In some embodiments, the linker is GGGGS. In some embodiments, the linker is (GGGGS)2, as shown in SEQ ID NO:65. In some embodiments, the linker is (GGGGS)3. In some embodiments, the linker is (GGGGS)4, as shown in SEQ ID NO:63. In some embodiments, the linker is (GGGGS)5, as shown in SEQ ID NO:64.
  • the second binding moiety is a single domain antibody.
  • the second binding moiety is a single domain antibody and comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:66, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:67, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in SEQ ID NO:68, or a variant thereof having a single or multiple site substitution, deletion or insertion.
  • the second binding moiety is a single domain antibody and comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:66, or a variant thereof with a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:67, or a variant thereof with a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in SEQ ID NO:68, or a variant thereof with a single or multiple site substitution, deletion or insertion.
  • the second binding moiety is a single domain antibody and comprises:
  • HCDR1 comprising the amino acid sequence shown in SEQ ID NO:66
  • HCDR2 comprising the amino acid sequence shown in SEQ ID NO:67
  • HCDR3 comprising the amino acid sequence shown in SEQ ID NO:68.
  • the single domain antibody is a VHH.
  • the single domain antibody comprises an amino acid sequence as shown in SEQ ID NO:69, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:69, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:69.
  • the second binding portion is a single domain antibody and comprises an amino acid sequence as shown in SEQ ID NO:69.
  • the bispecific antibody comprises the first binding portion that binds to the spike protein and the second binding portion that binds to the spike protein, which are connected via the linker.
  • the bispecific antibody comprises the following features:
  • the first binding portion comprises at least one, two, three, four, five or all of the HCDR1 shown in SEQ ID NO: 1 or 2, the HCDR2 shown in SEQ ID NO: 3 or 4, the HCDR3 shown in any one of SEQ ID NO: 5-42, the LCDR1 shown in SEQ ID NO: 43 or 44, the LCDR2 shown in SEQ ID NO: 45 or 46 and the LCDR3 shown in SEQ ID NO: 47 or 48; and/or
  • the second binding part is VHH, and the second binding part comprises at least one, two or three of HCDR1 shown in SEQ ID NO:66, HCDR2 shown in SEQ ID NO:67, and HCDR3 shown in SEQ ID NO:68; and/or
  • the C-terminus of the first binding moiety is connected to the N-terminus of the second binding moiety via a linker, and the C-terminus of the first binding moiety is the C-terminus of the heavy chain or the C-terminus of the light chain in the first binding moiety;
  • amino acid sequence of the linker is (GGGGS)n, wherein n is independently 1, 2, 3, 4 or 5.
  • the bispecific antibody comprises the following features:
  • the first binding portion comprises HCDR1 as shown in SEQ ID NO: 1 or 2, HCDR2 as shown in SEQ ID NO: 3 or 4, HCDR3 as shown in any one of SEQ ID NO: 5-42, LCDR1 as shown in SEQ ID NO: 43 or 44, LCDR2 as shown in SEQ ID NO: 45 or 46 and LCDR3 as shown in SEQ ID NO: 47 or 48; and/or
  • the second binding part is VHH, and the second binding part comprises HCDR1 as shown in SEQ ID NO:66, HCDR2 as shown in SEQ ID NO:67, and HCDR3 as shown in SEQ ID NO:68; and/or
  • the C-terminus of the first binding moiety is connected to the N-terminus of the second binding moiety via a linker, and the C-terminus of the first binding moiety is the C-terminus of the heavy chain or the C-terminus of the light chain in the first binding moiety;
  • the sequence of the linker is (GGGGS)n, wherein n is independently 1, 2, 3, 4 or 5.
  • the heavy chain variable region of the first binding portion comprises an amino acid sequence as shown in any one of SEQ ID NOs: 56, 57, 83-105, or an amino acid sequence having at least 80% identity with the sequence shown in any one of SEQ ID NOs: 56, 57, 83-105, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in any one of SEQ ID NOs: 56, 57, 83-105.
  • the light chain variable region of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO: 58 or 59, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO: 58 or 59, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 58 or 59.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:83, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:84, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:85, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:86, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:87, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:88, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:89, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:90, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:91, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:92, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:93, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:94
  • the light chain variable region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:95, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:96
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:97
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:98
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:99
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:100, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:101
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:102, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:103, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:104, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:105, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:56, and the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:58.
  • the heavy chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:57
  • the light chain variable region of the first binding portion comprises the amino acid sequence shown as SEQ ID NO:59.
  • the first binding moiety comprises a heavy chain constant region, a light chain constant region, an Fc region, or a combination thereof.
  • the light chain constant region is a kappa or lambda chain constant region.
  • the first binding moiety is of IgG, IgM, IgA, IgE, or IgD type, or a fragment thereof.
  • the first binding moiety is of IgG1, IgG2, IgG3, or IgG4 type, or a fragment thereof.
  • the C-terminus of the heavy chain constant region in the first binding moiety is truncated.
  • the C-terminus of the heavy chain constant region in the first binding moiety of IgG1 or IgG4 type lacks amino acids
  • the Fc region is a variant Fc region.
  • the variant Fc region has one or more amino acid modifications, such as substitutions, deletions, or insertions, relative to the parent Fc region.
  • the first binding moiety is a scFV, Fab, Fab', F(ab)2, or F(ab)2'.
  • the first binding moiety and/or the second binding moiety is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • the first binding moiety further comprises a heavy chain constant region and/or a light chain constant region.
  • the heavy chain constant region of the first binding portion comprises an amino acid sequence as shown in amino acid position 1 to amino acid position 328 of SEQ ID NO: 60 or 61, or an amino acid sequence having at least 80% identity with the sequence shown in amino acid position 1 to amino acid position 328 of SEQ ID NO: 60 or 61, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in amino acid position 1 to amino acid position 328 of SEQ ID NO: 60 or 61; and/or
  • the light chain constant region of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO:62, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:62, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:62.
  • the heavy chain constant region of the first binding moiety comprises the amino acid sequence as shown in SEQ ID NO:60 from amino acid 1 to amino acid 328, and the light chain constant region of the first binding moiety comprises the amino acid sequence as shown in SEQ ID NO:62. In some embodiments, the heavy chain constant region of the first binding moiety comprises the amino acid sequence as shown in SEQ ID NO:61 from amino acid 1 to amino acid 328, and the light chain constant region of the first binding moiety comprises the amino acid sequence as shown in SEQ ID NO:62.
  • the heavy chain constant region of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO: 60 or 61, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO: 60 or 61, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 60 or 61; and/or
  • the light chain constant region of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO:62, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:62, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:62.
  • the heavy chain constant region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO: 60
  • the light chain constant region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO: 62
  • the heavy chain constant region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO: 61
  • the light chain constant region of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO: 62.
  • the second binding moiety is VHH. In some embodiments, the second binding moiety The invention relates to a polypeptide comprising an amino acid sequence as shown in SEQ ID NO:69, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:69, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:69.
  • a bispecific antibody comprising a first binding moiety and a single domain antibody, and comprising the following features:
  • the first binding portion comprises a heavy chain and a light chain;
  • the heavy chain of the first binding portion comprises an amino acid sequence as shown in amino acid position 1 to amino acid position 451 of SEQ ID NO:72, or an amino acid sequence having at least 80% identity with the sequence shown in amino acid position 1 to amino acid position 451 of SEQ ID NO:72, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in amino acid position 1 to amino acid position 451 of SEQ ID NO:72; and/or
  • the light chain of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO:74, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:74, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:74; and/or
  • the C-terminus of the heavy chain of the first binding moiety is connected to the single domain antibody via a linker as shown in SEQ ID NO:63; and/or
  • the single-domain antibody comprises an amino acid sequence as shown in SEQ ID NO:69, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:69, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:69.
  • the heavy chain of the first binding moiety comprises the amino acid sequence shown in amino acid position 1 to amino acid position 451 in SEQ ID NO:72, and the light chain of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:74; the C-terminus (i.e., the CH3 end) of the heavy chain of the first binding moiety is connected to the single domain antibody via a linker shown in SEQ ID NO:63, and the single domain antibody comprises the sequence shown in SEQ ID NO:69.
  • a bispecific antibody comprising a first binding moiety and a single domain antibody, and comprising the following features:
  • the first binding portion comprises a heavy chain and a light chain; the heavy chain of the first binding portion comprises the amino acid sequence shown in SEQ ID NO:72, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:72, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:72; and/or
  • the light chain of the first binding portion comprises an amino acid sequence as shown in SEQ ID NO:74, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:74, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:74; and/or
  • the C-terminus of the light chain of the first binding moiety is coupled to the single domain antibody via a linker as shown in SEQ ID NO: 64. Valence connection; and/or
  • the single-domain antibody comprises an amino acid sequence as shown in SEQ ID NO:69, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:69, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:69.
  • the heavy chain of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:72
  • the light chain of the first binding moiety comprises the amino acid sequence shown in SEQ ID NO:74
  • the C-terminus (i.e., the CH3 end) of the light chain of the first binding moiety is connected to the single domain antibody via a linker shown in SEQ ID NO:64
  • the single domain antibody comprises the sequence shown in SEQ ID NO:69.
  • the bispecific antibody comprises a first polypeptide and a second polypeptide. In some embodiments, the bispecific antibody comprises two first polypeptides with identical sequences and two second polypeptides with identical sequences.
  • the first polypeptide comprises, from N-terminus to C-terminus, a heavy chain, a linker, a single domain antibody of the first binding moiety, or consists of them; the second polypeptide comprises, or consists of a light chain.
  • the first polypeptide comprises, or consists of, an amino acid sequence as shown in SEQ ID NO:77, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:77, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:77; and/or
  • the second polypeptide comprises an amino acid sequence as shown in SEQ ID NO:74, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:74, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:74, or consists of the same.
  • the first polypeptide comprises the amino acid sequence shown as SEQ ID NO:77
  • the second polypeptide comprises the amino acid sequence shown as SEQ ID NO:74.
  • the bispecific antibody is 2F8-VH-VHH18.
  • the first polypeptide comprises a heavy chain, or consists of it;
  • the second polypeptide comprises, from N-terminus to C-terminus, a light chain of the first binding moiety, a linker, a single domain antibody, or consists of them.
  • the first polypeptide comprises, or consists of, an amino acid sequence as shown in SEQ ID NO:72, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:72, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:72; and/or
  • the second polypeptide comprises an amino acid sequence as shown in SEQ ID NO:78, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:78, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:78, or consists of the same.
  • the first polypeptide comprises the amino acid sequence shown in SEQ ID NO:72
  • the second polypeptide comprises the amino acid sequence shown in SEQ ID NO:78.
  • the bispecific antibody is 2F8-VL-VHH18.
  • the bispecific antibody is an isolated bispecific antibody. In some embodiments, the isolated bispecific antibody is a monoclonal antibody. In some embodiments, the bispecific antibody is a bispecific monoclonal antibody.
  • the first binding portion of the bispecific antibody specifically binds to the Spike protein. In some embodiments, the second binding portion of the bispecific antibody specifically binds to the Spike protein.
  • the antibody targeting coronavirus is a single domain antibody, which can bind to the Spike protein.
  • Some embodiments provide a single domain antibody targeting a coronavirus, the single domain antibody comprising:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:66, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:67, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in SEQ ID NO:68, or a variant thereof having a single or multiple site substitution, deletion or insertion.
  • the single domain antibody comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:66, or a variant thereof with a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:67, or a variant thereof with a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in SEQ ID NO:68, or a variant thereof with a single or multiple site substitution, deletion or insertion.
  • the single domain antibody comprises HCDR1 as shown in SEQ ID NO:66, HCDR2 as shown in SEQ ID NO:67, and HCDR3 as shown in SEQ ID NO:68.
  • the single domain antibody is a VHH. In some embodiments, the single domain antibody comprises an amino acid sequence as shown in SEQ ID NO: 69, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO: 69, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 69.
  • the single domain antibody comprises or consists of an amino acid sequence as shown in SEQ ID NO:69.
  • the single domain antibody is an isolated antibody. In some embodiments, the single domain antibody is an isolated monoclonal antibody.
  • the antibody targeting coronavirus is a heavy chain antibody that can bind Spike protein.
  • variable region of the heavy chain antibody comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:66, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:67, or a variant thereof having a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in SEQ ID NO:68, or a variant thereof having a single or multiple site substitution, deletion or insertion.
  • the heavy chain antibody comprises:
  • HCDR1 which comprises the amino acid sequence shown in SEQ ID NO:66, or a variant thereof with a single or multiple site substitution, deletion or insertion
  • HCDR2 which comprises the amino acid sequence shown in SEQ ID NO:67, or a variant thereof with a single or multiple site substitution, deletion or insertion
  • HCDR3 which comprises the amino acid sequence shown in SEQ ID NO:68, or a variant thereof with a single or multiple site substitution, deletion or insertion.
  • variable region of the heavy chain antibody comprises HCDR1 as shown in SEQ ID NO:66, HCDR2 as shown in SEQ ID NO:67, and HCDR3 as shown in SEQ ID NO:68.
  • variable region of the heavy chain antibody comprises, or consists of, an amino acid sequence as shown in SEQ ID NO:69, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:69, or an amino acid sequence having one or more conservative amino acid substitutions with the sequence shown in SEQ ID NO:69.
  • variable region of the heavy chain antibody comprises, or consists of, the amino acid sequence shown in SEQ ID NO:69.
  • a heavy chain antibody comprises a variable region, a linker, and an Fc region.
  • the linker is a polypeptide comprising glycine and serine.
  • the sequence of the linker is (GmS)n, wherein each m is independently 2, 3, 4 or 5, and n is independently 1, 2, 3, 4 or 5.
  • the sequence of the linker is (GGGGS)n, wherein n is independently 1, 2, 3, 4 or 5.
  • the linker is GGGGS.
  • the linker is (GGGGS)2, as shown in SEQ ID NO:65.
  • the linker is (GGGGS)3.
  • the linker is (GGGGS)4, as shown in SEQ ID NO:63.
  • the linker is (GGGGS)5, as shown in SEQ ID NO:64.
  • the Fc region comprises an amino acid sequence as shown in SEQ ID NO:70, or an amino acid sequence having at least 80% identity with the sequence shown in SEQ ID NO:70, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:70.
  • the heavy chain antibody comprises an amino acid sequence as shown in SEQ ID NO: 79, or an amino acid sequence having at least 80% identity to the sequence shown in SEQ ID NO: 79, or an amino acid sequence having at least 80% identity to the sequence shown in SEQ ID NO: 79. Amino acid sequences having one or more conservative amino acid substitutions.
  • the heavy chain antibody comprises an amino acid sequence as shown in SEQ ID NO:79.
  • the nasal spray comprises: 50 mg/mL of an antibody targeting coronavirus, 5 mM histidine, 5 mM histidine hydrochloride, 80 mg/mL sucrose, 1 mg/mL Tween 80, 1 mg/mL HPMC4000 and 0.03% benzalkonium chloride; the pH of the nasal spray is 6.0 ⁇ 0.3; the antibody targeting coronavirus comprises a first polypeptide as shown in SEQ ID NO:77 and a second polypeptide as shown in SEQ ID NO:74.
  • the nasal spray is a liquid preparation.
  • the solvent of the nasal spray is water, such as purified water, water for injection, or ultrapure water.
  • the present invention provides use of the nasal spray described herein in the preparation of a medicament for preventing or treating a disease caused by a coronavirus.
  • the present invention provides use of the nasal spray described herein in preventing or treating diseases caused by coronavirus.
  • the present invention provides a method of treating a disease caused by a coronavirus, comprising administering an effective amount of the nasal spray described herein to a patient in need thereof.
  • the coronavirus is selected from SARS-CoV, SARS-CoV-2 and MERS-CoV. In some embodiments, the coronavirus is SARS-CoV-2.
  • the disease caused by the coronavirus is a disease caused by the new coronavirus (coronavirus disease 2019, COVID-19).
  • the patient is a mammal. In some embodiments, the patient is a human.
  • Another aspect of the present invention provides a method for preparing the nasal spray, comprising mixing the components in water (eg water for injection or purified water) to prepare the nasal spray.
  • water eg water for injection or purified water
  • the method for preparing the nasal spray comprises the following steps:
  • step (3) preparing an auxiliary material mother solution containing a buffer, a stabilizer, a surfactant, and a thickener, and adding the auxiliary material mother solution to the antibody concentrate prepared in step (2) to obtain a nasal spray.
  • the method for preparing the nasal spray comprises the following steps:
  • step (3) preparing an auxiliary material mother solution containing a buffer, a stabilizer, a surfactant, a thickener, and a preservative, and adding the auxiliary material mother solution to the antibody concentrate prepared in step (2) to obtain a nasal spray.
  • the present invention is beneficial in that:
  • the nasal spray of the present invention can improve the physicochemical stability of antibodies targeting coronaviruses, so that the antibodies targeting coronaviruses can be stably present in the preparation, and the nasal spray can maintain its stability under conditions such as room temperature, long-term refrigeration, and repeated freezing and thawing, and can be stored for a long time in a non-sterile environment at room temperature without deterioration, has a long shelf life, can be placed for a long time after opening, and there is no need to worry about bacterial contamination, thereby improving the quality of the product, extending the shelf life of the product, and improving the safety of clinical use.
  • Figure 1 is a non-denaturing polyacrylamide gel electrophoresis (PAGE) diagram of the preparations under shaking and 25°C conditions; Lane 1 is preparation 3, shaken at room temperature for 48 hours; Lane 2 is preparation 4, shaken at room temperature for 48 hours; Lane 3 is preparation 5, shaken at room temperature for 48 hours; Lane 4 is preparation 6, shaken at room temperature for 48 hours; Lane 5 is preparation 3, placed at 25°C for 7 days; Lane 6 is preparation 4, placed at 25°C for 7 days; Lane 7 is preparation 8, stored at 4°C; Lane 8 is preparation 6, placed at 4°C for 7 days.
  • PAGE polyacrylamide gel electrophoresis
  • Figure 2 is the non-denaturing PAGE diagram of the preparations at 25°C and 40°C; Lane 1 is preparation 5, stored at 25°C for 7 days; Lane 2 is preparation 6, stored at 25°C for 7 days; Lane 3 is preparation 6, stored at 40°C for 1 day; Lane 4 is preparation 6, stored at 40°C for 3 days; Lane 5 is preparation 6, stored at 40°C for 5 days; Lane 6 is preparation 6, stored at 40°C for 7 days; Lane 7 is preparation 8, stored at 4°C; Lane 8 is preparation 6, stored at 4°C for 7 days.
  • Figure 3 is the non-denaturing PAGE diagram of the preparations at 40°C; wherein, Lane 1 is preparation 3, placed at 40°C for 1 day; Lane 2 is preparation 4, placed at 40°C for 1 day; Lane 3 is preparation 5, placed at 40°C for 1 day; Lane 4 is preparation 3, placed at 40°C for 3 days; Lane 5 is preparation 4, placed at 40°C for 3 days; Lane 6 is preparation 5, placed at 40°C for 3 days; Lane 7 is preparation 6, placed at 4°C for 7 days; Lane 8 is preparation 8, stored at 4°C.
  • Figure 4 is a PAGE diagram of preparations under freeze-thaw and high temperature conditions; wherein, Lane 1 is preparation 3, freeze-thaw treatment (first frozen at -60°C for 12h, then placed at 25°C for 12h, and repeated for four cycles); Lane 2 is preparation 3, placed at 40°C for 1d; Lane 3 is preparation 3, placed at 40°C for 1d (containing methionine); Lane 4 is preparation 3, placed at 40°C for 2d; Lane 5 is preparation 3, placed at 40°C for 2d (containing methionine); Lane 6 is preparation 3, placed at 40°C for 3d; Lane 7 is preparation 3, placed at 40°C for 3d; Lane 8 is preparation 8, stored at 4°C; Lane 9 is Marker.
  • Lane 1 is preparation 3, freeze-thaw treatment (first frozen at -60°C for 12h, then placed at 25°C for 12h, and repeated for four cycles); Lane 2 is preparation 3, placed at 40°C for 1d; Lane 3 is preparation 3, placed at 40°C for 1d (containing methionine); Lane 4
  • FIG5 shows the changes in relative binding activity of the preparations with temperature and time.
