CN113121651B - Low neutralizing antibody adeno-associated virus capsid proteins - Google Patents
Low neutralizing antibody adeno-associated virus capsid proteins Download PDFInfo
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- CN113121651B CN113121651B CN202110419578.0A CN202110419578A CN113121651B CN 113121651 B CN113121651 B CN 113121651B CN 202110419578 A CN202110419578 A CN 202110419578A CN 113121651 B CN113121651 B CN 113121651B
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Classifications
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- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
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- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
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Abstract
The present invention relates to AAV capsid proteins, nucleic acid molecules encoding the capsid proteins, vectors comprising the capsid proteins, and medicaments comprising the vectors. The AAV vector of the invention has high solidity and can avoid neutralizing antibodies to a certain extent, and can be used as a delivery vector of therapeutic genes for treating various diseases.
Description
Technical Field
The present disclosure is in the field of gene therapy technology. In particular, the disclosure relates to novel adeno-associated virus (AAV) capsid proteins, nucleic acid molecules encoding the novel AAV capsid proteins. The present disclosure also relates to novel AAV vectors that are high in solids rate and are capable of circumventing neutralizing antibodies to some extent, and medicaments comprising the novel AAV vectors comprising the novel AAV capsid proteins.
Background
In recent years, gene therapy has been vigorously developed. Adeno-associated virus (AAV) has high transduction efficiency, long-term therapeutic effect and low pathogenicity in various organ tissues as a very promising vector in therapeutic gene delivery, which makes AAV vectors remarkably advantageous in the field of gene therapy (reference 1).
AAV vectors consist of a protein capsid and a transgene expression cassette carrying the gene of interest. AAV capsids are assembled from 60 capsid proteins, with a defined shape and structure. The intracellular proportion of the three proteins (VP 1, VP2 and VP 3) that make up the AAV capsid building block may fluctuate widely due to various factors, and post-translational modifications of specific capsid proteins may vary. These complex changes result in an increased probability of forming a empty AAV vector. The empty AAV vector does not carry the gene of interest and consists only of AAV protein capsids of a specific serotype. The therapeutic efficiency is closely related to the genetic material content of AAV vectors. Thus, the presence of a empty AAV vector may result in an increase in the required dose of AAV virus for medical applications, and may elicit an immune response against the vector capsid, resulting in unwanted side effects.
In addition, immune responses (e.g., neutralizing antibodies) against AAV deplete AAV capsids and transgene products, resulting in poor therapeutic efficacy (reference 2).
Therefore, in order to achieve better therapeutic effects, to increase the transduction capacity and potency of AAV vectors, it is desirable to suitably engineer AAV capsid proteins to obtain adeno-associated viral vectors with high real heart rates. In particular, it is desirable to obtain adeno-associated viral vectors which have a high solids content and which are capable of circumventing neutralizing antibodies to some extent.
Reference is made to:
1.Li et al.,Nat Rev Genet(2020)21:255-272
2.Zhang et al.,Hum Gene Ther(2020)31(7-8):448-458
disclosure of Invention
As a result of extensive studies, the inventors have found that novel AAV (e.g. AAV 5) capsid proteins can be obtained by replacing 1-10 amino acids (e.g. aa 573-579) of the variable region (e.g. VRVIII) of an AAV (e.g. AAV 5) capsid protein with a synthetic oligopeptide "QTLGFSQGGPNT". The novel AAV vector packaged by the novel AAV capsid protein has high solidity and can avoid neutralizing antibodies to a certain extent, and can be applied to the prevention, diagnosis and treatment of various diseases.
Thus, in a first aspect, the present disclosure provides a novel adeno-associated virus (AAV) capsid protein constructed by replacing 1-10 amino acids of the variable region VRVIII of the AAV capsid protein with an oligopeptide QTLGFSQGGPNT.
The adeno-associated virus (AAV) may be selected from any AAV serotype. Examples of AAV serotypes include native AAV (e.g., native AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV-DJ8, AAV-DJ9, AAVrh8R, AAVrh10, avian AAV, bovine AAV, canine AAV, equine AAV, and ovine AAV) and other artificially engineered AAV (e.g., artificially engineered AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV-DJ8, AAV-DJ9, AAVrh8R, AAVrh, avian AAV, bovine AAV, canine AAV, equine AAV, and ovine AAV), preferably AAV5.
In a preferred embodiment, the novel AAV capsid proteins described above are constructed by replacing aa573-579 of the variable region VRVIII of the AAV5 capsid protein with an oligopeptide QTLGFSQGGPNT.
