CN114903922B - Pharmaceutical formulations comprising adenoviruses and methods of preserving same - Google Patents
Pharmaceutical formulations comprising adenoviruses and methods of preserving same Download PDFInfo
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- CN114903922B CN114903922B CN202210107254.8A CN202210107254A CN114903922B CN 114903922 B CN114903922 B CN 114903922B CN 202210107254 A CN202210107254 A CN 202210107254A CN 114903922 B CN114903922 B CN 114903922B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/761—Adenovirus
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- 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
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- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application discloses a pharmaceutical preparation containing adenovirus and a preservation method thereof. The pharmaceutical preparation containing adenovirus adopts a citric acid buffer system, combines a nonionic surfactant and small-molecule saccharides with the C atom number less than or equal to 24 or sugar alcohols with the C atom number less than or equal to 24, and realizes the stability of the preparation. The adenovirus-containing pharmaceutical preparation can be prepared into a stable liquid preparation, the osmotic pressure is in a reasonable range, the injection requirement is met, the pH value is close to neutral, the adverse reaction probability of an organism can be effectively reduced, the raw materials are simple, and the safety is good.
Description
Technical Field
The application relates to the technical field of biological medicine, in particular to a medical preparation containing adenovirus and a preservation method thereof.
Background
The vaccine is an automatic immune preparation for preventing or treating infectious diseases, which is prepared by artificially attenuating, inactivating or utilizing transgenosis methods of pathogenic microorganisms (such as bacteria, rickettsia, viruses and the like) and metabolites thereof, and is the most common type of biological preparation. The common administration routes of the vaccine are mainly oral administration and injection, the current vaccine research is mainly focused on injection due to the molecular activity requirement of the vaccine, the common vaccine injection is a small water injection or a freeze-dried powder injection, the freeze-dried preparation becomes a basic dosage form of biological products due to high stability, but the process is complex, the period is longer and the cost is higher, and the liquid preparation is difficult to develop but has simple process, the period is shorter, and the freeze-dried titer loss and the cost is lower.
Adenovirus vectors are one of the most promising viral vectors for use at present, and are widely used in various preclinical and clinical studies including vaccine development, gene therapy, and oncolytic therapy. The biological activity of adenoviruses depends on the conformational integrity of at least one core sequence of nucleotides surrounded by an icosahedral envelope structure consisting of capsid proteins. Unlike traditional organic and inorganic drugs, adenovirus particles are very easily degraded and have poor stability. Thus, in order to ensure a reasonable shelf life, a good formulation of the adenovirus formulation is crucial. Adenovirus research has also focused on formulations of adenovirus intended for administration to humans. Not only should such formulations be safe, sterile and Good Manufacturing Practice (GMP) grade, they should also exhibit and promote long-term stability of the adenovirus, minimizing loss of adenovirus potency during manufacture, packaging and storage. The formulation should further prevent the adenovirus from adsorbing to the surface of the container in which it is packaged and stored, as well as to the mechanical surfaces used in the manufacturing process. Although much research has been put into the design of adenovirus formulations, there remains a need for improved adenovirus formulations.
Disclosure of Invention
The present application provides a pharmaceutical formulation comprising adenovirus that allows for long term storage of the adenovirus formulation, minimizes loss of adenovirus potency, and advantageously prevents the formation of visible particles, prevents the adsorption of adenovirus to packaging and storage container surfaces, and mechanical surfaces used in the manufacturing process.
The application provides a medical preparation, which comprises the following components in terms of total volume of the medical preparation:
(a) Recombinant adenovirus;
(b) Citrate buffer 5mM to 400mM;
(c) Nonionic surfactant (v/v) 0.01% to 1%; and
(D) 4% to 15% of a protective agent (w/v);
wherein the protective agent is one or a combination of more of sugar compounds with the C atom number less than or equal to 24 or sugar alcohols with the C atom number less than or equal to 24;
The pharmaceutical formulation has a pH of 5.0 to 7.0.
In some embodiments of the application, the pharmaceutical formulation is a liquid formulation.
In some embodiments of the application, the pharmaceutical formulation further comprises NaCl, the concentration (w/v) of NaCl is less than or equal to 35%, for example, the concentration (w/v) of NaCl is 0.
In some embodiments of the application, the citrate buffer is at a concentration of 10mM to 140mM, e.g., 20mM to 75mM, still more e.g., 40mM to 80mM, 30mM to 100mM, or preferably 20mM to 60mM.
In some embodiments of the application, the pH of the pharmaceutical formulation is from 5.5 to 6.8, for example the pH of the pharmaceutical formulation is in any of the ranges from 5.8 to 6.7, 6.0 to 6.8, or 6.2 to 6.7; also for example, the pH is in any of the ranges of 5.8 to 6.0, 6.0 to 6.2, 6.5 to 6.7, or 6.4 to 6.6.
In some embodiments of the application, the nonionic surfactant is a polysorbate, such as polysorbate 80 (tween 80, ps 80).
In some embodiments of the application, the concentration (v/v) of the nonionic surfactant in the pharmaceutical formulation is from 0.05% to 0.5%, for example from 0.08% to 0.2%, preferably 0.1%.
In some embodiments of the application, the carbohydrate is one or more of sucrose, trehalose, or lactose.
In some embodiments of the application, the protective agent concentration (w/v) in the pharmaceutical formulation is 4.2% to 10%, e.g., 4.4% to 7.5%, 4.4% to 7.2%, or 4.8% to 7.5%.
In some embodiments of the application, the pharmaceutical formulation further comprises glycine and/or mannitol.
In some embodiments of the application, the concentration (w/v) of glycine in the pharmaceutical formulation is 0.2% to 5%, for example 0.5% to 1%; the mannitol concentration (w/v) is 0.2% to 5%, for example 0.5% to 1%.
In some embodiments of the application, the pharmaceutical formulation comprises recombinant adenovirus having a titer ranging between 7.0lgIFU/mL and 12.0 lgIFU/mL; for example, the titer is in the range of 7.0lgIFU/mL to 11.0lgIFU/mL, or the titer is in the range of 8.0lgIFU/mL to 11.0lgIFU/mL, or the titer is in the range of 8.0lgIFU/mL to 10.0lgIFU/mL.
In the recombinant adenoviruses of the invention, the adenovirus vector is derived from a human adenovirus or a non-human simian adenovirus. In one embodiment, the adenoviral vector of the invention is derived from a human adenovirus such as Ad1, ad2, ad4, ad5, ad6, ad11, ad 24, ad34 or Ad35, in particular Ad5, ad11 or Ad35.
In some embodiments of the application, the recombinant adenovirus comprises an adenovirus vector from a non-simian adenovirus, such as a chimpanzee adenovirus vector or a gorilla adenovirus vector.
In some embodiments of the application, the adenovirus vector is a chimpanzee adenovirus vector, such as, for example, adC68, chAd3, chAd63, chAd83, chAd155, pan 5, pan 6, pan 7, or Pan 9. The adenovirus vector may also be derived from a non-simian adenovirus isolated from a short chimpanzee, such as PanAd1, panAd2, or PanAd3.
In some embodiments of the application, the recombinant adenovirus comprises a heterologous nucleic acid molecule.
In some embodiments of the application, the recombinant adenovirus comprises at least one of the following heterologous nucleic acid molecules:
(A) Nucleic acid molecules encoding the PreS protein of SARS-CoV-2; or (b)
(B) Nucleic acid molecules encoding the full-length S protein of SARS-CoV-2 virus.
In a specific embodiment, the amino acid sequence of the PreS protein comprises the amino acid sequence shown as SEQ ID NO.1, and the nucleic acid molecule encoding the PreS protein of SARS-CoV-2 comprises the nucleotide sequence shown as SEQ ID NO. 2;
In a specific embodiment, the amino acid sequence of the full-length S protein comprises the amino acid sequence shown as SEQ ID NO.3, and the nucleic acid molecule encoding the full-length S protein of SARS-CoV-2 virus comprises the nucleotide sequence shown as SEQ ID NO. 4.
In other embodiments of the application, the recombinant adenovirus may comprise a heterologous nucleic acid molecule that is a gene encoding an RSV antigen protein, a VZV antigen protein, a GFP protein or an IE63 protein.
In some embodiments of the application, the pharmaceutical formulation is a nasal spray formulation, a nasal drip formulation, an aerosol inhalation formulation, an intramuscular formulation, a subcutaneous formulation, or an oral formulation.
In some embodiments of the application, the pharmaceutical formulation consists of the following ingredients: recombinant adenovirus, citrate buffer 5mM to 400mM, nonionic surfactant 0.01% to 1% (v/v) and protectant 4% to 15% (w/v).
In some embodiments of the application, the pharmaceutical formulation consists of the recombinant adenovirus, the citrate buffer 5mM to 400mM, the non-ionic surfactant 0.01% to 1% (v/v), the protectant 4% to 15% (w/v), glycine 0.2% to 5% (w/v), and mannitol 0.2% to 5% (w/v). In particular embodiments, the component content may be further preferred as above.