  • the term “comprising” or “including” as used herein means that an antibody, composition or method, etc. includes the listed elements, such as components or steps, but does not exclude others.
  • the protein or nucleic acid may be composed of the sequence, or may have additional amino acids or nucleotides at one or both ends of the protein or nucleic acid, but still has the activity described in the present invention.
  • Substantially consisting of means that an antibody, composition or method, etc. excludes other elements that have a fundamental effect on the characteristics of the combination, but does not exclude elements that have no essential effect on the antibody, composition or method, etc.
  • Consisting of means excluding elements that are not specifically listed.
  • compositions are within the scope of the present invention.
  • a composition is described as including components A, B and C, a composition consisting essentially of A, B and C and a composition consisting of A, B and C are independently within the scope of the present invention.
  • Constant amino acid substitution refers to the replacement of one amino acid residue by another amino acid residue containing a side chain (R group) of similar chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions are unlikely to substantially change the functional properties of a protein.
  • amino acid classes containing side chains of similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid.
  • Homology refers to the sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing the positions that can be aligned in each sequence. When a position in the compared sequences is occupied by the same base or amino acid, the molecules are homologous at that position. The degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences.
  • At least 80% identity is about 80% identity, about 81% identity, about 82% identity, about 83% identity, about 85% identity, about 86% identity, about 87% identity, about 88% identity, about 90% identity, about 91% identity, about 92% identity, about 94% identity, about 95% identity, about 98% identity, about 99% identity, or a range (including endpoints) between any two of these values or any value therein.
  • Antibody and antigen-binding fragment refer to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen.
  • An antibody may be a complete antibody or any antigen-binding fragment thereof or a single chain thereof. Therefore, the term “antibody” includes molecules that contain a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen. Any protein or peptide that is at least a part of an immunoglobulin molecule that has a biological activity that is combined with antibodies.
  • Antibodies and antigen-binding fragments include but are not limited to the complementarity determining region (CDR) of the heavy chain or light chain or its ligand binding portion, the heavy chain variable region (VH), the light chain variable region (VL), the heavy chain constant region (CH), the light chain constant region (CL), the framework region (FR) or any part thereof, or at least a part of the binding protein.
  • the CDR region includes the CDR region (LCDR1-3) of the light chain and the CDR region (HCDR1-3) of the heavy chain.
  • Antibodies and antigen-binding fragments can specifically recognize and bind to polypeptides or polypeptide complexes of one or more (such as two) antigens.
  • Antibodies or antigen-binding fragments that specifically recognize and bind to multiple (such as two) antigens can be referred to as multispecific (such as bispecific) antibodies or antigen-binding fragments.
  • antibody fragment refers to a portion of an antibody, and the composition of the antibody fragment of the present invention can be similar to F(ab') 2 , F(ab) 2 , Fab', Fab, Fv, scFv, etc. in a monospecific antibody fragment. Regardless of its structure, the antibody fragment binds to the same antigen recognized by the intact antibody.
  • antibody fragment includes aptamers, spiegelmers, and bivalent antibodies.
  • antigen-binding fragment also includes any synthetic or genetically engineered protein that acts as an antibody by binding to a specific antigen to form a complex.
  • the antibodies and antigen-binding fragments disclosed in the present invention include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single-chain antibodies, epitope-binding fragments (e.g., Fab, Fab' and F(ab')2, single-chain Fv (scFv).
  • the antibodies disclosed in the present invention can be derived from any animal, including birds and mammals.
  • the antibodies are human, mouse, donkey, rabbit, goat, camel, llama, horse or chicken antibodies.
  • the "%" involved in the nasal spray components refers to the mass volume (w/v) percentage.
  • 0.1% thickener in the nasal spray means that 100 mL of the nasal spray contains 0.1 g of thickener, or the thickener content is 1 mg/mL.
  • Stability and “stable” herein refer to the fact that in a preparation containing an antibody (including an antibody fragment thereof), the antibody (including an antibody fragment thereof) does not or only rarely aggregates, degrades or fragments under given production, preparation, transportation and/or storage conditions.
  • a “stable” preparation maintains biological activity under given production, preparation, transportation and/or storage conditions.
  • the stability of the antibody (including an antibody fragment thereof) can be assessed by measuring the degree of aggregation, degradation or fragmentation of the preparation, such as by SEC-HPLC, IEC-HPLC, CE-SDS and the like.
  • buffer also known as a buffer system or buffer system, includes but is not limited to organic acid salts such as succinic acid, acetic acid, citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid or phthalic acid and their salts; Tris, triethylamine hydrochloride, or phosphate buffer.
  • amino acids and their salts can also be used as buffers.
  • amino acid components include but are not limited to glycine, histidine, arginine, lysine, ornithine, isoleucine, leucine, alanine, glutamic acid or aspartic acid.
  • the preparation contains a buffer
  • the buffer is prepared by the buffer.
  • the buffer is a histidine buffer
  • the histidine buffer forms a histidine buffer in a solvent (such as water for injection) or a nasal spray; for example, a nasal spray contains 10mM histidine buffer, which also means that the nasal spray contains 10mM histidine buffer.
  • the amount of buffer in the present invention refers to the total amount of buffer pairs in the buffer system that constitutes the buffer.
  • molar concentration is used as the unit of the amount of buffer, and its value refers to the molar concentration of the buffer pair in the buffer system of the buffer.
  • a histidine buffer composed of histidine and histidine hydrochloride is used as a buffer
  • a given concentration of histidine buffer such as 10mM
  • L-histidine and L-histidine hydrochloride such as L-histidine is 5mM
  • L-histidine hydrochloride is 5mM.
  • stabilizer refers to a pharmaceutical excipient that is used to protect the active pharmaceutical ingredient and/or formulation from chemical and/or physical degradation during production, storage and application.
  • Stabilizers include, but are not limited to, polyols, such as mannitol, sorbitol, glycerol, arabinol, propylene glycol, polyethylene glycol, etc.; carbohydrates, such as monosaccharides (e.g., fructose, mannose, galactose, glucose, sorbitol, etc.), oligosaccharides (e.g., disaccharides, such as lactose, sucrose, trehalose, cellobiose, maltose, etc.; triptolide, such as raffinose, gentian triptolide, pine triptolide, etc.; cyclodextrin or its derivatives, such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclo
  • surfactant includes, but is not limited to, Tween (e.g., Tween 20 and Tween 80); Poloxamer (e.g., Poloxamer 188); Triton; Sodium dodecyl sulfate (SDS); Sodium lauryl sulfate; Octyl glucoside sodium salt; Lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, or stearyl sulfobetaine; Lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, or stearyl sarcosine; Linoleyl betaine, myristyl betaine, or cetyl betaine; Lauryl sultaine, myristyl betaine, or cetyl betaine.
  • Tween e.g., Tween 20 and Tween 80
  • Poloxamer
  • Tween is also known as polysorbate (e.g., Tween 20 is known as polysorbate 20, and Tween 80 is known as polysorbate 80).
  • the surfactant is Tween 80.
  • Thickener is a substance (liquid or solid) that can increase the viscosity of a solution, suspension, or liquid/solid mixture without substantially changing its other properties.
  • Thickeners include, but are not limited to, povidone thickeners, cellulose ether thickeners, mucopolysaccharide thickeners, polyacrylic acid thickeners, and polyvinyl alcohol (e.g., polyvinyl alcohol 1788 (PVA1788)); for example, the povidone thickener is selected from povidone K30 (PVP-K30) or povidone K90 (PVP-K90), the cellulose ether thickener is selected from microcrystalline cellulose-sodium carboxymethylcellulose complex, hydroxypropyl methylcellulose (e.g., HPMC4000, HPMC400 or HPMC100), methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxyethylcellulose, the mucopolysaccharide thickener is selected from sodium hyaluronate or chondroitin
  • histidine hydrochloride also known as histidine hydrochloride
  • histidine hydrochloride can be anhydrous histidine hydrochloride or a histidine hydrochloride hydrate, such as histidine hydrochloride monohydrate.
  • "5mM histidine hydrochloride” means that 5mmol histidine hydrochloride or histidine hydrochloride monohydrate is dissolved in a solvent to form a 1L solution; 1.06mg histidine hydrochloride monohydrate includes 1.06mg histidine hydrochloride monohydrate or a corresponding amount of histidine hydrochloride.
  • trehalose which can be anhydrous trehalose or a trehalose hydrate, such as trehalose dihydrate.
  • the purified water described in the present invention is pharmaceutical water obtained by distillation, ion exchange, reverse osmosis or other suitable methods from drinking water, and does not contain any additives.
  • the water for injection described in the present invention is water obtained by distillation of purified water.
  • in need means that a patient has been identified as being in need of a particular approach or treatment. In some embodiments, identification can be made by any diagnostic means.
  • Patient refers to any mammal in need of diagnosis, prognosis or treatment, including humans, dogs, cats, rabbits, mice, horses, cows, etc.
  • Treatment refers to both therapeutic treatment and preventive or prophylactic measures, the purpose of which is to prevent, slow, ameliorate or stop an undesirable physiological change or disorder, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, alleviation, reduction or disappearance of the disease state (whether partial or complete), extension of the expected survival period compared to not receiving treatment, etc.
  • Patients in need of treatment include patients who already have a disease or disorder, patients who are susceptible to a disease or disorder, or patients in need of prevention of the disease or disorder, and patients who can or are expected to benefit from the administration of the antibodies or pharmaceutical compositions disclosed in the present invention for detection, diagnostic procedures and/or treatment.
  • an “effective amount” is an amount of an active compound or agent that is capable of eliciting a biological or medicinal response in a tissue, system, individual, animal or human.
  • the dosage of the preparation of the present invention for human body will vary with the patient's age, weight, gender, dosage form, health condition and severity of the disease.
  • the DNA encoding the antibody can be designed and synthesized according to the antibody amino acid sequence described herein in a conventional manner, placed in an expression vector, and then transfected into a host cell, and the transfected host cell is cultured in a culture medium to produce a monoclonal antibody.
  • the antibody expression vector includes at least one promoter element, an antibody coding sequence, a transcription termination signal, and a polyA tail.
  • Other elements include enhancers, Kozak sequences, and donor and acceptor sites for RNA splicing on both sides of the insertion sequence.
  • Efficient transcription can be obtained by the early and late promoters of SV40, the long terminal repeats from retroviruses such as RSV, HTLV1, HIVI, and the early promoters of cytomegalovirus, and promoters of other cells such as the actin promoter can also be used.
  • Suitable expression vectors may include pIRES1neo, pRetro-Off, pRetro-On, PLXSN, pLNCX, pcDNA3.1 (+/-), pcDNA/Zeo (+/-), pcDNA3.1/Hygro (+/-), PSVL, PMSG, pRSVcat, pSV2dhfr, pBC12MI and pCS2, etc.
  • Commonly used mammalian cells include HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells and CHO cells, etc.
  • the capillary electrophoresis instrument used was Beckman’s PA800 plus. After sample injection, the chromatogram was recorded, the data was integrated and processed, and the percentage of the monomer peak was calculated using the area normalization method.
  • Blocking Wash the ELISA plate twice with washing buffer PBST (PBS containing 0.05% Tween 20), then add 200 ⁇ L of blocking solution (3% BSA, solvent is PBST) to each reaction well and incubate at 37°C for 2 h.
  • PBST washing buffer PBST
  • blocking solution 3% BSA, solvent is PBST
  • reference substance 2F8-VH-VHH18 Take an appropriate amount of reference substance 2F8-VH-VHH18, add PBS to dilute to 1 mg/mL, and then dilute to 5 ⁇ g/mL with PBST. Taking this as the starting concentration, perform 3-fold gradient dilution with PBST to obtain reference substance solutions with different concentration gradients.
  • the reference substance concentrations are 5000 ng/mL, 1666.7 ng/mL, 555.6 ng/mL, 185.2 ng/mL, 61.73 ng/mL, 20.58 ng/mL, 6.859 ng/mL, 2.286 ng/mL, 0.762 ng/mL, and 0.254 ng/mL, respectively.
  • Termination Add 50 ⁇ L of 0.2 M sulfuric acid solution to each reaction well to terminate the color development reaction, and then read the results within 30 minutes.
  • Plate reading Set the detection wavelength to 450nm and the reference wavelength to 630nm. Use the analysis software provided by the microplate reader to read the readings. Fit the obtained readings with a four-parameter equation curve model.
  • control substance is the antibody 2F8-VH-VHH18 standard substance.
  • variable region and constant region of exemplary antibodies 1-24 and 2F8 is shown in Table 1, the composition of the framework region and CDR region of the heavy chain variable region is shown in Table 2, VH and CH (as shown in SEQ ID NO: 61) constitute the heavy chain of the antibody, and VL and CL (as shown in SEQ ID NO: 62) constitute the light chain of the antibody; wherein, antibody 2F8 (monospecific antibody) contains two heavy chains with the same sequence (as shown in SEQ ID NO: 72) and two light chains with the same sequence (as shown in SEQ ID NO: 74), the nucleic acid sequence corresponding to its heavy chain is shown in SEQ ID NO: 75, and the nucleic acid sequence corresponding to its light chain is shown in SEQ ID NO: 76; the amino acid sequence of the single domain antibody VHH18 is shown in SEQ ID NO: 69; the heavy chain antibody VHH18-Fc contains two heavy chains with the same sequence (as shown in SEQ ID NO: 79), the heavy chain antibody comprises
  • the bispecific antibody 2F8-VH-VHH18 contains two first polypeptides with the same sequence (as shown in SEQ ID NO:77) and two second polypeptides with the same sequence (as shown in SEQ ID NO:74), the first polypeptide comprises a heavy chain (as shown in amino acid 1 to amino acid 451 in SEQ ID NO:72), a linker L1 (GGGGSGGGGSGGGGSGGGGS, as shown in SEQ ID NO:63) and a single-domain antibody VHH18 (as shown in SEQ ID NO:69), the second polypeptide is a light chain, the nucleic acid sequence corresponding to the first polypeptide is shown in SEQ ID NO:80, and the nucleic acid sequence corresponding to the second polypeptide is shown in SEQ ID NO:76, the heavy chain of the first polypeptide and the second polypeptide constitute the first binding portion of the bispecific antibody 2F8-VH-VHH18, and the single-domain antibody is the second binding portion of the bi
  • the bispecific antibody 2F8-VL-VHH18 contains two first polypeptides with identical sequences (as shown in SEQ ID NO:72) and two second polypeptides with identical sequences (as shown in SEQ ID NO:78), the first polypeptide is a heavy chain, the second polypeptide comprises a light chain, a linker L2 (GGGGSGGGGSGGGGSG GGGSGGGGS, as shown in SEQ ID NO:64) and a single domain antibody, the nucleic acid sequence corresponding to the first polypeptide is shown in SEQ ID NO:75, and the nucleic acid sequence corresponding to the second polypeptide is shown in SEQ ID NO:81, the heavy chain of the first polypeptide and the light chain of the second polypeptide constitute the first binding part of the bispecific antibody 2F8-VL-VHH18, and the single domain antibody is the second binding part of the bispecific antibody 2F8-VL-VHH18.
  • the amino acid sequences of CDR, framework region, variable region, constant region and linker are shown in Table 3; the amino acid sequences of single domain antibody and heavy chain antibody are shown in Table 4; the amino acid sequences of exemplary monospecific antibody are shown in Table 5; the nucleic acid sequence of antibody 2F8 is shown in Table 6; the amino acid sequence of bispecific antibody is shown in Table 7; the nucleic acid sequences of bispecific antibody and heavy chain antibody are shown in Table 8. See Table 8.
  • the DNA sequences of the antibodies were cloned into expression vectors respectively, and then stably transformed into CHO cells. After suspension culture, the supernatant was harvested and subjected to Protein A affinity capture, anion and cation chromatography to obtain antibodies with a purity greater than 95%.
  • the antibody 2F8-VH-VHH18 samples were ultrafiltrated and exchanged to obtain 5 different buffer samples, and the samples after exchange were diluted to an antibody concentration of 10 mg/mL.
  • the B 22 of PB6.0 is negative and the kD is positive.
  • the proteins attract each other, but the formulation converts them into repulsive interactions, which may have the risk of aggregation; the B 22 of CB6.0 and CB5.0 is positive and the kD is negative.
  • the proteins repel each other, but the formulation promotes their mutual attraction, which has a great risk of aggregation; the kD and B 22 of PB7.0 and His6.0 are both positive.
  • the proteins show mutual repulsion and are not easy to aggregate.
  • Example 4 Spraying effect of different types and contents of thickeners in purified water
  • the experiment shows that the sprayable concentration range of PVP-K30 and PVA1788 is relatively wide, with the sprayable concentration range of PVP-K30 being 0-10% and that of PVA1788 being 0-5%; while the sprayable concentration range of HPMC4000 is about 0-0.2%, the sprayable concentration range of HPMC400 is 0-1%, and the sprayable concentration range of HPMC100 is 0-2%.
  • HPMC4000 has a good viscosity-increasing effect and can effectively reduce the spray range.
  • the spray range can be effectively reduced at 0.2%, and a small amount has little effect on the preparation.
  • the spray state is more divergent, forming a hollow plum blossom shape.
  • the spray shape is better, but the spray width of 0.1% is more in line with the distribution of nasal structure and the dosage is low.
  • Example 7 Effects of different concentrations of HPMC4000 and HPMC400 on the spray morphology and spray particle size distribution of the preparation
  • the buffer of the preparation in this example is 10 mM His6.0, and the antibody is antibody 2F8-VH-VHH18.
  • the specific preparation information is shown in Table 22.
  • the angle of CF-6 is the largest and exceeds the 60° set by the quality standard, and its area and width are the largest among these preparations. Its spray state is in a divergent state and does not meet the requirements. Analysis and comparison of the angle and width changes of CF-5 and CF-6 are significantly greater than those of the other four preparations, indicating that at the same concentration, the smaller the molecular weight of HPMC, the larger the spray angle and width. The ellipticity analysis results of each preparation are mostly below 1.3, indicating that the preparation spray is close to a circle. According to the width and angle, except for CF-6, the other preparations CF-1 to CF-5 are within the quality standard range.
  • the spray area of each preparation at 3cm is relatively stable, while the spray area at 6cm varies greatly. This may be because the particles are less affected by the inertia of movement after the spray distance increases, resulting in large fluctuations in the test results.
  • the area of CF-5 and CF-6 at 3cm is significantly larger than that of other preparations, indicating that the spray area increases with the decrease of HPMC molecular weight.
  • the spray range of the small molecular weight is larger, and this conclusion can also be drawn based on the angle change at 3cm.
  • the buffer of the preparation in this example is 10 mM His6.0, and the antibody is antibody 2F8-VH-VHH18.
  • the specific preparation information is shown in Table 25.
  • the buffer of the preparation in this example is 10 mM His6.0, and the antibody is antibody 2F8-VH-VHH18.
  • the specific preparation information is shown in Table 27.
  • solubility of methylparaben and propylparaben in the buffer solution has reached its maximum value and cannot be increased any further, and the antibacterial efficacy of the current maximum value still does not meet the standard; secondly, if the maximum solubility is selected, there will be a risk of precipitation once it is placed at low temperature.
  • the antibody of the preparation of this example is antibody 2F8-VH-VHH18, and the specific preparation information is shown in Table 29.
  • Antibacterial efficacy test results Note: “Gold” in the table refers to Staphylococcus aureus, “Copper” refers to Pseudomonas aeruginosa, “White” refers to Candida albicans, and “Black” refers to Aspergillus niger.
  • the evaluation criteria are: compared with 0h, the bacteria should be reduced by 2lg values on the second day; the bacteria should be reduced by at least 3lg values on the 7th day; the bacteria should be reduced by at least 3lg values on the 14th day. Compared with 0h on the 14th day, the fungi should be reduced by at least 2lg values.
  • NI Compared with the 14th day, the number of test bacteria increased by no more than 0.5lg on the 28th day.
  • the antibacterial efficacy experiment shows that under standard A, the antibacterial efficacy can meet the requirements after adding 0.03% benzalkonium chloride.
  • the binding activity of the preparation is very high at 4°C and 25°C, indicating that the addition of benzalkonium chloride has little effect on the binding activity at room temperature and below.
  • the binding activity of the antibody protein packaged in white high-density polyethylene bottles is higher than that in transparent tubes, indicating that the white high-density polyethylene plastic bottles have a protective effect on the protein under light.
  • the stability of the preparation is poor at a high temperature of 40°C, but it is more stable at 4°C and 25°C, indicating that the antibody is more sensitive to temperature.
  • the preparation produced very few fragments and aggregates at 4°C and 25°C. Oscillation had little effect on binding activity, and the PAGE results also showed that there were fewer fragments and aggregates under oscillation conditions.
  • the binding activity test showed that oscillation and low temperature had little effect on binding activity.
  • Example 10 Five samples of the preparation in Example 10 were placed at 30°C, 37°C, and 40°C for 1 h, 2 h, 8 h, 12 h, 24 h, 28 h, 32 h, 36 h, 48 h, 50 h, 52 h, 54 h, 56 h, 58 h, 60 h, 72 h, 74 h, 76 h, 78 h, 80 h, 82 h, 84 h, and 96 h, respectively, and the relative binding activity of the samples was examined. The results are shown in Figure 5.
  • the 40°C condition has the greatest impact on the binding activity, with the relative binding activity decreasing to 60% at 58 h. However, at 30°C and 37°C, the relative binding activity remained at around 80% at 150 h.
  • mixing method 1 take a sample placed at 4°C for 21 days, freeze and thaw it first, then oscillate it at room temperature for 48 hours, and then place it at 40°C for 4 days; take samples after freeze and thaw, oscillate it at room temperature for 48 hours, and place it at 40°C for 4 days, and the resulting samples are named 1-1, 1-2, and 1-3.
  • Mixing method 2 take a sample placed at 4°C for 21 days, place it at 40°C for 3 days, then place it at 25°C for 3 days, and then place it at -60°C for 4 days; take samples after 40°C for 3 days and -60°C for 4 days, and the resulting samples are named 2-1 and 2-2.