In a preferred embodiment, the amino acid sequence of the novel AAV capsid protein described above hybridizes with SEQ ID NO:1, preferably the amino acid sequence of the novel AAV capsid protein has at least 95% identity to the amino acid sequence of SEQ ID NO:1 has at least 96%, 97%, 98%, 99% or 100% identity. In a more preferred embodiment, the novel AAV capsid protein comprises SEQ ID NO:1, and a polypeptide having the amino acid sequence shown in 1. In a more preferred embodiment, the amino acid sequence of the novel AAV capsid protein is set forth in SEQ ID NO: 1.
In a second aspect, the present disclosure provides a nucleic acid molecule encoding the novel AAV capsid proteins described above.
In a preferred embodiment, the nucleotide sequence of the above nucleic acid molecule hybridizes with the nucleotide sequence of SEQ ID NO:2, preferably the nucleotide sequence of the above-mentioned nucleic acid molecule has at least 95% identity to the nucleotide sequence shown in SEQ ID NO:2 has at least 96%, 97%, 98%, 99% or 100% identity.
In a preferred embodiment, the above nucleic acid molecule comprises SEQ ID NO:2, and a nucleotide sequence shown in the following formula. In a more preferred embodiment, the nucleotide sequence of the above nucleic acid molecule is as set forth in SEQ ID NO: 2.
In a third aspect, the present disclosure provides a novel AAV vector comprising the novel AAV capsid protein described above.
In a preferred embodiment, the novel AAV vector described above further comprises a heterologous polynucleotide comprising a nucleotide sequence encoding a therapeutic protein. In a preferred embodiment, the novel AAV vector described above further comprises a viral genome, which may be a native AAV genome or a recombinant viral genome comprising a heterologous nucleic acid, which viral genome may encode a reporter protein, a native protein, a recombinant protein, an antigen, an antibody, and/or a polymeric oligonucleotide element (shRNA, miRNA) for use in nucleotide interference (RNAi) treatment, or the like.
In a preferred embodiment, the heterologous nucleic acid encodes one or more mammalian proteins, or is a sequence of an RNAi component (e.g., shRNA, siRNA, antisense oligonucleotide). In another preferred embodiment, the heterologous nucleic acid encodes a protein sequence of certain antibodies, antigens, synthetic proteins or polypeptides.
In a fourth aspect, the present disclosure provides the use of the novel AAV vector described above in the manufacture of a medicament for treating a disease.
In a fifth aspect, the present disclosure provides a medicament comprising the novel AAV vector described above and an agent that can render the viral vector ready for use.
In one embodiment, the agents that can render the viral vector into a drug include salts, organics, and surfactants.
In one embodiment, the above-described drugs are administered by systemic or local routes, such as by intravenous, intramuscular, subcutaneous, oral, topical contact, intraperitoneal and intralesional administration.
In a sixth aspect, the present disclosure provides a method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of the above-described medicament.
Drawings
FIG. 1 illustrates a method of screening candidate AAV capsid proteins.
Fig. 2 is a schematic diagram of AAVz 84. AAVz84 is obtained by replacing aa573-579 of the variable region VRVIII of the AAV5 capsid protein with oligopeptide QTLGFSQGGPNT, the amino acid sequence of which is shown in FIG. 2.
FIG. 3 shows 5X10 quantified by qPCR and silver staining 7 Titer of AAV (wild-type AAV5, AAV8 and AAV9; AAVz 84) particles produced by individual cells (culture medium+lysate), and real heart rate of AAV viral particles. Data are shown as mean ± SD, n=3.
FIG. 4 shows the amino acid sequence of AAVz84 capsid protein (SEQ ID NO: 1).
FIG. 5 shows the nucleic acid sequence encoding AAVz84 capsid protein (SEQ ID NO: 2).
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this document, the terms "comprising," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to").
The terms "patient" and "subject" are used interchangeably herein and in their conventional sense to refer to an organism suffering from or susceptible to a condition that can be prevented or treated by administration of the medicaments of the present disclosure, and include humans and non-human animals.
In one embodiment, the subject is a non-human animal (e.g., chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds including poultry, wild birds and game birds such as chickens, turkeys and other chickens, ducks, geese, etc.). In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.
Herein, the term "treatment" includes: (1) Inhibiting a condition, disease, or disorder, i.e., arresting, reducing, or delaying the progression of the disease or its recurrence or the progression of at least one clinical or sub-clinical symptom thereof; or (2) alleviating the disease, i.e., causing regression of at least one of the condition, disease, or disorder, or a clinical or subclinical symptom thereof.
As used herein, the term "therapeutically effective amount" refers to a dose that produces the therapeutic effect to which it is administered.