The application further provides a medical formulation comprising, based on the total volume of the medical formulation: adenovirus, citrate buffer 20mM to 60mM, sucrose or trehalose 4.4% to 7.2% (w/v), glycine 1% (w/v), mannitol 1% (w/v) and Tween 80 0.1% (v/v), the pH of the medical formulation being 5.8 to 6.7.
Correspondingly, the application also provides a preservation method of the pharmaceutical preparation containing adenovirus, which comprises the following steps: the pharmaceutical formulation as described above is stored at a temperature of-60 ℃ to 37 ℃.
In one embodiment, the pharmaceutical formulation is stored at a temperature of 0 ℃ to 25 ℃. In another embodiment, the pharmaceutical formulation is stored at 2 ℃ to 8 ℃. In another embodiment, the pharmaceutical formulation is stored between-20 ℃ and-60 ℃.
The beneficial effects are that:
The adenovirus-containing pharmaceutical preparation provided by the invention adopts a citrate buffer solution system and combines low molecular weight sugar or sugar alcohol as a protective agent, so that the stability of the preparation is realized. The adenovirus-containing pharmaceutical preparation can be prepared into a stable liquid preparation, has osmotic pressure within a reasonable range, meets injection requirements, has good storage stability, can keep good virus infection rate at a temperature of 0-37 ℃, ensures that virus particles have uniform and stable particle size, has no degradation or obvious aggregation, effectively avoids the loss of virus titer, can meet the storage and transportation requirements of the preparation, can greatly reduce the cost, and realizes the balance breakthrough of the stability and the medicinal performance of the adenovirus pharmaceutical liquid preparation. In addition, the pH value of the adenovirus preparation provided by the invention is close to neutral, and the materials used in the formula are safe and nontoxic, so that the probability of adverse reactions of organisms of an application object is effectively reduced.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the description of the embodiments will be briefly described below.
FIG. 1 is a graph showing particle size Distribution (DLS) of adenovirus preparation samples of groups B1 through B16 of Experimental example 2 after 28 days at 37 ℃; wherein the numbers 1, 2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 in the abscissa groups correspond to sample groups B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15 and B16, respectively;
FIG. 2 is a particle size Distribution (DLS) chart of a heat acceleration stability test at 37℃and 42℃for a C1 to C8 group adenovirus formulation sample in Experimental example 3;
FIG. 3 is a graph showing the results of detection of viral titers of samples of adenovirus preparations of groups D3 and D4 of Experimental example 4, frozen and thawed 1 to 5 times;
FIG. 4 is a graph showing the results of detection of the number of viral particles in the samples of adenovirus preparations of groups D3 and D4 of Experimental example 4, frozen and thawed 1 to 5 times;
FIG. 5 shows the results of detection of virus infection activity (VP/IFU specific activity) of 1 to 5 times of freeze thawing of adenovirus preparation samples of groups D3 and D4 in Experimental example 4;
FIG. 6 is a particle size distribution of virus particles of samples of adenovirus preparations of groups D3 and D4 of experimental example 4 freeze-thawed 1 to 5 times.
Detailed description of the preferred embodiments
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to fall within the scope of the application.
Embodiments of the present application provide a pharmaceutical formulation comprising an adenovirus. The following will describe in detail. The following description of the embodiments is not intended to limit the preferred embodiments. Various embodiments of the application may exist in a range of forms; it should be understood that the description in a range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the application; it is therefore to be understood that the range description has specifically disclosed all possible sub-ranges and individual values within that range. For example, it should be considered that a description of a range from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5, and 6, wherever applicable. In addition, whenever a numerical range is referred to herein, it is meant to include any reference number (fractional or integer) within the indicated range.
The adenovirus contained in the pharmaceutical preparation of the invention is recombinant adenovirus. In some embodiments, the pharmaceutical formulation comprises at least one recombinant adenovirus. Construction of adenovirus vectors in such recombinant adenoviruses is well understood in the art in light of the prior art and involves the use of standard molecular biology techniques. The adenovirus vector may be defective in at least one essential gene function of the E1 region (e.g., E1a region and/or E1b region) of the adenovirus genome, which E1 region is essential for replication of the virus. In some embodiments of the invention, the construction of the adenovirus vector comprises: the replication-defective adenovirus vector with the E1 region deletion is constructed, for example, a low-melting-point glue direct connection method is adopted to construct replication-defective adenovirus molecular clone with the E1 region deletion, and infectious virus particles are packaged in HEK293 cells. In some embodiments, the adenoviral vector of the invention is derived from a non-simian adenovirus, such as a chimpanzee adenovirus or a gorilla adenovirus. These adenovirus vectors generally have a low seropositive rate and/or low pre-existing neutralizing antibody titers in the human population. In other embodiments, the adenoviral vector of the invention is derived from a human adenovirus, e.g., at least one of Ad1, ad2, ad4, ad5, ad6, ad11, ad 24, ad34, ad35, in particular Ad5, ad11, or Ad35.
In other embodiments, the recombinant adenoviruses of the invention further comprise a heterologous nucleic acid molecule. Suitable heterologous nucleic acid molecules are well known to those skilled in the art and may include transgenic open reading frames, e.g., open reading frames encoding polypeptides/proteins. The invention is not particularly limited in the type or sequence of the heterologous nucleic acid molecule, and for example, in the case of preparation for immunization purposes, nucleic acid molecules or fragments thereof having an immune response to certain viruses are selected, as are well known to the skilled worker. In the present invention, any heterologous nucleic acid molecule or fragment may be used, for example, comprising a gene encoding an RSV antigen protein, a gene encoding a VZV antigen protein, a gene encoding a GFP protein or a gene encoding an IE63 protein, as long as it can achieve an immune and/or therapeutic effect of the formulation. In some embodiments, the heterologous nucleic acid molecule is a nucleic acid molecule derived from SARS-CoV-2 virus or a fragment thereof; or any nucleic acid molecule or fragment thereof that has an immune response to SARS-CoV-2 virus. As an exemplary embodiment, the heterologous nucleic acid molecule is the nucleotide sequence shown as SEQ ID NO.2 or SEQ ID NO. 4. However, these heterologous nucleic acid molecules are merely exemplary and not meant to be limiting, and it will be understood by those skilled in the art that the pharmaceutical formulations of the present invention may include recombinant adenoviruses comprising any other heterologous nucleic acid molecule.
The invention relates to pharmaceutical formulations comprising recombinant adenoviruses further to related pharmaceutical products, such as gene pharmaceuticals and/or vaccine formulations. In some embodiments, the pharmaceutical formulation is a formulation in liquid form that exhibits excellent adenovirus stability. These formulations are suitable for storage at 2-8℃and can also maintain good stability when stored at lower temperatures, for example, -20℃or less, -40℃or less, -65℃or less. They can also be stored stably at temperatures above 8 ℃, for example 25 ℃, 37 ℃ or even higher. In the present invention, the term "stability" refers to the relative resistance to degradation of adenovirus particles in a formulation, retaining their efficacy on the time scale of their intended usefulness. In the present invention, the adenovirus stability refers to that a preparation or a formulation containing adenovirus has no or only little decrease in virus titer within a certain period of time under specific conditions, which is within the acceptable range in the art, so as to achieve the effect that the virus titer maintains the effective medicinal effect of the formulation and meet the requirements of storage and transportation in the art; for example, the virus titer is reduced by lgTCID 50/mL or less than 0.5 or lgIFU/mL or less than 0.5 at 37 ℃ under 7-day acceleration experiment conditions or 37 ℃ under 14-day acceleration experiment conditions; for example, the virus titer is reduced by lgTCID 50/mL to less than 0.5 or lgIFU/mL to less than 0.5 after storage at 2-8deg.C for 270 days or less than-60deg.C for 1 year, 1.5 years, 2 years, 3 years or 5 years.
The pharmaceutical formulation of the present invention comprises a citric acid (citrate) salt buffer, 0.01% to 1% of a nonionic surfactant (v/v), and a protecting agent, wherein the protecting agent is one or a combination of a saccharide compound having a C (carbon) atom number of 24 or a sugar alcohol having a C atom number of 24 or less.
The citrate buffer solution can also be called as citrate buffer solution, and is prepared by mixing citric acid and/or sodium citrate and water; the pH of the pharmaceutical formulation may be varied by varying the amount of citric acid and/or sodium citrate in the citrate buffer, and it is well understood by those skilled in the art from the prior art that the pH of the pharmaceutical formulation may be adjusted to a specific value or range by adjusting the amount of citric acid and/or sodium citrate in the citrate buffer. In some embodiments of the application, the concentration of citrate buffer may be understood as the concentration of citrate ions in the citrate buffer.