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Abstract

一种靶向冠状病毒的抗体鼻喷剂，其包含：靶向冠状病毒的抗体或抗原结合片段、缓冲剂、稳定剂、表面活性剂和增稠剂，可选地还包含防腐剂。该鼻喷剂可以提高靶向冠状病毒的抗体的物理化学稳定性，鼻喷剂在室温、长期冷藏和反复冻融等条件下均能保持蛋白稳定性，可以提高临床使用的安全性和有效性。

Description

靶向冠状病毒的抗体鼻喷剂及其应用 技术领域
本发明属于药物制剂领域，具体涉及靶向冠状病毒的抗体鼻喷剂及其应用。
背景技术
鼻腔给药制剂是指直接用于鼻腔，发挥局部或全身治疗作用的一类制剂。鼻腔给药具有吸收迅速、起效快、可避免肝脏首过效应、生物利用度高、使用方便以及可绕开血脑屏障向脑内直接递送药物等优点。鼻用喷雾剂为目前鼻腔给药制剂中使用最广泛的剂型之一，与滴鼻剂相比，喷雾剂的给药剂量更准确，药物分布均匀，吸收起效快，生物利用度高；与气雾剂相比，制剂中无需添加抛射剂，避免了因为加入抛射剂而产生的不良反应，且成本较低。
鼻喷剂给药方式的特点决定了其对药物的要求与注射给药不同，注射剂通常是一次性用药，现配现用，通常是在医院内使用，具有低温储存条件，需专业医疗人员进行注射给药，而鼻喷剂通常为一瓶或一罐要反复使用多次，而且一般是患者在医院外自行使用，所以不具有低温储存条件。因此，蛋白鼻喷剂与注射剂相比，对溶液稳定性要求更高，要求在常温条件下稳定，这也是开发大分子鼻喷剂的技术难点。基于此，抗体蛋白注射体系不能直接作于鼻喷剂使用，因此需要开发一种在常温下稳定储存和多次使用的鼻喷制剂体系，以提高抗体蛋白鼻喷剂的临床安全性和有效性。
发明内容
本发明提供包含靶向冠状病毒的抗体或抗原结合片段鼻喷剂，可以使得蛋白在较高的浓度下保持稳定，此外，室温、长期冷藏和反复冻融的条件下均能保持稳定且具有很好的结合活性，提高临床使用安全性和有效性。
在一些实施方案中，本发明提供了一种鼻喷剂，其包含靶向冠状病毒的抗体或抗原结合片段。
在一些实施方案中，本发明提供了一种鼻喷剂，其包含：(1)靶向冠状病毒的抗体或抗原结合片段；(2)缓冲剂；(3)稳定剂；(4)表面活性剂；和(5)增稠剂。
在一些实施方案中，所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.5，或6.0±0.3；例如pH为约3.0，约4.0，约5.0、约5.2、约5.4、约5.6、约5.8、约6.0，约6.1，约6.2，约6.4，约6.6，约7.0，约8.0，或任意两个数值之间的范围(包括端点 值)。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段的浓度为1～200mg/mL，或1～150mg/mL，或1～100mg/mL，或10～100mg/mL，或10～80mg/mL，或10～70mg/mL，例如靶向冠状病毒的抗体或抗原结合片段的浓度为约1mg/mL，约10mg/mL，约20mg/mL，约30mg/mL，约35mg/mL，约40mg/mL，约50mg/mL，约70mg/mL，约80mg/mL，约90mg/mL，约100mg/mL，约120mg/mL，约150mg/mL，约180mg/mL，约200mg/mL，或任意两个数值之间的范围(包括端点值)。
在一些实施方案中，所述缓冲剂选自磷酸盐、柠檬酸、柠檬酸盐、醋酸、醋酸盐、琥珀酸盐、谷氨酸盐、组氨酸和组氨酸盐中的一种或几种。在一些实施方案中，所述缓冲剂选自磷酸缓冲剂、柠檬酸缓冲剂和组氨酸缓冲剂。在一些实施方案中，所述缓冲剂为柠檬酸和柠檬酸钠的组合。在一些实施方案中，所述缓冲剂为醋酸和醋酸钠的组合。在一些实施方案中，所述缓冲剂为磷酸氢二钠和磷酸二氢钠的组合。在一些实施方案中，所述缓冲剂为组氨酸和组氨酸盐酸盐的组合。在一些实施方案中，所述缓冲剂的浓度为1～50mM，或1～40mM，或1～30mM，或1～25mM，或1～20mM，或1～15mM，例如缓冲剂的浓度为约1mM，约4mM，约5mM，约10mM，约15mM，约17mM，约20mM，约25mM，约30mM，约35mM，约40mM，约50mM，或任意两个数值之间的范围(包括端点值)。
在一些实施方案中，所述稳定剂选自多元醇、糖类、氨基酸、盐类，或它们的组合。在一些实施方案中，所述稳定剂选自甘露醇、山梨醇、乳糖、海藻糖、蔗糖、氯化钠和精氨酸或其盐(如精氨酸盐酸盐)中的一种或几种。在一些实施方案中，所述稳定剂为蔗糖。在一些实施方案中，所述稳定剂的浓度为1～200mg/mL，或20～200mg/mL，或1～150mg/mL，或20～150mg/mL，或20～120mg/mL，或30～120mg/mL，或50～100mg/mL；例如稳定剂的浓度为约1mg/mL，约10mg/mL，约20mg/mL，约25mg/mL，约30mg/mL，约35mg/mL，约40mg/mL，约45mg/mL，约50mg/mL，约60mg/mL，约70mg/mL，约75mg/mL，约80mg/mL，约85mg/mL，约90mg/mL，约100mg/mL，约110mg/mL，约120mg/mL，约130mg/mL，约150mg/mL，约160mg/mL，约180mg/mL，约200mg/mL，或任意两个数值之间的范围(包括端点值)。
在一些实施方案中，所述表面活性剂选自泊洛沙姆(例如泊洛沙姆188)、吐温(例如吐温20和吐温80)。在一些实施方案中，所述表面活性剂为吐温80。在一些实施方案中，所述表面活性剂的浓度为0.01～10mg/mL，或0.05～10mg/mL，或0.1～10mg/mL，或0.1～5mg/mL，或0.2～5mg/mL，或0.5～1mg/mL；例如表面活性剂的浓度为约0.01mg/mL，约0.05mg/mL，约0.5mg/mL，约1mg/mL，约2mg/mL，约3mg/mL，约5mg/mL，约8 mg/mL，约10mg/mL，或任意两个数值之间的范围(包括端点值)。
在一些实施方案中，所述增稠剂选自聚维酮类增稠剂、纤维素醚类增稠剂、粘多糖类增稠剂、聚丙烯酸类增稠剂、聚乙烯醇，或它们的组合。在一些实施方案中，所述增稠剂选自聚维酮、聚乙烯醇、卡波姆和羟丙甲纤维素中的一种或几种。在一些实施方案中，所述增稠剂选自PVP-K30、卡波姆、PVA1788、HPMC4000、HPMC400和HPMC100中的一种或几种。在一些实施方案中，所述增稠剂的浓度为0.01％-30％，或0.01％-10％，或0.05％-15％，或0.05％-10％，或0.05％-5％，或0.05％-1％，或0.05％-0.5％，或0.1％-0.25％；例如增稠剂的浓度为约0.01％，约0.05％，约0.1％，约0.2％，约0.25％，约1％，约5％，约10％，约20％，约30％，或任意两个数值之间的范围(包括端点值)。
在一些实施方案中，所述鼻喷剂还包含防腐剂。在一些实施方案中，所述防腐剂选自苯甲醇、苯酚、羟苯甲酯、羟苯丙酯、苯扎溴铵和苯扎氯铵中的一种或几种。在一些实施方案中，所述防腐剂的浓度为0.001％-10％，或0.005％-10％，或0.005％-2.5％，或0.001％-2％，或0.001％-1％，或0.003％-2％，或0.006％-2％，或0.01％-2％，或0.01％-0.5％，或0.01％-0.05％，或0.01％-0.04％；例如防腐剂的浓度为约0.001％，约0.003％，约0.006％，约0.01％，约0.02％，约0.03％，约0.04％，约0.05％，约0.1％，约0.5％，约1％，约5％，约10％，或任意两个数值之间的范围(包括端点值)。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)缓冲剂：1～50mM；
(3)稳定剂：1～200mg/mL；
(4)表面活性剂：0.01～10mg/mL；和
(5)增稠剂：0.01％-30％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)缓冲剂：1～50mM；
(3)稳定剂：20～200mg/mL；
(4)表面活性剂：0.05～10mg/mL；和
(5)增稠剂：0.05％-15％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～150mg/mL；
(2)缓冲剂：1～40mM；
(3)稳定剂：20～200mg/mL；
(4)表面活性剂：0.1～10mg/mL；和
(5)增稠剂：0.01％-10％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～100mg/mL；
(2)缓冲剂：1～30mM；
(3)稳定剂：1～150mg/mL；
(4)表面活性剂：0.1～5mg/mL；和
(5)增稠剂：0.05％-5％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～100mg/mL；
(2)缓冲剂：1～25mM；
(3)稳定剂：20～150mg/mL；
(4)表面活性剂：0.1～5mg/mL；和
(5)增稠剂：0.05％-1％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～80mg/mL；
(2)缓冲剂：1～20mM；
(3)稳定剂：20～120mg/mL；
(4)表面活性剂：0.2～5mg/mL；和
(5)增稠剂：0.05％-0.5％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～70mg/mL；
(2)缓冲剂：1～15mM；
(3)稳定剂：50～100mg/mL；
(4)表面活性剂：0.5～1mg/mL；和
(5)增稠剂：0.1％-0.25％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)缓冲剂：1～50mM；
(3)稳定剂：1～200mg/mL；
(4)表面活性剂：0.01～10mg/mL；
(5)增稠剂：0.01％-30％；和
(6)防腐剂：0.001％-10％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)缓冲剂：1～50mM；
(3)稳定剂：20～200mg/mL；
(4)表面活性剂：0.05～10mg/mL；
(5)增稠剂：0.05％-15％；和
(6)防腐剂：0.005％-10％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～150mg/mL；
(2)缓冲剂：1～40mM；
(3)稳定剂：20～200mg/mL；
(4)表面活性剂：0.1～10mg/mL；
(5)增稠剂：0.01％-10％；和
(6)防腐剂：0.005％-2.5％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～100mg/mL；
(2)缓冲剂：1～30mM；
(3)稳定剂：1～150mg/mL；
(4)表面活性剂：0.1～5mg/mL；
(5)增稠剂：0.05％-5％；和
(6)防腐剂：0.001％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～100mg/mL；
(2)缓冲剂：1～25mM；
(3)稳定剂：20～150mg/mL；
(4)表面活性剂：0.1～5mg/mL；
(5)增稠剂：0.05％-1％；和
(6)防腐剂：0.003％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～80mg/mL；
(2)缓冲剂：1～20mM；
(3)稳定剂：20～120mg/mL；
(4)表面活性剂：0.2～5mg/mL；
(5)增稠剂：0.05％-0.5％；和
(6)防腐剂：0.006％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～70mg/mL；
(2)缓冲剂：1～15mM；
(3)稳定剂：50～100mg/mL；
(4)表面活性剂：0.5～1mg/mL；
(5)增稠剂：0.1％-0.25％；和
(6)防腐剂：0.01％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：35mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：90mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：90mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：90mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.25％；和
(6)防腐剂：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：90mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.2％；和
(6)防腐剂：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.003％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.006％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.01％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.02％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.03％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.04％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)缓冲剂：10mM；
(3)稳定剂：80mg/mL；
(4)表面活性剂：1mg/mL；
(5)增稠剂：0.1％；和
(6)防腐剂：0.05％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述缓冲剂选自磷酸盐、柠檬酸、柠檬酸盐、醋酸、醋酸盐、琥珀酸盐、谷氨酸盐、组氨酸和组氨酸盐中的一种或几种。在一些实施方案中，所述缓冲剂选自磷酸缓冲剂、柠檬酸缓冲剂、组氨酸缓冲剂。在一些实施方案中，所述缓冲剂选自柠檬酸和柠檬酸钠的组合、醋酸和醋酸钠的组合、磷酸氢二钠和磷酸二氢钠的组合、组氨酸和组氨酸盐酸盐的组合。
在一些实施方案中，所述稳定剂选自多元醇、糖类、氨基酸、盐类，或它们的组合。在一些实施方案中，稳定剂选自甘露醇、山梨醇、乳糖、海藻糖、蔗糖、氯化钠、精氨酸或其盐(例如精氨酸盐酸盐中)中的一种或几种。
在一些实施方案中，所述表面活性剂选自泊洛沙姆(例如泊洛沙姆188)、吐温(例如吐温20和吐温80)。
在一些实施方案中，所述增稠剂选自聚维酮类增稠剂(例如PVP-K30、PVP-K90)、纤维素醚类增稠剂(例如微晶纤维素-羧甲基纤维素钠复合物、羟丙甲纤维素、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠或羟乙基纤维素)、粘多糖类增稠剂(例如透明质酸钠或硫酸软骨素)、聚丙烯酸类增稠剂(例如卡波姆)、聚乙烯醇，或它们的组合。在一些实施方案中，所述增稠剂选自聚维酮、聚乙烯醇、卡波姆和羟丙甲纤维素中的一种或几种。在一些实施方案中，所述增稠剂选自PVP-K30、卡波姆、PVA1788、HPMC4000、HPMC400和HPMC100中的一种或几种。
在一些实施方案中，所述防腐剂选自苯甲醇、苯酚、羟苯甲酯、羟苯丙酯、苯扎溴铵和苯扎氯铵中的一种或几种。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)组氨酸缓冲剂：1～50mM；
(3)蔗糖：1～200mg/mL；
(4)吐温80：0.01～10mg/mL；和
(5)羟丙甲纤维素：0.01％-30％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)组氨酸缓冲剂：1～50mM；
(3)蔗糖：20～200mg/mL；
(4)吐温80：0.05～10mg/mL；和
(5)羟丙甲纤维素：0.05％-15％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～150mg/mL；
(2)组氨酸缓冲剂：1～40mM；
(3)蔗糖：20～200mg/mL；
(4)吐温80：0.1～10mg/mL；和
(5)羟丙甲纤维素：0.01％-10％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～100mg/mL；
(2)组氨酸缓冲剂：1～30mM；
(3)蔗糖：1～150mg/mL；
(4)吐温80：0.1～5mg/mL；和
(5)羟丙甲纤维素：0.05％-5％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～100mg/mL；
(2)组氨酸缓冲剂：1～25mM；
(3)蔗糖：20～150mg/mL；
(4)吐温80：0.01～5mg/mL；和
(5)羟丙甲纤维素：0.05％-1％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～80mg/mL；
(2)组氨酸缓冲剂：1～20mM；
(3)蔗糖：20～120mg/mL；
(4)吐温80：0.2～5mg/mL；和
(5)羟丙甲纤维素：0.05％-0.5％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～70mg/mL；
(2)组氨酸缓冲剂：1～15mM；
(3)蔗糖：50～100mg/mL；
(4)吐温80：0.5～1mg/mL；和
(5)羟丙甲纤维素：0.1％-0.25％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)组氨酸缓冲剂：1～50mM；
(3)蔗糖：1～200mg/mL；
(4)吐温80：0.01～10mg/mL；
(5)羟丙甲纤维素：0.01％-30％；和
(6)苯甲醇或苯扎氯铵：0.001％-10％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
(2)组氨酸缓冲剂：1～50mM；
(3)蔗糖：20～200mg/mL；
(4)吐温80：0.05～10mg/mL；
(5)羟丙甲纤维素：0.05％-15％；和
(6)苯甲醇或苯扎氯铵：0.005％-10％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～150mg/mL；
(2)组氨酸缓冲剂：1～40mM；
(3)蔗糖：20～200mg/mL；
(4)吐温80：0.1～10mg/mL；
(5)羟丙甲纤维素：0.01％-10％；和
(6)苯甲醇或苯扎氯铵：0.005％-2.5％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：1～100mg/mL；
(2)组氨酸缓冲剂：1～30mM；
(3)蔗糖：1～150mg/mL；
(4)吐温80：0.1～5mg/mL；
(5)羟丙甲纤维素：0.05％-5％；和
(6)苯甲醇或苯扎氯铵：0.001％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～100mg/mL；
(2)组氨酸缓冲剂：1～25mM；
(3)蔗糖：20～150mg/mL；
(4)吐温80：0.1～5mg/mL；
(5)羟丙甲纤维素：0.05％-1％；
(6)苯甲醇或苯扎氯铵：0.003％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～80mg/mL；
(2)组氨酸缓冲剂：1～20mM；
(3)蔗糖：20～120mg/mL；
(4)吐温80：0.2～5mg/mL；
(5)羟丙甲纤维素：0.05％-0.5％；和
(6)苯甲醇或苯扎氯铵：0.006％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：10～70mg/mL；
(2)组氨酸缓冲剂：1～15mM；
(3)蔗糖：50～100mg/mL；
(4)吐温80：0.5～1mg/mL；
(5)羟丙甲纤维素：0.1％-0.25％；和
(6)苯甲醇或苯扎氯铵：0.01％-2％；
所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：35mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：90mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯甲醇：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：90mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯甲醇：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：90mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.25％；和
(6)苯甲醇：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：90mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.2％；和
(6)苯甲醇：1％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.003％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.006％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.01％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.02％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.03％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.04％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述鼻喷剂包含：
(1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
(2)组氨酸缓冲剂：10mM；
(3)蔗糖：80mg/mL；
(4)吐温80：1mg/mL；
(5)羟丙甲纤维素：0.1％；和
(6)苯扎氯铵：0.05％；
所述鼻喷剂的pH为5.5～6.5，或6.0±0.3，例如pH为约6.0。
在一些实施方案中，所述羟丙甲纤维素选自不同粘度的HPMC，优选HPMC4000、HPMC400或HPMC100。
单特异抗体