In this context, the term "improvement" refers to an improvement in a symptom associated with a disease, and may refer to an improvement in at least one parameter that measures or quantifies the symptom.
Herein, the term "preventing" a condition, disease, or disorder includes: preventing, delaying or reducing the incidence and/or likelihood of the occurrence of at least one clinical or subclinical symptom of a condition, disease or disorder developing in a subject who may have or be susceptible to the condition, disease or disorder but who has not yet experienced or exhibited the clinical or subclinical symptom of the condition, disease or disorder.
Herein, the term "topical administration" or "topical route" refers to administration having a local effect.
As used herein, the term "vector" refers to a macromolecule or series of macromolecules that encapsulate a polynucleotide, which facilitates delivery of the polynucleotide into a target cell in vitro or in vivo. The classification of vectors includes, but is not limited to, plasmids, viral vectors, liposomes, and other gene delivery vectors. Polynucleotides to be delivered are sometimes referred to as "transgenes" and include, but are not limited to, coding sequences for certain proteins or synthetic polypeptides that can enhance, inhibit, attenuate, protect, trigger or prevent certain biological and physiological functions, coding sequences of interest in vaccine development (e.g., polynucleotides expressing proteins, polypeptides or peptides suitable for eliciting an immune response in a mammal), coding sequences of RNAi components (e.g., shRNA, siRNA, antisense oligonucleotides), or selectable markers.
As used herein, the term "immune response" refers to the process in which host tissues and cells participate after encountering immunogens such as AAV capsid proteins and transgenes. It involves proliferation, migration and differentiation of immunocompetent cells (e.g., T lymphocytes, B cells, monocytes, macrophages) in the lymphatic reticulum, blood, spleen, or other related tissues, resulting in the production of antibodies or the development of cell-mediated reactivity. In other words, the host induces an active immune response upon exposure to the immunogen through infection or vaccination. Active immunization is obtained by "transferring preformed substances (e.g., antibodies, transfer factors, thymus grafts, interleukin-2)" from an immunized or non-immunized host, while passive immunization is not.
As used herein, the term "mosaic" AAV capsid nucleic acid coding sequence or capsid protein refers to an AAV capsid sequence that is designed and engineered artificially by methods of DNA shuffling, error-prone PCR, and site-directed mutagenesis.
As used herein, the terms "transduction," "transfection," and "transformation" refer to the process by which a heterologous polynucleotide is delivered to a host cell for transcription and translation to produce a polypeptide product, including the use of recombinant viruses to introduce the heterologous polynucleotide into the host cell.
As used herein, the term "gene delivery" refers to the introduction of heterologous polynucleotides into a cell for gene delivery, including targeting, binding, uptake, transport, replicon integration, and expression.
As used herein, the term "gene expression" or "expression" refers to the process by which transcription, translation, and post-translational modification of a gene produce an RNA or protein product of the gene.
As used herein, the term "infection" refers to the process by which a virus or viral particle comprising a polynucleotide component delivers a polynucleotide into a cell and produces its RNA and protein products, as well as the replication process of the virus in a host cell.
Herein, the term "polypeptide" refers to a polymer of at least 20 amino acids linked by peptide bonds. The terms "polypeptide" and "protein" are synonymously referred to herein as polymers consisting of more than 20 amino acids. The term also includes synthetic amino acid polymers.
As used herein, the term "polynucleotide" or "nucleic acid" refers to polymeric forms of nucleotides of any length, including deoxynucleotides, ribonucleotides, hybrid sequences thereof, and the like. Polynucleotides may include modified nucleotides, such as methylated or capped nucleotides or nucleotide analogs.
In this context, the term "recombinant" in relation to a polynucleotide means that the polynucleotide is a synthetic product obtained by multiple cloning steps, different from the natural polynucleotide. Recombinant viruses are viral particles comprising recombinant polynucleotides.
Herein, the nucleic acid sequence is in single stranded form, oriented 5'-3' from left to right. The nucleic acid sequences and amino acid sequences referred to herein refer to the forms recommended by the IUPACIUB biochemical nomenclature committee. The amino acid sequence is in single letter symbol or three letter symbol.
In one embodiment, the present disclosure provides a novel AAV5 capsid protein constructed by replacing aa573-579 of the variable region VRVIII of AAV5 capsid protein with oligopeptide QTLGFSQGGPNT. As an example of a novel AAV5 capsid protein, the amino acid sequence of AAVz84 capsid protein is set forth in SEQ ID NO:1, the nucleotide sequence of the nucleic acid molecule encoding AAVz84 is set forth in SEQ ID NO: 2.