The "protectant" of the present application may also be referred to as a "stabilizer" and may be used alone or in combination with other additives to prevent low temperature damage to the adenovirus vector being frozen or cryogenically preserved, or to protect the vaccine against high temperatures and extreme temperature changes (e.g., adverse conditions such as freeze thawing). In the present application, the protective agent is preferably one or a combination of more of a saccharide compound having a C (carbon) atom number of 24 or less or a sugar alcohol having a C atom number of 24 or less. In some embodiments of the application, the saccharide compound is one or more of a monosaccharide, disaccharide, or trisaccharide; in some embodiments, the saccharide compound has a C atom number of 12 or less, for example, a C atom number of 12 or a C atom number of 6, and the saccharide compound is preferably a monosaccharide or disaccharide; in some embodiments, the carbohydrate is one or more of sucrose, trehalose, or lactose. In some embodiments, other saccharide compounds or derivatives thereof may also be added to the pharmaceutical formulation as protective agents, such as hydroxypropyl cyclodextrin, dextran, and the like. It will be appreciated by those skilled in the art that the effect of the added material on the safety of the pharmaceutical product for human use should be considered when adding other saccharide compounds or derivatives thereof. In the present application, it is preferable to add one or more of sucrose, trehalose or lactose as a protective agent for the safety of human pharmaceutical products. In some embodiments of the application, the protective agent concentration (w/v) is 4% to 15%, such as 4.2% to 10%, and still more such as 4.4% to 7.5%, based on the total volume of the pharmaceutical formulation. In some embodiments, the concentration (w/v) of the carbohydrate having a C atom number of 24 or sugar alcohol having a C atom number of 24 is 4.4% to 9%, such as 4.8% to 7.5% or 4.4% to 7.2%. In other embodiments, the protectant includes a saccharide having a concentration (w/v) of from 4.8% to 7.5% of 24C atoms or a sugar alcohol having a concentration of 24C atoms or less, and a saccharide having a concentration (w/v) of from 2.5% to 5% of 30C atoms or more.
In some embodiments, the citrate buffer is at a molar concentration of 10mM to 140mM, e.g., 20mM to 75mM, 20mM to 60mM, 30mM to 100mM, or 40mM to 80mM; illustratively, the citrate buffer is at a molar concentration of 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, or 80mM.
In some embodiments, the pharmaceutical formulation is a liquid formulation having a pH of between 5.0 and 7.0, for example, a pH in any of the ranges of 5.5 to 6.8, 5.8 to 6.7, 6.0 to 6.8, or 6.2 to 6.7; also for example, the pH is 5.8 to 6.0, 5.8 to 6.2, 6.0 to 6.2, 6.5 to 6.7 or 6.4 to 6.6.
The pharmaceutical formulation of the present invention may further comprise glycine and mannitol, the glycine concentration (w/v) being from 0.2% to 5%, for example from 0.5% to 1%, based on the total volume of the pharmaceutical formulation; the mannitol concentration (w/v) is 0.2% to 5%, for example 0.5% to 1%. In some embodiments, the concentration of glycine and mannitol, respectively, is 1%. The addition of glycine and mannitol has been shown to be beneficial for the stability of adenovirus.
In some embodiments, the pharmaceutical formulation does not contain NaCl or other forms of sodium salt, or the concentration of NaCl or other forms of sodium salt is kept below 35% (w/v%) in order to achieve good recombinant adenovirus stability, e.g., 25% (w/v%) and below, or 10% (w/v%) and below. In some embodiments, the concentration of NaCl in the pharmaceutical formulation is 0.
In some embodiments, the addition of ethanol, disodium EDTA, and glycerin is acceptable in the pharmaceutical formulation, but the addition of these ingredients does not significantly improve the performance of the formulation.
In some embodiments, the pharmaceutical formulation consists of one or more of the recombinant adenoviruses described above, citrate buffer, nonionic surfactant, and sugar compounds having less than or equal to 24 carbon atoms or sugar alcohols having less than or equal to 24 carbon atoms.
In other embodiments, the pharmaceutical formulation consists of one or more of the recombinant adenoviruses described above, citrate buffer, nonionic surfactant, carbohydrate having no more than 24C (carbon) atoms, or sugar alcohol having no more than 24C (carbon) atoms, glycine, and mannitol.
The "formulation" and "preparation" of the present invention are used interchangeably and refer to a composition containing an active ingredient having a prophylactic or therapeutic effect, pharmaceutically acceptable excipients, and the like. In some embodiments, the active ingredient having a prophylactic or therapeutic effect refers to a recombinant adenovirus that can elicit the immune response of a subject (e.g., mammal), or a recombinant adenovirus that can be used as a gene therapy; in some embodiments, the formulation or preparation is prepared into a variety of different dosage forms, such as liquid formulations, lyophilized formulations, tablets, ointments, and the like, via different kinds of pharmaceutically acceptable excipients and processes; in some embodiments, the formulation or preparation is administered by nasal spray, nasal drops, aerosol inhalation, intramuscular injection, subcutaneous injection, or oral administration. The pharmaceutical formulations of the present invention provide stability to recombinant adenoviruses, either singly or in multivalent, at different viral concentrations, and can be administered to a variety of mammals, suitable mammals within the scope of the invention include, but are not limited to: primates, domestic animals (e.g., sheep, cattle, horses, monkeys, pigs, etc.), laboratory test animals (e.g., rabbits, mice, etc.), pets (e.g., cats, dogs, etc.), and wild animals (e.g., wolves, foxes, deer, etc.) are housed. In some embodiments, the mammal is a test mouse. In some embodiments, particularly applicable to humans, may be administered as a vaccine that may provide a prophylactic and/or therapeutic effect to previously uninfected or antibody-free individuals.
Unless otherwise specified, in the present invention, the concentration of each component represents the mass/volume percent (w/v), volume/volume percent (v/v), or volume molar concentration (mM, mmol/L) of each component in the final formulated adenovirus-containing liquid formulation, based on the total volume of the pharmaceutical formulation (formulation) being formulated.
The present invention is specifically described below with reference to examples, but is not intended to limit the present invention to the following examples.
The formulations employed in the examples of the present invention are shown in table 1 below. The apparatus, reagents or materials used in the present invention are commercially available or may be prepared using existing techniques unless otherwise specified.
TABLE 1 sources of formulations and basic information
The recombinant adenovirus adopted by the embodiment of the invention comprises the following components: rAdC68XY3-GFP adenovirus, new crown rAdC XY3-PreS adenovirus, new crown rAdC XY3-S adenovirus. The embodiment of the invention adopts the purified liquid of the adenovirus, wherein the information of the corresponding used viruses in each experimental batch is shown in table 2.
TABLE 2 recombinant adenovirus related information for use in the examples of the invention
The detection method adopted by the embodiment of the invention is an operation means known in the art, and can be completed by a common technician without creative labor based on the prior art. For example, the TCID50 method can be used to detect adenovirus titer, which can be detected in a wide range, and can be used to detect not only higher concentration samples but also lower concentration samples. Adenovirus titer-TCID 50 method reference [ (]G., archiv f experiment Pathol u Pharmakol,162:480-483,1931).
The ICC method can also be used for detecting adenovirus titer, and the sensitivity is higher when compared in the same order of magnitude range. The ICC process can be performed with reference to the following steps: referring to the instructions of kit Adeno-X RAPID TITER KIT (Clontech, 632250), adenovirus was diluted in a gradient and inoculated onto 293A cells grown as a monolayer, followed by continued cell culture. After a certain period of culture, the adenovirus Hexon protein-recognizing antibody and the second antibody recognizing the antibody are used to form color spots on the cells infected with adenovirus via antibody combination and staining. Stain was observed by microscopy and counted.
Adenovirus particle number can be calculated using OD 260 method: adding the lysate into the sample to be tested, and measuring the absorbance value of 260nm by an ultraviolet spectrophotometer. The number of adenovirus particles was calculated according to the formula adenovirus particles/ml=od value x dilution x 1.1 x 1012. The number of adenovirus particles can also be calculated by HPLC.
EXAMPLE 1 preparation of recombinant adenovirus stock solution
1.1 Construction of recombinant plasmids
The present example selects pShuttle-CMV plasmid, into which no foreign gene was inserted, as a vector of the recombinant plasmid. pShuttle-CMV is a shuttle plasmid containing a CMV enhancer, a CMV promoter, a T7 promoter, a chimeric intron, and a bGH poly (A) tailing signal, and has NotI and KpnI double cleavage sites, and kanamycin (KANAMYCIN, kana) resistance. Inserting a target heterologous nucleic acid molecule into the multiple cloning site of the pShuttle-CMV plasmid to obtain a recombinant plasmid containing a target gene, wherein the heterologous nucleic acid molecules adopted in the embodiment are respectively as follows: nucleic acid molecules (nucleotide sequence shown as SEQ ID NO. 6) for encoding GFP protein (amino acid sequence shown as SEQ ID NO. 5), nucleic acid molecules (nucleotide sequence shown as SEQ ID NO. 2) for encoding PreS protein (amino acid sequence shown as SEQ ID NO. 1) of SARS-CoV-2, and nucleic acid molecules (nucleotide sequence shown as SEQ ID NO. 4) for encoding full-length S protein (amino acid sequence shown as SEQ ID NO. 3) of SARS-CoV-2 virus.