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段为单特异抗体或抗原结合片段，所述单特异抗体或抗原结合片段可以结合Spike蛋白。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3中的一个或多个。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和 如SEQ ID NO:47或48所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:6所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:9所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:15所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:16所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:18所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:19所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:20所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:21所示的HCDR3、如SEQ  ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:22所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:23所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:24所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:25所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:28所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:29所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:30所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所 示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:32所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:33所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:34所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:35所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:36所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:37所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:39所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:40所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:41所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:2所示的HCDR1、如SEQ ID NO:4所示的HCDR2、如SEQ ID NO:42所示的HCDR3、如SEQ ID NO:44所示的LCDR1、如SEQ ID NO:46所示的LCDR2和如SEQ ID NO:48所示的LCDR3。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和/或轻链可变区；所述重链可变区包含SEQ ID NO:56、57、83-105任一项所示的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或所述轻链可变区包含SEQ ID NO:58或59所示的氨基酸序列，或与SEQ ID NO:58或59所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:83所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:84所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:85所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:86所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:87所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可 变区；所述重链可变区包含SEQ ID NO:88所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:89所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:90所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:91所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:92所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:93所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:94所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:95所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:96所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:97所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:98所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:99所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:100所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:101所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:102所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:103所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:104所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:105所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:56所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链可变区和轻链可变区；所述重链可变区包含SEQ ID NO:57所示的氨基酸序列，所述轻链可变区包含SEQ ID NO:59所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链恒定区和/或轻链恒定区；所述重链恒定区包含如SEQ ID NO:60或61所示的氨基酸序列，或与SEQ ID NO:60或61所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:60或61所示序 列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或所述轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列，或与SEQ ID NO:62所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:62所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和/或轻链；所述重链包含如SEQ ID NO:56、57、83-105任一项所示的重链可变区和如SEQ ID NO:60或61所示的重链恒定区；所述轻链包含如SEQ ID NO:58或59所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:83所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:84所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:85所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:86所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:87所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:88所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:89所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:90所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:91所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:92所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:93所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:94所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:95所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:96所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:97所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:98所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:99所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:100所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重 链包含如SEQ ID NO:101所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:102所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:103所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:104所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:105所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:56所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:58所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:57所示的重链可变区和如SEQ ID NO:61所示的重链恒定区；所述轻链包含如SEQ ID NO:59所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
在一些实施方案中，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:71或72所示的氨基酸序列，或与SEQ ID NO:71或72所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:71或72所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或所述轻链包含如SEQ ID NO:73或74所示的氨基酸序列，或与SEQ ID NO:73或74所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:73或74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体包含重链和轻链；所述重链包含SEQ ID NO:71所示的氨基酸序列，所述轻链包含SEQ ID NO:73所示的氨基酸序列。
在一些实施方案中，所述靶向冠状病毒的抗体包含重链和轻链；所述重链包含SEQ ID NO:72所示的氨基酸序列，所述轻链包含SEQ ID NO:74所示的氨基酸序列。
双特异抗体
在一些实施方案中，所述靶向冠状病毒的抗体为双特异抗体，所述双特异抗体包含通过连接子连接的结合Spike蛋白的第一结合部分以及结合Spike蛋白的第二结合部分。
1)结合spike蛋白的第一结合部分
在一些实施方案中，所述结合spike蛋白的第一结合部分包含：
(a)HCDR1，其包含如SEQ ID NO:1或2所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:3或4所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和/或(c)HCDR3，其包含如SEQ ID NO:5-42任一项所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述第一结合部分包含：
(a)HCDR1，其包含如SEQ ID NO:1或2所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:3或4所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和(c)HCDR3，其包含如SEQ ID NO:5-42任一项所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述第一结合部分包含：
(a)HCDR1，其包含如SEQ ID NO:1或2所示的氨基酸序列；(b)HCDR2，其包含如SEQ ID NO:3或4所示的氨基酸序列；和(c)HCDR3，其包含如SEQ ID NO:5-42任一项所示的氨基酸序列。
在一些实施方案中，所述第一结合部分包含：
(a)HCDR1，其包含如SEQ ID NO:1或2所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:3或4所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(c)HCDR3，其包含如SEQ ID NO:5-42任一项所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(d)LCDR1，其包含如SEQ ID NO:43或44所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(e)LCDR2，其包含如SEQ ID NO:45或46所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和/或(f)LCDR3，其包含如SEQ ID NO:47或48所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述第一结合部分包含：
(a)HCDR1，其包含如SEQ ID NO:1或2所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:3或4所示的氨基酸序列， 或其有单一或多个位点取代、缺失或插入的变体；(c)HCDR3，其包含如SEQ ID NO:5-42任一项所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(d)LCDR1，其包含如SEQ ID NO:43或44所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(e)LCDR2，其包含如SEQ ID NO:45或46所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和(f)LCDR3，其包含如SEQ ID NO:47或48所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述变体为保守氨基酸取代变体。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3中的一个、两个、三个、四个、五个或全部。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:6所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:9所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:15所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:16所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:18所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:19所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:20所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:21所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:22所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:23所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:24所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:25所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:28所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:29所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:30所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:32所示的HCDR3、如SEQ ID NO:43所示的 LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:33所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:34所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:35所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:36所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:37所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:39所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:40所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:41所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3。
在一些实施方案中，所述第一结合部分包含如SEQ ID NO:2所示的HCDR1、如SEQ ID NO:4所示的HCDR2、如SEQ ID NO:42所示的HCDR3、如SEQ ID NO:44所示的LCDR1、如SEQ ID NO:46所示的LCDR2和如SEQ ID NO:48所示的LCDR3。
在一些实施方案中，所述第一结合部分包含重链可变区和/或轻链可变区。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:56、57、83-105任一项所示的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列具有至少 80％同一性的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的轻链可变区包含如SEQ ID NO:58或59所示的氨基酸序列，或与SEQ ID NO:58或59所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:56、57、83-105任一项所示的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；所述第一结合部分的轻链可变区包含如SEQ ID NO:58或59所示的氨基酸序列，或与SEQ ID NO:58或59所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:83所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:84所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:85所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:86所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:87所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:88所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:89所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:90所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:91所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:92所示的氨基 酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:93所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:94所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:95所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:96所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:97所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:98所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:99所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:100所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:101所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:102所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:103所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:104所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:105所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:56所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:57所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:59所示的氨基酸序列。