It is known to those skilled in the art that AAV capsid proteins contain VP1, VP2 and VP3 proteins, with VP2 and VP3 proteins undergoing transcription and translation processes at the start codon within the VP1 protein, i.e., the VP1 sequence comprises VP2 and VP3 sequences. The present disclosure provides the amino acid sequence of VP1 protein of AAVz84 capsid (SEQ ID NO: 1).
In one embodiment, the disclosure provides another novel AAV capsid protein constructed by replacing 1-10 amino acids of the variable region VRVIII of the AAV capsid with an oligopeptide having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or 100%) identity to "QTLGFSQGGPNT". In one embodiment, the AAV capsid protein may be any AAV serotype capsid protein, including native AAV capsid proteins (e.g., capsid proteins of native AAV type 1-11, avian AAV, bovine AAV, canine AAV, equine AAV, and ovine AAV) and other engineered AAV capsid proteins (e.g., capsid proteins of engineered AAV type 1-11, avian AAV, bovine AAV, canine AAV, equine AAV, and ovine AAV). Genomic sequences, ITR sequences, rep and Cap proteins of different AAV serotypes are known in the art. These sequences may be found in the literature or in public databases, such as the GenBank database.
Conservative substitutions of amino acids are known in the art. In one embodiment, the AAV capsid proteins of the present disclosure may undergo conservative substitutions of amino acids in the same group as: a) Glycine and alanine; b) Valine, isoleucine, leucine and proline; c) Aspartic acid and glutamic acid; d) Asparagine and glutamine; e) Serine, threonine lysine, arginine and histidine; f) Phenylalanine, tryptophan and tyrosine; g) Methionine and cysteine. In some embodiments, non-conservative substitutions between the different groups of amino acids described above are also permissible.
In one embodiment, an AAV vector of the present disclosure can be loaded with a heterologous polynucleotide for delivering a gene into a target cell. Thus, AAV vectors of the present disclosure can be used to deliver nucleic acids to cells in vitro or in vivo.
In one embodiment, the heterologous polynucleotide delivered by the AAV vector encodes a polypeptide that acts as a reporter (i.e., a reporter protein). Reporter proteins are used to indicate cells that are successfully infected with AAV. Such reporter proteins include, but are not limited to, green fluorescent protein, beta-galactosidase, alkaline phosphatase, luciferase, and chloramphenicol acetyl transferase.
In one embodiment, the heterologous polynucleotide delivered to the target cell by the AAV vector encodes a native protein for therapeutic use, which native protein is codon optimized or non-codon optimized.
In one embodiment, the heterologous polynucleotide delivered to the target cell by the AAV vector encodes a synthetic polypeptide including, but not limited to, afiibrecept, various recombinant interleukins (e.g., interleukin-1 and interleukin-18), TNF- α antagonistic soluble receptor, activin type II soluble receptor, anti-VEGF antibody, anti-sclerostin antibody, anti-RANKL antibody, anti-C5 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-CGRP antibody, anti-HER 2 antibody, anti-EGFR antibody, antibodies to pro-inflammatory cytokines, and receptors thereof.
In one embodiment, the heterologous polynucleotide delivered by the AAV vector may consist of RNAi components (e.g., siRNA, shRNA, snRNA, microRNA, ribozymes, antisense oligonucleotides, and antisense polynucleotides) that can knock down any endogenous genes that are activated in an aberrant manner or heterologous genes that invade the host cell, e.g., viral or bacterial polynucleotides known in the art. The RNAi component typically has 60-100% identity in sequence to its target gene and results in at least a 30% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%) reduction in the corresponding protein product.
In one embodiment, the heterologous polynucleotide delivered by the AAV vector comprises regulatory sequences, such as a transcription/translation control signal, an origin of replication, a polyadenylation signal, an Internal Ribosome Entry Site (IRES) or 2A signal (e.g., P2A, T2A, F a), a promoter and an enhancer (e.g., a CMV promoter or other hybrid CMV promoter with vertebrate β -actin, β -globulin, or β -globulin regulatory elements, an EF1 promoter, ubiquitin promoter, T7 promoter, SV40 promoter, VP16, or VP64 promoter). The use of promoters and enhancers depends on their tissue-specific expression profile. Promoters/enhancers may also be induced by chemicals or hormones (e.g., doxycycline or tamoxifen), depending on the need to trigger gene expression at the desired time point. Furthermore, the promoter/enhancer may be a natural sequence or a synthetic sequence, i.e. a prokaryotic or eukaryotic sequence.
In one embodiment, the inducible regulatory element for gene expression may be a tissue-specific or tissue-philic promoter/enhancer element.