1.2 Construction of recombinant adenovirus plasmids
In this example, a self-constructed recombinant plasmid and a commercially available adenovirus vector plasmid were selected to construct a recombinant adenovirus plasmid.
1.3 Linearization of recombinant adenovirus plasmids
The recombinant adenovirus plasmid obtained in 1.2 was digested with restriction enzymes to linearize the recombinant adenovirus plasmid.
1.4 Preparation of recombinant adenoviruses
The gene fragment recovered after cleavage in 1.3 was subjected to transfection using Lipofectamine 2000 kit in this example, and HEK293 cells were selected as the expression system. The gene fragment recovered after cleavage in 1.3 was transfected into HEK293 cells with a confluence of 60% to 70% according to the instructions of Lipofectamine 2000 kit.
In the "seed cells" step described in Lipofectamine 2000 kit, the medium used to culture HEK293 cells was MEM medium, and MEM medium was replaced with DMEM medium two hours prior to transfection. Five hours after transfection, the medium was replaced with DMEM medium containing 10% (volume percent) fetal bovine serum.
At day of transfection, cytopathic effect was observed under an inverted microscope until 60% of HEK293 cells appeared to be plaque and cells were collected. Repeatedly freezing and thawing the collected cells for three times at room temperature (25 ℃) and-80 ℃, centrifuging at a rotating speed of 1200 Xg for five minutes, collecting supernatant containing recombinant adenovirus, sub-packaging the supernatant, and storing in an ultralow temperature refrigerator at-80 ℃ for later use. Identifying the gene in the recombinant adenovirus genome as the target gene.
1.5 Amplification and purification of recombinant adenoviruses
The recombinant adenovirus prepared in the step 1.4 is amplified and subjected to virus purification by using an anion chromatography method, the adenovirus purification can be performed according to the adenovirus purification step described in Sofiya Fedosyuk etal, vaccine 37 (2019), and then the obtained recombinant adenovirus purification liquid is subjected to preparation buffer replacement and further refined purification by using a 4FF molecular sieve chromatographic column. The recombinant adenoviruses obtained were respectively named: rAdC68XY3-GFP, rADC68XY3-PreS, rADC68XY3-S.
EXAMPLE 2 preparation of recombinant adenovirus preparation
And (3) taking the adenovirus purified liquid prepared in the embodiment 1, adding different auxiliary materials according to different groups, and finally obtaining the corresponding liquid preparation formula. Filtering after fully and uniformly mixing, sub-packaging, and then placing the sample into a biochemical incubator at a corresponding temperature for accelerating stability investigation.
Experimental example 1 preparation of adenovirus liquid preparation with different buffer systems and stability experiment
Formulations containing rAdC XY3-GFP adenovirus were prepared according to the formulations shown in Table 3, samples A1 to A14 of the prepared rAdC XY3-GFP adenovirus formulations were placed in a 37℃biochemical incubator (apparatus No. PERD 1702020), sampled on days 0, 7, 14 and 28, and examined for changes in virus titer (lgTCID 50/mL) at various time points, and the results of the test using the TCID50 method were shown in Table 4.
TABLE 3 preparation ingredients of rAdC XY3-GFP adenovirus in Experimental example 1
Remarks:
1. buffer concentration is calculated as the molar concentration of citrate ions in the resulting formulation;
2. w/v represents the gram weight of solute added per 100 ml of solvent;
3. The pH of the pharmaceutical formulation solution is adjusted by the ratio of salt and corresponding acid in the buffer, for example by adjusting the ratio of citric acid and sodium citrate, by adjusting the ratio of histidine and sodium histidine, the person skilled in the art knows how to adjust the ratio of salt and corresponding acid in the buffer to bring the pharmaceutical formulation to a specific pH.
The test virus titre test was carried out at 37℃in an accelerated stability test for the pharmaceutical formulations comprising A1 to A14, respectively, and the test results are shown in Table 4 below:
Tables 4 A1 to A14 group preparations accelerated stability at 37℃Experimental Virus titre Change (1 gTCID s0/mL)
Group of | 0d | 37℃7d | 37℃14d | 37℃28d |
A1 | 7.8 | 7.9 | 6.8 | 5.7 |
A2 | 7.8 | 7.9 | 6.9 | 5.6 |
A3 | 7.8 | 7.8 | 6.6 | 5.8 |
A4 | 7.8 | 7.9 | 6.9 | 5.8 |
A5 | 7.8 | 8 | 7.5 | 6.4 |
A6 | 7.8 | 7.8 | 7.9 | 6.8 |
A7 | 7.8 | 7.9 | 7.2 | 6 |
A8 | 7.8 | 8.0 | 7.3 | 6.2 |
A9 | 8.4 | 6.7 | 5.6 | 3.6 |
A10 | 8.3 | 6.5 | 4.4 | <3.6 |
A11 | 8.5 | 6 | 3.8 | <3.6 |
A12 | 8.2 | 5.6 | 3.9 | <3.6 |
A13 | 8.5 | 4.5 | <3.6 | <3.6 |
A14 | 8.5 | 6.8 | 4.6 | <3.6 |
As can be seen from table 4, the adenovirus liquid preparation comprising citrate buffer system has better preservation effect on adenovirus than the adenovirus liquid preparation comprising HISTIDINE buffer system (HISTIDINE), the adenovirus liquid preparation comprising phosphate buffer system (EBSS) and the adenovirus liquid preparation comprising Tris buffer salt system, namely: the drop value of the virus titer of A1 to A8 is obviously smaller than that of A10 to A14 after being placed at 37 ℃ for 28 days, which proves that the adenovirus liquid preparation containing the citrate buffer system is more beneficial to improving the stability of adenovirus, and possibly, the citric acid has the effect of inhibiting free radical oxidation.
Experimental example 2 preparation of adenovirus liquid preparation containing different kinds of auxiliary materials and stability experiment
Formulations containing rAdC XY3-PreS adenovirus (lot number: PE 20200914) were prepared according to the formulations shown in Table 5, and samples B1 to B16 of the prepared rAdC XY3-PreS adenovirus formulations were placed in a 37℃biochemical incubator (apparatus No. PERD 1702020) and sampled on days 0, 7, 14 and 28, respectively, and examined for virus titer, virus particle number change, particle size change and osmotic pressure at each time point.
TABLE 5 components of the rAdC XY3-PreS adenovirus-containing formulation of Experimental example 2
Remarks: refer to table 3 remarks.
(1) Viral titer change
Table 6 shows the results of accelerated stability experiments using TCID50 method to test samples of the B1 to B16 group formulations at 37 ℃. As can be seen from the data in Table 6, all samples of B1 through B16 showed no more than 0.6 in virus titer (lgTCID 50/mL) when left at 37℃for 14 days, and no more than 0.7 in virus titer (lgTCID 50/mL) when left at 28 days for groups B2, B4, B6, B8, B9, B11, B15 and B16, indicating good stability of the liquid formulations of these groups.
Tables 6B1 to B16 group preparation samples accelerated stability test virus titer change at 37 ℃ (lgTCID 50/mL)
Specifically, according to Table 6, the samples of the formulations of group B10 showed significantly greater changes in viral titers on days 14 and 28 than the formulations of the other groups, and it was seen that the protective effect against adenovirus was significantly reduced when only dextran was added without the addition of small-molecule saccharides such as sucrose, trehalose, etc. Comparing the viral titers of the preparation samples of groups B4, B5 and B6, it can be seen that the change in viral titer (lgTCID 50/mL value) of group B6 (15% sucrose) was minimal, followed by the greatest decrease in viral titer of group B4 (7.5% sucrose) and group B5 (4.8% sucrose) when left at 37℃for 28 days. When sucrose concentration was reduced to 4.8% (w/v), the decrease in viral titer was more pronounced in group B5 on days 7, 14 and 28, and it was seen that high sucrose concentration had a positive effect on the stability of the adenovirus formulation of this example.
The virus titer (lgTCID 50/mL) was decreased by 0.5 in group B2 (containing 1% glycine and 1% mannitol) and 1.1 in group B3 (without glycine and mannitol) when stored at 37℃for 28 days. The decrease in viral titer (lgTCID 50/mL) was 0.5 and 1 for group B15 (60 mM citrate) compared to group B1 (20 mM citrate), indicating that the addition of glycine, mannitol and high concentrations of citrate are more beneficial to chimpanzee adenovirus stability.