在一些实施方案中，所述第一结合部分还包含重链恒定区、轻链恒定区、Fc区或其组合。在一些实施方案中，轻链恒定区是κ或λ链恒定区。在一些实施方案中，第一结合部分是IgG、IgM、IgA、IgE或IgD其中一种同种型，或其片段。在一些实施方案中，同种型是IgG1、IgG2、IgG3或IgG4，或其片段。在一些实施方案中，第一结合部分中重链恒定区的C-末端被截短。在一些实施方案中，IgG1或IgG4型的第一结合部分中重链恒定区的C-末端缺少氨基酸残基G和K。没有限制地，所述第一结合部分是嵌合抗体、人源化抗体或是全人源抗体。在某一方面，所述第一结合部分是全人源化抗体。
在一些实施方案中，所述第一结合部分包含重链和/或轻链。
在一些实施方案中，所述重链包含如SEQ ID NO:71或72所示的氨基酸序列，或与SEQ ID NO:71或72所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:71或72所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述轻链包含如SEQ ID NO:73或74所示的氨基酸序列，或与SEQ ID NO:73或74所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:73或74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:71所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:73所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:72所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:74所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:71中第1位氨基酸至第450位氨基酸或SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示的氨基酸序列，或与SEQ ID NO:71中第1位氨基酸至第450位氨基酸或SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:71中第1位氨基酸至第450位氨基酸或SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的轻链包含如SEQ ID NO:73或74所示的氨基酸序列，或与SEQ ID NO:73或74所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:73或74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:71中第1位氨基酸至第450位氨基酸或SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:73或74所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:71中第1位氨基酸至 第450位氨基酸所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:73所示的氨基酸序列。在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:74所示的氨基酸序列。
在一些实施方案中，所述第一结合部分包含2条序列相同的重链和2条序列相同的轻链。
2)连接子
在一些实施方案中，所述连接子为包含甘氨酸和丝氨酸的多肽。
在一些实施方案中，所述连接子的序列为(GmS)n，其中每个m独立为2、3、4或5，n独立为1、2、3、4或5。在一些实施方案中，所述连接子的序列为(GGGGS)n，所述n独立为1、2、3、4或5。在一些实施方案中，所述连接子为GGGGS。在一些实施方案中，所述连接子为(GGGGS)2，如SEQ ID NO:65所示。在一些实施方案中，所述连接子为(GGGGS)3。在一些实施方案中，所述连接子为(GGGGS)4，如SEQ ID NO:63所示。在一些实施方案中，所述连接子为(GGGGS)5，如SEQ ID NO:64所示。
3)结合spike蛋白的第二结合部分
在一些实施方案中，所述第二结合部分为单域抗体。
在一些实施方案中，所述第二结合部分为单域抗体，且包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和/或(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述第二结合部分为单域抗体，且包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述第二结合部分为单域抗体，且包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列；和(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列。
在一些实施方案中，所述单域抗体为VHH。
在一些实施方案中，所述单域抗体包含如SEQ ID NO:69所示的氨基酸序列，或与SEQ ID NO:69所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:69所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第二结合部分为单域抗体，且包含如SEQ ID NO:69所示的氨基酸序列。
4)双特异抗体
在一些实施方案中，所述双特异抗体包含上述结合spike蛋白的第一结合部分以及结合spike蛋白的第二结合部分，通过上述连接子连接。
在一些实施方案中，所述双特异抗体包含以下特征：
所述第一结合部分至少包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3中的一个、两个、三个、四个、五个或全部；和/或
所述第二结合部分为VHH，所述第二结合部分至少包含如SEQ ID NO:66所示的HCDR1、如SEQ ID NO:67所示的HCDR2、如SEQ ID NO:68所示的HCDR3中的一个、两个或三个；和/或
所述第一结合部分的C-末端通过连接子与第二结合部分的N-末端进行连接，所述第一结合部分的C-末端为第一结合部分中重链的C-末端或轻链的C-末端；和/或
所述连接子的氨基酸序列为(GGGGS)n，所述n独立为1、2、3、4或5。
在一些实施方案中，所述双特异抗体包含以下特征：
所述第一结合部分包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3；和/或
所述第二结合部分为VHH，所述第二结合部分包含如SEQ ID NO:66所示的HCDR1、如SEQ ID NO:67所示的HCDR2、如SEQ ID NO:68所示的HCDR3；和/或
所述第一结合部分的C-末端通过连接子与第二结合部分的N-末端进行连接，所述第一结合部分的C-末端为第一结合部分中重链的C-末端或轻链的C-末端；和/或
所述连接子的序列为(GGGGS)n，所述n独立为1、2、3、4或5。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:56、57、83-105任一项所示的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的轻链可变区包含如SEQ ID NO:58或59所示的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:83所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:84所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:85所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:86所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:87所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:88所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:89所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:90所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:91所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:92所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:93所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:94所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:95所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:96所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:97所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:98所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:99所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:100所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:101所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:102所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:103所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:104所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:105所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:56所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:58所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链可变区包含如SEQ ID NO:57所示的氨基酸序列，所述第一结合部分的轻链可变区包含如SEQ ID NO:59所示的氨基酸序列。
在一些实施方案中，第一结合部分包含重链恒定区、轻链恒定区、Fc区或其组合。在一些实施方案中，轻链恒定区是κ或λ链恒定区。在一些实施方案中，第一结合部分是IgG、IgM、IgA、IgE或IgD型，或其片段。在一些实施方案中，第一结合部分是IgG1、IgG2、IgG3或IgG4型，或其片段。在一些实施方案中，第一结合部分中重链恒定区的C-末端被截短。在一些实施方案中，IgG1或IgG4型的第一结合部分中重链恒定区的C-末端缺少氨基酸 残基G和K。在一些实施方案中，Fc是变体Fc区。在一些实施方案中，相对于亲本Fc区，变体Fc区具有一个或多个氨基酸修饰，如取代、缺失或插入。在一些实施方案中，所述第一结合部分为scFV、Fab、Fab’、F(ab)2或F(ab)2’。
在一些实施方案中，所述第一结合部分和/或第二结合部分是嵌合抗体、人源化抗体或全人源抗体。
在一些实施方案中，所述第一结合部分还包含重链恒定区和/或轻链恒定区。
在一些实施方案中，所述第一结合部分的重链恒定区包含如SEQ ID NO:60或61中第1位氨基酸至第328位氨基酸所示的氨基酸序列，或与SEQ ID NO:60或61中第1位氨基酸至第328位氨基酸所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:60或61中第1位氨基酸至第328位氨基酸所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列，或与SEQ ID NO:62所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:62所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链恒定区包含如SEQ ID NO:60中第1位氨基酸至第328位氨基酸所示的氨基酸序列，所述第一结合部分的轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列。在一些实施方案中，所述第一结合部分的重链恒定区包含如SEQ ID NO:61中第1位氨基酸至第328位氨基酸所示的氨基酸序列，所述第一结合部分的轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链恒定区包含如SEQ ID NO:60或61所示的氨基酸序列，或与SEQ ID NO:60或61所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:60或61所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列，或与SEQ ID NO:62所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:62所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链恒定区包含如SEQ ID NO:60所示的氨基酸序列，所述第一结合部分的轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列。在一些实施方案中，所述第一结合部分的重链恒定区包含如SEQ ID NO:61所示的氨基酸序列，所述第一结合部分的轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列。
在一些实施方案中，所述第二结合部分为VHH。在一些实施方案中，所述第二结合部 分包含如SEQ ID NO:69所示的氨基酸序列，或与SEQ ID NO:69所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:69所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
一些实施方案中提供了一种双特异抗体，所述双特异抗体包含第一结合部分和单域抗体，且包含以下特征：
所述第一结合部分包括重链和轻链；所述第一结合部分的重链包含如SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示的氨基酸序列，或与SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示的序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的轻链包含如SEQ ID NO:74所示的氨基酸序列，或与SEQ ID NO:74所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的重链的C-末端通过如SEQ ID NO:63所示连接子与单域抗体进行连接；和/或
所述单域抗体包含如SEQ ID NO:69所示的氨基酸序列，或与SEQ ID NO:69所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:69所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:74所示的氨基酸序列；第一结合部分的重链的C-末端(即CH3末端)通过如SEQ ID NO:63所示连接子与单域抗体进行连接，所述单域抗体包含如SEQ ID NO:69所示的序列。
一些实施方案中提供了双特异抗体，所述双特异抗体包含第一结合部分和单域抗体，且包含以下特征：
所述第一结合部分包含重链和轻链；所述第一结合部分的重链包含如SEQ ID NO:72所示的氨基酸序列，或与SEQ ID NO:72所示的序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:72所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的轻链包含如SEQ ID NO:74所示的氨基酸序列，或与SEQ ID NO:74所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
所述第一结合部分的轻链的C-末端通过如SEQ ID NO:64所示连接子与单域抗体进行共 价连接；和/或
所述单域抗体包含如SEQ ID NO:69所示的氨基酸序列，或与SEQ ID NO:69所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:69所示序列相比具有一或多个保守氨基酸取代的的氨基酸序列。
在一些实施方案中，所述第一结合部分的重链包含如SEQ ID NO:72所示的氨基酸序列，所述第一结合部分的轻链包含如SEQ ID NO:74所示的氨基酸序列；第一结合部分的轻链的C-末端(即CH3末端)通过如SEQ ID NO:64所示连接子与单域抗体进行连接，所述单域抗体包含如SEQ ID NO:69所示的序列。
在一些实施方案中，双特异抗体包含第一多肽和第二多肽。在一些实施方案中，双特异抗体包含2条序列相同的第一多肽和2条序列相同的第二多肽。
在一些实施方案中，所述第一多肽从N-端至C-端依次包含第一结合部分的重链、连接子、单域抗体，或由其组成；所述第二多肽包含轻链，或由其组成。
在一些实施方案中，所述第一多肽包含如SEQ ID NO:77所示的氨基酸序列，或与SEQ ID NO:77所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:77所示序列相比具有一或多个保守氨基酸取代的氨基酸序列，或由其组成；和/或
所述第二多肽包含如SEQ ID NO:74所示的氨基酸序列，或与SEQ ID NO:74所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列，或由其组成。
在一些实施方案中，所述第一多肽包含如SEQ ID NO:77所示的氨基酸序列，所述第二多肽包含如SEQ ID NO:74所示的氨基酸序列。
在一些实施方案中，所述双特异抗体为2F8-VH-VHH18。
在一些实施方案中，所述第一多肽包含重链，或由其组成；所述第二多肽从N-端至C-端依次包含第一结合部分的轻链、连接子、单域抗体，或由其组成。
在一些实施方案中，所述第一多肽包含如SEQ ID NO:72所示的氨基酸序列，或与SEQ ID NO:72所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:72所示序列相比具有一或多个保守氨基酸取代的氨基酸序列，或由其组成；和/或
所述第二多肽包含如SEQ ID NO:78所示的氨基酸序列，或与SEQ ID NO:78所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:78所示序列相比具有一或多个保守氨基酸取代的氨基酸序列，或由其组成。
在一些实施方案中，所述第一多肽包含如SEQ ID NO:72所示的氨基酸序列，所述第二多肽包含如SEQ ID NO:78所示的氨基酸序列。
在一些实施方案中，所述双特异抗体为2F8-VL-VHH18。
在一些实施方案中，所述双特异抗体为分离的双特异抗体。在一些实施方案中，分离的双特异抗体为单克隆抗体。在一些实施方案中，所述双特异抗体为双特异单克隆抗体。
在一些实施方案中，所述双特异抗体第一结合部分特异性结合Spike蛋白。在一些实施方案中，所述双特异抗体第二结合部分特异性结合Spike蛋白。
单域抗体
在一些实施方案中，所述靶向冠状病毒的抗体为单域抗体，所述单域抗体可以结合Spike蛋白。
一些实施方案提供了靶向冠状病毒的单域抗体，所述单域抗体包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和/或(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述单域抗体包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述单域抗体包含如SEQ ID NO:66所示的HCDR1、如SEQ ID NO:67所示的HCDR2和如SEQ ID NO:68所示的HCDR3。
在一些实施方案中，所述单域抗体为VHH。在一些实施方案中，所述单域抗体包含如SEQ ID NO:69所示的氨基酸序列，或与SEQ ID NO:69所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:69所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，所述单域抗体包含如SEQ ID NO:69所示的氨基酸序列，或由其组成。
在一些实施方案中，单域抗体为分离的抗体。在一些实施方案中，单域抗体为分离的单克隆抗体。
重链抗体
在一些实施方案中，所述靶向冠状病毒的抗体为重链抗体，所述重链抗体可以结合 Spike蛋白。
一些实施方案提供了靶向冠状病毒的重链抗体，重链抗体的可变区包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和/或(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述重链抗体包含：
(a)HCDR1，其包含如SEQ ID NO:66所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；(b)HCDR2，其包含如SEQ ID NO:67所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体；和(c)HCDR3，其包含如SEQ ID NO:68所示的氨基酸序列，或其有单一或多个位点取代、缺失或插入的变体。
在一些实施方案中，所述重链抗体的可变区包含如SEQ ID NO:66所示的HCDR1、如SEQ ID NO:67所示的HCDR2和如SEQ ID NO:68所示的HCDR3。
在一些实施方案中，所述重链抗体的可变区包含如SEQ ID NO:69所示的氨基酸序列，或与SEQ ID NO:69所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:69所示序列相比具有一或多个保守氨基酸取代的氨基酸序列，或由其组成。