In one embodiment, an AAV vector of the present disclosure comprises an AAV capsid protein and a viral genome, which may be a native AAV genome or a recombinant vector of a heterologous polynucleotide for therapeutic purposes. In one embodiment, the heterologous polynucleotide encodes a mammalian protein or RNAi component (e.g., shRNA, siRNA, antisense oligonucleotide). In one embodiment, the heterologous polynucleotide encodes the amino acid sequence of certain antibodies, antigens, synthetic proteins, or polypeptides.
In one embodiment, the translation product of the viral genome will enhance, inhibit, attenuate, protect, trigger or prevent one or more endogenous signal pathways involved in metabolic regulation and health maintenance in a mammal.
In one embodiment, AAV viral particles of the present disclosure can be administered to a host cell in vitro, and then the cell is implanted into a subject. Thus, the heterologous nucleic acid packaged in the virus is introduced into the subject by the cell for transcription and/or translation, producing a protein or RNA product that is secreted from the cell into the subject or that modulates the biological activity of the host cell, thereby acting therapeutically.
In one embodiment, the AAV vectors of the present disclosure are administered to a human or other mammal in a pharmaceutical formulation (e.g., injection, tablet, capsule, powder). The pharmaceutical formulation may also contain other ingredients such as pharmaceutical excipients, water-soluble or organic solvents (e.g. water, glycerol, ethanol, methanol, isopropanol, chloroform, phenol or polyethylene glycol), salts (e.g. sodium chloride, potassium chloride, phosphate, acetate, bicarbonate, tris-HCl and Tris-acetate), dissolution delaying agents (e.g. paraffin), surfactants, antimicrobial agents, liposomes, lipid complexes, immunosuppressants (e.g. cortisone, prednisone, cyclosporine), non-steroidal anti-inflammatory drugs (NSAIDs such as aspirin, ibuprofen, acetaminophen) microspheres, hard matrices, semi-solid carriers, nanospheres or nanoparticles. AA in pharmaceutical formulationsThe titer of the V particles may be 10 5 -10 14 vg/mL. Furthermore, AAV may be delivered in single or multiple doses by inhalation, systemic or local (e.g., intravenous, subcutaneous, parenteral, intramuscular, intraventricular, oral, intraperitoneal, and intrathecal) administration.
In one embodiment, the present disclosure provides a medicament comprising an AAV vector of the present disclosure and an agent (e.g., salts, organics, and surfactants) that can render the AAV vector into a medicament. Drugs can be used to transduce cells in vitro or transduce mammals in vivo (e.g., rodents, primates, and humans) to treat a variety of diseases.
In one embodiment, the disclosure relates to a method of producing an AAV vector from a cell. The cells support efficient transfection of plasmids encoding AAV Rep/Cap proteins, helper genes, and recombinant vectors encoding native viral genomes or heterologous proteins. AAV vectors of the present disclosure can be produced from HEK293 cells using three plasmid transfection methods well known to those skilled in the art. For example, AAV vectors of the present disclosure are produced by co-transfecting a forward plasmid encoding a GFP-like recombinant protein, an AAV Rep/Cap plasmid, a pHelper plasmid into HEK293 cells.
Standard methods well known to those skilled in the art can be used to produce polypeptides, antibodies or antigen binding fragments; altering the nucleic acid sequence; producing transformed cells; constructing a recombinant AAV vector; modifying capsid proteins; packaging a vector expressing AAV Rep and Cap sequences; transient transfection and stable transfection of packaging cells.
The present disclosure is described in further detail below with reference to the drawings and examples. The following examples are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure. The experimental procedure, in which specific conditions are not specified in the examples, is performed according to conventional conditions known in the art or according to conditions recommended by the manufacturer.
Examples
Example 1: engineering and screening AAV
As shown in fig. 1: first, engineered AAV libraries and helper plasmids were transfected into HEK293 cells. Next, HEK293 cell lysates containing AAV were added to the cultured C2C12 myoblasts along with Ad5 (adenovirus type 5). Cell lysates were enriched and C2C12 cells were repeatedly infected 4-5 times. The viral genomic bands of candidate AAV capsids were enriched and sequenced by PCR on C2C12 cell lysates. By screening, serotype sequences with high enrichment were selected to give serotype mutants AAVz84 (fig. 2).
AAVz84 particles were purified by AAVX (Thermo Scientific) affinity chromatography plus iodixanol ultracentrifugation and concentrated to 200-500 μl for the next experiment to determine the solids fraction of the carrier and the positive serum ratio of neutralizing antibodies.