The virus titer (lgTCID 50/mL) was somewhat decreased and slowed (0.9 and 1.6, respectively) in group B12 compared to the glycerol-free formulation of group B5, indicating that glycerol has a somewhat enhanced effect on the stability of the adenovirus formulation.
There was no significant difference in virus titer between group B4 and group B8, and surface sucrose and trehalose had comparable effect on enhancing the stability of the formulation, but sucrose was more preferable from the viewpoint of cost.
Compared with the group without the auxiliary materials, the reduction value of the virus titer (lgTCID 50/mL) at each time point is very small, which shows that the effect of the histidine, the ethanol and the EDTA disodium on enhancing the adenovirus stability in the adenovirus preparation system is not obvious. The decrease in viral titer (lgTCID 50/mL) was smaller in the B2 group without sodium chloride compared to the B7 group without sodium chloride when left at 37℃for 28 days, further indicating that low levels or absence of sodium chloride are more beneficial for adenovirus stability in the inventive adenovirus formulation system.
(2) Number of viral particles
The number of virus particles of B1 to B16 group rAdC XY3-PreS adenovirus preparation samples was measured by HPLC, and the measurement results are shown in Table 7. Compared with 0 day, the virus particle number of the group B1 to group B16 samples is less than 25% after being placed at 37 ℃ for 7 days, and the particle number is stable; most groups maintained relatively stable numbers of viral particles on day 14 and day 28.
Tables 7B1 to B16 sample virus particle count (10 12 VP/mL, HPLC method) of adenovirus preparation
(3) Particle size detection
The chimpanzee adenovirus stock solutions (containing different stabilizers) were tested for particle size by DLS after 28 days at 37 ℃ and the test results are shown in table 8. As can be seen from Table 8 and FIG. 1, the vast majority of samples had particle sizes ranging from 125 to 175nm. The results showed that adenovirus in the adenovirus formulation samples of B1 to B16 did not significantly aggregate and were more stable after 28 days of standing at 37 ℃.
Tables 8B1 to B16 adenovirus preparation sample Virus particle size detection results (DLS)
(4) Osmotic pressure detection
The results of the osmolarity test on the blank stabilizer formulation without adenovirus are shown in Table 9. As can be seen from the results in table 9, the osmotic pressure of the formulation containing 15% sucrose (group B6) and 2.5% (group B12) glycerol exceeded the predetermined criteria. The osmotic pressure of the two groups B4 and B5 is proper, the auxiliary materials are simple to add, and the corresponding preparation samples added with rAdC XY3-PreS adenovirus have small change of virus titer.
Tables 9B1 to B16 group blank stabilizer osmotic pressure test results
According to experimental example 2, sucrose, trehalose, dextran or hydroxypropyl cyclodextrin can improve the stability of adenovirus to a certain extent, but the safety of the dextran and the hydroxypropyl cyclodextrin as pharmaceutical excipients is yet to be confirmed; the high concentration sucrose and the high concentration citrate buffer have better effect of improving the stability of adenovirus. Glycine, mannitol and glycerol have positive effects on improving the stability of the experimental adenovirus, but the osmotic pressure of the glycerol-containing formula is higher; when the content of NaCl and histidine is low or the content of NaCl and histidine is not contained, the stability of the recombinant adenovirus is better, so that the recombinant adenovirus preparation of the invention can not contain NaCl.
Experimental example 3 preparation of adenovirus liquid preparation containing different amounts of auxiliary materials and stability experiment
Formulations containing rAdC XY3-PreS adenovirus (PE 20201026-1-A3) were prepared according to the formulations shown in Table 10, and the prepared rAdC XY3-PreS adenovirus formulation samples C1 through C7 were placed in 37℃biochemical incubator or 42℃biochemical incubator (apparatus No. PERD1702020, PERD 1711056), sampled on days 0, 7, 14 and 28, respectively, and examined for virus titer, virus particle number change, particle size change and osmotic pressure at various time points.
Table 10 C1-C7 group rAdC XY3-PreS adenovirus preparation sample composition
(1) Viral titer
The results of the test for accelerating the thermal stability of C1 to C7 group samples containing rAdC XY3-PreS adenovirus formulations at 42℃and 37℃by ICC are shown in Table 11.
Table 11 group C1 to C7 samples 37 ℃ C./42 ℃ accelerated stability test Virus titre Change (ICC method, lgIFU/mL)
As can be seen from table 11, the adenovirus formulations of groups C1 to C7 were prepared from sucrose, tween 80 and citrate buffer, which all had good stability. And, all groups C1, C3 and C6 contain glycine and mannitol, the change of virus titer (lgIFU/mL) is smaller than 0.5 after the virus is placed for 7 days at 42 ℃, the protection effect is obviously better than that of groups C2, C4 and C7 which do not contain glycine and mannitol, and the glycine and mannitol are shown to have further enhancement effect on the stability of rAdC XY3-PreS adenovirus.
(2) Number of viral particles
The number of virus particles in C1 to C7 group samples containing rAdC XY3-PreS adenovirus formulations was measured by HPLC and the results are shown in Table 12.
Tables 12 number of adenovirus formulation viral particles of group C1 to C7 (HPLC method)
As can be seen from the data in Table 12, the samples of groups C1 to C7 were left at 37℃for 28 days, and the number of virus particles was not significantly reduced, indicating that the formulation stability was good. After 7 days at 42 ℃, the number of viruses in group C4 was reduced to a greater extent than in groups C1 and C3. The detection result of the number of virus particles is basically consistent with the detection result of virus titer.
(3) Particle size detection
The particle size of the C1 to C7 group samples after standing at 37℃and 42℃was measured by DLS, and the measurement results are shown in FIG. 2. As can be seen from FIG. 2, the particle size distribution of each group was not significantly different under the two conditions, and was similar to the particle size (120 to 160 nm) of adenovirus particles in the group A0 day sample. The results show that adenovirus in the C1 to C7 group samples had no apparent aggregation behavior after 7 days of standing at 42℃or 28 days of standing at 37 ℃.
(4) Osmotic pressure detection
Osmotic pressure measurements were performed on groups C1 to C7 of the formulations containing rAdC XY3-PreS adenovirus, and the results are shown in Table 13.
Tables 13C1 to C7 adenovirus formulation sample osmolarity test results
Group of | C1 | C2 | C3 | C4 | C5 | C6 | C7 |
Osmotic pressure of stock solution (mOsmol/kg) | 659 | 440 | 529 | 321 | 547 | 748 | 552 |
Comparing groups C1 and C2, groups C3 and C4, and groups C6 and C7, respectively, it can be seen that the osmotic pressure increase by adding 1% glycine and 1% mannitol is 120mOsmol/kg to 200mOsmol/kg. Comparing group C1 and group C5, it was found that the osmotic pressure increased by about 110mOsmol/kg when citrate buffer was increased from 20mM to 60 mM. In the accelerated stability experiment, the protection effect of the C1, C3 and C6 groups is better, but the osmotic pressure of the C6 group is higher, and the osmotic pressure of the C1 group is slightly higher than the general standard of the osmotic pressure of the injection, so that the C1 and C3 groups are more preferable injection formulations.
According to the experimental example 3, the formulation of the C1-C7 adenovirus preparation provided by the embodiment of the invention adopts a citrate buffer system, so that good preparation stability effect can be achieved. Especially, in the heat stability acceleration experiments of rAdC XY3-PreS adenovirus samples of the C1 group formula and the C3 group formula at 37 ℃ and 42 ℃, the drop of the virus titer value lgIFU/m is less than 0.5 in 14 days, the drop of the virus titer value lgIFU/mL is less than 1 in 28 days, the number of virus particles and the change of particle size are small, and the good stability effect is achieved.
Experimental example 4 preparation of rAdC XY3-PreS adenovirus formulations of different batches and stability experiments
To further confirm the formulation of the adenovirus formulations identified in experimental examples 1-3, the D1-D5 formulations were prepared as shown in table 14 with rAdC XY3-PreS chimpanzee adenovirus stock solution having an internal batch of PE20201026-1-B3, and were placed in 37 ℃ carbon dioxide incubator, sampled at days 0, 7, 14 and 28, and examined for changes in virus titer, changes in virus particle count, changes in particle size, and osmotic pressure of stock solution at various time points; and meanwhile, part of samples are frozen and thawed for 1 to 5 times at the temperature below minus 60 ℃ and at the room temperature respectively, sampling is carried out according to the times of freezing and thawing, and virus titer change, virus particle number change, specific activity and particle size change under different times of freezing and thawing are inspected.
Tables 14D1 to D5 adenovirus formulation ingredients
(1) Acceleration stability
The results of the accelerated stability test of the D1 to D5 group rAdC XY3-PreS adenovirus formulation samples at 37℃using the TCID50 method are shown in Table 15.