在一些实施方案中，所述重链抗体的可变区包含如SEQ ID NO:69所示的氨基酸序列，或由其组成。
在一些实施方案中，重链抗体包含可变区、连接子和Fc区。
在一些实施方案中，所述连接子为包含甘氨酸和丝氨酸的多肽。在一些实施方案中，所述连接子的序列为(GmS)n，其中每个m独立为2、3、4或5，n独立为1、2、3、4或5。在一些实施方案中，所述连接子的序列为(GGGGS)n，所述n独立为1、2、3、4或5。在一些实施方案中，所述连接子为GGGGS。在一些实施方案中，所述连接子为(GGGGS)2，如SEQ ID NO:65所示。在一些实施方案中，所述连接子为(GGGGS)3。在一些实施方案中，所述连接子为(GGGGS)4，如SEQ ID NO:63所示。在一些实施方案中，所述连接子为(GGGGS)5，如SEQ ID NO:64所示。
在一些实施方案中，Fc区包含如SEQ ID NO:70所示的氨基酸序列，或与SEQ ID NO:70所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:70所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，重链抗体包含如SEQ ID NO:79所示的氨基酸序列，或与SEQ ID NO:79所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:79所示序列相比 具有一或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中，重链抗体包含如SEQ ID NO:79所示的氨基酸序列。
在一些实施方案中，所述鼻喷剂包含：50mg/mL靶向冠状病毒的抗体、5mM组氨酸、5mM组氨酸盐酸盐、80mg/mL蔗糖、1mg/mL吐温80、1mg/mLHPMC4000和0.03％苯扎氯铵；所述鼻喷剂的pH为6.0±0.3；所述靶向冠状病毒的抗体包含如SEQ ID NO:77所示的第一多肽和如SEQ ID NO:74所示的第二多肽。
在一些实施方案中，所述鼻喷剂为液体制剂。在一些实施方案中，所述鼻喷剂的溶剂为水，例如纯化水、注射用水或超纯水。
在一些实施方案中，本发明提供了本文所述的鼻喷剂在制备预防或治疗冠状病毒引发的疾病的药物中的用途。
在一些实施方案中，本发明提供了本文所述的鼻喷剂在预防或治疗冠状病毒引发的疾病中的用途。
在一些实施方案中，本发明提供了一种治疗冠状病毒引发的疾病的方法，所述方法包括向有需要的患者施用有效量的本文所述的鼻喷剂。
在一些实施方案中，所述冠状病毒选自SARS-CoV、SARS-CoV-2和MERS-CoV。在一些实施方案中，所述冠状病毒为SARS-CoV-2。
在一些实施方案中，所述冠状病毒引发的疾病为新型冠状病毒引发的疾病(2019冠状病毒病，COVID-19)。
在一些实施方案中，所述患者是哺乳动物。在一些实施方案中，所述患者是人。
在一些实施方案中，本发明提供了一种包含本文所述的鼻喷剂的容器。在一些实施方案中，容器为喷雾装置。
本发明另一方面提供了所述鼻喷剂的制备方法，包括将各组分在水(例如注射用水或纯化水)中混合制成鼻喷剂。
在一些实施方案中，所述鼻喷剂的制备方法包括以下步骤：
(1)配置缓冲体系；
(2)通过UF/DF超滤，采用步骤(1)制备的缓冲体系对抗体溶液进行超滤换液，然后进行浓缩得到抗体浓缩物；
(3)配制含有缓冲剂、稳定剂、表面活性剂、增稠剂的辅料母液，将辅料母液添加到步骤(2)制备的抗体浓缩物中，得到鼻喷剂。
在一些实施方案中，所述鼻喷剂的制备方法包括以下步骤：
(1)配置缓冲体系；
(2)通过UF/DF超滤，采用步骤(1)制备的缓冲体系对抗体溶液进行超滤换液，然后进行浓缩得到抗体浓缩物；
(3)配制含有缓冲剂、稳定剂、表面活性剂、增稠剂、防腐剂的辅料母液，将辅料母液添加到步骤(2)制备的抗体浓缩物中，得到鼻喷剂。
本发明的有益之处在于：
本发明的鼻喷剂可以提高靶向冠状病毒的抗体的物理化学稳定性，使得靶向冠状病毒的抗体能稳定存在于制剂中，鼻喷剂在室温、长期冷藏和反复冻融等条件下均能保持其稳定性，且在室温非无菌环境保持长期储存而不变质，具有较长保质期，在开启后可长时间放置，无需担心染菌，提高了产品的质量，延长了产品的货架期，提高了临床使用安全性。
附图说明
图1为振荡及25℃条件下制剂非变性聚丙烯酰胺凝胶电泳(PAGE)图；其中Lane 1为制剂3，室温振荡48h；Lane 2为制剂4，室温振荡48h；Lane 3为制剂5，室温振荡48h；Lane 4为制剂6，室温振荡48h；Lane 5为制剂3，25℃放置7d；Lane 6为制剂4，25℃放置7d；Lane 7为制剂8，4℃存储；Lane 8为制剂6，4℃放置7d。
图2为25℃和40℃条件下制剂非变性PAGE图；其中Lane 1为制剂5，25℃放置7d；Lane 2为制剂6，25℃放置7d；Lane 3为制剂6，40℃放置1d；Lane 4为制剂6，40℃放置3d；Lane 5为制剂6，40℃放置5d；Lane 6为制剂6，40℃放置7d；Lane 7为制剂8，4℃存储；Lane 8为制剂6，4℃放置7d。
图3为40℃条件下制剂非变性PAGE图；其中，其中Lane 1为制剂3，40℃放置1d；Lane 2为制剂4，40℃放置1d；Lane 3为制剂5，40℃放置1d；Lane 4为制剂3，40℃放置3d；Lane 5为制剂4，40℃放置3d；Lane 6为制剂5，40℃放置3d；Lane 7为制剂6，4℃放置7d；Lane 8为制剂8，4℃存储。
图4为冻融及高温条件下制剂PAGE图；其中，其中Lane 1为制剂3，冻融处理(先在-60℃冻至12h，然后25℃放置12h，如此循环四周期)；Lane 2为制剂3，40℃放置1d；Lane 3为制剂3，40℃放置1d(含甲硫氨酸)；Lane 4为制剂3，40℃放置2d；Lane 5为制剂3，40℃放置2d(含甲硫氨酸)；Lane 6为制剂3，40℃放置3d；Lane 7为制剂3，40℃放置3d；Lane 8为制剂8，4℃存储；Lane 9为Marker。
图5为制剂相对结合活性随温度时间变化。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案，具体实施例不代表对本发明保护 范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
除非本文另有定义，与本发明结合使用的科学和技术术语及其缩略语应具有本发明所属领域的普通技术人员通常理解的含义。
术语“一种”实体是指一种或多种该实体，例如“一种制剂”应当被理解为一种或多种制剂，因此，术语“一种”(或“一个”)、“一种或多种”和“至少一种”可以在本文中互换使用。
本文所用的术语“包含”或“包括”意味着抗体、组合物或方法等包括所列举的元素，例如组份或步骤，但不排除其它。其在本申请中用于描述蛋白质或核酸的序列时，所述蛋白质或核酸可以是由所述序列组成，或者在所述蛋白质或核酸的一端或两端可以具有额外的氨基酸或核苷酸，但仍然具有本发明所述的活性。“基本上由……组成”意味着抗体、组合物或方法等排除对组合的特征有根本影响的其它元素，但不排除对抗体、组合物或方法等无本质上影响的元素。“由……组成”意味着排除未特别列举的元素。由这些过渡术语中的每一者定义的实施方案均在本发明的范围内。举例来说，当组合物被描述为包括成分A、B以及C时，基本上由A、B以及C组成的组合物和由A、B以及C组成的组合物独立地在本发明的范围内。
“保守氨基酸取代”是指一个氨基酸残基被另一个含有化学性质(例如电荷或疏水性)相似的侧链(R基团)的氨基酸残基所取代。一般而言，保守氨基酸取代不大会在实质上改变蛋白质的功能性质。含有化学性质相似侧链的氨基酸类别的实例包括：1)脂族侧链：甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸；2)脂族羟基侧链：丝氨酸和苏氨酸；3)含酰胺的侧链：天冬酰胺和谷氨酰胺；4)芳族侧链：苯丙氨酸、酪氨酸和色氨酸；5)碱性侧链：赖氨酸、精氨酸和组氨酸；6)酸性侧链：天冬氨酸和谷氨酸。
“同源性”或“同一性”或“相似性”是指两个肽之间或两个核酸分子之间的序列相似性。可以通过比较每个序列中可以比对的位置来确定同源性。当被比较的序列中的位置被相同的碱基或氨基酸占据时，则分子在该位置是同源的。序列之间的同源程度是由序列共有的匹配或同源位置的数目组成的一个函数。“至少80％同一性”为约80％同一性、约81％同一性、约82％同一性、约83％同一性、约85％同一性、约86％同一性、约87％同一性、约88％同一性、约90％同一性、约91％同一性、约92％同一性、约94％同一性、约95％同一性、约98％同一性、约99％同一性，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
“抗体”、“抗原结合片段”是指特异性识别和结合抗原的多肽或多肽复合物。抗体可以是完整的抗体及其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有具有与抗原结 合的生物学活性的免疫球蛋白分子的至少一部分的任何蛋白质或肽。抗体和抗原结合片段包括但不局限重链或轻链或其配体结合部分的互补决定区(CDR)、重链可变区(VH)、轻链可变区(VL)、重链恒定区(CH)、轻链恒定区(CL)、框架区(FR)或其任何部分，或结合蛋白的至少一部分。CDR区包括轻链的CDR区(LCDR1-3)和重链的CDR区(HCDR1-3)。抗体及抗原结合片段可以特异性识别和结合一个或多个(如两个)抗原的多肽或多肽复合物。特异性识别和结合多个(如两个)抗原的抗体或抗原结合片段可以被称为多特异性(如双特异性)抗体或抗原结合片段。
术语“抗体片段”或“抗原结合片段”指抗体的一部分，本发明抗体片段的组成形式可类似于单特异性抗体片段中的F(ab’)2、F(ab)2、Fab'、Fab、Fv、scFv等。不管其结构如何，抗体片段与被完整抗体识别的同一抗原结合。术语“抗体片段”包括适体、镜像异构体和双价抗体。术语“抗原结合片段”还包括通过与特定抗原结合形成复合物起抗体作用的任何合成或基因工程蛋白质。
本发明公开的抗体、抗原结合片段包括但不限于多克隆、单克隆、多特异性、全人源、人源化、灵长类化、嵌合抗体、单链抗体、表位结合片段(例如Fab、Fab'和F(ab')2、单链Fv(scFv)。
本发明公开的抗体可以来源于任何动物，包括鸟类和哺乳动物。较佳地，抗体是人源、鼠源、驴源、兔源、山羊源、骆驼源、美洲驼源、马源或鸡源抗体。
需要说明的是，本发明中，除非特别说明之外，所涉及到鼻喷剂组分的“％”是指质量体积(w/v)百分比，比如鼻喷剂中含0.1％增稠剂表示100mL鼻喷剂中含有0.1g增稠剂，或增稠剂含量为1mg/mL。
“约”或“大约”指相关技术领域技术人员容易知道的相应数值的常规误差范围。在一些实施方式中，本文中提到“约”或“大约”指所描述的数值以及其±10％、±5％或±1％的范围。
本文的“稳定性”、“稳定”，是指包含抗体(包括其抗体片段)的制剂中，抗体(包括其抗体片段)在给定的生产、制备、运输和/或贮存条件下不发生、或仅极少地发生聚集、降解或片段化。“稳定”制剂在给定的生产、制备、运输和/或贮存条件下保持生物学活性。可通过例如SEC-HPLC、IEC-HPLC、CE-SDS等技术测量的所述制剂的聚集、降解或片段化程度等，从而评估所述抗体(包括其抗体片段)的稳定性。
术语“缓冲剂”，也被称为缓冲系统或缓冲体系，其包括但不限于有机酸盐，如琥珀酸、醋酸、柠檬酸，抗坏血酸，葡糖酸，碳酸，酒石酸或苯二甲酸及其盐；Tris，三乙胺盐酸盐，或磷酸缓冲剂。此外，氨基酸及其盐也可以用作缓冲剂。这样的氨基酸组分包括但不限于甘氨酸、组氨酸、精氨酸、赖氨酸、鸟氨酸、异亮氨酸、亮氨酸、丙氨酸、谷氨酸或天冬 氨酸。本发明中，如涉及到制剂中含有缓冲液或者缓冲体系，也是指制剂中含有缓冲剂，缓冲液是由缓冲剂配置而成。在一些实施方式中，缓冲剂为组氨酸缓冲剂，组氨酸缓冲剂在溶剂(例如注射用水)或鼻喷剂中形成组氨酸缓冲液；例如，在鼻喷剂中含有10mM组氨酸缓冲剂，也指在鼻喷剂中含有10mM组氨酸缓冲液。
本发明中缓冲剂的量，是指组成缓冲剂的缓冲体系中缓冲对的总量。在一些实施方式中，采用摩尔浓度作为缓冲剂的量的单位，其数值指缓冲剂的缓冲体系中缓冲对的摩尔浓度。如，由组氨酸和组氨酸盐酸盐组成的组氨酸缓冲剂作为缓冲剂时，给定浓度的组氨酸缓冲剂(如10mM)是L-组氨酸和L-组氨酸盐酸盐的组合浓度(如L-组氨酸为5mM，L-组氨酸盐酸盐为5mM)。
术语“稳定剂”表示一种药用赋形剂，其用于保护活性药物成分和/或制剂免于在生产、储存和应用过程中发生化学和/或物理降解。稳定剂包括但不限于多元醇，例如甘露醇、山梨醇、丙三醇、阿拉伯醇、丙二醇、聚乙二醇等；糖类，例如单糖(例如果糖、甘露糖、半乳糖、葡萄糖、山梨糖等)，寡糖(例如二糖，如乳糖、蔗糖、海藻糖、纤维二糖、麦芽糖等；三塘，如棉籽糖、龙胆三塘、松三塘等；环糊精或其衍生物，例如α-环糊精、β-环糊精、γ-环糊精、其羟丙基化衍生物(例如羟丙基倍他环糊精(又名羟丙基-β-环糊精，简称HP-β-CD))、羟乙基化衍生物、乙基化衍生物和甲基化衍生物、磺丁基醚β-环糊精、支链环糊精、环糊精聚合物等)，多糖(例如麦芽糖糊精、葡聚糖、淀粉、糖原、纤维素、壳多糖等)，糖的衍生物(例如糖醇(例如甘露醇、山梨醇、木糖醇、麦芽糖醇、乳糖醇、葡萄糖醇等)，糖酸(例如葡萄糖酸、葡萄糖二酸等)，糖胺，糖苷(例如甲基葡萄糖苷等)等)；离子稳定剂，它们包括盐如氯化钠(NaCl)等；或氨基酸如精氨酸、精氨酸-HCl、脯氨酸、甘氨酸、甲硫氨酸等。
术语“表面活性剂”包括但不限于吐温(Tween，如吐温20和吐温80)；泊洛沙姆(例如泊洛沙姆188)；Triton；十二烷硫酸钠(SDS)；月桂硫酸钠；辛基配糖物钠盐；月桂基磺基甜菜碱、肉豆蔻基磺基甜菜碱、亚油烯基磺基甜菜碱或硬脂基磺基甜菜碱；月桂基肌氨酸、肉豆蔻基肌氨酸、亚油烯基肌氨酸或硬脂基肌氨酸；亚油烯基甜菜碱、肉豆蔻基甜菜碱或鲸蜡基甜菜碱；月桂酰胺基丙基甜菜碱、椰油酰胺基丙基甜菜碱、亚油酰胺基丙基甜菜碱、肉豆蔻酰胺基丙基甜菜碱、棕榈酰胺基丙基甜菜碱或异硬脂酰胺基丙基甜菜碱(例如月桂酰胺基丙基)；肉豆蔻酰胺基丙基二甲胺、棕榈酰胺基丙基二甲胺或者异硬脂酰胺基丙基二甲胺；甲基椰油酰基牛磺酸钠或甲基油基牛磺酸二钠；聚乙二醇，聚丙二醇，和乙烯与丙烯二醇的共聚物(例如Pluronics，PF68等)；等等。吐温也称作聚山梨酯(例如，吐温20称作聚山梨酯20，吐温80称作聚山梨酯80)。在一些实施方式中，表面活性剂为吐温80(Tween 80)。
“增稠剂”是能够提高溶液、悬浮液、或液体/固体混合物等的粘度而基本不改变它的其他性质的物质(液体或固体)。增稠剂包括但不限于聚维酮类增稠剂、纤维素醚类增稠剂、粘多糖类增稠剂、聚丙烯酸类增稠剂、聚乙烯醇(例如聚乙烯醇1788(PVA1788))；例如，聚维酮类增稠剂选自聚维酮K30(PVP-K30)或聚维酮K90(PVP-K90)，纤维素醚类增稠剂选自微晶纤维素-羧甲基纤维素钠复合物、羟丙甲纤维素(例如HPMC4000、HPMC400或HPMC100)、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠或羟乙基纤维素，粘多糖类增稠剂选自透明质酸钠或硫酸软骨素，聚丙烯酸类增稠剂选自卡波姆。
本发明的鼻喷剂可以用辅料或其水合物配制。比如组氨酸盐酸盐，又称盐酸组氨酸，可以是无水组氨酸盐酸盐，也可以是组氨酸盐酸盐水合物，如组氨酸盐酸盐一水合物。如“5mM组氨酸盐酸盐”，为5mmol组氨酸盐酸盐或组氨酸盐酸盐一水合物溶解在溶剂里形成1L溶液；1.06mg组氨酸盐酸盐一水合物，包括1.06mg组氨酸盐酸盐一水合物或相应量的组氨酸盐酸盐。另如海藻糖，可以是无水海藻糖，也可以是海藻糖水合物，如海藻糖二水合物。
本发明所述的纯化水(PurifiedWater)为饮用水经蒸馏法、离子交换法、反渗透法或其他适宜的方法制得的制药用水，不含任何添加剂。本发明所述的注射用水(Water for Injection)为纯化水经蒸馏所得的水。
如本文所用，“有需要”是指已将患者鉴定为需要特定方法或治疗。在一些实施例中，可以通过任何诊断方式进行识别。
“患者”指需要诊断、预后或治疗的任何哺乳动物，包括人类、狗、猫、兔子、鼠、马、牛等。
“治疗”是指治疗性治疗和预防性或防治性措施，其目的是预防、减缓、改善或停止不良的生理改变或紊乱，例如疾病的进程，包括但不限于以下无论是可检测还是不可检测的结果，症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善、缓和、减轻或消失(无论是部分还是全部)、延长与不接受治疗时预期的生存期限等。需要治疗的患者包括已经患有病症或紊乱的患者，容易患有病症或紊乱的患者，或者需要预防该病症或紊乱的患者，可以或预期从施用本发明公开的抗体或药物组合物用于检测、诊断过程和/或治疗中受益的患者。
“有效量”是指能引起组织、系统、个体、动物或人类的在生物学或医学上反应的活性化合物或药剂的量。
本发明的制剂对人体的施用量会随着患者的年龄、体重、性别、用药形态、健康状况及疾病危重程度而不同。
抗体的制备
可以按常规方法根据本文所述抗体氨基酸序列设计合成编码抗体的DNA，将其置入表达载体中，然后转染宿主细胞，在培养基中培养被转染的宿主细胞产生单克隆抗体。在一些实施方案中，表达抗体载体包括至少一个启动子元件，抗体编码序列，转录终止信号和polyA尾巴。其他元件包括增强子，Kozak序列及插入序列两侧RNA剪接的供体和受体位点。可以通过SV40的前期和后期启动子，来自逆转录病毒的长末端重复序列如RSV、HTLV1、HIVI及巨细胞病毒的早期启动子来获得高效的转录，也可应用其它一些细胞的启动子如肌动蛋白启动子。合适的表达载体可包括pIRES1neo、pRetro-Off、pRetro-On、PLXSN、pLNCX、pcDNA3.1(+/-)、pcDNA/Zeo(+/-)、pcDNA3.1/Hygro(+/-)、PSVL、PMSG、pRSVcat、pSV2dhfr、pBC12MI和pCS2等。常用的哺乳动物细胞包括HEK293细胞、Cos1细胞、Cos7细胞、CV1细胞、鼠L细胞和CHO细胞等。
本文中引用的所有出版物、专利和专利申请全部内容通过参考并入本文用于所有目的。
以下实施例中所使用的方法可以如下：
SEC-HPLC的分析方法：
1，准备液相色谱系统和东曹(上海)生物科技有限公司(TOSOH)TSK-GEL G3000SWXL色谱柱(柱规格为7.8*300mm，5μm)。开启液相色谱仪并打开仪器操作软件，调用方法，打开泵进流动相，设置紫外检测器波长，柱温设定为室温，调流速0.5mL/min，平衡30-60min至基线平稳。
2，进样，记录色谱图，积分后按照峰面积归一法计算供试液的单体或多聚体百分含量。
IEC-HPLC的分析方法：
1，准备液相色谱系统和ProPac ECX-10弱酸阳离子交换分离柱。开启电源，打开液相数据分析系统，调用方法，打开泵，以94％流动相A(20mM 3-吗啉丙磺酸(MOPS)，pH6.9)，0.2mL/min初始条件平衡色谱柱，待压力稳定后调流速至0.8mL/min平衡30-60min至基线稳定平稳。
2，进样，对检测的色谱图进行手动积分，按照峰面积归一法计算三个赖氨酸变体(lys0、lys1和lys2)总的百分含量。
CE-SDS(NR)的分析方法：
毛细管电泳仪采用Beckman的PA800 plus，样品进样后，记录色谱图，积分处理数据，采用面积归一化方法计算单体峰的百分含量。
相对结合活性检测方法：
1)包被：取96孔酶标板(Corning，9018)，每孔加入100μL SARS-CoV-2(COVID-19)S protein RBD,His Tag蛋白(ACRO Biosystems，货号：SPD-C52H3)稀释液(用PBS稀释至1μg/mL，混匀，现配现用)，4℃包被过夜。
2)封闭：将酶标板用清洗缓冲液PBST(含0.05％Tween 20的PBS)洗涤2次，然后向每个反应孔中加入封闭液(3％BSA，溶剂为PBST)200μL，37℃孵育2h。
3)样品配制：
3.1)对照品稀释
取对照品2F8-VH-VHH18适量，加入PBS稀释至1mg/mL，然后用PBST稀释至5μg/mL，以此为起始浓度，用PBST进行3倍梯度稀释，得到不同浓度梯度的对照品溶液，对照品浓度分别为5000ng/mL、1666.7ng/mL、555.6ng/mL、185.2ng/mL、61.73ng/mL、20.58ng/mL、6.859ng/mL、2.286ng/mL、0.762ng/mL、0.254ng/mL。
3.2)待测样品稀释：
取待测样品适量，用PBS稀释至抗体浓度为1mg/mL，然后按照同对照品稀释方法进行稀释。
4)加样：将封闭好的酶标板取出，用PBST洗涤2次后取各浓度的对照品溶液和待测样品溶液各100μL加入相应的反应孔，37℃孵育2h。
5)加酶标二抗：取出酶标板，用PBST洗涤5次后向反应孔中加入HRP标记的羊抗人IgG-Fc抗体(Sigma，货号：A8667-2ML)稀释液(在PBST中稀释至1:10000)，每孔100μL，37℃孵育1h。
6)显色：取出酶标板，用PBST洗涤8次后向反应孔中加入TMB(Tetramethylbenzidine)显色液(Biopanda，TMB-S-001)，每孔100μL，37℃避光孵育12～18min。
7)终止：向每个反应孔中加入0.2M硫酸溶液50μL终止显色反应，然后于30min内进行读数。
8)读板：设定检测波长为450nm，参比波长为630nm，用酶标仪自带分析软件进行读数，对所得读数以四参数方程曲线模型进行拟合，方程为y＝(A-D)/(1+(x/C)^B)+D，其中A为吸光值下限，B代表曲线斜率，C为最大反应值一半对应的抗体浓度(EC50)，D为吸光值 上限。
9)结果计算：按如下公式计算结果
其中，对照品为抗体2F8-VH-VHH18标准品。
实施例1 靶向冠状病毒的抗体的制备
示例性抗体1-24和2F8的可变区和恒定区组成见表1，重链可变区的框架区和CDR区组成见表2，VH与CH(如SEQ ID NO:61所示)组成抗体的重链，VL与CL(如SEQ ID NO:62所示)组成抗体的轻链；其中，抗体2F8(单特异抗体)含有两条序列相同的重链(如SEQ ID NO:72所示)和两条序列相同的轻链(如SEQ ID NO:74所示)，其重链对应的核酸序列如SEQ ID NO:75所示，其轻链对应的核酸序列如SEQ ID NO:76所示；单域抗体VHH18的氨基酸序列如SEQ ID NO:69所示；重链抗体VHH18-Fc含有2条序列相同的重链(如SEQ ID NO:79所示)，重链抗体包含单域抗体、连接子L3(GGGGSGGGG S，如SEQ ID NO:65所示)和Fc，其重链对应的核酸序列如SEQ ID NO:82所示。双特异抗体2F8-VH-VHH18含有两条序列相同的第一多肽(如SEQ ID NO:77所示)和两条序列相同的第二多肽(如SEQ ID NO:74所示)，第一多肽包含重链(如SEQ ID NO:72中第1位氨基酸至第451位氨基酸所示)、连接子L1(GGGGSGGGGSGGGGSGGGGS，如SEQ ID NO:63所示)和单域抗体VHH18(如SEQ ID NO:69所示)，第二多肽为轻链，其第一多肽对应的核酸序列如SEQ ID NO:80所示，其第二多肽对应的核酸序列如SEQ ID NO:76所示，第一多肽的重链和第二多肽组成双特异抗体2F8-VH-VHH18的第一结合部分，单域抗体为双特异抗体2F8-VH-VHH18的第二结合部分。双特异抗体2F8-VL-VHH18含有2条序列相同的第一多肽(如SEQ ID NO:72所示)和2条序列相同的第二多肽(如SEQ ID NO:78所示)，第一多肽为重链，第二多肽包含轻链、连接子L2(GGGGSGGGGSGGGGSG GGGSGGGGS，如SEQ ID NO:64所示)和单域抗体，其第一多肽对应的核酸序列如SEQ ID NO:75所示，其第二多肽对应的核酸序列如SEQ ID NO:81所示，第一多肽的重链和第二多肽的轻链组成双特异抗体2F8-VL-VHH18的第一结合部分，单域抗体为双特异抗体2F8-VL-VHH18的第二结合部分。CDR、框架区、可变区、恒定区和连接子的氨基酸序列见表3；单域抗体和重链抗体的氨基酸序列见表4；示例性单特异抗体的氨基酸序列见表5；抗体2F8的核酸序列见表6；双特异抗体的氨基酸序列见表7；双特异抗体、重链抗体的核酸序 列见表8。
表1.抗spike蛋白抗体(单特异抗体)的可变区和恒定区组成
表2.抗体重链可变区的框架区和CDR区组成