Example 2: yield and solidity of AAVz84
Purification by affinity chromatography plus iodixanol ultracentrifugation to give a 5X10 fraction 7 AAV (AAVz 84, AAV5, AAV8, and AAV 9) viral particles produced in the individual cells. The virus particles were then diluted 10000-fold, digested with DNase I for 1 hour at 37 ℃, and left at 100 ℃ for 10 minutes to inactivate DNase I. The viral yields were quantified by qPCR and silver staining experiments. Next, 6 titer gradients (1X 10) diluted 10-fold with AAV8 virus standard of known titer 10 、1x10 9 、1x10 8 、1x10 7 、1x10 6 、1x10 5 vg/ml) is used as a standard substance, and the ratio of qPCR quantitative results to silver staining quantitative results is calculated to obtain the solid rate of AAV. As shown in fig. 3, qPCR quantified the number of solid AAVz84 viral genomes produced by HEK293 cells was comparable to wild type AAV5, 8, 9, indicating that substitution of synthetic oligopeptides did not negatively affect viral production. Furthermore, figure 3 shows that the filled rate of AAVz84 viral particles is significantly higher than wild-type AAV5, 8, 9. It can be seen that AAVz84 has a relatively high solids rate.
Example 3: positive serum ratio of neutralizing antibody of AAVz84
Determination of neutralizing antibody titre: huh7 cells were isolated at 5X10 4 The density of individual/wells was seeded on 48-well plates. Monkey sera numbered 1-10 were serially diluted 4-fold in a gradient from 1:1 and 5x10 9 vg AAV mix, serum-virus mix was left at 4℃for 1 hourWhen (1). Then, the serum-virus mixture and host were added to Huh7 cells and incubated at 37℃for 2 hours. Then, 10% FBS+DMEM serum was replaced, and 48 hours later, the virus-expressed Luciferase activity was measured with a microplate reader. The corresponding serum dilution when the Luciferase activity was reduced by half compared to the negative control serum group was the neutralizing antibody titer (as shown in table 1 below), and titers of less than or equal to 1:4 were the neutralizing antibody positive serum.
TABLE 1 neutralizing antibody titre
Monkey number | AAV2 | AAV9 | AAVz84 |
1 | 1:4 | <1:1 | <1:1 |
2 | 1:8 | <1:1 | <1:1 |
3 | <1:1 | <1:1 | <1:1 |
4 | 1:4 | <1:1 | <1:1 |
5 | 1:32 | 1:16 | 1:2 |
6 | 1:4 | 1:4 | <1:1 |
7 | 1:16 | 1:16 | 1:4 |
8 | 1:32 | 1:4 | 1:8 |
9 | 1:16 | 1:8 | 1:2 |
10 | 1:8 | 1:16 | <1:1 |
As can be seen from Table 1, the number of neutralizing antibody positive monkeys (2/10) for AAVz84 virus particles was significantly lower than AAV2 (9/10) and AAV9 (6/10). From this, it can be seen that AAVz84 serotypes circumvent neutralizing antibodies to some extent.
The above experimental results indicate that the filled-in rate of AAVz84 obtained by substituting aa573-579 of variable region VRVIII of AAV5 capsid protein with oligopeptide QTLGFSQGGPNT is significantly increased compared to wild type AAV5, AAV8 and AAV 9. Thus, when AAVz84 of the present disclosure is used clinically as a therapeutic vector, the incidence of potential adverse effects is reduced, and better therapeutic effects can be achieved, as compared to wild-type AAV5, 8, 9. In addition, the AAVz84 vectors of the present disclosure can circumvent neutralizing antibodies to some extent, providing better options for patients who are not receptive to wild-type AAV due to high titers of neutralizing antibodies.
While the present disclosure has been shown and described with respect to certain preferred embodiments thereof, it will be understood by those of ordinary skill in the art that the foregoing is a further detailed description of the present disclosure with reference to specific embodiments and is not intended to limit the practice of the present disclosure to such descriptions. Various changes in form and detail may be made therein by those skilled in the art, including a few simple inferences or alternatives, without departing from the spirit and scope of the present disclosure.