Tables 15D1 to D5 adenovirus formulation samples for thermal stability test at 37℃viral titres (lgTCID 50/mL)
Group of | 0d | 37℃7d | 37℃14d |
D1 | 7.83 | 7.87 | 7.63 |
D2 | 7.83 | 7.73 | 7.43 |
D3 | 7.93 | 7.90 | 7.83 |
D4 | 7.9 | 7.87 | 7.83 |
D5 | 7.97 | 7.77 | 7.47 |
As can be seen from table 15, the virus titer of the groups D1 to D5 did not change much after standing for 14 days at 37 ℃, indicating that the formulations of the experimental groups all had better stability. Wherein the change of the virus titer values (lgTCID 50/mL) of the D3 and D4 groups samples is less than 0.1, and the virus titer (lgTCID 50/mL) of the D5 group 14 days is reduced by 0.5. Compared with D1 and D4, the difference between D2 and D3 is only the buffer dosage, and further proves that the buffer with higher concentration has better effect on the stability of the preparation.
(2) Number of viral particles
The number of viral particles was measured for the D1 to D5 samples by OD 260 method, and the measurement results are shown in Table 16. After 28 days of standing at 37℃the number of chimpanzee adenovirus particles for the five formulations was in the range of 4.0E+11VP/mL to 6.0E+11VP/mL. The percentage change in particles ranged from 75% to 115% relative to the 0 day test results. As can be seen, the D1-D5 group samples were left at 37℃for 28 days without significant differences in particle count.
Tables 16D1 to D5 group virus particle count (OD 260)
(3) Particle size detection
The particle sizes of the D1 to D5 group samples were measured by DLS and the measurement results are shown in Table 17 after being left at 37℃for 0 day, 7 days, 14 days and 28 days. As can be seen from Table 17, the particle sizes of the other groups of samples, except the group D2, are not significantly changed, which indicates that the virus particles are not aggregated basically, and the stability is good.
Tables 17D1 to D5 sample particle size (nm) of adenovirus preparation
Group of | 0d | 37℃7d | 37℃14d |
D1 | 130.0 | 137.3 | 145.0 |
D2 | 119.8 | 135.3 | 1850.0 |
D3 | 123.9 | 124.8 | 124.5 |
D4 | 131.8 | 133.3 | 132.4 |
D5 | 119.3 | 117.1 | 118.3 |
(4) Osmotic pressure detection
The results of the osmolarity measurement of the samples of groups D1 to D5 are shown in table 18. The osmotic pressure of each group of samples is not more than 600 mOsmol/kg, and all the samples meet the general standards of injection in the field.
Tables 18D1 to D5 adenovirus formulation sample osmotic pressure
Group of | D4 | D3 | D5 | D1 | D2 |
Osmotic pressure (mOsmol/kg) | 587 | 522 | 233 | 510 | 417 |
(5) Freezing and thawing test
The effect of freeze thawing on adenovirus stability was examined for the formulations of groups D4 and D3, respectively, in terms of virus titer, virus particle number, specific activity (infection activity), and particle size change, and the results are shown in FIGS. 3 to 6. From FIGS. 3 to 6, it is clear that the virus titer value of the formulations of the group D4 and the group D3 does not change more than 0.2lgTCID 50/mL after repeated freeze thawing for 5 times, the number of virus particles changes less than 10%, and the particle sizes are stable (about 135nm and 123nm respectively). By calculation, the specific activity (VP/IFU) is in the range of 80 to 150, and the vast majority is in the range of 100 to 120. The results show that adenovirus in both the formulation formulations of D4 and D3 exhibited good stability during 5 freeze thawing.
In summary, formulations of adenovirus containing sucrose, tween 80, mannitol, glycine and citrate buffer salt system can maintain good stability, and stability is better when citrate buffer salt concentration is relatively high. Specifically, the chimpanzee adenovirus formulation samples of the D4 and D3 formulations showed good stability in the acceleration experiment at 14 days, the virus particle number and particle size change of the two samples at 28 days was small, the specific activity was in the range of 80 to 160, the osmotic pressure was also suitable, and good stability was exhibited during 5 freeze thawing. Meanwhile, the formula is verified to have better enhancing effect on the stability of the preparation when being suitable for adenovirus preparations in different batches.
Experimental example 5 preparation and stability of adenovirus formulations with different pH values
The difference between this experimental example 5 and the group D3 in experimental example 4 is only that the pH value is different, the total concentration of citrate is 60mM, and three different pH value groups (D3-a, D3-b, D3-c) are set in total: 5.9, 6.1 and 6.6. The formulations of each set are shown in table 19. Samples of the preparation of PE20201026-1-B3 lot rAdC XY3-PreS adenovirus were placed in biochemical chambers (apparatus No. PERD1702020& PERD 1711056) at 37℃or 42℃and sampled at days 0, 7, 14 and 28, respectively, and examined for changes in viral titer, viral particle count and particle size at each time point.
Table 19 table of formulations of adenovirus formulations at different pH
Remarks: refer to table 3 remarks.
The ICC method is used for detecting the virus titer obtained by the accelerated stability test of the D3-a, D3-b and D3-c samples at 42 ℃, the OD 260 method is used for detecting the number of virus particles of the samples, and the detection results are respectively shown in the table 20 and the table 21. As can be seen from tables 20 and 21, rAdC XY3-PreS adenoviruses had a change in virus titer (lgIFU/mL) of about 0.3 to 0.4 at 42℃for 7 days at three pH values (5.8 to 6.0,6.0 to 6.2,6.5 to 6.7), and had little difference at different pH values, and the number of virus particles did not significantly change between the three groups after 7 days at 42 ℃. The pH value is 5.8-6.7 based on the existing formula, and the chimpanzee adenovirus has better stability.
Table 20A list of changes in viral titers for accelerated experiments at 42℃for adenovirus formulations at different pH (lgIFU/mL)
Group of | D3-a | D3-b | D3-c |
pH | 5.9 | 6.1 | 6.6 |
0d | 9.36 | 9.47 | 9.45 |
42℃7d | 9.09 | 9.08 | 9.10 |
TABLE 21 detection results of the number of viral particles of adenovirus formulations at different pH (OD 260 method)
Group of | pH | Number of virus particles at 42℃for 7 days (VP/mL) |
D3-a | 5.9 | 3.10E+11 |
D3-b | 6.1 | 3.10E+11 |
D3-c | 6.6 | 3.04E+11 |
The invention discovers that the concentration of sugar compounds or sugar alcohols, a citrate buffer system, glycine and mannitol play a main role in the stability of recombinant adenovirus through preparation research. The liquid preparation formula containing adenovirus provided by the invention is stable in multiple freeze thawing cycles, and the possibility of stable storage at 2-8 ℃ also greatly reduces the storage and transportation cost of adenovirus vaccines, and has great value.
Experimental example 6 preparation and stability of adenovirus formulations containing different heterologous nucleic acid molecules
Formulations containing rAdC XY3-GFP, rADC68XY3-PreS, and rADC68XY3-S were prepared according to the formulations shown in Table 22.
Tables 22E1 to E3 sample components of preparations of three adenoviruses
Remarks: refer to table 3 remarks.
(1) Viral titer
The results of the 42℃and 37℃thermostability acceleration experiments for testing samples of the E1 to E3 groups containing different recombinant adenovirus formulations using the ICC method are shown in Table 23.
Tables 23A list of changes in viral titers for 37 ℃ C./42 ℃ C. Accelerated stability experiments for samples of groups E1 to E3 (ICC method, lgIFU/mL)
As can be seen from table 23, the samples of the E1 to E3 groups showed ideal stability in both the 37 ℃ accelerated stability test virus titer test and the 42 ℃ accelerated stability test virus titer test, wherein the samples of the E1 to E3 groups showed little change in virus titer in the 42 ℃ accelerated stability test virus titer test, and the virus titer at day 7 was less than 0.15 in terms of a decrease or increase in virus titer as compared to day 0.
The above detailed description of a pharmaceutical formulation comprising adenovirus, which is provided by the present application, applies specific examples herein to illustrate the principles and embodiments of the present application, the above examples being provided only to assist in understanding the methods of the present application and the core ideas thereof; meanwhile, as those skilled in the art will have variations in specific embodiments and application ranges in accordance with the ideas of the present application, the present description should not be construed as limiting the present application in view of the above.