表3.氨基酸序列





表4.单域抗体和重链抗体的氨基酸序列
表5.单特异抗体的氨基酸序列
表6.抗体2F8的核酸序列

表7.双特异抗体的氨基酸序列

表8.双特异抗体、重链抗体的核酸序列


将抗体的DNA序列分别克隆入表达载体，然后稳转CHO细胞，悬浮培养后收获上清，进行ProteinA亲和捕获，阴离子及阳离子层析获得纯度大于95％的抗体。
实施例2 缓冲液种类及pH筛选
1)pH5～7筛选
不同缓冲液的配制见下表9：
表9.不同缓冲液的配制

分别取抗体2F8-VH-VHH18样品超滤换液得5个不同缓冲液样品。将换液后的样品稀释到抗体浓度10mg/mL。
表10.五组样品UNcle检测Tm、Tagg数据
表10的数据中，由Tm1值可以看出，His6.0(61.5℃)＞PB6.0(60℃)＞CB6.0(59.9℃)＞PB7.0(59.5℃)＞CB5.0(58.9℃)，由Tagg值可以看出，His6.0(59.82℃)＞PB6.0(58.55℃)＞CB5.0(57.49℃)＞CB6.0(57.33℃)＞PB7.0(57.09℃)，表明在组氨酸(His)、组氨酸盐酸盐(His·HCl)组成的His6.0缓冲体系下抗体2F8-VH-VHH18较稳定。
表11.五组样品UNcle检测DLS数据
由表11可看出，PB7.0、PB6.0、His6.0的PDI＜0.2，粒径均一，且His6.0粒径较小。
表12.五组样品UNcle检测kD、B22数据


注：kD为正值，说明制剂配方促使蛋白间相互排斥；kD为负值，说明制剂配方促使蛋
白间相互吸引。B22为正值，说明蛋白之间相互排斥；B22为负值，说明蛋白间相互吸引。
结合表12的kD、B22分析，PB6.0的B22为负值，kD为正值，蛋白之间相互吸引，制剂配方将其转换为排斥性相互作用，有可能有聚集的风险；CB6.0、CB5.0的B22为正值，kD为负值，蛋白之间相互排斥，但制剂配方促使其相互吸引，有很大的聚集风险；PB7.0、His6.0的kD、B22均为正值，蛋白表现为相互排斥，不易发生聚集。
2)pH7.5～8筛选
不同缓冲液的配制见下表13：
表13.不同缓冲液的配制
将抗体2F8-VH-VHH18样品超滤换液至10mM PB7.5、10mM PB8.0的缓冲体系中，将换液后的样品稀释到抗体浓度10mg/mL。
表14.三组样品UNcle检测Tm、Tagg数据
表15.三组样品UNcle检测DLS数据
结合Tm、Tagg以及粒径数据，可以看出His6.0具有最高的Tm及Tagg数值，粒径更小且更均一。
综合pH5.0-8.0的检测结果，得出最佳的pH为6.0，缓冲液优选10mM His6.0。
实施例3 通过性状考察筛选与抗体2F8-VH-VHH18互溶的增稠剂
分别将不同增稠剂PVP-K30(阿拉丁，批号：H2126154)、卡波姆(阿拉丁，批号：G2120286)、PVA1788(南京威尔，批号：20201102-2)、HPMC4000(安徽山河药用辅料股份有限公司，批号：210334)、HPMC400(阿拉丁，批号：A1917094)和HPMC100(阿拉丁，批号：C2112231)与抗体2F8-VH-VHH18混合，缓冲液为10mM His6.0，混合后增稠剂的浓度为0.1％，抗体的浓度为20mg/mL，观察溶液是否澄清，考察增稠剂和抗体2F8-VH-VHH18的相容性，结果见表16。
表16.相容性结果
由表16结果可知，卡波姆和抗体互不相容，会有白色絮状物产生；而其它增稠剂都可与蛋白相容。
实施例4不同种类及含量的增稠剂在纯化水中的喷雾效果
表17.不同种类及含量的增稠剂在纯化水中的喷雾效果


注：以上所称“羽流”指喷雾后从喷嘴发散而形成的喷雾形状，特指宽度。
由实验可知，PVP-K30、PVA1788可喷射浓度范围比较宽，PVP-K30的可喷浓度范围在0～10％，PVA1788可喷浓度范围在0～5％；而HPMC4000的可喷浓度范围约在0～0.2％，HPMC400的可喷浓度范围在0～1％，HPMC100的可喷浓度范围在0～2％。说明HPMC4000具有良好的增粘作用，能有效减小喷雾范围，在0.2％的时候即可有效减小喷雾范围，且用量较少对制剂影响小。
实施例5不同浓度的HPMC4000在不含抗体2F8-VH-VHH18的制剂中的喷雾性状考察
表18.制剂信息
表19.不同浓度的HPMC4000在不含抗体2F8-VH-VHH18的制剂中的喷雾性状

根据喷雾结果可以看出，在HPMC4000浓度为0.05％时，其喷雾状态较发散，成空心梅花形状，在HPMC4000浓度为0.1％和0.2％时其喷雾形态均较好，但0.1％喷雾宽度更符合鼻腔结构分布，且用量低。
实施例6 HPMC4000对抗体2F8-VH-VHH18的稳定性影响考察
表20.RP-HPLC检测结果
表21.SEC-HPLC检测结果
从RP-HPLC和SEC-HPLC结果可知HPMC4000作为增稠剂对抗体2F8-VH-VHH18的稳定性影响不大。
实施例7不同浓度的HPMC4000和HPMC400对制剂喷雾形态和喷雾粒径分布的影响
本实施例制剂的缓冲液为10mM His6.0，抗体为抗体2F8-VH-VHH18，具体制剂信息见表22。
表22.制剂设计及理化检测结果

表23.喷雾形态检测结果
从表23可看出，CF-6的角度最大且超过了质量标准所定的60°，且其面积和宽度在这几个制剂中属于最大，其喷雾状态处于发散状态，不符合要求。分析对比CF-5和CF-6的角度和宽度变化，明显大于其它四个制剂，说明在相同的浓度下，HPMC分子量越小其喷雾角度和宽度增大。各制剂椭圆率分析结果大多都处于1.3以下，说明制剂喷雾接近圆形，根据宽度和角度，除了CF-6外，其它制剂CF-1到CF-5都在质量标准范围内。
依据不同位置的喷雾面积比较来看，各制剂在3cm处的喷雾面积比较稳定，而在6cm处喷雾面积变化较大，这可能是由于喷雾距离增大后颗粒受运动惯性影响较小，导致其检测结果波动大。CF-5和CF-6在3cm处的面积较其它制剂明显大，说明喷雾面积随着HPMC分子量的减小而增大，在相同的浓度下，分子量小的其喷雾范围大，依据3cm处的角度变化也可得出此结论。
表24.喷雾粒径分布检测结果
制剂大部分雾滴粒径分布在10μm-100μm之间，符合要求。而CF-6的喷雾粒径明显整体趋小，且<10μm的粒径分布比其他制剂的多，雾滴容易进入肺部。
综合喷雾几何形状和喷雾粒径分布来看，在蔗糖、吐温80和蛋白含量一定时，体系中HPMC4000浓度为0.1％-0.25％时，其喷雾形态和喷雾粒径分布皆可符合要求，而分子量小的HPMC400在相同的浓度下其喷雾角度和宽度均会增大。
实施例8低浓度羟苯甲酯和羟苯丙酯制剂筛选
本实施例制剂的缓冲液为10mM His6.0，抗体为抗体2F8-VH-VHH18，具体制剂信息见表25。
表25.制剂设计
表26.抑菌效力检测结果
根据结果看出，各个制剂结果都达不到要求，分析是抑菌剂在蔗糖和蛋白质丰富的制剂中含量较低的缘故。
实施例9高浓度羟苯甲酯和羟苯丙酯制剂筛选
本实施例制剂的缓冲液为10mM His6.0，抗体为抗体2F8-VH-VHH18，具体制剂信息见表27。
表27.制剂设计
表28.抑菌效力检测结果

羟苯甲酯和羟苯丙酯在缓冲液中的溶解度已经达到最大值，无法再继续增大，而当前最大值的抑菌效力依旧达不到标准；其次如果选用最大溶解度，一旦放置低温会有析出风险。
实施例10防腐剂苯扎氯铵及浓度的筛选
本实施例制剂的抗体为抗体2F8-VH-VHH18，具体制剂信息见表29。
表29.制剂设计
1、抑菌效力检测
表30.抑菌效力检测结果


注：表中“金”指金黄色葡萄球菌，“铜”指铜绿假单胞菌，“白”指白色念球菌，“黑”指黑曲霉。评价标
准为：与0h比较，第2天细菌应减少2个lg值；第7天细菌菌数应至少减少3lg值；第14天细菌应至少减少3lg值。第14天与第0h比较，真菌应至少减少2lg值。NI:第28天与第14d比较，试验菌增加的数量不超过0.5lg。
通过抑菌效力实验可以看出，在A标准下，加入0.03％的苯扎氯铵后其抑菌效力可满足要求。
2、与SARS-CoV-2S蛋白RBD结合活性检测
表31.不同浓度的苯扎氯铵制剂的结合活性检测结果


注：光照：光照强度2000-3000lx，光照温度25℃
根据表31的结合活性结果可以看出，在4℃和25℃条件下，制剂的结合活性都很高，说明在室温及以下，加入苯扎氯铵对结合活性影响不大。光照条件下，用白色高密度聚乙烯瓶装的抗体蛋白的结合活性比用透明管装的结合活性高，从而说明白色高密度聚乙烯塑料瓶在光照下对蛋白具有保护作用。
3、不同浓度的苯扎氯铵制剂的抗体稳定性
表32.SEC-HPLC检测结果
从SEC-HPLC检测结果看4℃下抗体稳定性好。
根据图1的非变性PAGE看出在振荡、室温及4℃条件下，制剂3-6蛋白稳定性很好，没有聚体和碎片产生。
根据图2的非变性PAGE结果看出，对比40℃和25℃的制剂6，40℃温度条件下产生大量的碎片和聚体，而25℃产生较少。而在25℃时制剂5和制剂6产生聚体和碎片不多，但制剂6略微比制剂5产生的碎片多点，颜色略深。
根据图2和图3非变性PAGE可得知，在高温40℃条件下制剂稳定性不好，但是在4℃和25℃条件下，其稳定性较好，说明抗体对温度较为敏感。
由图4结果看出，冻融四个周期制剂3蛋白依旧完整，说明冻融对蛋白没有影响。
根据非变性PAGE检测结果可以看出，制剂在4℃和25℃时，其产生碎片和聚体很少。振荡对于结合活性影响不大，PAGE结果也可以看出振荡条件下制剂碎片和聚体较少。结合活性测试可以得出，振荡和低温对结合活性影响较小。
表33.苯扎氯铵对制剂pH和渗透压的影响