Sequence listing
<110> belief medicine technologies (Shanghai) Limited
<120> Low neutralizing antibody adeno-associated Virus capsid protein
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 729
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<223> amino acid sequence of AAVz84 capsid protein
<400> 1
Met Ser Phe Val Asp His Pro Pro Asp Trp Leu Glu Glu Val Gly Glu
1 5 10 15
Gly Leu Arg Glu Phe Leu Gly Leu Glu Ala Gly Pro Pro Lys Pro Lys
20 25 30
Pro Asn Gln Gln His Gln Asp Gln Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Asn Tyr Leu Gly Pro Gly Asn Gly Leu Asp Arg Gly Glu Pro Val
50 55 60
Asn Arg Ala Glu Glu Val Ala Arg Glu His Asp Ile Ser Tyr Asn Glu
65 70 75 80
Gln Leu Glu Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Glu Lys Leu Ala Asp Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Lys Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Phe
115 120 125
Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Thr Gly Lys Arg Ile
130 135 140
Asp Asp His Phe Pro Lys Arg Lys Lys Ala Arg Thr Glu Glu Asp Ser
145 150 155 160
Lys Pro Ser Thr Ser Ser Asp Ala Glu Ala Gly Pro Ser Gly Ser Gln
165 170 175
Gln Leu Gln Ile Pro Ala Gln Pro Ala Ser Ser Leu Gly Ala Asp Thr
180 185 190
Met Ser Ala Gly Gly Gly Gly Pro Leu Gly Asp Asn Asn Gln Gly Ala
195 200 205
Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys Asp Ser Thr Trp
210 215 220
Met Gly Asp Arg Val Val Thr Lys Ser Thr Arg Thr Trp Val Leu Pro
225 230 235 240
Ser Tyr Asn Asn His Gln Tyr Arg Glu Ile Lys Ser Gly Ser Val Asp
245 250 255
Gly Ser Asn Ala Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr
260 265 270
Phe Asp Phe Asn Arg Phe His Ser His Trp Ser Pro Arg Asp Trp Gln
275 280 285
Arg Leu Ile Asn Asn Tyr Trp Gly Phe Arg Pro Arg Ser Leu Arg Val
290 295 300
Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Val Gln Asp Ser Thr
305 310 315 320
Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp
325 330 335
Asp Asp Tyr Gln Leu Pro Tyr Val Val Gly Asn Gly Thr Glu Gly Cys
340 345 350
Leu Pro Ala Phe Pro Pro Gln Val Phe Thr Leu Pro Gln Tyr Gly Tyr
355 360 365
Ala Thr Leu Asn Arg Asp Asn Thr Glu Asn Pro Thr Glu Arg Ser Ser
370 375 380
Phe Phe Cys Leu Glu Tyr Phe Pro Ser Lys Met Leu Arg Thr Gly Asn
385 390 395 400
Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser Ser
405 410 415
Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val Asp
420 425 430
Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln
435 440 445
Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
450 455 460
Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser Gly
465 470 475 480
Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met Glu
485 490 495
Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met Thr
500 505 510
Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met Ile
515 520 525
Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu Glu
530 535 540
Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn Arg
545 550 555 560
Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Gln Thr Leu Gly
565 570 575
Phe Ser Gln Gly Gly Pro Asn Thr Pro Ala Thr Gly Thr Tyr Asn Leu
580 585 590
Gln Glu Ile Val Pro Gly Ser Val Trp Met Glu Arg Asp Val Tyr Leu
595 600 605
Gln Gly Pro Ile Trp Ala Lys Ile Pro Glu Thr Gly Ala His Phe His
610 615 620
Pro Ser Pro Ala Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Met
625 630 635 640
Met Leu Ile Lys Asn Thr Pro Val Pro Gly Asn Ile Thr Ser Phe Ser
645 650 655
Asp Val Pro Val Ser Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
660 665 670
Thr Val Glu Met Glu Trp Glu Leu Lys Lys Glu Asn Ser Lys Arg Trp
675 680 685
Asn Pro Glu Ile Gln Tyr Thr Asn Asn Tyr Asn Asp Pro Gln Phe Val
690 695 700
Asp Phe Ala Pro Asp Ser Thr Gly Glu Tyr Arg Thr Thr Arg Pro Ile
705 710 715 720
Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725
<210> 2
<211> 2190
<212> DNA
<213> Artificial sequence (Artificial Sequence)
<220>
<223> nucleic acid sequence encoding AAVz84 capsid protein
<400> 2
atgtcttttg ttgatcaccc tccagattgg ttggaagaag ttggtgaagg tcttcgcgag 60