Sequence listing
<110> Whanbo biotechnology Co., ltd
<120> Pharmaceutical preparation comprising adenovirus and method for preserving the same
<130> WHP220017CN
<141> 2022-01-28
<150> 202110181056.1
<151> 2021-02-09
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catcgttagg tttcctaata tcactaacct gtgcccattc ggagaagtgt ttaatgccac 1080
caggttcgcc agtgtctacg cttggaaccg caagaggatt tctaactgcg tcgccgacta 1140
ctcagtgctg tacaacagcg ctagtttctc cacattcaaa tgttacggag tgtctccaac 1200
caagctgaat gacctgtgtt tcactaacgt gtacgccgat agtttcgtta tcagaggcga 1260
cgaggtgcgc cagatcgctc ccggacagac tggcaaaatt gctgactaca actacaagct 1320
ccctgacgac ttcaccgggt gcgtgattgc atggaacagc aacaatctgg attccaaagt 1380
aggagggaat tataactacc tgtaccgcct ctttagaaag tccaacctga aaccctttga 1440
aagggatatt tccacagaga tctatcaggc cggctctacc ccttgtaacg gcgtggaggg 1500
ctttaattgt tactttcctc tgcagagcta tgggttccag ccaacaaatg gcgtgggcta 1560
tcagccatat agggtggtgg tgctgagttt cgaactcctg catgcccctg ctaccgtgtg 1620
cggccctaag aagtctacca atctggtgaa aaataagtgc gtgaacttta acttcaatgg 1680
cctgacagga accggcgtgc tgacagaaag caacaaaaag ttcctgcctt tccagcaatt 1740
cggcagagat atcgccgata ccactgacgc tgtgagagac ccccagaccc tggagattct 1800
cgacataaca ccctgctcct tcggcggagt gagcgtcatt acaccaggaa caaacacttc 1860
caatcaggtg gccgtgctgt atcaggatgt gaactgtaca gaggtgcctg tggcaatcca 1920
cgctgaccag ctgaccccaa cctggcgggt ttatagtaca ggtagtaatg tgtttcagac 1980
aagagccggt tgcctgattg gggccgaaca cgttaacaat tcttacgaat gtgacatccc 2040
tatcggagcc ggcatttgcg cctcctatca aacccagacc aacagcccag gaagtgctag 2100
cagcgtggct agtcagtcca tcatcgcata tactatgagt ctgggagccg agaatagcgt 2160
ggcctactcc aataacagca ttgccatccc aaccaatttt accatctctg tgaccactga 2220
gattctgcca gtgtcaatga ctaaaacctc agttgattgc acaatgtata tctgtggcga 2280
ctctaccgag tgctctaacc tgctcctgca gtatgggtct ttttgtaccc agctgaacag 2340
ggctctgacc ggaattgccg tggagcagga taaaaacact caagaggtgt tcgcacaggt 2400
gaagcagatc tataagactc cccctatcaa ggatttcgga ggcttcaact tcagccagat 2460
cctgcctgac ccatccaaac ccagcaagag atcctttatt gaagatctgc tgttcaacaa 2520
ggtgaccctc gccgacgccg gctttatcaa gcagtacggt gactgcctgg gggacattgc 2580
cgctagagat ctcatttgcg ctcagaagtt taacggcctg accgtgctgc caccactcct 2640
caccgatgag atgatcgccc agtatacttc tgccctgctg gctggcacca tcacctccgg 2700
atggaccttc ggcgccggcg cagcactgca gatcccattc gccatgcaga tggcttatcg 2760
cttcaatggg atcggcgtga cccagaatgt gctgtacgag aatcagaagc tgatcgccaa 2820
ccagtttaat agcgccatcg gaaagatcca ggacagcctg agcagcactg ccagcgctct 2880
gggcaagctc caggacgttg tgaaccagaa cgctcaggcc ctgaacactc tggtgaaaca 2940
gctgtcatcc aattttggag ccatcagttc agtcctgaat gatatcctgt ctagactgga 3000
cccacccgag gctgaggttc agatcgaccg gctgatcacc ggcagactgc agagcctcca 3060
gacttatgtg acccagcagc tgatcagggc cgccgagatt agagccagcg ccaacctcgc 3120
tgctaccaaa atgagcgagt gcgttctggg acagtctaag cgcgtggact tttgtgggaa 3180
aggataccac ctgatgagct ttcctcagag cgctcctcat ggcgtggtgt tcctgcacgt 3240
gacttatgtg cctgcccagg aaaagaactt cacaacggcc cctgccattt gtcacgacgg 3300
aaaggcccac ttcccacgcg aaggcgtgtt tgtgtctaat ggaactcact ggttcgtgac 3360
tcagagaaat ttctatgagc cacagattat cacaactgat aacacctttg tgagcgggaa 3420
ttgtgacgtg gttatcggca ttgtgaataa taccgtctat gaccccctgc agccagaact 3480
ggacagcttt aaggaagagc tggataagta cttcaagaac cacacatccc cagacgtgga 3540
tctgggggac atcagtggca tcaacgcctc tgtggtgaat atccagaagg agatcgatcg 3600
gctgaatgag gtggccaaga acctgaacga gtctctgatc gacctgcagg agctggggaa 3660
atacgagcag ggcggctaca tccctgaggc ccccagggac ggccaggcct acgtgaggaa 3720
ggacggcgag tgggtgctgc tgtccacctt cctgtagtga taaggtacc 3769
<210> 3
<211> 1285
<212> PRT
<213> Artificial sequence
<400> 3
Met Gly Lys Arg Ser Ala Gly Ser Ile Met Trp Leu Ala Ser Leu Ala
1 5 10 15
Val Val Ile Ala Cys Ala Gly Ala Ser Gln Cys Val Asn Leu Thr Thr
20 25 30
Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe Thr Arg Gly Val
35 40 45
Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu His Ser Thr Gln
50 55 60
Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp Phe His Ala Ile
65 70 75 80
His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro Val Leu
85 90 95
Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu Lys Ser Asn Ile
100 105 110
Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr Gln Ser
115 120 125
Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys Val Cys Glu
130 135 140
Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr Tyr His Lys Asn
145 150 155 160
Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn
165 170 175
Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu
180 185 190
Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn
195 200 205
Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Asn Leu
210 215 220
Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val Asp
225 230 235 240
Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala Leu
245 250 255
His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr Ala
260 265 270
Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe Leu
275 280 285
Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ala
290 295 300
Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr Val
305 310 315 320
Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr Glu
325 330 335
Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
340 345 350
Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
355 360 365
Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
370 375 380
Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
385 390 395 400
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
405 410 415
Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
420 425 430
Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
435 440 445
Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
450 455 460
Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
465 470 475 480
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
485 490 495
Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
500 505 510
Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
515 520 525
Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn
530 535 540
Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly
545 550 555 560
Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln
565 570 575
Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln
580 585 590
Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser
595 600 605
Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr
610 615 620
Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln
625 630 635 640
Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln
645 650 655
Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr
660 665 670
Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr
675 680 685
Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala Ser Gln Ser Ile
690 695 700
Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser
705 710 715 720
Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr
725 730 735
Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met
740 745 750
Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr
755 760 765
Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val
770 775 780
Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile
785 790 795 800
Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln
805 810 815
Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp
820 825 830
Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln
835 840 845
Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala
850 855 860
Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu
865 870 875 880
Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser
885 890 895
Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met
900 905 910
Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu
915 920 925
Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly
930 935 940
Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu
945 950 955 960
Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys
965 970 975
Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile
980 985 990
Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu
995 1000 1005
Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu
1010 1015 1020
Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys
1025 1030 1035 1040
Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly
1045 1050 1055
Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val
1060 1065 1070
Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr
1075 1080 1085
Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu
1090 1095 1100
Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn
1105 1110 1115 1120
Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly
1125 1130 1135
Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro
1140 1145 1150
Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe
1155 1160 1165
Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile
1170 1175 1180
Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1185 1190 1195 1200
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly
1205 1210 1215
Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe
1220 1225 1230
Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys
1235 1240 1245
Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser
1250 1255 1260
Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val
1265 1270 1275 1280
Lys Leu His Tyr Thr
1285
<210> 4
<211> 3858
<212> DNA
<213> Artificial sequence
<400> 4
atgggcaaga ggtccgccgg cagcatcatg tggctggcct ccctggccgt cgtgattgcc 60
tgcgccggcg cttctcagtg tgtgaatctg acaacacgga cccagctgcc tcccgcctat 120
accaactcct tcaccagggg ggtgtactac cctgataagg tgtttcggtc atctgtgctg 180
catagcaccc aggatctgtt cctgcccttc tttagcaacg tgacttggtt ccacgccatc 240
cacgtgagtg gcacaaatgg aaccaagagg ttcgacaatc ctgtgctgcc tttcaacgac 300
ggagtgtact tcgccagcac tgaaaagtcc aatatcatta ggggctggat ctttggcaca 360
accctggact ccaaaaccca gtccctgctg atcgtgaaca acgccaccaa cgttgtgatt 420
aaggtgtgtg agtttcagtt ttgcaatgac cccttccttg gcgtgtatta tcataagaat 480
aataagtctt ggatggagtc tgagttcaga gtgtactcct cagccaataa ttgcaccttc 540
gaatacgtga gccagccatt cctgatggat ctggagggta aacagggcaa ttttaagaac 600
ctgcgcgaat ttgtgtttaa gaatattgat ggatatttca agatctactc taaacatacc 660
cccatcaatc tcgtgagaga tctgccacag ggctttagcg ccctggaacc actcgtggac 720
ctgccaatcg gcatcaatat tacacggttc cagacccttc tggccctgca tcggtcttac 780
ctgacccctg gcgatagttc ctccggctgg actgccgggg ccgccgccta ttacgtggga 840
tacctgcagc ccaggacatt tctcctgaaa tataatgaga acggcaccat caccgacgca 900
gtggattgtg ctctggaccc actgtccgag accaaatgca cactgaagtc tttcacagtg 960
gagaaaggca tctatcagac ttccaacttt cgcgttcagc ccacagagag catcgttagg 1020
tttcctaata tcactaacct gtgcccattc ggagaagtgt ttaatgccac caggttcgcc 1080
agtgtctacg cttggaaccg caagaggatt tctaactgcg tcgccgacta ctcagtgctg 1140
tacaacagcg ctagtttctc cacattcaaa tgttacggag tgtctccaac caagctgaat 1200
gacctgtgtt tcactaacgt gtacgccgat agtttcgtta tcagaggcga cgaggtgcgc 1260
cagatcgctc ccggacagac tggcaaaatt gctgactaca actacaagct ccctgacgac 1320
ttcaccgggt gcgtgattgc atggaacagc aacaatctgg attccaaagt aggagggaat 1380
tataactacc tgtaccgcct ctttagaaag tccaacctga aaccctttga aagggatatt 1440
tccacagaga tctatcaggc cggctctacc ccttgtaacg gcgtggaggg ctttaattgt 1500
tactttcctc tgcagagcta tgggttccag ccaacaaatg gcgtgggcta tcagccatat 1560
agggtggtgg tgctgagttt cgaactcctg catgcccctg ctaccgtgtg cggccctaag 1620
aagtctacca atctggtgaa aaataagtgc gtgaacttta acttcaatgg cctgacagga 1680
accggcgtgc tgacagaaag caacaaaaag ttcctgcctt tccagcaatt cggcagagat 1740
atcgccgata ccactgacgc tgtgagagac ccccagaccc tggagattct cgacataaca 1800
ccctgctcct tcggcggagt gagcgtcatt acaccaggaa caaacacttc caatcaggtg 1860
gccgtgctgt atcaggatgt gaactgtaca gaggtgcctg tggcaatcca cgctgaccag 1920
ctgaccccaa cctggcgggt ttatagtaca ggtagtaatg tgtttcagac aagagccggt 1980
tgcctgattg gggccgaaca cgttaacaat tcttacgaat gtgacatccc tatcggagcc 2040
ggcatttgcg cctcctatca aacccagacc aacagcccac ggcgggctcg gagcgtggct 2100
agtcagtcca tcatcgcata tactatgagt ctgggagccg agaatagcgt ggcctactcc 2160
aataacagca ttgccatccc aaccaatttt accatctctg tgaccactga gattctgcca 2220
gtgtcaatga ctaaaacctc agttgattgc acaatgtata tctgtggcga ctctaccgag 2280
tgctctaacc tgctcctgca gtatgggtct ttttgtaccc agctgaacag ggctctgacc 2340
ggaattgccg tggagcagga taaaaacact caagaggtgt tcgcacaggt gaagcagatc 2400
tataagactc cccctatcaa ggatttcgga ggcttcaact tcagccagat cctgcctgac 2460
ccatccaaac ccagcaagag atcctttatt gaagatctgc tgttcaacaa ggtgaccctc 2520
gccgacgccg gctttatcaa gcagtacggt gactgcctgg gggacattgc cgctagagat 2580
ctcatttgcg ctcagaagtt taacggcctg accgtgctgc caccactcct caccgatgag 2640
atgatcgccc agtatacttc tgccctgctg gctggcacca tcacctccgg atggaccttc 2700
ggcgccggcg cagcactgca gatcccattc gccatgcaga tggcttatcg cttcaatggg 2760
atcggcgtga cccagaatgt gctgtacgag aatcagaagc tgatcgccaa ccagtttaat 2820
agcgccatcg gaaagatcca ggacagcctg agcagcactg ccagcgctct gggcaagctc 2880
caggacgttg tgaaccagaa cgctcaggcc ctgaacactc tggtgaaaca gctgtcatcc 2940
aattttggag ccatcagttc agtcctgaat gatatcctgt ctagactgga caaagtcgag 3000
gctgaggttc agatcgaccg gctgatcacc ggcagactgc agagcctcca gacttatgtg 3060
acccagcagc tgatcagggc cgccgagatt agagccagcg ccaacctcgc tgctaccaaa 3120
atgagcgagt gcgttctggg acagtctaag cgcgtggact tttgtgggaa aggataccac 3180
ctgatgagct ttcctcagag cgctcctcat ggcgtggtgt tcctgcacgt gacttatgtg 3240
cctgcccagg aaaagaactt cacaacggcc cctgccattt gtcacgacgg aaaggcccac 3300
ttcccacgcg aaggcgtgtt tgtgtctaat ggaactcact ggttcgtgac tcagagaaat 3360
ttctatgagc cacagattat cacaactgat aacacctttg tgagcgggaa ttgtgacgtg 3420
gttatcggca ttgtgaataa taccgtctat gaccccctgc agccagaact ggacagcttt 3480
aaggaagagc tggataagta cttcaagaac cacacatccc cagacgtgga tctgggggac 3540
atcagtggca tcaacgcctc tgtggtgaat atccagaagg agatcgatcg gctgaatgag 3600
gtggccaaga acctgaacga gtctctgatc gacctgcagg agctggggaa atacgagcag 3660
tatatcaagt ggccctggta catctggctg gggtttatcg ctggactgat tgctatcgtg 3720
atggtgacca tcatgctgtg ttgcatgact agctgctgta gctgcctgaa gggatgttgc 3780
agctgcggca gctgctgtaa gttcgatgag gacgactctg agccagtgct gaaaggcgtg 3840
aaactgcact acacctag 3858
<210> 5
<211> 239
<212> PRT
<213> Artificial sequence
<400> 5
Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu
1 5 10 15
Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly
20 25 30
Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile
35 40 45
Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr
50 55 60
Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys
65 70 75 80
Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu
85 90 95
Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu
100 105 110
Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly
115 120 125
Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr
130 135 140
Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn
145 150 155 160
Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser
165 170 175
Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly
180 185 190
Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu
195 200 205
Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe
210 215 220
Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
225 230 235
<210> 6
<211> 720
<212> DNA
<213> Artificial sequence
<400> 6
atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 60
ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 120
ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 180
ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 240
cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 300
ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 360
gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 420
aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 480
ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 540
gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 600
tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 660
ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 720
Claims (9)
1. A pharmaceutical formulation, characterized in that it consists of, based on the total volume of the pharmaceutical formulation:
(a) Recombinant adenovirus;
(b) Citrate buffer 60 mM to 140 mM;
(c) Nonionic surfactant v/v 0.01% to 1%;
(d) 4.4 to 9% of protective agent w/v;
(e) Glycine w/v 0.5% to 1%; and
(F) Mannitol w/v 0.5% to 1%;
Wherein the protective agent is selected from one or more of sucrose, trehalose or lactose; the pharmaceutical formulation is a liquid formulation having a pH of 5.8 to 6.6.
2. The pharmaceutical formulation of claim 1, wherein the recombinant adenovirus is rAdC XY3-PreS adenovirus or rAdC XY3-S adenovirus; wherein the rAdC XY3-PreS adenovirus comprises a nucleic acid molecule encoding a PreS protein of SARS-CoV-2, and the nucleic acid molecule encoding the PreS protein of SARS-CoV-2 comprises a nucleotide sequence as shown in SEQ ID NO. 2; the rAdC XY3-S adenovirus comprises a nucleic acid molecule encoding the full-length S protein of SARS-CoV-2, and the nucleic acid molecule encoding the full-length S protein of SARS-CoV-2 comprises a nucleotide sequence as shown in SEQ ID NO. 4.
3. The pharmaceutical formulation of claim 1, wherein the nonionic surfactant is polysorbate.
4. A pharmaceutical formulation according to claim 3, wherein the non-ionic surfactant is polysorbate 80.
5. The pharmaceutical formulation of any one of claims 1 to 4, wherein the recombinant adenovirus has a titer ranging from 7.0 lgIFU/mL to 12.0 lgIFU/mL.
6. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the pharmaceutical formulation is a nasal spray formulation, a nasal drip formulation, an aerosol inhalation formulation, an intramuscular injection formulation, a subcutaneous injection formulation, or an oral formulation.
7. A method of preserving a pharmaceutical formulation comprising an adenovirus, comprising: storing a pharmaceutical formulation as claimed in any one of claims 1 to 6 at a temperature of-60 ℃ to 37 ℃.
8. The method of preserving a pharmaceutical formulation containing an adenovirus according to claim 7, wherein said pharmaceutical formulation is stored at a temperature of from 0 ℃ to 25 ℃.
9. The method of preserving a pharmaceutical formulation containing an adenovirus according to claim 8, wherein said pharmaceutical formulation is stored at a temperature of from 2 ℃ to 8 ℃.
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