注：“/”代表未检测，光照：光照强度2000-3000lx，光照温度25℃
根据以上结果可以看出，除了在振荡条件下对制剂的渗透压和pH影响较大外，其它条件对制剂的pH和渗透压影响皆不大，pH范围都在5.7-6.3之间，渗透压范围在280-320mosmol/kg之间。
实施例11制剂在不同温度下与SARS-CoV-2S蛋白RBD的结合活性
取实施例10制剂5分装样品分别放置在30℃、37℃、40℃放置1h、2h、8h、12h、24h、28h、32h、36h、48h、50h、52h、54h、56h、58h、60h、72h、74h、76h、78h、80h、82h、84h、96h，考察样品的相对结合活性，结果如图5。
根据图5看出，40℃条件对结合活性影响最大，在58h时相对结合活性降低至60％。而30℃和37℃的温度下，在150h时相对结合活性依旧保持在80％左右。
实施例12
考察实施例10制剂5在多种条件下其对制剂相对结合活性的影响。取分装样品按照表34的混合方式及放置条件进行放置考察。
其中，混合方式1：取4℃放置21d的样品，先进行冻融，然后室温振荡48h，再40℃放置4d；分别于冻融后、室温振荡48h后、40℃放置4d后取样，所得样品依次命名为1-1，1-2，1-3。混合方式2：取4℃放置21d的样品，先40℃放置3d，然后25℃放置3d，再-60℃放置4d；分别于40℃放置3d后、-60℃放置4d后取样，所得样品依次命名为2-1，2-2。
表34.样品的混合方式及放置条件

注：冻融：-60℃放置12h，然后25℃放置12h，如此循环4次
表35.检测与SARS-CoV-2S蛋白RBD结合活性结果
根据表35实验数据看出，冻融、室温振荡对相对结合活性影响不是很大，且在经过冻融后再进行振荡，其相对结合活性依旧较高，但是放置在40℃下抗体的相对结合活性会明显降低，说明高温对制剂影响较大。

Claims (19)

  1. 一种鼻喷剂，其包含：
    (1)靶向冠状病毒的抗体或抗原结合片段；
    (2)缓冲剂；
    (3)稳定剂；
    (4)表面活性剂；和
    (5)增稠剂；
    所述鼻喷剂的pH为3.0～8.0，或4.0～8.0，或5.0～7.0，或5.5～6.5，或6.0±0.3；
    或者，所述靶向冠状病毒的抗体或抗原结合片段的浓度为1～200mg/mL，或1～150mg/mL，或1～100mg/mL，或10～100mg/mL，或10～80mg/mL，或10～70mg/mL；
    或者，所述缓冲剂选自磷酸盐、柠檬酸、柠檬酸盐、醋酸、醋酸盐、琥珀酸盐、谷氨酸盐、组氨酸和组氨酸盐中的一种或几种；或者，所述缓冲剂选自磷酸缓冲剂、柠檬酸缓冲剂、组氨酸缓冲剂；或者，所述缓冲剂选自柠檬酸和柠檬酸钠的组合、醋酸和醋酸钠的组合、磷酸氢二钠和磷酸二氢钠的组合、组氨酸和组氨酸盐酸盐的组合；或者，所述缓冲剂的浓度为1～50mM，或1～40mM，或1～30mM，或1～25mM，或1～20mM，或1～15mM；
    或者，所述稳定剂选自多元醇、糖类、氨基酸、盐类，或它们的组合；或者，所述稳定剂选自甘露醇、山梨醇、乳糖、海藻糖、蔗糖、氯化钠、精氨酸或其盐中的一种或几种；或者，所述稳定剂的浓度为1～200mg/mL，或20～200mg/mL，或1～150mg/mL，或20～150mg/mL，或20～120mg/mL，或30～120mg/mL，或50～100mg/mL；
    或者，所述表面活性剂选自泊洛沙姆和吐温；或者，所述表面活性剂选自泊洛沙姆188、吐温20和吐温80中的一种或几种；或者，所述表面活性剂的浓度为0.01～10mg/mL，或0.05～10mg/mL，或0.1～10mg/mL，或0.1～5mg/mL，或0.2～5mg/mL，或0.5～1mg/mL；
    或者，所述增稠剂选自聚维酮类增稠剂、纤维素醚类增稠剂、粘多糖类增稠剂、聚丙烯酸类增稠剂、聚乙烯醇，或它们的组合；或者，所述增稠剂选自聚维酮、聚乙烯醇、卡波姆和羟丙甲纤维素中的一种或几种；或者，所述增稠剂选自PVP-K30、卡波姆、PVA1788、HPMC4000、HPMC400和HPMC100中的一种或几种；或者，所述增稠剂的浓度为0.01％-30％，或0.01％-10％，或0.05％-15％，或0.05％-10％，或0.05％-5％，或0.05％-1％，或0.05％-0.5％，或0.1％-0.25％。
  2. 如权利要求1所述的鼻喷剂，其中所述鼻喷剂还包含防腐剂；或者，所述防腐剂选自苯甲醇、苯酚、羟苯甲酯、羟苯丙酯、苯扎溴铵和苯扎氯铵中的一种或几种；或者，所述防腐剂的浓度为0.001％-10％，或0.005％-10％，或0.005％-2.5％，或0.001％-2％，或0.001％-1％，或0.003％-2％，或0.006％-2％，或0.01％-2％，或0.01％-0.5％，或0.01％-0.05％，或0.01％-0.04％。
  3. 一种鼻喷剂，其包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
    (2)组氨酸缓冲剂：1～50mM；
    (3)蔗糖：1～200mg/mL；
    (4)吐温80：0.01～10mg/mL；和
    (5)羟丙甲纤维素：0.01％-30％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
    (2)组氨酸缓冲剂：1～50mM；
    (3)蔗糖：20～200mg/mL；
    (4)吐温80：0.05～10mg/mL；和
    (5)羟丙甲纤维素：0.05％-15％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～150mg/mL；
    (2)组氨酸缓冲剂：1～40mM；
    (3)蔗糖：20～200mg/mL；
    (4)吐温80：0.1～10mg/mL；和
    (5)羟丙甲纤维素：0.01％-10％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～100mg/mL；
    (2)组氨酸缓冲剂：1～30mM；
    (3)蔗糖：1～150mg/mL；
    (4)吐温80：0.1～5mg/mL；和
    (5)羟丙甲纤维素：0.05％-5％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：10～100mg/mL；
    (2)组氨酸缓冲剂：1～25mM；
    (3)蔗糖：20～150mg/mL；
    (4)吐温80：0.1～5mg/mL；和
    (5)羟丙甲纤维素：0.05％-1％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：10～80mg/mL；
    (2)组氨酸缓冲剂：1～20mM；
    (3)蔗糖：20～120mg/mL；
    (4)吐温80：0.2～5mg/mL；和
    (5)羟丙甲纤维素：0.05％-0.5％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：10～70mg/mL；
    (2)组氨酸缓冲剂：1～15mM；
    (3)蔗糖：50～100mg/mL；
    (4)吐温80：0.5～1mg/mL；和
    (5)羟丙甲纤维素：0.1％-0.25％；
    所述鼻喷剂的pH为3.0～8.0。
  4. 一种鼻喷剂，其包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
    (2)组氨酸缓冲剂：1～50mM；
    (3)蔗糖：1～200mg/mL；
    (4)吐温80：0.01～10mg/mL；
    (5)羟丙甲纤维素：0.01％-30％；和
    (6)苯甲醇或苯扎氯铵：0.001％-10％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～200mg/mL；
    (2)组氨酸缓冲剂：1～50mM；
    (3)蔗糖：20～200mg/mL；
    (4)吐温80：0.05～10mg/mL；
    (5)羟丙甲纤维素：0.05％-15％；和
    (6)苯甲醇或苯扎氯铵：0.005％-10％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～150mg/mL；
    (2)组氨酸缓冲剂：1～40mM；
    (3)蔗糖：20～200mg/mL；
    (4)吐温80：0.1～10mg/mL；
    (5)羟丙甲纤维素：0.01％-10％；和
    (6)苯甲醇或苯扎氯铵：0.005％-2.5％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：1～100mg/mL；
    (2)组氨酸缓冲剂：1～30mM；
    (3)蔗糖：1～150mg/mL；
    (4)吐温80：0.1～5mg/mL；
    (5)羟丙甲纤维素：0.05％-5％；和
    (6)苯甲醇或苯扎氯铵：0.001％-2％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：10～100mg/mL；
    (2)组氨酸缓冲剂：1～25mM；
    (3)蔗糖：20～150mg/mL；
    (4)吐温80：0.1～5mg/mL；
    (5)羟丙甲纤维素：0.05％-1％；和
    (6)苯甲醇或苯扎氯铵：0.003％-2％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：10～80mg/mL；
    (2)组氨酸缓冲剂：1～20mM；
    (3)蔗糖：20～120mg/mL；
    (4)吐温80：0.2～5mg/mL；
    (5)羟丙甲纤维素：0.05％-0.5％；和
    (6)苯甲醇或苯扎氯铵：0.006％-2％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：10～70mg/mL；
    (2)组氨酸缓冲剂：1～15mM；
    (3)蔗糖：50～100mg/mL；
    (4)吐温80：0.5～1mg/mL；
    (5)羟丙甲纤维素：0.1％-0.25％；和
    (6)苯甲醇或苯扎氯铵：0.01％-2％；
    所述鼻喷剂的pH为3.0～8.0；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：35mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：90mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯甲醇：1％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：90mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯甲醇：1％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：90mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.25％；和
    (6)苯甲醇：1％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：90mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.2％；和
    (6)苯甲醇：1％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.003％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.006％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.01％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.02％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.03％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.04％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3；
    或者，所述鼻喷剂包含：
    (1)靶向冠状病毒的抗体或抗原结合片段：50mg/mL；
    (2)组氨酸缓冲剂：10mM；
    (3)蔗糖：80mg/mL；
    (4)吐温80：1mg/mL；
    (5)羟丙甲纤维素：0.1％；和
    (6)苯扎氯铵：0.05％；
    所述鼻喷剂的pH为5.5～6.5，或6.0±0.3。
  5. 如权利要求3或4所述的鼻喷剂，其中所述羟丙甲纤维素选自HPMC4000、HPMC400和HPMC100中的一种或几种；或者，所述羟丙甲纤维素为HPMC4000。
  6. 如权利要求1-5任一项所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体或抗原结合片段结合Spike蛋白；所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3中的一个或多个；或者，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的 LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3。
  7. 如权利要求6所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:6所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:9所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:15所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:16所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:18所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:19所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:20所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:21所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:22所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:23所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:24所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:25所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ  ID NO:3所示的HCDR2、如SEQ ID NO:28所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:29所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:30所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:32所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:33所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:34所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:35所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:36所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:37所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:39所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:40所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:41所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述靶向冠状病毒的抗体或抗原结合片段包含如SEQ ID NO:2所示的HCDR1、如SEQ ID NO:4所示的HCDR2、如SEQ ID NO:42所示的HCDR3、如SEQ ID NO:44所示的LCDR1、如SEQ ID NO:46所示的LCDR2和如SEQ ID NO:48所示的LCDR3。
  8. 如权利要求1-7任一项所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体或抗原 结合片段包含重链可变区和/或轻链可变区；所述重链可变区包含如SEQ ID NO:56、57、83-105任一项所示的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或所述轻链可变区包含如SEQ ID NO:58或59所示的氨基酸序列，或与SEQ ID NO:58或59所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
  9. 如权利要求6-8任一项所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体或抗原结合片段包含重链恒定区和/或轻链恒定区；所述重链恒定区包含如SEQ ID NO:60或61所示的氨基酸序列，或与SEQ ID NO:60或61所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:60或61所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或所述轻链恒定区包含如SEQ ID NO:62所示的氨基酸序列，或与SEQ ID NO:62所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:62所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
  10. 如权利要求1-9任一项所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体或抗原结合片段包含重链和/或轻链；所述重链包含如SEQ ID NO:56、57、83-105任一项所示的重链可变区和如SEQ ID NO:60或61所示的重链恒定区；所述轻链包含如SEQ ID NO:58或59所示的轻链可变区和如SEQ ID NO:62所示的轻链恒定区。
  11. 如权利要求1-9任一项所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体或抗原结合片段包含重链和轻链；所述重链包含如SEQ ID NO:71或72所示的氨基酸序列，或与SEQ ID NO:71或72所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:71或72所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或所述轻链包含如SEQ ID NO:73或74所示的氨基酸序列，或与SEQ ID NO:73或74所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:73或74所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
  12. 如权利要求1-5任一项所述的鼻喷剂，其特征在于，所述靶向冠状病毒的抗体为双特异抗体，所述双特异抗体包含结合Spike蛋白的第一结合部分以及结合Spike蛋白的第二结合部分，所述第一结合部分包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示的LCDR2和如SEQ ID NO:47或48所示的LCDR3中的一个或多个；所述第一结合部分的C-末端或N-末端通过连接子与所述第二结合部分连接。
  13. 如权利要求12所述的鼻喷剂，其特征在于，所述连接子为包含甘氨酸和丝氨酸的多肽；或者，所述连接子的序列为(GmS)n，其中每个m独立为2、3、4或5，n独立为1、2、3、4或5；或者，所述连接子的序列为(GGGGS)n，所述n独立为1、2、3、4或5；或者，所述连接子包含如SEQ ID NO:63-65任一项所示的氨基酸序列。
  14. 如权利要求12或13所述的鼻喷剂，其特征在于，所述第一结合部分包含如SEQ ID NO:1或2所示的HCDR1、如SEQ ID NO:3或4所示的HCDR2、如SEQ ID NO:5-42任一项所示的HCDR3、如SEQ ID NO:43或44所示的LCDR1、如SEQ ID NO:45或46所示 的LCDR2和如SEQ ID NO:47或48所示的LCDR3。
  15. 如权利要求12-14任一项所述的鼻喷剂，其特征在于，所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:6所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:9所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:15所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:16所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:18所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:19所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:20所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:21所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:22所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:23所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:24所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:25所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的 HCDR2、如SEQ ID NO:28所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:29所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:30所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:32所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:33所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:34所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:35所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:36所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:37所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:39所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:40所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:3所示的HCDR2、如SEQ ID NO:41所示的HCDR3、如SEQ ID NO:43所示的LCDR1、如SEQ ID NO:45所示的LCDR2和如SEQ ID NO:47所示的LCDR3；或
    所述第一结合部分包含如SEQ ID NO:2所示的HCDR1、如SEQ ID NO:4所示的HCDR2、如SEQ ID NO:42所示的HCDR3、如SEQ ID NO:44所示的LCDR1、如SEQ ID NO:46所示的LCDR2和如SEQ ID NO:48所示的LCDR3。
  16. 如权利要求12-15任一项所述的鼻喷剂，其特征在于，所述第一结合部分包含重链 可变区和/或轻链可变区；其中
    所述第一结合部分的重链可变区包含如SEQ ID NO:56、57、83-105任一项所示的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:56、57、83-105任一项所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
    所述第一结合部分的轻链可变区包含如SEQ ID NO:58或59所示的氨基酸序列，或与SEQ ID NO:58或59所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:58或59所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
  17. 如权利要求12-16任一项所述的鼻喷剂，其特征在于，所述第二结合部分包含如SEQ ID NO:66所示的HCDR1、如SEQ ID NO:67所示的HCDR2和如SEQ ID NO:68所示的HCDR3中的一个、二个或三个；或者，所述第二结合部分包含如SEQ ID NO:66所示的HCDR1、如SEQ ID NO:67所示的HCDR2和如SEQ ID NO:68所示的HCDR3；或者，所述第二结合部分为单域抗体或重链抗体；或者，所述第二结合部分包含如SEQ ID NO:69或79所示的氨基酸序列。
  18. 如权利要求12-17任一项所述的鼻喷剂，其特征在于，所述双特异抗体包含第一多肽和第二多肽；其中
    所述第一多肽包含如SEQ ID NO:72或77所示的氨基酸序列，或与SEQ ID NO:72或77所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:72或77所示序列相比具有一或多个保守氨基酸取代的氨基酸序列；和/或
    所述第二多肽包含如SEQ ID NO:74或78所示的氨基酸序列，或与SEQ ID NO:74或78所示序列具有至少80％同一性的氨基酸序列，或与SEQ ID NO:74或78所示序列相比具有一或多个保守氨基酸取代的氨基酸序列。
  19. 权利要求1-18任一项所述的鼻喷剂在预防或治疗冠状病毒引发的疾病或制备预防或治疗冠状病毒引发的疾病的药物中的用途；
    或者，所述冠状病毒为SARS-CoV、SARS-CoV-2或MERS-CoV；或者，所述冠状病毒引发的疾病为新型冠状病毒引发的疾病。
PCT/CN2024/084227 2023-03-28 2024-03-27 靶向冠状病毒的抗体鼻喷剂及其应用 WO2024199312A1 (zh)

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