tttttgggcc ttgaagcggg cccaccgaaa ccaaaaccca atcagcagca tcaagatcaa 120
gcccgtggtc ttgtgctgcc tggttataac tatctcggac ccggaaacgg tctcgatcga 180
ggagagcctg tcaacagggc agaagaggtc gcgcgagagc acgacatctc gtacaacgag 240
cagcttgagg cgggagacaa cccctacctc aagtacaacc acgcggacgc cgagtttcag 300
gagaagctcg ccgacgacac atccttcggg ggaaacctcg gaaaggcagt ctttcaggcc 360
aagaaaaggg ttctcgaacc ttttggcctg gttgaagagg gtgctaagac ggcccctacc 420
ggaaagcgga tagacgacca ctttccaaaa agaaagaagg ctcggaccga agaggactcc 480
aagccttcca cctcgtcaga cgccgaagct ggacccagcg gatcccagca gctgcaaatc 540
ccagcccaac cagcctcaag tttgggagct gatacaatgt ctgcgggagg tggcggccca 600
ttgggcgaca ataaccaagg tgccgatgga gtgggcaatg cctcgggaga ttggcattgc 660
gattccacgt ggatggggga cagagtcgtc accaagtcca cccgaacctg ggtgctgccc 720
agctacaaca accaccagta ccgagagatc aaaagcggct ccgtcgacgg aagcaacgcc 780
aacgcctact ttggatacag caccccctgg gggtactttg actttaaccg cttccacagc 840
cactggagcc cccgagactg gcaaagactc atcaacaact actggggctt cagaccccgg 900
tccctcagag tcaaaatctt caacattcaa gtcaaagagg tcacggtgca ggactccacc 960
accaccatcg ccaacaacct cacctccacc gtccaagtgt ttacggacga cgactaccag 1020
ctgccctacg tcgtcggcaa cgggaccgag ggatgcctgc cggccttccc tccgcaggtc 1080
tttacgctgc cgcagtacgg ttacgcgacg ctgaaccgcg acaacacaga aaatcccacc 1140
gagaggagca gcttcttctg cctagagtac tttcccagca agatgctgag aacgggcaac 1200
aactttgagt ttacctacaa ctttgaggag gtgcccttcc actccagctt cgctcccagt 1260
cagaacctct tcaagctggc caacccgctg gtggaccagt acttgtaccg cttcgtgagc 1320
acaaataaca ctggcggagt ccagttcaac aagaacctgg ccgggagata cgccaacacc 1380
tacaaaaact ggttcccggg gcccatgggc cgaacccagg gctggaacct gggctccggg 1440
gtcaaccgcg ccagtgtcag cgccttcgcc acgaccaata ggatggagct cgagggcgcg 1500
agttaccagg tgcccccgca gccgaacggc atgaccaaca acctccaggg cagcaacacc 1560
tatgccctgg agaacactat gatcttcaac agccagccgg cgaacccggg caccaccgcc 1620
acgtacctcg agggcaacat gctcatcacc agcgagagcg agacgcagcc ggtgaaccgc 1680
gtggcgtaca acgtcggcgg gcagatggcc accaaccaga ctctgggctt cagccaaggt 1740
gggcctaata cacccgcgac cggcacgtac aacctccagg aaatcgtgcc cggcagcgtg 1800
tggatggaga gggacgtgta cctccaagga cccatctggg ccaagatccc agagacgggg 1860
gcgcactttc acccctctcc ggccatgggc ggattcggac tcaaacaccc accgcccatg 1920
atgctcatca agaacacgcc tgtgcccgga aatatcacca gcttctcgga cgtgcccgtc 1980
agcagcttca tcacccagta cagcaccggg caggtcaccg tggagatgga gtgggagctc 2040
aagaaggaaa actccaagag gtggaaccca gagatccagt acacaaacaa ctacaacgac 2100
ccccagtttg tggactttgc cccggacagc accggggaat acagaaccac cagacctatc 2160
ggaacccgat accttacccg acccctttaa 2190
Claims (11)
- AAV capsid protein, wherein the AAV capsid protein is constructed by replacing aa573-579 of the variable region VRVIII of the AAV5 capsid protein with an oligopeptide QTLGFSQGGPNT.
- 2. The AAV capsid protein according to claim 1, wherein the AAV capsid protein has an amino acid sequence set forth in SEQ ID NO: 1.
- 3. A nucleic acid molecule, wherein the nucleic acid molecule encodes the AAV capsid protein of claim 1 or 2.
- 4. A nucleic acid molecule according to claim 3, wherein the nucleotide sequence of the nucleic acid molecule is as set forth in SEQ ID NO: 2.
- An AAV vector, wherein the AAV vector comprises the AAV capsid protein of claim 1 or 2.
- 6. The AAV vector of claim 5, wherein the AAV vector further comprises a heterologous polynucleotide comprising a nucleotide sequence encoding a therapeutic protein.
- 7. Use of an AAV vector according to claim 5 or 6 in the manufacture of a medicament for the treatment of a disease.
- 8. A medicament comprising the AAV vector of claim 5 or 6 and an agent that can render the viral vector patent.
- 9. The medicament of claim 8, wherein the agents capable of rendering the viral vector into a drug include salts, organics and surfactants.
- 10. The medicament of claim 8 or 9, wherein the medicament is administered by a systemic route or a local route.
- 11. The medicament of claim 10, wherein the medicament is administered intravenously, intramuscularly, subcutaneously, orally, topically, intraperitoneally, and intralesionally.
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